Psychoneuroendocrinology: The Scientific Basis of Clinical Practice

PSYCHONEUROENDOCRINOLOGY The Scientific Basis of Clinical Practice

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PSYCHONEUROENDOCRINOLOGY The Scientific Basis of Clinical Practice Edited by

Owen M. Wolkowitz, M.D. Anthony J. Rothschild, M.D.

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U. S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. Copyright © 2003 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 07 06 05 04 6 5 4 3 2 First Edition Typeset in Adobe’s Berling Roman and Galahad Regular American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Psychoneuroendocrinology : the scientific basis of clinical practice / edited by Owen M. Wolkowitz, Anthony J. Rothschild. p. cm. Includes bibliographical references and index. ISBN 0-88048-857-3 (alk. paper) 1. Psychoneuroendocrinology. 2. Mental illness—Endocrine aspects. I. Wolkowitz, Owen M., 1952– II. Rothschild, Anthony J. QP356.45 .P795 2003 616.89—dc21 2002028228 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

To Janet, Gavin, and Mikaela and to the memory of my parents O.M.W.

To Judy, Rachel, and Amanda; to my mother and the memory of my father A.J.R.

This book is also dedicated to our dear colleague and contributor to this volume, Dr. Martin Szuba, who passed away. Marty was a generous and gentle colleague, a thoughtful and compassionate man, and a psychiatrist who worked hard for his patients and taught his students well.

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Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi

Part I

Introduction Chapter 1 Introduction and Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Owen M. Wolkowitz, M.D., and Anthony J. Rothschild, M.D.

Chapter 2 Historical Roots of Psychoneuroendocrinology . . . . . . . . . . . . . . . . . . 9

Steven E. Lindley, M.D., Ph.D., and Alan F. Schatzberg, M.D.

Part II

Peptide Hormones Chapter 3 Neuropeptides and Hypothalamic Releasing Factors in Psychiatric Illness . . . . . . . . . . . . . . . . . . . . . . . 29

Dominique L. Musselman, M.D., M.S., and Charles B. Nemeroff, M.D., Ph.D.

Chapter 4 Chronobiology and Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Robert L. Sack, M.D., Alfred J. Lewy, M.D., Ph.D., Magda Rittenbaum, M.D., and Rod J. Hughes, Ph.D.

Chapter 5 Prolactin, Growth Hormone, Insulin, Glucagon, and Parathyroid Hormone: Psychobiological and Clinical Implications . . . . . . . . . . . 107

Mady Hornig, M.D., and Jay D. Amsterdam, M.D.

Part III

Adrenocortical Hormones Chapter 6 The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness . . 139

Anthony J. Rothschild, M.D.

Chapter 7 Psychiatric Manifestations of Hyperadrenocorticism and Hypoadrenocorticism (Cushing’s and Addison’s Diseases). . . . . . . 165

Monica N. Starkman, M.D., M.S.

Chapter 8 Psychiatric Effects of Glucocorticoid Hormone Medications . . . . . . 189

Victor I. Reus, M.D., and Owen M. Wolkowitz, M.D.

Chapter 9 Dehydroepiandrosterone in Psychoneuroendocrinology . . . . . . . . . 205

Owen M. Wolkowitz, M.D., and Victor I. Reus, M.D.

Part IV

Gonadal Hormones Chapter 10 Menstrual Cycle–Related and PerimenopauseRelated Affective Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

David R. Rubinow, M.D., and Peter J. Schmidt, M.D.

Chapter 11 Endogenous Gonadal Hormones in Postpartum Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Lisa S. Weinstock, M.D., and Lee S. Cohen, M.D.

Chapter 12 Clinical Psychotropic Effects of Gonadal Hormone Medications in Women . . . . . . . . . . . . . . . . . . . . . . . . . . 303

Uriel Halbreich, M.D., Steven J. Wamback, B.S., and Linda S. Kahn, Ph.D.

Chapter 13 Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids . . . 331

Harrison G. Pope Jr., M.D., and David L. Katz, M.D., J.D.

Part V

Thyroid Hormones Chapter 14 Thyroid Function in Psychiatric Disorders . . . . . . . . . . . . . . . . . . . 361

David O’Connor, M.D., Harry Gwirtsman, M.D., and Peter T. Loosen, M.D., Ph.D.

Chapter 15 Psychiatric and Behavioral Manifestations of Hyperthyroidism and Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . 419

Michael Bauer, M.D., Ph.D., Martin P. Szuba, M.D., and Peter C. Whybrow, M.D.

Chapter 16 Thyroid Hormone Treatment of Psychiatric Disorders . . . . . . . . . . 445

Stephen Sokolov, M.D., F.R.C.P.C., and Russell Joffe, M.D.

Part VI

Laboratory Testing Chapter 17 Laboratory Evaluation of Neuroendocrine Systems . . . . . . . . . . . . . 469

David Michelson, M.D., and Philip W. Gold, M.D.

Chapter 18 Endocrine Imaging in Depression . . . . . . . . . . . . . . . . . . . . . . . . . . 499

Kishore M. Gadde, M.D., and K. Ranga R. Krishnan, M.D.

Part VII

Stress Chapter 19 Stress and Neuroendocrine Function: Individual Differences and Mechanisms Leading to Disease. . . . . . . . . . . . . . . 513

Bruce S. McEwen, Ph.D. Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547

Contributors

Jay D. Amsterdam, M.D. Professor of Psychiatry, University of Pennsylvania School of Medicine, and Director, Depression Research Unit, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania Michael Bauer, M.D., Ph.D. Head, Department of Psychiatry and Psychotherapy, Humboldt University at Berlin, Berlin, Germany; Visiting Professor of Psychiatry, Neuropsychiatric Institute and Hospital, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, California Lee S. Cohen, M.D. Director, Perinatal and Reproductive Psychiatry Clinical Research Program, Massachusetts General Hospital; Associate Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts Kishore M. Gadde, M.D. Assistant Clinical Professor, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Philip W. Gold, M.D. Chief, Clinical Neuroendocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

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Harry Gwirtsman, M.D. Associate Professor, Department of Psychiatry, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee Uriel Halbreich, M.D. Professor of Psychiatry and Research Professor of Gynecology/Obstetrics, Director of BioBehavioral Research, State University of New York at Buffalo, BioBehavioral Program, Buffalo, New York Mady Hornig, M.D. Director of Translational Research, Center for Immunopathogenesis and Infectious Diseases, and Associate Professor, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York Rod J. Hughes, Ph.D. Circadian, Neuroendocrine and Sleep Disorders Section, Endocrine Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Russell Joffe, M.D. Dean and Professor of Psychiatry, UMDNJ–New Jersey Medical School, Newark, New Jersey Linda S. Kahn, Ph.D. Research Assistant Professor, BioBehavioral Research Program, State University of New York, Buffalo, New York David L. Katz, M.D., J.D. Senior Director of Medical Affairs, The Advisory Board Company, Washington, D.C. K. Ranga R. Krishnan, M.D. Professor and Chair, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Alfred J. Lewy, M.D., Ph.D. Professor of Psychiatry and Associate Chairman, Department of Psychiatry, and Director, Sleep and Mood Disorders Laboratory, Oregon Health and Science University, Portland, Oregon

Contributors

xiii

Steven E. Lindley, M.D., Ph.D. Clinical Faculty, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Associate Director for Research, National Center for PTSD, Palo Alto VA Health Care System, Palo Alto, California Peter T. Loosen, M.D., Ph.D. Professor, Departments of Psychiatry and Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee Bruce S. McEwen, Ph.D. Professor and Head, Laboratory of Neuroendocrinology, Rockefeller University, New York, New York David Michelson, M.D. Medical Director, Lilly Research Laboratories, Indianapolis, Indiana; Associate Professor of Psychiatry, Indiana University Dominique L. Musselman, M.D., M.S. Associate Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia Charles B. Nemeroff, M.D., Ph.D. Reunette W. Harris Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia David O’Connor, M.D. Department of Psychiatry, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee Harrison G. Pope Jr., M.D. Professor of Psychiatry, Harvard Medical School; Chief, Biological Psychiatry Laboratory, McLean Hospital, Belmont, Massachusetts Victor I. Reus, M.D. Professor of Psychiatry, University of California School of Medicine, San Francisco, California

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Magda Rittenbaum, M.D. Resident in Neurology, Oregon Health and Science University, Portland, Oregon Anthony J. Rothschild, M.D. Irving S. and Betty Brudnick Professor of Psychiatry and Director of Clinical Research, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts David R. Rubinow, M.D. Clinical Director and Chief, Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, Maryland Robert L. Sack, M.D. Professor of Psychiatry and Medical Director, Sleep Disorders Medicine Service, Oregon Health and Science University, Portland, Oregon Alan F. Schatzberg, M.D. Kenneth T. Norris Jr. Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California Peter J. Schmidt, M.D. Chief, Unit on Reproductive Endocrinology, Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, Maryland Stephen Sokolov, M.D., F.R.C.P.C. Assistant Professor, Department of Psychiatry, University of Toronto; Staff Psychiatrist, Mood Disorders Clinic, Department of Psychiatry, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Ontario, Canada Monica N. Starkman, M.D., M.S. Associate Professor, Department of Psychiatry, University of Michigan Medical Center, Ann Arbor, Michigan Martin P. Szuba, M.D.† Assistant Professor of Psychiatry, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

†

Deceased.

Contributors

xv

Steven J. Wamback, B.S. State University of New York, Buffalo, New York Lisa S. Weinstock, M.D. Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Peter C. Whybrow, M.D. Professor and Executive Chairman, Department of Psychiatry and Biobehavioral Sciences; Director, Neuropsychiatric Institute and Hospital, University of California at Los Angeles, Los Angeles, California Owen M. Wolkowitz, M.D. Professor of Psychiatry and Director, Psychopharmacology Assessment Clinic, University of California School of Medicine, San Francisco, California

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Part I Introduction

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Chapter 1 Introduction and Overview Owen M. Wolkowitz, M.D. Anthony J. Rothschild, M.D.

T

he importance of endocrinology for psychiatric practice has never been stronger than it is now. We are currently witnessing a paradigm shift in understanding endocrinologic aspects of psychiatric illness. Hormonal aberrations (and even so-called normal changes that occur with aging and in response to physical or emotional stress) are increasingly viewed less as epiphenomena, diagnostic tests, or “windows into the brain” and more as vital pathophysiological changes and as potential targets for novel hormonally based pharmacotherapies. The recent discovery of neurosteroids, which indicates that the brain itself is a steroidogenic organ, further blurs the boundaries between endocrinology and neuropsychiatry. An enormous amount of information has now been gathered regarding hormone effects on the brain and behavior. Excellent textbooks of psychoneuroendocrinology, some encyclopedic in their coverage, have already been published. The goal of this volume is to be no less authoritative but to fill an important niche: to show how the principles and emerging findings of psychoneuroendocrinology can inform modern clinical practice and lead to new breakthroughs in future practice. With that goal in mind, leading authorities, all of whom are internationally renowned researchers and most of whom are active clinicians themselves, were invited to contribute the individual chapters. They were asked to review not only the latest empirical scientific findings in their areas of expertise but to highlight the clinical significance of these findings and to provide, wherever appropriate, clinical guidelines for the management of patients. This book, then, was designed with the clinician, as well as the researcher-scientist, in mind, and we hope that it will prove useful to psychi-

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atrists, neurologists, endocrinologists, obstetrician-gynecologists, internists, family and general practitioners, psychologists, nurses, and advanced students. More broadly, we hope that it will be of interest to anyone seeking to learn more about the bidirectional interaction of the mind and the body and of the psyche and the soma. Psychoneuroendocrinologic investigation has generally followed three paths, each of which is discussed in this volume: 1) alterations in endogenous hormone levels observed in primary psychiatric illness; 2) psychiatric concomitants or sequelae of hormonal dysregulation in primary endocrinologic illness; and 3) behavioral effects of exogenously administered hormones or hormone antagonists (both the study of the side effects of hormonal medications and the use of hormones and hormone antagonists as psychotropic medications). In this volume, each of these paths is explored in turn for each hormonal system presented (e.g., the hypothalamic-pituitary-adrenal axis hormones, gonadal hormones, and thyroid hormones). In addition, special topics of interest are included, such as the role of neuropeptides and hypothalamic releasing factors in psychiatric illness, the use of laboratory tests and imaging procedures in evaluating hormonal function in psychiatric patients, the place of newer alternative hormonal medications such as melatonin and dehydroepiandrosterone (DHEA) in therapeutics, and consideration of the particular role of stress in precipitating illness. Drs. Lindley and Schatzberg begin this volume with a lively history of psychoneuroendocrinology, recounting the many false starts in this field, pointing optimistically to more promising recent advances, and emphasizing where the field is now headed. This account of the development of the field sets the stage for the chapters that follow. In particular, their account of the earliest conceptualizations of the role of stress in mental and physical illness nicely complements the final chapter of the volume (by Dr. McEwen), which points to very newly developed conceptualizations. Drs. Musselman and Nemeroff then review the work of their own group and that of others in elucidating the role of neuropeptides and hypothalamic releasing factors in neuroendocrine regulation and in psychiatric illness. Moving from the historical contexts of the neuroendocrine window and the pharmacologic bridge approaches, they consider whether neuropeptide changes are secondary to or are causal of aspects of psychiatric illness, and they point the way to the development of novel psychopharmacologic agents. Drs. Sack, Lewy, Rittenbaum, and Hughes review the physiological roles and therapeutic potential of melatonin, distinguishing fact from current fad. They emphasize the potential of melatonin and melatonin

Introduction and Overview

5

analogs as chronobiotic drugs (i.e., they reset circadian rhythms) in conditions such as jet lag, shiftwork maladaptation, and other sleep disorders, as well as their (separate) hypnotic properties. Drs. Hornig and Amsterdam review the psychiatric manifestations of the most common endocrinopathy, diabetes mellitus, along with those of the least common ones—such as those affecting secretion of prolactin, parathyroid hormone, glucagon, and growth hormone and those associated with panhypopituitarism. In addition to reviewing the behavioral correlates of disturbances in each of these systems, they concisely review the use of several of these hormones as “windows into the brain” in pharmacologic challenge studies. Dr. Rothschild summarizes and synthesizes data pertaining to the best-studied of psychoneuroendocrine topics: corticosteroids in psychiatric illness. It has been estimated that well over 8,000 scientific articles have appeared in the medical literature regarding the utility (or lack thereof) of the dexamethasone suppression test in psychiatric patients. Dr. Rothschild comments on the proper (and improper) use of tests of the hypothalamic-pituitary-adrenal (HPA) axis and discusses the incidence and significance of HPA axis aberrations in psychiatric illnesses. He concludes with suggestions for novel therapies aimed at normalizing HPA axis secretion. Dr. Starkman reviews the particular endocrine disease that has both historically and currently stimulated the greatest discussion about the dependence of behavior, mood, and memory on hormonal activity. In her review of Cushing’s syndrome and its counterpart, Addison’s disease, Dr. Starkman considers the relative roles of corticotropin-releasing hormone and adrenocorticotropic hormone versus cortisol (and other less wellstudied hormones) in determining behavioral outcome in these conditions, as well as their relative utility in differential diagnosis and treatment planning. She also reviews studies of behavioral response after treatment of these disorders and summarizes data from her own group on certain intriguing neuroanatomical changes seen in Cushing’s syndrome. Drs. Reus and Wolkowitz examine exogenous corticosteroid effects on mood and cognition in their chapter on steroid psychosis. Behavioral effects of steroid medications have been recognized since the time of their introduction into clinical practice, but few controlled trials have studied their incidence, character, etiology, and response to treatment. Drs. Reus and Wolkowitz review the latest developments in understanding these side effects (which affect literally thousands of patients yearly), and they review currently available prophylactic and treatment strategies. Drs. Wolkowitz and Reus then review the rapidly expanding database concerning the role of DHEA in memory, mood, and neuropsychiatric ill-

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ness. DHEA and its metabolite, DHEA sulfate, are the most plentiful adrenal corticosteroids in humans, yet their functions remain uncertain. Moderating between claims of a youth-enhancing super-hormone and therapeutic nihilism, the authors put the current DHEA hype into scientific perspective and point to possible novel treatments involving this interesting hormone. Drs. Rubinow and Schmidt review the prevalent psychiatric disorders associated with the menstrual cycle and the perimenopausal years in women. In addition to reviewing the normal physiology of these occurrences and posing questions regarding hormonal causality of these behavioral disturbances, they highlight current approaches to diagnosis and treatment. Drs. Weinstock and Cohen review postpartum behavioral changes, distinguishing between postpartum “blues,” depression, and psychosis. In addition to reviewing what is known about the endocrine and nonendocrine causes of these disorders, they suggest prophylactic and therapeutic approaches for patients who are experiencing or are at risk for contracting these conditions. Dr. Halbreich, Mr. Wamback, and Dr. Kahn review the mood and cognitive effects of exogenously administered female gonadal hormones (e.g., oral contraceptives and estrogen replacement therapy), paying particular attention to the specific behavioral effects of estrogen alone versus estrogen-progestin combinations. The chapter includes abundant clinical recommendations, often derived from the authors’ clinical experience, in areas where controlled data are not yet available. Drs. Pope and Katz extensively review the literature on use of anabolic and androgenic steroids, including studies from their own laboratory. Although they acknowledge that much remains to be discovered regarding vulnerability to anabolic steroid–induced behavioral changes, the authors provide general conclusions, treatment recommendations, and forensic guidelines. Drs. O’Connor, Gwirtsman, and Loosen provide a thorough review of thyroid function in psychiatric disorders. Included are delineations of different levels of thyroid dysfunction (e.g., peripheral thyroid hormone levels, thyroid-stimulating hormone levels, and antithyroid antibodies) in disorders as diverse as mood disorders, alcoholism, anxiety disorders, premenstrual dysphoric disorder, eating disorders, and schizophrenia. Important, but often overlooked, effects of somatic treatments on thyroid function are also reviewed. Drs. Bauer, Szuba, and Whybrow delineate psychiatric syndromes seen in patients with hyperthyroidism or hypothyroidism. Examination of the psychiatric sequelae of such endocrinologic diseases illuminates

Introduction and Overview

7

the importance of hormonal homeostasis for proper central nervous system functioning. In addition to describing the psychiatric comorbidities of thyroid disease, the authors comment on laboratory evaluations of such diseases and emphasize psychiatric responses to therapeutic endocrine correction. The observed relationships between thyroid disease states and psychiatric symptomatology led to a sizable number of studies evaluating exogenously administered thyroid hormones as psychopharmacologic agents. These trials are reviewed and synthesized by Drs. Sokolov and Joffe, whose own research group has conducted much of this research. Of special interest to clinicians is the authors’ comparison of the efficacy of different thyroid hormones (e.g., T3 versus T4) as well as T3 versus lithium in augmenting antidepressant response. Drs. Michelson and Gold provide a detailed overview of laboratory testing in clinical psychoneuroendocrinology. With proper attention to methodology and to the correct use and interpretation of these tests, accurate diagnosis and treatment are greatly facilitated. Clinicians involved in the evaluation and care of psychiatric, endocrine, and general medical patients will find this chapter both practical and thorough. Drs. Gadde and Krishnan describe another approach to diagnosing and investigating neuroendocrine alterations in psychiatric illnesses: radiographic imaging of endocrine tissues and other organs. Although computed tomographic or magnetic resonance imaging of organs such as the pituitary and the adrenal gland may not be routinely indicated in evaluating psychiatric illness, abnormalities in volumetric measurements of these and other structures speak directly to endocrine-associated physical alterations that relate to major behavioral disturbances. Dr. McEwen closes the volume with a provocative and compelling chapter examining the relationship between stress and illness. An assumption underlying much of this volume is that changes in the body’s internal milieu can significantly alter behavioral and affective experience. In a complementary way, changes in the individual’s external milieu often provoke hormonal adaptations. Drawing on a wide body of experimental data, Dr. McEwen distinguishes between the protective and destructive effects of hormonal responses to stress and introduces the concept of allostatic load to explain some of the health consequences of chronic stress.

In his 1956 book, The Stress of Life, Hans Selye (the father of stress physiology) wrote

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PSYCHONEUROENDOCRINOLOGY We are on our guard against external intoxicants, but hormones are parts of our bodies; it takes more wisdom to recognize and overcome the foe who fights from within.... What can we do about this? Hormones are probably not the only regulators of our emotional level. Besides, we do not yet know enough about their workings to justify any attempt at regulating our emotional key by taking hormones.

Now, more than 45 years after Selye wrote these words and with the cumulative benefit of the observations reviewed in this volume, we are in a much stronger position to “regulate our emotional key” by recognizing and correcting hormonal imbalances that may result in behavioral disturbances.

Chapter 2 Historical Roots of Psychoneuroendocrinology Steven E. Lindley, M.D., Ph.D. Alan F. Schatzberg, M.D.

C

linical psychoneuroendocrinology is a relatively young area of research, but its historical roots go back to antiquity. Psychoneuroendocrinology is grounded in advances in basic scientific knowledge, evolving from developments in endocrinology, neurochemistry, and behavioral pharmacology and from clinical observations. The subsequent chapters of this book contain reviews of the exciting recent advances in the field of psychoneuroendocrinology, emphasizing areas of possible direct clinical utility. The purpose of this chapter is to take a step back and examine some of the early scientific and social developments that shaped the development of the field from the beginning of history to the 1960s (Table 2–1). Specifically, we examine 1) how it was first appreciated that endocrine abnormalities can affect behavior; 2) how the nature of endocrine communication was discovered, which led to the discovery of chemical neurotransmission; 3) what observations indicated that endocrine secretions are regulated by the brain; and finally 4) the development of the modern understanding of how psychological states can alter endocrine systems. In reviewing these developments, we focus on the hypothalamic-pituitaryadrenal (HPA) axis, in part because it is one of our interests, but also because the HPA axis has been the most intensely studied neuroendocrine system in psychiatry. We emphasize past missteps and dead ends to pro-

Work for this chapter was supported by NIMH Grant MH50604, a NARSAD Young Investigator Award, and a DANA Research Fellowship.

9

10 TABLE 2–1.

469–399 B.C. 130–200 1628 1719 1811 1849 1849 1855 1855 1856 1884 1889 1891 1894 1899 1905 1907 1921 1926 1932 1936 1940s 1946 1954

A.D.

PSYCHONEUROENDOCRINOLOGY Early conceptual advances in the psychoneuroendocrinology of the hypothalamicpituitary-adrenal axis: antiquity to 1950s Hippocrates on black bile and melancholia Galen of Pergamum—anatomy of humors Harvey’s description of the circulation First chemical analysis of brain by Hensing Vauquelin’s chemical composition of the brain Berthold’s description of testicular replacement Pavlov’s neural reflexes Bernard’s observation of internal secretions from the liver Addison’s description of adrenal atrophy Brown-Séquard’s description of effects of adrenalectomy Thudichum’s work on brain chemical constitution Brown-Séquard’s advocacy of organotherapy Murray injects thyroid extracts into myxedema patient Oliver and Schäfer’s vasoconstrictor effects of adrenal extracts Abel and Crawford isolate epinephrine Bayliss and Starling discover secretin; coin the term hormone Langley hypothesizes receptors Loewi demonstrates release on chemical neurotransmitters Cannon’s concept of homeostasis Cushing’s syndrome described Selye’s concept of stress as general adaptation syndrome Harris’s work on hypothalamic neurohumoral pituitary control von Euler demonstrates norepinephrine neuronally released Vogt demonstrates norepinephrine unevenly distributed in central nervous system

vide clues for avoiding future mistakes in this very exciting and expanding field. This review is not meant to be exhaustive, and it relies mostly on the insight and material provided by other authors (Bleuler 1982; Hughes 1977; McCann 1992a; Money 1983; Peart 1979; Sawyer 1988; Tattersall 1994; Tourney 1969; Tower 1981; Welbourn 1992; Wilson 1984), but its goal is to try to set the historical stage for the chapters that follow.

Ancient Concepts The beginnings of psychoneuroendocrinology can be traced to black bile and phlegm. The concepts of the four humors and the brain as the source of intelligence and mental illness were described in the writings of Alc-

Historical Roots of Psychoneuroendocrinology

11

maeon of Croton (a pupil of Pythagoras, around 500 B.C.), Hippocrates of Cos (469–399 B.C.), and other ancient philosophers. These ideas were developed, in part, based on data derived from animal experimentation. It was believed at that time that the four bodily humors—yellow and black bile, blood, and phlegm—could cause mental illness by influencing the brain. For instance, phlegm, which was believed to cool the brain, could accumulate in sites throughout the body, such as in joints and semen. Treatment for an excess of phlegm included removal from the body by ejaculation (Peart 1979). A less enjoyable therapy involved black bile. Black bile, a product of the spleen, was thought to be the cause of melancholia. The treatment for melancholia involved black hellebore, the Christmas rose, a cathartic and diuretic herb (Mora 1975). Roman physicians expanded on these theories. The writings of Galen (A.D. 130–200) contributed significantly to the advancement of anatomy and pathology, but they also solidified the belief in humoral causes of disease. Galen’s philosophy, which became known as Galenism, had a strong influence on the practice of psychiatry until the middle of the nineteenth century (Mora 1975). Galen described intraarterial “vital spirits” that were converted by the brain into “animal spirits.” The waste products of this reaction were funneled down the infundibular stalk to the pituitary gland, through ducts in the sphenoid and ethmoid bones to the nasopharynx, where they appeared as nasal mucus or “pituita” (from Harris, quoted in Sawyer 1988, p. 23). Galen’s treatments included phlebotomy for melancholia, a practice that continued for the next one and a half millennia, and sexual activity for hysterical symptoms, which he hypothesized to be the result of a lack of sexual relations (Mora 1975).

Early Modern Endocrinology During the Renaissance period, scientists described the anatomy of most of the endocrine glands, but their function was unknown until the late eighteenth century. In 1716, the Academia des Sciences de Bordeaux offered a prize for an answer to the question “what is the role of the adrenals?” The judge did not award the prize to any of the conflicting theories offered and closed his criticism with the words “perhaps some day chance will reveal what all of this work was unable to do” (Nelson 1988, p. 87). To understand the role of endocrine glands in general, one needed to appreciate their lack of a direct physical connection to the rest of the body, an idea that did not develop until the eighteenth century (Bleuler 1982). In 1742, Théophile de Bordeu, a medical practitioner in Paris,

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noted that glands, as well other tissues, influence each other by releasing products into the bloodstream (Peart 1979, p. 274), and Albert von Haller in 1766 hypothesized that glands without ducts, such as the thyroid, pour special substances into the circulation (Welbourn 1992, p. 138). By 1844, a recognizable modern concept of endocrine glands was described by the physiologist Johannes Mueller, who wrote, “Glands without ducts exercise their plastic influences on the fluids within them and those which circulate through them and return to the general circulatory system” (see Bleuler 1982, p. 2). Clues to the chemical nature of endocrine products were first obtained from the most externally accessible gland, the testes (Money 1983). The physiological and behavioral effects of the testes had been observed with the first castrations of domesticated animals and in eunuchs. Aristotle (384–322 B.C.) wrote about the effects of castration in both animals and humans, and Galen concluded, “Is it then astonishing that a certain power is communicated from the testicles to the whole body?... This faculty is the cause in man of masculinity” (quoted in Peart 1979, p. 272). However, these early investigators and philosophers attributed the loss of testicular functioning to semen, not hormones. Evidence to the contrary was provided by the experiments of John Hunter, an English anatomist and surgeon, in the mid-eighteenth century. In experiments with cockerels, he noted that testicular replacement produces secondary sex characteristics in castrated animals. However, because he was mainly interested in organ transplantation, he published only a few brief reports on his observations (reviewed in Money 1983; Welbourn 1992). Not until 1849 did Arnold Adolph Berthold describe evidence for what are now known as hormones. Berthold observed that transplantation of testes reversed the effects of castration on sexual and aggressive behaviors and physical characteristics in chickens, confirming Hunter’s findings. But Berthold attributed this effect to internal secretions from the gland. Furthermore, he commented that the effects of testicular secretions must influence “the whole organism of which, it must be admitted, the nervous system forms a very substantial part,” foreshowing our understanding of the effect of androgens on the central nervous system (CNS) (Sawyer 1988). Because his experiments involved problems with immune rejection associated with organ transplantation, they were difficult to replicate and were largely ignored until the early twentieth century (Peart 1979; Welbourn 1992). In 1855 Claude Bernard, professor of physiology at the Collége de France, Paris, coined the term internal secretion to describe the secretion of newly synthesized glucose from the liver. In the same year, Thomas Addison correctly ascribed a role to the adrenal glands in his descriptions

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of a syndrome in patients with gross adrenal disease (Addison’s disease). The next year, Charles-Edouard Brown-Séquard, more famous for his description of the syndrome associated with spinal cord hemisection, reported that bilateral adrenalectomy was fatal in many animals, usually within 24 hours. He concluded that the syndrome was similar to that found in patients dying from Addison’s disease (Tattersall 1994). The first endocrine therapy was developed as a treatment for thyroid disease. Goiters were described throughout recorded history and were attributed to iodine deficiency. Because of the similarities between patients with cretinism and myxedema and patients who had undergone thyroidectomy, Felix Semon proposed in 1883 that both cretinism and myxedema resulted from a degeneration of the thyroid gland. A “myxedema committee” that was set up at St. Thomas’ Hospital in London investigated his theory. Five years later, after obtaining further clinical and animal data, this committee agreed with Semon that myxedema was indeed caused by loss of thyroid secretions. Three years later, George Murray, a medical resident, successfully treated a myxedematous patient with glycerinated sheep thyroid extract with the help of the myxedema committee. This was the first successful endocrinologic replacement treatment, and it understandably generated a great deal of enthusiasm (see accounts in Peart 1979; Welbourn 1992).

The Era of Organotherapy The enthusiasm generated by the advances described above was soon dampened by a peculiar setback, which was set into motion by a scientist who had made tremendous contributions to both neurology and endocrinology, Charles-Edouard Brown-Séquard (Beach 1981; Tattersall 1994; Welbourn 1992; Wilson 1984). On June 1, 1889, at age 72, Dr. BrownSéquard announced to the Société de Biologie in Paris the results of an endocrine experiment. Serving as his own experimental subject, he had injected himself subcutaneously with dog and guinea pig testicular extracts. He stated that he had conducted these experiments because “it is well known that seminal losses from any cause produce a mental and physical disability which is in proportion to their frequency” (Tattersall 1994, p. 729). He reported that this treatment had remarkable effects on his physiology, including his being able to move 7 kg more weight, greater regularity of his bowel function, a decrease in mental fatigue, and a 25% increase in the jet of his urine. He asked the elder members of the society to make an effort to replicate his findings (Tattersall 1994; Welbourn 1992).

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The initial reaction of the scientific community and the public in general was skepticism and ridicule. For example, an editorial in Wiener Medizinische Wochenschrift stated, “Professor Brown-Séquard’s audience appears to have received an impression of the intellectual capacity of the aged scientist very different from the one which he, in his elevated frame of mind, evidently expected to produce. This lecture must be regarded as further proof of the necessity of retiring professors who have attained their threescore years and ten” (Beach 1981, p. 332). Despite this initial reaction, by the end of 1889, 12,000 physicians had tested his extract and had reported remarkable cures for a wide variety of illnesses. Besides senile disability, efficacy for this treatment was reported for glycosuria, neurasthenia, tabes dorsalis (314 cures out of 415 trials), pulmonary tuberculosis, heart disease, leprosy, malaria, Addison’s disease, and cancer (Tattersall 1994). Dr. Brown-Séquard reportedly believed that the extract increased the “nervous force” in the body, allowing one to better fight disease. A number of pharmaceutical companies, including Burroughs, Wellcome, began to manufacture various organ extracts, a craze that continued into the 1920s (Tattersall 1994). The bad reputation that these organ extract therapies—generally called organotherapy—received in the general medical community resulted in a loss of respectability for endocrinology. It was said that “any young physician who dared embark on a career in the field of internal secretions was looked [at] askance, [was] considered naive and gullible[,] or [was] suspected of straying into the realm of quackery and heading for the endocrine gold fields” (Tattersall 1994, p. 730). Even the reported efficacy of thyroid replacement for myxedema was viewed with skepticism because of the similarities to organotherapy (Peart 1979). Furthermore, because of the remarkable psychological effects reported, many endocrinologists doubted whether scientific methods could be applied to investigating the psychological effects of hormones (from Beach 1981).

Birth of Modern Endocrinology Despite its negative impact, organotherapy did generate advances in endocrinology that eventually led to the development of neurochemistry and modern biological psychiatry. In 1893, an English general practitioner named George Oliver began experimenting with extracts of various tissues. During these investigations, he is reported to have fed an adrenal extract to his son and observed evidence of vasoconstriction—an experiment that would not pass even the most lenient human subjects commit-

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tee today. Dr. Oliver approached Edward A. Schäfer, a professor of physiology at his former medical school, with his findings. Using an experimental dog that he had already prepared for the measurement of arterial blood pressure, a skeptical Dr. Schäfer was surprised at the large increase in blood pressure produced by the extract (Peart 1979; Welbourn 1992; Wilson 1984). Oliver and Schäfer concluded that they had found the secretion that was missing in Addison’s disease patients. Investigations conducted the following winter revealed that the substance was restricted to the adrenal medulla and was missing at autopsy in two patients with Addison’s disease (Peart 1979; Welbourn 1992; Wilson 1984). The general scientific community was excited by these findings, and several researchers turned their attention to identifying this substance. Within 5 years, John Jacob Abel and Albert Crawford, both of Johns Hopkins University, had isolated the extract and named it epinephrine. A Japanese chemist named Jokichi Takamine later purified the substance in crystalline form and gave it the name adrenaline, producing the first purified hormone. This accomplishment set off a race to isolate other hormones (Peart 1979; Welbourn 1992; Wilson 1984). Although it could not be known then, the isolation of epinephrine also marked the beginning of the modern era of neurochemistry by illustrating the interrelationship between endocrine secretions and neural transmission. During this period, chemical messengers were being investigated at another level in a separate line of research. In 1902, William Bayliss and Ernst Starling began an investigation of the regulation of pancreatic secretions in dogs. They discovered that extracts of the intestinal mucosa stimulated pancreatic secretions in the absence of neuronal input. They named this hypothetical chemical messenger in the extract secretin and proposed a new classification for this extract: a hormone, meaning “I arouse to activate” (Peart 1979; Welbourn 1992; Wilson 1984). They defined a hormone as “being produced in particular organs, carried in the blood current, acting as chemical messengers, and influencing cell processes in distant organs.… They provide chemical coordination of the organism, working side by side with that of the nervous system” (Welbourn 1992, p. 146).

Growth of an Appreciation for Psychiatric Aspects of Endocrinologic Disorders With the expansion of knowledge in hormones came a greater appreciation for the psychiatric aspects of endocrine disease. But, as noted by

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Bleuler (1982, p. 6), “most early descriptive studies of the behavioral consequences of endocrine disorders based their findings on single observations and therefore often over-generalized their findings, sometimes with unfortunate results.” For example, Benjamin Rush is quoted as stating that the larger size of the thyroid gland in women “was necessary to guard against the female system from the influence of the more numerous causes of irritation and vexation of the mind to which they are exposed than the male sex” (Kathol 1992, p. 400). Sometimes these simplistic generalizations led to invasive therapies. In 1872, Robert Battery, a Georgia surgeon, advocated ovariectomy for dysmenorrhea. Over time the clinical indications for ovariectomy were broadened to include psychiatric conditions such as neurosis (Welbourn 1992). A theory that schizophrenia resulted from a defect in adrenal hormone production led to adrenalectomies in a number of schizophrenic patients (Bleuler 1982). Despite these clinical misadventures, the availability of efficacious treatments for endocrine disorders produced many real dramatic psychiatric cures, as illustrated in the following 1892 description by Drs. Shaw and Stansfield of the treatment a female patient with myxedema (see Kathol 1992, p. 403): Following the birth of her second child she had an attack of lactational melancholia and inflicted a wound on her throat....Symptoms of myxedema were first noticed when she was pregnant with her third child. The principal mental symptoms were mental confusion and inability to concentrate or employ herself. She had considerable insight into her mental state and became languid and disinterested in her occupation and her children....The mental condition became worse and she was certified and sent to the Banstead Asylum in April 1891....To the ordinary symptoms of myxedema were added occasional stupor, aphonia, rigidity, and erotomania. She would periodically get into other patients’ beds and when being bathed, unless the nurses were careful, would seize and almost strangle them in excess of her sexual desire. All sorts of remedies were tried to no avail: hot baths, massage, injections of pilocarpine (until, indeed, profuse salivations resulted), tonics and electricity....Finally it was decided to treat the patient with glycerine extract of the thyroid of the sheep. The committee purchased the sheep, killed them, and dissected out the thyroid. A 20% glycerine extract was made by pounding and macerating the gland for forty-eight hours and then straining it through several layers of very fine muslin. The patient was given an injection every second day. The reaction was remarkable. In ten weeks’ time, Mrs. H was out on trial and at the expiration of her trial she was discharged and recovered.

Such successes with hormonal therapy generated curiosity as to whether hormones were involved in the pathophysiology of psychiatric disorders

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in general. Emil Kraepelin theorized about endocrine etiologies for dementia praecox, and Sigmund Freud wondered if the damaging effects of hormones on the psyche could be the basis of the “actual neurosis” (Bleuler 1982). Endocrinologists also shared this enthusiasm. In the first edition of the journal Endocrinology in January 1917, Charles E. De Medicis Sajous, commenting on recent evidence suggesting adrenalin was located in neurons, wrote In the great field of neurology and psychiatry, to which work beyond compution and praise has been devoted, discouragement has remained the dominant note precisely where efforts on behalf of sufferers should have proved more telling. Nowhere has therapeutics remained less efficient....And yet, no single line of medical thought offers greater opportunity for development through the intermediary of the ductless glands. (Sajous 1917, p. 1)

Growth of Modern Neurochemistry From Roots in Endocrinology The link between psychology and endocrinology is exemplified by the growth of neurochemistry out of endocrinology. An appreciation for the chemical nature of neural transmission started with the discovery of epinephrine at the turn of the century, although the first chemical investigations of the brain began with the first recorded chemical analysis of the brain in 1719 (Tower 1981). However, when it came to the mechanism of how neurons communicated, most of the attention remained focused on the electrical nature of neuronal transmission. There was evidence in the late nineteenth century suggestive of chemical neurotransmission, from investigations of neuroactive compounds such as nitrous oxide, ether, bromide, and phenobarbital. Claude Bernard demonstrated that curare blocked nerve transmission at the nerve-muscle junction (Tower 1981). In 1877, the electrophysiologist Du Bois-Reymond suggested that nerves might act chemically as well as electrically (Brooks 1988). It was Oliver and Schäfer’s isolation of adrenal extract that sparked the modern development of neurochemistry. Starting in 1905, Thomas Renton Elliott began publishing papers noting the similarities between the effects of adrenaline and those produced by stimulation of the sympathetic nervous system. He suggested that adrenaline might be acting as a chemical neural transmitter (Fleming 1984). In 1914, Sir Henry Dale noted similarities with acetylcholine and parasympathetic stimulation and described the “muscarinic” and “nicotinic” actions of acetylcholine. Then,

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in a series of simple experiments in 1921, Otto Loewi demonstrated that a chemical signal released on stimulation of the vagus nerve, which he termed vagustoff, could mimic vagus stimulation when placed on a denervated heart, an effect that was blocked by atropine. Dale and Loewi won the Nobel Prize for their work on the chemical nature of neural transmission (Fleming 1984; Peart 1979; Welbourn 1992; Wilson 1984). Despite this conceptual breakthrough, technical limitations would slow further advances on chemical neurotransmission until after World War II. In 1946, the Swedish physiologist Ulf von Euler (and later in Germany) demonstrated that mammalian sympathetic nerves release norepinephrine as a transmitter. In 1954, Vogt observed that norepinephrine is distributed unevenly in the CNS, a finding that strongly suggested its function as central neurotransmitter rather than an artifact from sympathetic nerve endings (Cooper et al. 1991). Since that time, the field has expanded at a tremendous rate, with the discovery of increasing numbers of transmitter substances and receptors, and has served as the cornerstone of modern biological psychiatry.

Development of Neuroendocrinology Another set of developments was taking place during the first half of the twentieth century that would further link hormones with brain function: the discoveries of endocrine secretions from the pituitary and of CNS control of these secretions. These developments have been outlined in detail by a number of investigators in the field (Brooks 1988; Hughes 1977; McCann 1975, 1992a, 1992b; Sawyer 1988). Although its anatomy had been investigated, the function of the pituitary remained a mystery until the description of two cases of acromegaly by Pierre Marie in 1886. In 1927 Philip Smith demonstrated that the pituitary gland produced hormones that stimulated the adrenal cortex, thyroid, and gonads and also stimulated growth. By the early 1930s, the remaining pituitary hormones had been discovered (reviewed in McCann 1992b). The role of the hypothalamus in control of the pituitary was also first suggested from clinical observations of patients with endocrine disorders as early as the beginning of the twentieth century. In 1901, Alfred Fröhlich in Vienna diagnosed the adiposogenital syndrome in a 14-year-old obese boy with arrested sexual development that Fröhlich attributed to damage in the hypothalamus (Sawyer 1988). In 1921, Percival Bailey and Frédéric Bremer confirmed and extended early findings that lesions of discrete areas of the hypothalamus in dogs induced the adiposogenital

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syndrome, experimentally demonstrating hypothalamic control over the pituitary. This and other work led to Harvey Cushing’s 1929 description of the hypothalamus: “Here in this well-concealed spot, almost to be covered by a thumb nail, lies the very main-spring of primitive existence” (see Brooks 1988, p. 657). The way the hypothalamus directs the pituitary was postulated by Hinsey and Markee in 1933, when they suggested that hypothalamic neurohypophyseal hormones might control the secretions of the anterior pituitary. In the late 1940s, in a series of experiments involving pituitary stalk lesions, Geoffrey W. Harris provided experimental evidence that factors released into the portal blood from the hypothalamus exerted control over pituitary secretion (McCann 1992b). By the 1950s, the search turned to the identification of these hypothalamic releasing and inhibiting factors. Some of these factors proved more difficult to isolate then others; the chemical identity of corticotropin-releasing hormone was not discovered until 1981 (Vale et al. 1981). As the hypothalamic neurohumoral factors were isolated and were also found to be present, along with their receptors, in brain regions outside the medial basal hypothalamus, the line separating endocrine and neuronal control became blurred even further.

Homeostasis and Stress The growth of knowledge about hormones and chemical neural transmission led to the development of two important concepts for modern psychoneuroendocrinology: homeostasis and stress. The Harvard University physiologist Walter Bradford Cannon began to develop the concept of homeostasis from work that he began while a medical student in 1896. At that time, he observed the impact of emotional states on physiology while working on a research project on the digestive system. As reviewed by Fleming (1984), he brought together contemporary knowledge of the functioning of the adrenal gland with the work he began as a medical student on the autonomic nervous system to formulate a theory of psychoendocrine relationships. In his book Bodily Changes in Pain, Hunger, Fear and Rage (Cannon 1915), he postulated that strong emotions influenced physiology through the “sympathico-adrenal medullary system” and described the fight-or-flight response. Expanding on Claude Bernard’s concept of a “milieu interior” that was held in balance, Cannon theorized that the purpose of a fight-or-flight response was to maintain the body’s physiological balance. He coined the term homeostasis to describe this

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process, which he defined as the process by which the body’s regulatory mechanisms allow it to maintain physiological stability despite environmental changes. He thereby linked the impact of emotional states on the endocrine systems with a normal physiological function (Fleming 1984). Cannon referred to “stresses and strains” as the physical and psychological forces that could disturb homeostatic processes (Cannon 1935). This concept of stress was greatly expanded a decade and a half later in the work of the physician-physiologist Hans Selye from the Université de Montréal. Selye developed his theories from work he began in the 1930s. During failed attempts to isolate a new sex hormone, Selye observed that the toxic, nonspecific effects of his extract often included adrenal cortical hypertrophy, atrophy of the thymus, and gastrointestinal ulcers (Mason 1975). By examining the effects of a variety of stressors—including bacteria inoculation, toxins, physical trauma, and exposure to heat and cold— on the responses of the anterior pituitary and adrenal cortex, he developed his theory of the organism’s “general adaptation syndrome” to stress (Selye 1950). The popularization of his work on the stress response continues to have a lasting effect on all areas of medical science (reviewed in Mason 1975) .

HPA Axis Activity and Depression The seminal studies of Cannon and Selye sparked a great deal of interest in psychiatry, because since antiquity many psychiatric disorders— depressive disorders in particular—had been linked to “stress” (Board and Persky 1957). Early studies were limited methodologically and relied on indirect measures of adrenal function, such as changes in lymphocyte and eosinophil levels, alterations in levels of inorganic phosphates, and variations in urinary concentrations of potassium, sodium, and uric acid. In retrospect, it is not surprising that many of these early studies generated conflicting results. In the 1950s, as more direct measures of urinary and plasma cortisol levels became available, a number of researchers demonstrated that stressful life situations, states of arousal, and various states of emotional distress in humans were linked with these indices of increased adrenal activity (Bliss et al. 1955, 1956; Bryson and Mertin 1954; Cleghorn and Graham 1950; Friedman et al. 1963; Price et al. 1957; Renold et al. 1951; Rubin and Mandell 1966). In these early HPA axis studies, clinical depression was a focus of inquiry because it was viewed as a common, time-limited state of profound emotional distress and therefore should have an influence on adrenal

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activity (Board and Persky 1957; Bryson and Mertin 1954; Rizzo et al. 1954). In 1956, using a direct measure of adrenal activity, plasma concentration of 17-hydroxycorticosteroid, a group of researchers from Michael Reese Hospital demonstrated increased levels of this substance in patients with severe depression (Board and Persky 1957; Board et al. 1956). This finding has been widely replicated since that time, using various direct measures of adrenal activity (Carpenter and Bunney 1971; Gibbons 1964; Gibbons and McHugh 1966; Gibbons et al. 1960; Kocsis et al. 1984; McClure 1966; Rothschild et al. 1993; Sachar 1967; Sachar et al. 1973; Stokes et al. 1984). In the study of depression, through the application of increasingly sophisticated measurements of HPA activity—such as the dexamethasone suppression test (DST), described by Carroll and co-workers in 1981—increasingly consistent observations have been reported. The DST has since become one of the most widely studied measurements in biological psychiatry (reviewed by Arana et al. 1985). As a result of the isolation of corticotropin-releasing hormone (Vale et al. 1981), investigators have been able to examine more directly the state of CNS control of adrenal activity in depressed subjects (reviewed by Gold and Chrousos 1985; Nemeroff 1993). With the appreciation of HPA hyperactivity in depression, interest has been focused on how this hypersecretion affects CNS functioning (reviewed by Rothschild et al. 1989; Wolkowitz 1994; Wolkowitz et al. 1985, 1987, 1989, 1993a, 1993b); this finding may contribute to the pathophysiology of the symptoms of depression, particularly in patients with psychotic depression (reviewed in Schatzberg and Rothschild 1988; Schatzberg et al. 1985). It has also has led to attempts to manipulate the HPA axis for therapeutic benefit in depressed patients (O’Dwyer et al. 1995; Rothschild and Schatzberg 1992; Ur et al. 1992; Wolkowitz et al. 1992), which could possibly fulfill the hopes of the early researchers in psychoneuroendocrinology.

The Present and the Future Much has happened in the field of psychoneuroendocrinology since the 1960s, as reviewed in the other chapters of this book. The number of investigators in the field has increased at an exponential rate. Technical advances have increased the understanding of psychoneuroendocrine interactions to the molecular level; the level of complexity has also increased, with discovery of an ever-expanding number of neurotransmitters, peptides, hormones, and receptors. The promises for therapeutic

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breakthroughs have never been greater. However, as Ralph Gerard is quoted in Tower’s review of neurochemistry, “the bright area of knowledge ever spreads and, although the dark surface of ignorance is presumably decreasing, the perimeter of contact with the unknown also increases” (Tower 1981).

References Arana GW, Baldessarini RJ, Ornsteen M: The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Arch Gen Psychiatry 42:1193–1204, 1985 Beach FA: Historical origins of modern research on hormones and behavior. Horm Behav 15:325–376, 1981 Bleuler M: The development of psychoneuroendocrinology, in Handbook of Psychiatry and Endocrinology. Edited by Beumont PJV, Burrows GD. New York, Elsevier Biomedical Press, 1982, pp 1–13 Bliss EL, Migeon CJ, Hardin Branch CH, et al: Adrenocortical function in schizophrenia. Am J Psychiatry 112:358–365, 1955 Bliss EL, Migeon J, Hardin Branch CH, et al: Reaction of the adrenal cortex to emotional stress. Psychosom Med 18:56–76, 1956 Board F, Wadeson R, Persky H: Depressive affect and endocrine functions. Archives of Neurology and Psychiatry 78:612–620, 1957 Board F, Persky H, Hamburg DA: Psychological stress and endocrine function: blood levels of adrenocortical and thyroid hormones in acutely disturbed patients. Psychosom Med 18:324–333, 1956 Brooks CM: The history of thought concerning the hypothalamus and its functions. Brain Res Bull 20:657–667, 1988 Bryson RW, Mertin DF: 17-Ketosteroid excretion in a case of manic-depression psychosis. Lancet 365–367, 1954 Cannon WB: Bodily Changes in Pain, Hunger, Fear and Rage: An Account of Recent Researches Into the Function of Emotional Excitement. New York, Appleton, 1915 Cannon WB: Stresses and strains of homeostasis. American Journal of the Medical Sciences 189:1–14, 1935 Carpenter WT Jr, Bunney WE Jr: Adrenal cortical activity in depressive illness. Am J Psychiatry 128:31–40, 1971 Carroll BJ, Feinberg M, Greden JR, et al: A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 38:15–22, 1981 Cleghorn RA, Graham BF: Studies of adrenal cortical activity in psychoneurotic subjects. Am J Psychiatry 106:668–672, 1950 Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 6th Edition. New York, Oxford University Press, 1991 Fleming D: Walter B. Cannon and homeostasis. Soc Res (New York) 51:609–640, 1984

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Friedman SB, Mason JW, Hamburg DA: Urinary 17-hydroxycorticosteroid levels in parents of children with neoplastic disease. Psychosom Med 25:364–376, 1963 Gibbons JL: Cortisol secretion rate in depressive illness. Arch Gen Psychiatry 10: 572–575, 1964 Gibbons JL, McHugh PR: Plasma cortisol in depressive illness. Psychiatry Res 1: 162–171, 1966 Gibbons JL, Gibbons JG, Maxwell AE, et al: An endocrine study of depressive illness. J Psychosom Res 5:32–41, 1960 Gold PW, Chrousos GP: Clinical studies with corticotropin releasing factor: implications for the diagnosis and pathophysiology of depression, Cushing’s disease, and adrenal insufficiency. Psychoneuroendocrinology 10(4):401– 419, 1985 Hughes AFW: A history of endocrinology. J Hist Med Allied Sci 32(3):292–313, 1977 Kathol RG: Psychiatric abnormalities in endocrine disorders, in Neuroendocrinology. Edited by Nemeroff CB. Boca Raton, FL, CRC Press, 1992, pp 397– 412 Kocsis JH, Brockner N, Butler T, et al: Dexamethasone suppression in major depression. Biol Psychiatry 19(8):1255–1259, 1984 Mason JW: A historical view of the stress field. J Human Stress 1(1):6–12, 1975 McCann SM: In search of hypothalamic hormones, in Pioneers in Neuroendocrinology, Vol 2. Edited by Meites J, Donovan BT, McCann SM. New York, Plenum Press, 1975, pp 267–286 McCann SM: The early history of the releasing factors. Endocrinology 130(1):8– 9, 1992a McCann SM: An introduction to neuroendocrinology: basic principles and historical considerations, in Neuroendocrinology. Edited by Nemeroff CB. Boca Raton, FL, CRC Press, 1992b, pp 1–22 McClure DL: The diurnal variation of plasma cortisol levels in depression. J Psychosom Res 10:189–195, 1966 Money J: The genealogical descent of sexual psychoendocrinology from sex and heath theory: the eighteenth to the twentieth centuries. Psychoneuroendocrinology 8(4):391–400, 1983 Mora G: Historical and theoretical trends in psychiatry, in Comprehensive Textbook of Psychiatry, 2nd Edition. Edited by Freedman AM, Kaplan HI, Sadock BJ. Baltimore, MD, Waverly Press, 1975, pp 1–53 Nelson DH: Pituitary-adrenal system, in Endocrinology: People and Ideas. Edited by McCann SM. Bethesda, MD, American Physiological Society, 1988, pp 87–116 Nemeroff CB: The psychoneuroendocrinology of depression: hypothalamic-pituitary adrenal axis dysregulation. Strecker Monograph Series 30:1–36, 1993 O’Dwyer AM, Lightman SL, Marks MN, et al: Treatment of major depression with metyrapone and hydrocortisone. J Affect Disord 33(2):123–128, 1995 Peart WS: Humors and hormones. Harvey Lect 73:259–290, 1979

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Price DB, Thaler M, Mason JW: Preoperative emotional states and adrenal cortical activity. Archives of Neurology and Psychiatry 77:656–656, 1957 Renold AE, Quigley TB, Kennard HE, et al: Reaction of the adrenal cortex to physical and emotional stress in college oarsman. N Engl J Med 244:744– 757, 1951 Rizzo ND, Fox HM, Laidlaw JC, et al: Concurrent observations of behavioral changes and of adrenocortical variations in a cyclothymic patient during a period of 12 months. Ann Intern Med 41:798–815, 1954 Rothschild AJ, Schatzberg AF: Theoretical basis for response to steroid suppression in major depression (letter; comment). J Clin Psychopharmacol 12(2): 142–144, 1992 Rothschild AJ, Benes F, Hebben N, et al: Relationships between brain CT scan findings and cortisol in psychotic and nonpsychotic depressed patients. Biol Psychiatry 26(6):565–575, 1989 Rothschild AJ, Samson JA, Bond TC, et al: Hypothalamic-pituitary-adrenal axis activity and 1-year outcome in depression. Biol Psychiatry 34(6):392–400, 1993 Rubin RT, Mandell AJ: Adrenal cortical activity in pathological emotional state: a review. Am J Psychiatry 123(4):387–400, 1966 Sachar EJ: Corticosteroids in depressive illness. Arch Gen Psychiatry 17:544–553, 1967 Sachar EJ, Hellman L, Roffwarg HP, et al: Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry 28:19–24, 1973 Sajous CED: The future of internal secretions. Endocrinology 1(1):1–11, 1917 Sawyer CH: Anterior pituitary neuronal control concepts, in Endocrinology: People and Ideas. Edited by McCann SM. Bethesda, MD, American Physiological Society, 1988, pp 23–40 Schatzberg AF, Rothschild AJ: The roles of glucocorticoid and dopaminergic systems in delusional (psychotic) depression. Ann N Y Acad Sci 537:462–471, 1988 Schatzberg AF, Rothschild AJ, Langlais PJ, et al: A corticosteroid/dopamine hypothesis for psychotic depression and related states. J Psychiatr Res 19(1): 57–64, 1985 Selye H: Stress and the general adaptation syndrome. Br Med J, June 17, 1950, pp 1383–1392 Stokes PE, Stoll PM, Koslow SH, et al: Pretreatment DST and hypothalamicpituitary-adrenocortical function in depressed patients and comparison groups: a multicenter study. Arch Gen Psychiatry 41(3):257–267, 1984 Tattersall RB: Charles-Edouard Brown-Sequard: double-hyphenated neurologist and forgotten father of endocrinology. Diabet Med 11(8):728–731, 1994 Tourney G: History of biological psychiatry in America. Am J Psychiatry 126:29– 42, 1969 Tower DB: Neurochemistry in historical perspective, in Basic Neurochemistry, 3rd Edition. Edited by Siegel GJ, Albers RW, Agranoff BW, et al. Boston, MA, Little, Brown, 1981, pp 1–16

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Ur E, Dinan TG, O’Keane V, et al: Effect of metyrapone on the pituitary-adrenal axis in depression: relation to dexamethasone suppressor status. Neuroendocrinology 56(4):533–538, 1992 Vale W, Spiess J, Rivier C, et al: Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397, 1981 Welbourn RB: The emergence of endocrinology. Gesnerus 49(Pt 2):137–150, 1992 Wilson LG: Internal secretions in disease: the historical relations of clinical medicine and scientific physiology. J Hist Med Allied Sci 39:263–302, 1984 Wolkowitz OM: Prospective controlled studies of the behavioral and biological effects of exogenous corticosteroids. Psychoneuroendocrinology 19(3):233– 255, 1994 Wolkowitz OM, Sutton ME, Doran AR, et al: Dexamethasone increases plasma HVA but not MHPG in normal humans. Psychiatry Res 16(2):101–109, 1985 Wolkowitz OM, Doran AR, Breier A, et al: The effects of dexamethasone on plasma homovanillic acid and 3-methoxy-4-hydroxyphenylglycol: evidence for abnormal corticosteroid-catecholamine interactions in major depression. Arch Gen Psychiatry 44(9):782–789, 1987 Wolkowitz OM, Doran A, Breier A, et al: Specificity of plasma HVA response to dexamethasone in psychotic depression. Psychiatry Res 29(2):177–186, 1989 Wolkowitz OM, Reus VI, Manfredi F, et al: Antiglucocorticoid strategies in hypercortisolemic states. Psychopharmacol Bull 28(3):247–251, 1992 Wolkowitz OM, Reus VI, Manfredi F, et al: Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 150(5):810–812, 1993a Wolkowitz OM, Weingartner H, Rubinow DR, et al: Steroid modulation of human memory: biochemical correlates. Biol Psychiatry 33(10):744–746, 1993b

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Part II Peptide Hormones

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Chapter 3 Neuropeptides and Hypothalamic Releasing Factors in Psychiatric Illness Dominique L. Musselman, M.D., M.S. Charles B. Nemeroff, M.D., Ph.D.

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n the search for the underlying pathophysiology of the major psychiatric disorders, neuropeptides in general, and hypothalamic releasing factors in particular, have been scrutinized closely. Undoubtedly one rationale for such intensive study in patients with primary psychiatric disorders is the higher-than-expected psychiatric morbidity in patients with primary endocrine disorders such as Addison’s disease or Cushing’s syndrome. However, a core assumption, the neuroendocrine window strategy, remains the essential impetus for continuing investigation of the major endocrine axes in psychiatric disorders. This strategy is based on a large body of literature that indicates that the secretion of the target endocrine organ (e.g., the adrenal cortex or thyroid) is largely controlled by the organ’s pituitary trophic hormone, which in turn is controlled primarily by the secretion of its hypothalamic release and release-inhibiting hormones (Figure 3–1). There is now considerable evidence that the secretion of these hypothalamic hypophysiotropic hormones is controlled by the classic neurotransmitters, including serotonin (5-hydroxytryptamine [5-HT]), acetylcholine, and norepinephrine, all previously posited to play a preeminent role in the pathophysiology of affective, anxiety, and psychotic disorders.

The authors are supported by NIH Grants DK-17298, MH-42088, MH-49523, MH-39415, MH-40524, and 1P50MH-58922.

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Relations between brain neurotransmitter systems, hypothalamic peptidergic (releasing-factor) neurons, anterior pituitary, and peripheral endocrine organs, illustrating feedback loops.

FIGURE 3–1.

Note. Dark black line represents inhibitory signal. TRH=thyroid-stimulating hormone; LHRH=luteinizing hormone–releasing hormone; SRIF=somatotropin release inhibitory factor (somatostatin); MIF=melanocyte stimulating hormone release–inhibiting hormone; CRH= corticotropin-releasing hormone; GRF= gonadotropin-releasing factor; TSH=thyroidstimulating hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; PRL=prolactin; GH=growth hormone; ACTH= adrenocorticotropic hormone. Source. Reprinted from Nemeroff CB: Psychoneuroendocrinology: Current Concepts. Kalamazoo, MI, The Upjohn Company, 1990, p. 22. Used with permission.

However, the hypothesis that information about higher central nervous system (CNS) neuronal activity (for example, the activity of serotonergic neurons) in a particular disease state can be obtained simply by measuring the activity of a specific endocrine axis is far from proven and is fraught with difficulty. The differing behavioral and neurobiological effects of antidepressants, anxiolytics, and antipsychotics—as well as drugs that induce or worsen depression (such as reserpine), anxiety (cholecystokinin), and psychosis (psychostimulants, phencyclidine)—have provided yet another impetus for scrutiny of neuroendocrine pathophysiology in the major psychiatric

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illnesses. This second core assumption, the psychopharmacologic bridge technique, posits that if a drug produces therapeutic effects and has specific biochemical actions, an etiologic relationship between the therapeutic effects, the biochemical changes, and the cause of the syndrome may exist (Janowsky et al. 1993). For example, tricyclic antidepressants block reuptake of norepinephrine and serotonin, monoamine oxidase inhibitors inhibit the metabolism of catecholamines, and downregulation or decrease in the number of b-adrenergic receptors (associated with most antidepressant treatments) occurs in association with the clinically successful treatment of depression. Therefore, what the pharmacologic bridge technique and the neuroendocrine window strategy provide is 1) clear evidence that alterations of a variety of endocrine axes exist within patients with major psychiatric disorders, and 2) an appreciation of the complexity of neuropeptide circuits in the CNS. The pharmacologic bridge technique also provides evidence of altered neurotransmitter transporter or receptor-mediated signal transduction in depression and other psychiatric disorders. Whether alterations in peripheral endocrine organ hormone secretion contribute primarily to the pathogenesis of psychiatric disorders and whether altered secretion of pituitary and hypothalamic hormones primarily contribute to the signs and symptoms of a specific mental illness remain subjects of considerable controversy. In this chapter we briefly outline the major findings concerning neuropeptides and hypothalamic releasing factors in psychiatric diseases.

Corticotropin-Releasing Hormone The neuroendocrine axis that has been most intensively scrutinized in psychiatric disorders is the hypothalamic-pituitary-adrenal (HPA) axis (Figure 3–2 and Table 3–1). There are literally hundreds of reports documenting HPA axis hyperactivity in drug-free depressed patients. In this section we briefly review evidence for CNS (i.e., corticotropin-releasing hormone [CRH]) involvement, pituitary (i.e., adrenocorticotropic hormone [ACTH]) involvement, and adrenal (i.e., glucocorticoid) involvement in the pathophysiology of the HPA axis in depression and anorexia nervosa. CRH, which is composed of 41 amino acids, is the primary physiological mediator of secretion of ACTH and b-endorphin from the anterior pituitary (Vale et al. 1981). Within the hypothalamus, CRH-containing neurons project from the paraventricular nucleus to the median eminence (Swanson et al. 1983). Activation of this CRH-containing neural circuit

32

FIGURE 3–2.

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The hypothalamic-pituitary-adrenal axis.

Note. Dark black line represents inhibitory signal. CRH=corticotropin-releasing hormone; ACTH=adrenocorticotropic hormone; MSH = melanocyte stimulating hormone. Source. Reprinted from Nemeroff CB: Psychoneuroendocrinology: Current Concepts. Kalamazoo, MI, The Upjohn Company, 1990, p. 29. Used with permission.

occurs in response to stress, resulting in an increase in synthesis and release of ACTH, b-endorphin, and other pro-opiomelanocortin (POMC) products. Convergent findings suggest that dysregulation of hypothalamic or extrahypothalamic CRH neurons are involved in the pathophysiology of major depression. Multiple studies of drug-free patients with major depression have revealed elevated CRH concentrations in cerebrospinal fluid (Arato et al. 1986; Banki et al. 1987, 1992b; France et al. 1988; Nemeroff et al. 1984; Risch et al. 1992), although not all studies agree (Geracioti et al. 1997). Postmortem CRH concentrations in cerebrospinal fluid collected from the intracisternal space of depressed persons who had committed suicide and control subjects who had died suddenly were also revealed to be markedly greater in the depressed group than in the control subjects (Arato et al. 1989). Elevated cerebrospinal fluid concen-

Neuropeptides and Hypothalamic Releasing Factors TABLE 3–1.

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Alterations in the activity of the limbic-hypothalamicpituitary-adrenal axis in depression

Increased corticotropin-releasing hormone (CRH) in cerebrospinal fluida,b Blunted adrenocorticotropic hormone (ACTH) and b-endorphin response to CRH stimulationa Decreased density of CRH receptors in frontal cortex of suicide victims Diminished hippocampal volume Pituitary gland enlargement in depressed patientsb Adrenal gland enlargement in depressed patientsb and suicide victims Increased ACTH production during depression Increased cortisol production during depressiona Plasma glucocorticoid, ACTH, and b-endorphin nonsuppression after dexamethasone administrationa Increased urinary free cortisol concentrations a

State dependent. Significantly correlated to postdexamethasone cortisol concentrations.

b

trations of CRH are believed to be a reflection of increased synaptic concentrations of the peptide, likely due to central CRH hypersecretion (Post et al. 1982). The increase in cerebrospinal fluid CRH concentrations that occurs during depression normalizes on recovery. In patients with major depression with psychotic features and elevated cerebrospinal fluid CRH concentrations, clinical recovery after electroconvulsive therapy is associated with significant reductions in cerebrospinal fluid CRH concentrations (Nemeroff et al. 1991). Treatment with antidepressants also results in reduction in cerebrospinal fluid CRH concentrations in healthy volunteers after administration of desipramine (Veith et al. 1992) and in depressed patients after treatment with fluoxetine (DeBellis et al. 1993) or amitriptyline (Heuser et al. 1998). Therefore, elevated cerebrospinal fluid CRH concentrations may represent a state, rather than a trait, marker of depression—that is, a marker of the state of depression rather than a marker of vulnerability to depression (Nemeroff et al. 1991). Furthermore, high or increasing cerebrospinal fluid CRH concentrations despite symptomatic improvement of major depression during antidepressant treatment may be the harbinger of early relapse (Banki et al. 1992b), as Nemeroff and Evans (1984) have previously reported (see below) for dexamethasone suppression test (DST) nonsuppression (Arana et al. 1985). In the standard DST paradigm, patients ingest 1 mg of dexamethasone, a synthetic glucocorticoid, at 2100. Blood samples are obtained at 1600 and 2100 the next day for measurement of plasma cortisol concentrations. Individuals without major depression generally “suppress” or diminish

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endogenous production of cortisol as demonstrated by plasma cortisol concentrations of less than 5.0 mg/dL. Another method for assessing the activity of the HPA axis is the CRH stimulation test, in which CRH (usually 100 mg or 1 mg/kg) is administered intravenously and the ensuing ACTH (or b-endorphin) and cortisol responses are measured (Hermus et al. 1984; S.J. Watson et al. 1988). In drug-free depressed patients, the ACTH and b-endorphin response to exogenously administered ovine CRH is blunted compared with nondepressed subjects (Amsterdam et al. 1988; Gold et al. 1984, 1986b; Holsboer et al. 1984; Kathol et al. 1989; Young et al. 1990). Krishnan et al. (1993) also reported that the blunted ACTH response to CRH occurs in depressed DST nonsuppressors but not in DST suppressors. This neuroendocrine abnormality, like the elevation in cerebrospinal fluid CRH concentration, is state dependent, returning to normal after successful treatment of depression (Amsterdam et al. 1988). (See also Chapter 17 for a more detailed description of CRH testing.) The blunted ACTH response to exogenously administered CRH in depressed patients is likely due (at least in part) to chronic hypersecretion of CRH from the nerve terminals in the median eminence, resulting in downregulation of anterior pituitary CRH receptors with resultant decreased pituitary responsiveness to CRH. Direct evidence for hypersecretion of CRH was provided by Raadsheer and colleagues (1994, 1995), who demonstrated a marked increase in the number of paraventricular nucleus CRH neurons and CRH mRNA expression in postmortem hypothalamic tissue from depressed patients compared with nondepressed control subjects. Such downregulation of CRH receptors in the pituitary in response to excessive CRH secretion was previously documented in laboratory animals (Aguilera et al. 1986; Holmes et al. 1987; Wynn et al. 1983, 1984, 1988). Moreover, in postmortem tissue from those who have committed suicide a decrease in the density of CRH receptors was observed in the frontal cortex (Nemeroff et al. 1988), although a discrepant report does exist (Hucks et al. 1997). On the basis of laboratory animal studies documenting corticotroph cell hypertrophy and hyperplasia in response to CRH, as well as other neuroendocrine alterations in depression (see below), Krishnan et al. (1991) sought to determine whether depressed patients exhibited pituitary gland enlargement. Using magnetic resonance imaging, these authors demonstrated pituitary gland enlargement in depressed patients in comparison to age- and sex-matched control subjects. In a second study, the magnitude of pituitary gland enlargement was significantly correlated to postdexamethasone cortisol concentrations, a measure of HPA axis hyperactivity (Axelson et al. 1992) (see Chapter 18).

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Cortisol hypersecretion in depression has been documented by elevated plasma corticosteroid concentrations (Carpenter and Bunney 1971; Gibbons and McHugh 1962), increased levels of cortisol metabolites (Sachar et al. 1970), and elevated 24-hour urinary free cortisol concentrations. Sachar and colleagues (1970) also reported that cortisol production is increased during depression and returns to normal in most subjects after recovery. Hypercortisolemia appears to be state dependent, like the hypersecretion of CRH and the blunting of the ACTH response to CRH in patients with major depression. Surprisingly, such elevations of plasma cortisol concentrations are not proportional to increases in ACTH concentrations (Linkowski et al. 1985). Moreover, patients exhibit a heightened cortisol response to pharmacologic doses of ACTH, which appears to be due to adrenocortical hypertrophy, not to increased adrenocortical sensitivity (Amsterdam et al. 1983; Kalin et al. 1982; Krishnan et al. 1990) (see below). Based on postmortem reports of enlarged adrenal glands in suicide victims (Zis and Zis 1987) and similar findings from a computed tomographic pilot study of depressed patients (Amsterdam et al. 1987), we conducted a computed tomographic study of 38 depressed patients and confirmed the findings of increased adrenal gland size (Nemeroff et al. 1992). This adrenal hypertrophy likely explains the fact that unlike the blunted ACTH and b-endorphin response to CRH, the plasma cortisol response is not different between depressed patients and healthy control subjects (Amsterdam et al. 1987; Gold et al. 1984, 1986b; Holsboer et al. 1984; Kathol et al. 1989; Young et al. 1990). Enlargement of adrenal glands in depressed patients has now been confirmed using magnetic resonance imaging. It is state dependent (Rubin et al. 1995), waxing and waning in parallel with exacerbation and denouement of clinical depressive symptoms. Such hypertrophy of the adrenal gland in patients with major depression may reflect current adrenocortical capacity (Nemeroff et al. 1993), because one study has reported that adrenal gland size is not correlated with plasma cortisol concentration, lifetime number of depressive episodes, severity of depression, or presence of melancholia (Rubin et al. 1996) (see Chapter 18). DST nonsuppression—like hypercortisolemia, hypersecretion of CRH, blunting of the ACTH response to CRH, and adrenal gland hypertrophy—appears to be state dependent (see Chapter 6). Hypersecretion of CRH during and immediately preceding a depressive episode with secondary pituitary and adrenal gland hypertrophy likely contributes to the multitude of studies reporting that patients with depression manifest HPA axis hyperactivity. Impairment of the normal negative feedback of cortisol on HPA axis activity may exist in the particular subset of depressed patients who exhibit DST nonsuppression. Indeed, elevated

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cerebrospinal fluid CRH concentrations have specifically been shown to occur in depressed patients who are DST nonsuppressors (Pitts et al. 1990; Roy et al. 1987). In healthy volunteers, however, there is evidence that a negative correlation exists between cerebrospinal fluid CRH and simultaneous cortisol plasma concentrations (Kling et al. 1994). Moreover, diminished cerebrospinal fluid CRH concentrations have been documented in depressed patients with normal plasma cortisol concentrations (Geracioti et al. 1997). The recent refinement of the DST is the combined dexamethasoneCRH test. Generally used within clinical research settings, this test is believed to be the most sensitive method of examining HPA axis activity. (See Chapter 17 for details on administration of the dexamethasoneCRH test.) If patients with depression who have been pretreated with dexamethasone are challenged with CRH, a paradoxical increase in ACTH and cortisol release is observed in comparison with control subjects. In nondepressed individuals, pretreatment with dexamethasone suppresses any major elevations of ACTH and cortisol plasma concentrations in response to CRH stimulation. Initial reports indicate the sensitivity of the dexamethasone-CRH test for major depression (about 80%) greatly exceeds that of either the DST (an average of 44%) or the CRH stimulation test (Heuser et al. 1994). The dexamethasone-CRH test is thought to reveal subtle alterations of the negative feedback regulation of the HPA axis (Holsboer-Trachsler et al. 1991). Unlike with the traditional DST, the failure of dexamethasone to prevent CRH stimulation of the HPA axis is not dependent on plasma concentrations of dexamethasone (Holsboer et al. 1987; Ritchie et al. 1990). In contrast to the CRH stimulation test, increases in ACTH plasma concentrations during the dexamethasone-CRH test may demonstrate the secretory stimulus of vasopressin on pituitary ACTH release. Nevertheless, the abnormally increased HPA response to a combined dexamethasoneCRH test gradually diminishes after successful antidepressant treatment (Holsboer-Trachsler et al. 1991) and predicts risk for relapse within 6 months of antidepressant treatment (Zobel et al. 1999). Of particular interest are the findings of Holsboer et al. (1995), who reported that asymptomatic first-degree relatives of patients with major depression exhibit abnormalities in the dexamethasone-CRH test compared with healthy control subjects but not as severe as patients with major depression. Future investigations will undoubtedly study relationships between cerebrospinal fluid CRH and plasma glucocorticoid concentrations; symptom profile studies; and volumetric measures of hippocampal, pituitary, and adrenal glands in depressed patients to further elucidate the relationship among these findings.

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Cerebrospinal fluid CRH concentrations have been measured in a variety of other psychiatric disorders, including the anxiety disorders, schizophrenia, somatization disorders, and Alzheimer’s disease (Table 3–2).

TABLE 3–2.

Hypothalamic-pituitary-adrenal axis activity in anxiety and other psychiatric disorders

Posttraumatic stress disorder Increased cerebrospinal fluid corticotropin-releasing hormone (CRH) concentrations Diminished adrenocorticotropic hormone (ACTH) response to CRH stimulation Plasma cortisol nonsuppression after low-dose (i.e., 0.5 mg) dexamethasone administration Normal or decreased 24-hour urinary free cortisol concentrations Diminished hippocampal volume Panic disorder Normal cerebrospinal fluid CRH concentrations Diminished ACTH response to CRH administration Obsessive-compulsive disorder Normal or increased cerebrospinal fluid CRH concentrations Alcohol dependence Increased cerebrospinal fluid CRH concentrations in acute alcohol withdrawal Anorexia nervosa Increased cerebrospinal fluid CRH concentrations Plasma cortisol nonsuppression after dexamethasone administration Increased plasma cortisol concentrations Increased urinary free cortisol Alzheimer’s disease Increased cerebrospinal fluid CRH concentrations early in the disease Normal cerebrospinal fluid CRH concentration as the disease progresses Diminished cerebrospinal fluid CRH concentration in the later stages of the illness Reduced cerebrospinal fluid CRH concentrations Huntington’s disease Parkinson’s disease Spinocerebellar degeneration Normal cerebrospinal fluid CRH concentrations Generalized anxiety disorder Schizophrenia Somatization disorders Abstinent patients with alcohol dependence

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Involvement of CRH in anxiety disorders has been well documented from both animal and human studies. As reviewed by Arborelius and colleagues (1999), patients with posttraumatic stress disorder (i.e., Vietnam combat veterans) exhibit significantly elevated cerebrospinal fluid CRH concentrations (Baker et al. 1999; Bremner et al. 1997) as well as a diminished response to CRH challenge (M.A. Smith et al. 1989). Unlike patients with major depression, patients with posttraumatic stress disorder exhibit normal 24-hour urinary free cortisol concentrations (Baker et al. 1999) or even reduced plasma concentrations of cortisol, especially after dexamethasone administration (Heim et al. 1997; Yehuda 1997). Although cerebrospinal fluid CRH concentrations are not increased in patients with panic disorder (Fossey et al. 1996; Jolkkonen et al. 1993), a diminished ACTH response to CRH administration has been observed (Roy-Byrne et al. 1986). Increased (Altemus et al. 1992) or normal concentrations (Chappell et al. 1996; Fossey et al. 1996) of cerebrospinal fluid CRH have been documented in patients with obsessive-compulsive disorder, although significant decreases in cerebrospinal fluid CRH concentrations occur with a therapeutic response to clomipramine (Altemus et al. 1994). Patients with generalized anxiety disorder, however, exhibit similar cerebrospinal fluid CRH concentrations in comparison to psychiatrically healthy control subjects (Banki et al. 1992a; Fossey et al. 1996). Not surprisingly, increased concentrations of cerebrospinal fluid CRH occur in alcohol withdrawal, a condition of sympathetic arousal and increased anxiety (Adinoff et al. 1996; Hawley et al. 1994). In contrast, cerebrospinal fluid CRH concentrations are reduced (Geracioti et al. 1994) or normal (Roy et al. 1990) in abstinent individuals with chronic alcoholism who have normal cortisol plasma concentrations. In sum, although HPA-axis hyperactivity exists in patients with certain anxiety disorders, such perturbations do not exist in the patterns suggestive of CRH hypersecretion as documented in patients with major depression (Arborelius et al. 1999). Normal cerebrospinal fluid CRH concentrations are usually found in schizophrenic patients (Banki et al. 1987, 1992c; Nemeroff et al. 1984; Nishino et al. 1998), and these patients exhibit normal ACTH and cortisol responses to CRH (Roy et al. 1986). However, after maintenance haloperidol was replaced by placebo, cerebrospinal fluid CRH plasma concentrations significantly increased in male schizophrenic patients and was unrelated to psychotic, depression, or anxiety symptoms (Forman et al. 1994). Reductions in cerebrospinal fluid CRH concentrations are generally reported in patients with neurodegenerative brain disorders, such as Huntington’s disease, Parkinson’s disease, end-stage Alzheimer’s disease (Edvinsson et al. 1993; Heilig et al. 1995; Suemaru et al. 1993), or

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spinocerebellar degeneration (Suemaru et al. 1995). However, increased cerebrospinal fluid CRH concentrations have been documented in patients with Alzheimer’s disease who exhibit DST nonsuppression (Martignoni et al. 1990) and in patients with dementia and depression (Banki et al. 1992a). Elevated cerebrospinal fluid CRH concentrations have also been reported in patients with Tourette’s syndrome in comparison to control subjects (Chappell et al. 1996). Unfortunately, most of these studies have failed to carefully measure dimensional indices of comorbid depressive symptoms that would be expected to be associated with elevations of cerebrospinal fluid CRH concentrations across these seemingly disparate psychiatric and neurological disorders. Another psychiatric syndrome with evidence of HPA axis hyperactivity and CRH hypersecretion is anorexia nervosa. In fact, many patients with anorexia nervosa also exhibit comorbid depressive symptoms. Elevated cerebrospinal fluid CRH concentrations have been reported in patients with anorexia nervosa (Hotta et al. 1986; Kaye et al. 1987). As in individuals with depression, patients with anorexia nervosa exhibit elevated plasma cortisol levels, increased secretion of urinary free cortisol, and DST nonsuppression (Brambilla et al. 1985). Kaye and colleagues (1987) reported that cerebrospinal fluid concentrations of CRH are significantly correlated with depression severity ratings in patients with weight correction. Moreover, normalized pituitaryadrenal function and cerebrospinal fluid CRH concentrations occur on weight recovery. As in major depression, underweight anorexic patients exhibited a blunted ACTH response after intravenous CRH administration (Gold et al. 1986a; Hotta et al. 1986). ACTH responses to CRH normalize after weight gain. Hotta and colleagues (1986) report that this normalization occurs immediately after correction of weight loss. However, the ACTH response to CRH has also been reported to normalize only after 6 months following weight gain. In summary, underweight patients with anorexia nervosa have been observed to exhibit elevated cerebrospinal fluid CRH concentrations and a blunted ACTH response to CRH, and normalization of both perturbations occurs on recovery of weight. Further research will seek to elucidate the role of CRH in anorexia nervosa and to determine whether it is associated only with the frequent comorbid major depression. Given the putative role of CRH in the stress response and the disease state of major depression, multiple pharmacologic treatment strategies have been considered, including inhibition of CRH synthesis, secretion, and metabolism, and neutralization of CRH by antibodies (Chalmers et al. 1996). Currently in development in multiple laboratories is another exciting strategy, the use of small-molecule, nonpeptide CRH receptor

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antagonists capable of crossing the blood-brain barrier (Deak et al. 1999). A CRH receptor antagonist could be targeted to either of the two subtypes of CRH receptors: the CRH1 or CRH2 receptors. CRH1 receptors exist within the pituitary, cerebellum, neocortex, and sensory structures. The CRH2 receptor, whose role is less well defined, is localized within subcortical areas such as the amygdala and hypothalamus, or peripheral organs such as cardiac and skeletal muscle, lung, and intestine (Chalmers et al. 1995; Lovenberg et al. 1995; Perrin et al. 1995). The distinctive distribution of CRH1 receptor subserves its function as the primary neuroendocrine pituitary receptor responsible for the CRH-stimulated ACTH release and its importance in cortical, cerebellar, and sensory functions. The localization of the CRH2 receptor is considered to relay not only the neuroendocrine actions but also autonomic and behavioral actions of CRH (Chalmers et al. 1995; Dieterich et al. 1997). Furthermore, with the discovery of urocortin (Vaughan et al. 1995), the preferred ligand for the CRH2 receptor, a series of experiments must now be undertaken concerning a role for this novel peptide in mood and anxiety disorders. Certain CRH receptor antagonists diminish fear (Deak et al. 1999; Schultz et al. 1996) or learned helplessness responses (Mansbach et al. 1997) in animals. These are in the last stages of drug development for human use and will likely produce a novel class of antidepressants or anxiolytics (Arborelius et al. 1999).

Endogenous Opioid Peptides The isolation of the endogenous opioid–like neuropeptides methionineenkephalin (met-enkephalin) and leucine-enkephalin (leu-enkephalin) by Hughes and colleagues in 1975 and the discovery of b-endorphin in 1976 by Li and Chung were followed by determination of a third endogenous opioid peptide system, the dynorphins (Goldstein et al. 1979). In the approximately 20 years since their discovery, intensive examination of these peptides has provided evidence for their involvement in a variety of physiological processes, including regulation of pain, mood, respiration, cardiovascular function, gastrointestinal activity, satiety, and sexual behavior. Now recognized as brain neurotransmitters, endogenous opioid peptides exist within a variety of organs such as the pituitary, thyroid, adrenal gland, gastrointestinal tract, placenta, and peripheral nervous system (see review by A.I. Smith and Funder 1988). At the genomic level, three genes are responsible for the precursors of opioid peptides: POMC,

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proenkephalin, and prodynorphin. Consequently, there are at least three classes of opioid peptides with different biosynthetic and neuronal pathways: the b-endorphins, the enkephalins, and the dynorphins. In the adenohypophysis (Bloom et al. 1976), POMC is processed to yield only ACTH and b-lipotropin. b-Lipotropin is then processed to yield at least three compounds, including b-, g-, and a-endorphin. The second endogenous opioid system is composed of the enkephalins whose precursor is proenkephalin. This enkephalin family contains among its opioid compounds met-enkephalin and leu-enkephalin. Derived from prodynorphin is the third group of endogenous opioid peptides, including dynorphin A, dynorphin B, and neoendorphin, which is located almost exclusively in the posterior pituitary. Investigation of the role of endogenous opioid peptides in psychiatric illness has largely focused on schizophrenia, the major mood disorders, the eating disorders, and childhood autism and self-injurious behavior (Frecska and Davis 1991). Clinical investigations have used various approaches, including measurement of endogenous opioid concentrations in cerebrospinal fluid and plasma, neuroendocrine challenge tests with determination of opioid responses, administration of opioid receptor agonists or antagonists in clinical trials, postmortem regional brain measurements, and even removal of opioid peptides from plasma of schizophrenic patients via hemodialysis or peritoneal dialysis. Intensive research conducted over two decades has produced no evidence that endogenous opioid peptides play an important role in either the pathophysiology or treatment of schizophrenia (see below). However, the investigations of patients with affective illness indicate that alterations of certain endogenous opioid peptides (e.g., b-endorphin) occur in conjunction with HPA axis hyperactivity in patients with major depression. These findings are not surprising, because b-endorphin and ACTH share a common precursor, POMC, within the anterior pituitary, and both are concomitantly released during stress (Guillemin et al. 1977). Most investigators (Black et al. 1986; Gerner and Sharp 1982; Inturrisi et al. 1982; Naber et al. 1981; Pickar et al. 1982), but not all (Risch 1982), have reported normal concentrations of cerebrospinal fluid b-endorphin in patients with major depression. Because of these negative findings and a lack of other evidence, extensive scrutiny of cerebrospinal fluid enkephalin and dynorphin concentrations in patients with affective disorder has not been conducted. In contrast, increased concentrations of basal plasma b-endorphin in patients with major depression are usually observed (Brambilla et al. 1986; Breier 1989; Gispen-de-Wied et al. 1987; Risch 1982), although there is one discrepant report of no significant alterations of basal plasma b-endorphin in depressed patients (Young et al.

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1990). However, depressed patients with increased urinary free cortisol concentrations exhibit positive correlations between their urinary free cortisol and cerebrospinal fluid opioid concentrations compared with healthy individuals (Rubinow et al. 1981). Such a correlation between plasma cortisol and b-endorphin concentrations has also been observed in depressed patients (Cohen et al. 1984). Similar to the ACTH response to intravenous CRH challenge (see above), the b-endorphin response to exogenously administered ovine CRH is blunted in depressed patients compared with nondepressed subjects (Young et al. 1990). Moreover, nonsuppression of plasma b-endorphin occurs in depressed patients in a manner similar to cortisol nonsuppression after dexamethasone administration. b-Endorphin nonsuppression to dexamethasone has been observed even in patients whose baseline b-endorphin levels were similar to those of healthy control subjects (Maes et al. 1990; Meador-Woodruff et al. 1987; Rupprecht et al. 1988). In these patients, postdexamethasone levels of cortisol and b-endorphin were strongly correlated (Maes et al. 1990; Rupprecht et al. 1988). In contrast, depressed patients have been reported to exhibit increased secretion of b-endorphin in response to cholinergic stimulation (Risch et al. 1982), thyrotropin-releasing hormone (TRH), and luteinizing hormone– releasing hormone (LHRH) in comparison with control subjects (Brambilla et al. 1986). Unfortunately, neither opioid agonists nor opioid antagonists have been found to be effective in the treatment of unipolar disorder, bipolar disorder, or schizophrenia. The short-acting opiate antagonist naloxone can prevent the induction of hallucination and thought disorganization after administration of exogenous opiates (such as b-endorphin) ( Jasinski et al. 1967; Pickar et al. 1984). Used as single agents, opioid antagonists were ineffective in patients with schizophrenia but were initially thought to be effective as an adjuvant treatment (Bissette et al. 1986a; Pickar et al. 1981a, 1981b, 1982a). In the international collaborative World Health Organization trial, neuroleptic augmentation with repeated doses of naloxone was comparable to placebo in reducing psychotic symptoms of schizophrenia patients (Pickar et al. 1989). A single report does exist in which long-term administration (for more than 30 days) of the highly potent opioid receptor antagonist nalmefene was more effective than placebo in decreasing psychotic symptoms (Rapaport et al. 1993). Several case reports document reductions in self-injurious behavior in patients with autism and mental retardation after administration of one of the opioid receptor antagonists naloxone (Barrett et al. 1980; Bernstein et al. 1984; Davidson et al. 1983; Gillman and Sandyk 1985; Richardson and Zaleski 1983; Sandman et al. 1983, 1987; Sandyk 1985) and naltrex-

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one (Campbell et al. 1989; Casner et al. 1996; Herman et al. 1987). However, there are some negative reports (Beckwith et al. 1986; Szymanski et al. 1987). A few reports document the efficacy of naltrexone in diminishing self-injurious behaviors in patients with borderline personality disorder as well (Roth et al. 1996). With minor exception, these reports are generally limited by open-label design, a relatively brief duration of treatment, small numbers of patients, characterization of patients by behavior rather than etiology, or a retrospective perspective (Casner et al. 1996). It has been hypothesized that such self-injury results in pain-induced endorphin release with continued stereotyped behaviors by the patient in an attempt to maintain increased endogenous opioid levels. In concordance with this hypothesis, investigators have reported increased cerebrospinal fluid endorphin concentrations in self-injurious autistic children compared with autistic patients without such behaviors (Gillberg et al. 1985). In fact, increased plasma concentrations of b-endorphin (Sandman 1988) and met-enkephalin (Coid et al. 1983) have been detected in self-injurious, developmentally disabled individuals in comparison with control subjects. Although the aforementioned results are very preliminary, they certainly serve as an impetus for further scrutiny.

Vasopressin Arginine vasopressin (AVP), the antidiuretic hormone, is one of the two posterior pituitary hormones. The most well-known AVP pathway consists of AVP-containing neurons whose cell bodies lie within the lateral magnocellular subdivision of the hypothalamic paraventricular and supraoptic nuclei. These AVP-containing neurons terminate in the neurohypophysis and secrete AVP into the systemic circulation, although they have collaterals to the hypothalamo-hypophyseal portal system as well (Chrousos 1992). Another group of AVP-containing neurons project from the medial parvocellular subdivision of the paraventricular nucleus to the median eminence. Within the median eminence, the parvocellularderived AVP is released from axon terminals, secreted into the hypothalamo-hypophyseal portal circulation, and carried to the anterior lobe of the pituitary gland (Swanson et al. 1983). Moreover, extrahypothalamic AVP-containing neurons lie within limbic structures such as the septum and amygdala, as well as the brainstem and spinal cord (Sawchenko and Swanson 1982; Swanson 1987). AVP-containing neurons also receive afferent innervation from many different neuronal cell groups and send axonal projections from the cerebral cortex throughout the CNS.

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It is thought that AVP and the other well-known posterior pituitary hormone, the nonapeptide oxytocin, play a role in modulating neural activity in hypothalamic, limbic, and autonomic circuits. Osmotic and chemoreceptor stimulation, hemorrhage, and hypotension activate the magnocellular neurons of the paraventricular nucleus and increase secretion of AVP from the neurohypophysis and extrahypothalamic brain regions (Cunningham and Sawchenko 1991). AVP allows the reabsorption of water back into the body by increasing the permeability of the distal and collecting ducts of the kidney tubules. The normal, narrow reference range of osmolality in humans is 280–295 mOsm/kg. To protect the body from a hyperosmolar state, maximal stimulation of AVP occurs at 295 mOsm/kg; antidiuretic hormone is not secreted as hypo-osmolarity approaches (i.e., near 280 mOsm/kg). In humans an increase in plasma osmolality as minute as 2% stimulates a twofold to threefold surge in plasma levels of AVP. When plasma osmolality is normal, AVP is secreted in large amounts during hypovolemia and hypotension. However, approximately 40 times more AVP is required to increase blood pressure compared with antidiuresis. Chronic stress or adrenalectomy increases the activity of the parvocellular AVP system (DeGoeij et al. 1992; Whitnall 1989). Interestingly, AVP and CRH are the major hypothalamic secretagogues for ACTH release. AVP administered together with CRH produces a synergistic release of pituitary POMC-derived peptides, that is, ACTH and b-endorphin in humans (DeBold et al. 1984) and animals (Plotsky 1991). CRH and AVP are co-localized in the parvocellular cells of the human hypothalamus and may be secreted together into the human hypothalamic-hypophyseal portal circulation (Mouri et al. 1993). The ratio of AVP to CRH in the hypothalamic-hypophyseal portal circulation varies in different species (Plotsky 1991) and according to the nature of the stress (Canny et al. 1989; Caraty et al. 1990). Similar to the clinical investigations regarding CRH, a variety of patient groups have been studied. Alterations of cerebrospinal fluid AVP have been reported in patients with major depression, bipolar disorder, schizophrenia, anorexia, obesity, alcoholism, Alzheimer’s disease, and Parkinson’s disease (Demitrack et al. 1989; Legros et al. 1993). Cerebrospinal fluid AVP concentrations in patients with major depression are reportedly reduced in comparison with control subjects, although the source of cerebrospinal fluid AVP is likely extrahypothalamic and not, in contrast to its purported hypersecretion, from the paraventricular nucleus in major depression (Gjerris et al. 1984, 1985; Linkowski et al. 1984). Basal plasma concentrations of AVP (secreted from the magnocellular neurons of the paraventricular nucleus after osmotic or barorecep-

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tor stimulation) within depressed patients have also been reported to be decreased in comparison with age-matched control subjects (Laruelle et al. 1990), although other researchers have found no difference (Gold et al. 1981). Interestingly, AVP secretion in response to an infusion of hypertonic saline is diminished in depressed patients compared with control subjects (Gold et al. 1981). A blunted ACTH response to exogenous AVP administration in depressed patients was reported by Kathol et al. (1989), but the finding was not replicated by two other studies (Carroll et al. 1993; Meller et al. 1987). Remarkably, an increase in the number of paraventricular nucleus AVP neurons co-localized with CRH cells has been reported in depressed patients compared with control subjects (Purba et al. 1996; Raadsheer et al. 1994). This is of interest in view of the ability of AVP to potentiate the actions of CRH at the corticotroph. In contrast to the findings suggestive of diminished hypothalamic-vasopressinergic activity in depressed patients are the findings suggestive of hypersecretion of AVP observed in bipolar patients in the manic phase. Elevations in cerebrospinal fluid AVP concentrations have been documented in manic patients (Legros et al. 1983), as have significant increases in plasma AVP concentrations in relation to patients with unipolar depression and control subjects (Legros and Ansseau 1989). AVP dysregulation has also been demonstrated in anorexia nervosa. Underweight anorexia nervosa patients exhibit osmotic dysregulation characterized by AVP release dissociated from gradual increases in plasma osmolality (Gold et al. 1983) in comparison with control subjects, in whom increases in plasma osmolality are accompanied by a linear rise in plasma AVP (Robertson et al. 1976). Although the AVP response to increased plasma osmolality may normalize with weight recovery, some anorexia nervosa patients demonstrate persisting defects in osmoregulation after weight stabilization for more than 6 months. Furthermore, patients with anorexia nervosa exhibit a cerebrospinal fluid to plasma AVP ratio greater than 1, in contrast to healthy control subjects, who exhibit a cerebrospinal fluid to plasma AVP ratio less than 1. This reversal of the cerebrospinal fluid to plasma AVP ratio persists well after weight recovery for some anorexia nervosa patients. Disturbances of AVP function have been thought to exist in aging individuals, particularly those with neurodegenerative syndromes (e.g., Parkinson’s disease), due to their cognitive dysfunction and associated perturbations of fluid and electrolyte homeostasis (Leake et al. 1991). Patients with Alzheimer’s disease were initially reported to exhibit CNS AVP hyposecretion as evidenced by reduced AVP brain concentrations (Fujiyoshi et al. 1987), diminished AVP cerebrospinal fluid concentrations (Bevilacqua et al. 1986; Mazurek et al. 1986a, 1986b; Raskind et

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al. 1986), a blunted AVP and b-endorphin response to cholinergic challenge with intravenous physostigmine (Raskind et al. 1989), and a diminished ACTH and cortisol response to a combined intravenous CRH/AVP stimulation test (Dodt et al. 1991). However, further investigation of AVP-producing neurons within the paraventricular nucleus and supraoptic nucleus of the hypothalamus revealed that the neurons expressing AVP in the paraventricular nucleus and supraoptic nucleus do not decline in number (and may even increase) during aging or in Alzheimer’s disease (Van der Woude et al. 1995). During aging or in Alzheimer’s disease, there may be increased (“activated”) peptide synthesis within the AVPproducing neurons, as evidenced by increased plasma concentrations of AVP and hypertrophy of AVP neurons (Vogels et al. 1990) with enlarged nuclei and Golgi apparatus (Lucassen et al. 1993). Other investigators have even observed that cerebrospinal fluid AVP concentrations in patients with Alzheimer’s disease are similar to concentrations seen in control subjects (Jolkkonen et al. 1989), as are postmortem brain AVP concentrations (Leake et al. 1991; van Zwieten et al. 1996) and AVPmRNA levels (Lucassen et al. 1997). Another challenge study also documented that patients with Alzheimer’s disease exhibit plasma AVP responses to osmotic stimulation induced by hypertonic saline infusion that are quite similar to those seen in healthy control subjects (Peskind et al. 1995). The discordant results within the extant literature of AVP perturbations in patients with Alzheimer’s disease are no doubt due to multiple studies with small sample sizes, assay variability, and the inherent difficulties of postmortem brain studies (e.g., fixation time, postmortem delay). Moreover, despite early hopes for AVP as a cognitive enhancing agent, neither vasopressin nor its analogs have been effective in the treatment of patients with memory disorders such as Alzheimer’s disease or Korsakoff’s syndrome (Legros and Timsit-Berthier 1988). Multiple groups have investigated whether alterations of cerebrospinal fluid AVP concentrations exist in patients with schizophrenia. Schizophrenic patients have been observed to exhibit increased (Linkowski et al. 1984), diminished (Linkowski et al. 1984; Van Kammen al. 1981), or similar (Beckmann et al. 1985) cerebrospinal fluid concentrations of AVP in comparison with healthy control subjects. However, two so-called challenge studies—one utilizing apomorphine (a dopamine receptor agonist) and the other methylphenidate (a dopamine releasing agent)—have provided tantalizing clues regarding alterations of AVP secretion in patients with schizophrenia. Legros and colleagues (1992) observed that, in comparison with healthy control subjects, schizophrenic patients exhibit a blunted vasopressin (and oxytocin) response following an apomorphine challenge. Moreover, after methylphenidate administra-

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tion, schizophrenic patients with psychogenic polydipsia exhibit significant increases in vasopressin plasma concentrations despite concomitant hyponatremia compared with patients with polydipsia but not hyponatremia. Clearly, hypothalamic and extrahypothalamic AVP circuits are regulated independently. Whether the perturbations of AVP secretion in patients with neuropsychiatric disorders are state dependent or trait dependent requires further elucidation.

Growth Hormone and Somatostatin Growth hormone is synthesized and secreted from the somatotroph cells of the anterior pituitary. Its secretion is modulated primarily by two hypothalamic hypophysiotropic hormones—growth hormone–releasing hormone (GHRH) and somatostatin—and secondarily by classic neurotransmitters such as dopamine, norepinephrine, and 5-HT that innervate the releasing factor–containing neurons (Table 3–3). Located primarily in the arcuate nucleus of the hypothalamus, GHRH stimulates the synthesis and release of growth hormone. Inhibition of growth hormone release is mediated primarily by somatostatin, a tetradecapeptide, which is found primarily in the periventricular nucleus of the hypothalamus. Somatostatin, unlike GHRH, is widely distributed in extrahypothalamic brain regions, including the cerebral cortex, hippocampus, and amygdala. Both GHRH and somatostatin are released from nerve terminals in the median eminence and are transported via the hypothalamohypophyseal portal system to act on the growth hormone–producing somatotrophs of the anterior pituitary. Release of growth hormone is stimulated by levodopa (Boyd et al. 1970), a catecholamine precursor, and by apomorphine, a dopamine receptor agonist (Lal et al. 1973). Growth hormone release also occurs after the administration of the serotonin precursors L-tryptophan and 5-hydroxytryptophan (5-HTP) (Imura et al. 1973; Muller et al. 1974). Serotonin receptor antagonists methysergide and cyproheptadine interfere with the growth hormone response to hypoglycemia (Toivola et al. 1972). Clonidine, a central a2-adrenergic receptor agonist (Lal et al. 1975), and norepinephrine (Toivola et al. 1972) also stimulate the release of growth hormone. In contrast, phentolamine, a nonspecific a-adrenergic receptor antagonist, inhibits growth hormone secretion (Toivola et al. 1972). Growth hormone secretion varies in a daily circadian pattern that decreases in magnitude as one ages. Under normal basal conditions, growth hormone is secreted in pulses that are highest during the initial hours of the night (Finkelstein et al. 1972).

48 TABLE 3–3.

PSYCHONEUROENDOCRINOLOGY Releasing and inhibiting factors for growth hormone

Growth hormone–releasing factors Growth hormone–releasing hormone Dopamine Levodopa Apomorphine (dopamine receptor agonist) Norepinephrine Clonidine (nonspecific a-adrenergic receptor agonist) Serotonin L-Tryptophan 5-Hydroxytryptophan Factors that inhibit growth hormone release Somatostatin Phentolamine (nonspecific a-adrenergic receptor antagonist) Methysergide (serotonin receptor antagonist) Cyproheptadine (serotonin receptor antagonist)

The growth hormone response to exogenously administered GHRH has been studied in drug-free depressed patients. At present, this test has not been standardized to body weight, which significantly correlates with the growth hormone response to GHRH in healthy subjects (Krishnan et al. 1988). Further confounding factors include the influence of sex, age, and menstrual cycle on the growth hormone response to GHRH. The existing data on responses to GHRH in subjects with depression is discordant, possibly because of the factors listed above (Nemeroff and Krishnan 1992). However, the vast majority of studies have reported a marked attenuation of the growth hormone response to noradrenergic agents (e.g., clonidine, desipramine) (Charney et al. 1982; Checkley et al. 1981; Dinan and Barry 1990; Matussek et al. 1980; Siever 1987; Siever et al. 1982) and, to a lesser extent, dopaminergic agonists (apomorphine) (Ansseau et al. 1988) in depressed patients. In depressed patients, dysregulation of the secretion of growth hormone is also indicated by other findings (Table 3–4). Not only is nocturnal growth hormone secretion diminished in depressed patients (Schilkrut et al. 1975), but hypersecretion of growth hormone during the waking hours has been reported in unipolar and bipolar patients compared with nondepressed control subjects (Mendlewicz et al. 1985). With the characterization of the genes encoding GHRH and its receptor, alterations in the CNS of depressed patients that underlie the diminished growth hormone response to norepinephrine and dopamine agonists can now be studied in postmortem tissue.

Neuropeptides and Hypothalamic Releasing Factors TABLE 3–4.

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Growth hormone disturbances associated with major depression

Blunted growth hormone response to noradrenergic or dopaminergic agents Reduction of nocturnal growth hormone secretion Hypersecretion of growth hormone during waking hours

A substantial body of literature also exists regarding alterations of somatostatin in patients with major depression and other neuropsychiatric disorders such as Alzheimer’s disease and multiple sclerosis (see the extensive review by Rubinow and colleagues 1995). Somatostatin not only inhibits growth hormone release, but it also has multiple inhibitory effects on various neuroendocrine systems, including reducing secretion of thyroid-stimulating hormone (TSH) and CRH. Although somatostatin does not alter ACTH concentrations in nondepressed control subjects (Ambrosi et al. 1990; Patel 1992), somatostatin infusion diminishes hypoglycemia-induced increases of cortisol concentration (Rubinow et al. 1992). In preclinical studies, somatostatin influences a variety of vegetative functions (including appetite and locomotor activity), as well as analgesia and learning (Rubinow et al. 1995; Vecsei and Widerlov 1990; Walsh et al. 1985) There are at least seven studies documenting diminished cerebrospinal fluid concentrations of somatostatin in patients with major depression (Agren and Lundqvist 1984; Bissette et al. 1986b; Gerner and Yamada 1982; Kling et al. 1993; Molchan et al. 1991; Rubinow et al. 1983, 1984, 1995). Indeed, hypercortisolemia and diminished cerebrospinal fluid somatostatin-like immunoreactivity (SLI) have often been observed in patients with psychiatric disorders (Wolkowitz et al. 1987). Reduced cerebrospinal fluid somatostatin concentrations have been reported in patients exhibiting dexamethasone nonsuppression (whether schizophrenic or depressed) and are negatively correlated with the maximum postdexamethasone cortisol plasma concentration in patients with major depression (Doran et al. 1986). In fact, administration of supraphysiological doses of prednisone to healthy volunteers is accompanied by significant reductions of cerebrospinal fluid SLI (Wolkowitz et al. 1987). Although there is some evidence of normalization of cerebrospinal fluid somatostatin concentration after recovery from depression (Agren and Lundqvist 1984; Post et al. 1988; Rubinow et al. 1984), other studies have noted no significant changes in cerebrospinal fluid somatostatin concentrations of depressed patients despite clinical improvement with antidepressant (Banki et al. 1992b) or electroconvulsive therapy treatment (Nemeroff et al. 1991). Interestingly, administration of certain psychotropic medi-

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cations is known to 1) decrease cerebrospinal fluid somatostatin concentrations (e.g., carbamazepine [Rubinow et al. 1992], diphenylhydantoin, and fluphenazine [Doran et al. 1989]); 2) increase cerebrospinal fluid somatostatin concentrations (e.g., haloperidol [Gattaz et al. 1986]; or 3) have no effect (e.g., desmethylimipramine or lithium carbonate [Rubinow et al. 1992]). Reductions of cerebrospinal fluid somatostatin concentrations have also been consistently observed in patients with Alzheimer’s disease (Bissette et al. 1986b; Oram et al. 1981; Soininen et al. 1984; Wood et al. 1983), as have reductions in somatostatin in brain—particularly in the frontal, parietal, and temporal cortices—on postmortem examination (Lowe et al. 1988). Obvious alterations of CNS growth hormone and somatostatin concentrations and function exist in major depression, although whether these changes represent fundamental contributors to this syndrome or are merely epiphenomena remains to be determined. Diminished concentrations of the inhibitory neuropeptide somatostatin might plausibly allow CRH hypersecretion and increased HPA axis activity. Further elucidation of somatostatin receptor function and the effects and utility of somatostatin receptor agonists and antagonists will provide important information regarding the pathophysiology of major depression and neurodegenerative disorders such as Alzheimer’s disease.

Cholecystokinin First identified in the gastrointestinal tract as a 33–amino acid peptide, cholecystokinin (CCK) (Mutt and Jorpes 1968) was discovered in the mammalian CNS in 1975. Utilizing a gastrin antiserum that avidly crossreacts with CCK, Vanderhaeghen and colleagues (1975) found abundant gastrin-like material in the brains of many vertebrate species, including humans. Amino acid sequence analysis determined this substance to be the carboxyl-terminal amidated peptide CCK 8 (Dockray et al. 1978). In the gut, CCK exists predominantly in its larger forms of CCK 22, 33, 39, and 58, with smaller quantities of CCK 8. In the brain, its major amidated form is CCK 8. Interestingly, CCK is found in higher concentrations in the brain than in the gastrointestinal tract. In the brain, only neuropeptide Y exists in higher concentrations than CCK. CCK and high densities of its receptors exist in areas of the mammalian brain associated with emotion, motivation, and sensory processing, such as the cortex, striatum, hypothalamus,

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hippocampus, and amygdala (Dietl and Palacios 1989; Hokfelt et al. 1980; Innis and Snyder 1980; Saito et al. 1980; Tang and Man 1991). CCK is often co-localized with dopamine in the mesolimbic and mesocortical areas. Of the two major subtypes of CCK receptors that exist, the CCKA receptor is primarily found in the bowel, pancreas, and gallbladder, whereas the CCKB receptor predominates in the brain. Cholecystokinin has been reported to reduce the release of dopamine (Fuxe et al. 1980; Lane et al. 1986; Voigt et al. 1986); conversely, the release of CCK is modulated by dopamine (Meyer and Krauss 1983; Meyer et al. 1984). Moreover, preclinical studies indicated that dopaminergic neuronal activity may be either facilitated or inhibited by CCK (Crawley et al. 1985; Hommer and Skirboll 1983; Vaccarino and Rankin 1989; Van Ree et al. 1983). Therefore, initial investigation of a putative role for CCK in the pathophysiology of neuropsychiatric disorders focused on the potential involvement of the peptide in schizophrenia. Concentrations of CCK in cerebrospinal fluid of medication-free schizophrenic patients were reported to be decreased (Garver et al. 1991a; Lotstra et al. 1985; Verbanck et al. 1984), increased (Gerner et al. 1985), or unchanged (Gerner and Yamada 1982; Gjerris et al. 1984; Rafaelsen and Gjerris 1985) compared with control subjects. Unfortunately, the CCK analog cerulein produced no therapeutic benefit to medication-free schizophrenic patients (Hommer et al. 1985), and the efficacy of ongoing antipsychotic drug treatment of schizophrenic patients was not improved with co-administration of a decapeptide closely related to CCK, ceruletide (Hommer et al. 1985), or the CCK antagonist proglumide (Hicks et al. 1989; Innis et al. 1986). Investigation of possible perturbations of CCK function in patients with mood disorders has also demonstrated rather disappointing findings. There is a single report of diminished concentrations of cerebrospinal fluid CCK in patients with bipolar disorder (Verbanck et al. 1984), but similar findings have not been made in unipolar depression (Gerner and Yamada 1982; Gjerris et al. 1984; Lotstra et al. 1985; Rafaelsen and Gjerris 1985). Impetus for study of the role of CCK in the pathophysiology of panic disorder and other anxiety disorders was provided by the finding that intravenous injection of cholecystokinin tetrapeptide (CCK 4) induced panic symptoms in healthy individuals (De Montigny 1989). In a subsequent double-blind study, patients with panic disorder experienced panic attacks after intravenous administration of CCK but not after saline challenge (Bradwejn et al. 1990). Furthermore, compared with healthy control subjects, patients with panic disorder exhibit an increased sensitivity to CCK 4, a preferential CCKB receptor agonist (Bradwejn et al. 1991a, 1991b, 1992), although both panic disorder patients and control subjects

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experience panic attacks with increasing doses of CCK-4 (Bradwejn et al. 1991a, 1991b). These findings were extended in investigations in which pentagastrin (another CCKB receptor agonist) provoked panic attacks in patients with panic disorder and, to a lesser extent, in patients with generalized anxiety disorder (Brawman-Mintzer et al. 1997) and healthy control subjects (Abelson and Nesse 1990; van Megen et al. 1994). Of note is that patients with panic disorder exhibit diminished cerebrospinal fluid CCK concentrations in comparison with control subjects (Lydiard et al. 1992). The development of CCKB receptor antagonists may be a potentially novel treatment for panic disorder and other anxiety disorders. Certain CCKA or CCKB receptor antagonists have demonstrable anxiolytic (Hendrie and Dourish 1990; Hughes et al. 1990; Ravard and Dourish 1990; Ravard et al. 1990), antidepressant (Kelly and Leonard 1992), or memoryenhancing (Lemaire et al. 1992) effects in animals. Moreover, in patients with panic disorder, administration of L-365,260, a benzodiazepine-derived CCKB receptor antagonist, blocks CCK 4–induced panic (Bradwejn et al. 1994). In control subjects without panic disorder, L-365,260 did not exhibit an anxiolytic effect but did not induce adverse changes in mood, appetite, or memory (Grasing et al. 1996). Another compound, CI-988, has been studied in patients with generalized anxiety disorder but was not more effective than placebo as an anxiolytic (Adams et al. 1995). Nevertheless, efforts continue toward the development of an alternative, effective anxiolytic that does not have the adverse sedative and cognitive effects of benzodiazepines.

Neurotensin Discovered in 1973 by Carraway and Leeman in bovine hypothalamus, the tridecapeptide neurotensin exerts a variety of actions on endocrine and gastrointestinal systems, in addition to its function within the CNS. The highest concentrations of neurotensin are within the hypothalamus, particularly the posterior hypothalamus and mammillary bodies. Significant concentrations of neurotensin are also found within the substantia nigra, ventral tegmental area, and central nucleus of the amygdala, as well as the dorsal hippocampus, septum, dorsal pallidum, and nucleus accumbens (Jennes et al. 1982; Manberg et al. 1982). Although a discussion of the anatomical localization of neurotensin is beyond the scope of this chapter (see Bissette and Nemeroff 1995 for review), the most extensively characterized neurotensin pathway is the mesolimbic-cortical projection

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of neurotensin-containing neurons from the ventral tegmental area to the frontal cortex and nucleus accumbens (Kalivas and Miller 1984). Partly because of the extensive co-localization of neurotensin and dopamine in the rat brain and the neuroleptic-like effects of neurotensin, intensive investigation of the hypothesis that this peptide is an endogenous neuroleptic continues (Binder et al. 2001). Decreased neurotensin concentrations in the cerebrospinal fluid of drug-free schizophrenic patients in comparison with healthy sex- and age-matched control subjects have been observed in several studies (Garver et al. 1991b; Lindstrom et al. 1988; Widerlov et al. 1982). Although one study determined no significant difference in cerebrospinal fluid neurotensin concentrations between drug-free schizophrenic patients and control subjects (Breslin et al. 1994), even these researchers observed a bimodal distribution of cerebrospinal fluid neurotensin in their cohort of schizophrenic patients. Indeed, reductions in cerebrospinal fluid neurotensin concentrations have not been observed in other psychiatric syndromes, notably major depression, anorexia-bulimia, or premenstrual syndrome (Nemeroff et al. 1989a). Preclinical studies have demonstrated that administration of typical antipsychotic drugs such as haloperidol and chlorpromazine is associated with increases in neurotensin concentrations and neurotensin mRNA expression in both the caudate nucleus and nucleus accumbens. The atypical antipsychotic clozapine increases neurotensin concentrations in the nucleus accumbens but not in the striatum, which likely contributes to the lower incidence of extrapyramidal side effects observed with clozapine treatment (Govoni et al. 1980; Kinkead and Nemeroff 1994; Levant and Nemeroff 1992). Microdialysis studies have revealed that these increases in tissue concentrations are mirrored by increases in extracellular fluid concentrations of neurotensin (Radke et al. 1996). Moreover, concentrations of neurotensin in the aforementioned brain regions are not altered by tricyclic antidepressants, antihistamines, or benzodiazepines. Antipsychotic drug treatment of schizophrenic patients is also followed by significant increases in cerebrospinal fluid neurotensin concentrations (Breslin et al. 1994; Widerlov et al. 1982). Another technique that has been used to study neurotensin alterations associated with psychopathology is postmortem brain investigation, although it can be confounded by antipsychotic treatment administered during the patient’s life, which may alter concentrations of neurotensin in the brain. Postmortem examinations of seven subcortical brain regions of schizophrenic patients, including nucleus accumbens and caudate nucleus tissue, have not demonstrated significant alterations of neurotensin concentrations (Kleinman et al. 1983; Nemeroff et al. 1983). In the studies examining seven areas of cortical tissue, only Brodmann’s area 32 of

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the schizophrenic brain exhibited a significant group mean increase in neurotensin concentration relative to the control group (Nemeroff et al. 1983). Bean and colleagues (1992) found no difference between schizophrenic patients and control subjects in concentrations of neurotensin mRNA or in its genomic sequence in ventral midbrain neurons. Interestingly, polymorphisms have been detected in the neurotensin receptor mRNA sequences from human brain tissue (M. Watson et al. 1993). Whether such mRNA polymorphisms are associated with functional alterations of the neurotensin receptor (and in turn are associated with the clinical psychopathology of schizophrenia) remains to be determined. Postmortem regional CNS investigations of other neuropsychiatric diseases, however, have revealed alterations in neurotensin concentrations in brain tissue. Diminished concentrations of neurotensin in the amygdala of Alzheimer’s disease patients have been documented (Benzing et al. 1990; Nemeroff et al. 1989b). In contrast, increased neurotensin concentrations have been observed in the caudate nucleus and globus pallidus of Huntington’s disease patients (Nemeroff et al. 1983). Although the number of neurotensin receptors on dopamine neurons in the substantia nigra decreases as these neurons degenerate (Sadoul et al. 1984; Uhl et al. 1984), postmortem neurotensin concentrations in various brain regions (including the caudate nucleus, nucleus accumbens, and ventral tegmental area) in subjects with Parkinson’s disease are remarkably similar to those found in age- and sex-matched control subjects (Bissette et al. 1985). This may be due to the finding that neurotensin and dopamine, though co-localized in the mesolimbic system of rodents, is not co-localized in primates. Development of specific neurotensin receptor agonists and antagonists may allow further determination of the physiological effects of altered neurotensin receptor activity. A specific neurotensin receptor agonist affords the tantalizing possibility of antipsychotic activity, whereas a neurotensin antagonist might disrupt the actions of endogenous neurotensin, thus providing even greater information of the role of this peptide in dopamine neurotransmission and hormonal regulation within the CNS.

Neuropeptide Y Originally cloned from a pheochromocytoma by Minth and colleagues in 1984, neuropeptide Y is a 36–amino acid peptide whose gene is expressed in cells derived from neural crest (Allen and Balbi 1993). Neurons dis-

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playing neuropeptide Y immunoreactivity are abundant within the limbic areas of the CNS (De Quidt and Emson 1986; Hendry 1993). Neuropeptide Y is also present within neurons of the hypothalamus, brainstem, and spinal cord. Present in most sympathetic nerve fibers, neuropeptide Y can be detected in vascular beds throughout the body and occurs in parasympathetic nerves as well (Sundler et al. 1993). Receptors for neuropeptide Y are also widely distributed. Not only do neuropeptide Y–containing neurons innervate CRH-containing cells of the paraventricular nucleus (Liposits et al. 1988), but administration of neuropeptide Y increases hypothalamic CRH levels (Haas and George 1987, 1989) as well as its release (Tsagarakis et al. 1989). The relationship of neuropeptide Y to CRH is further substantiated by the partial blockade of the neuropeptide Y–stimulated ACTH response by a CRH receptor antagonist. Moreover, neuropeptide Y potentiates the effects of exogenously administered CRH in animals (Inoue et al. 1989). Although an initial investigation (Berrettini et al. 1987) did not find significantly diminished cerebrospinal fluid neuropeptide Y concentrations in depressed patients, Widerlov and colleagues (1988) subsequently reported that patients with major depression do exhibit decreased cerebrospinal fluid neuropeptide Y concentrations compared with sex- and age-matched control subjects. Negative correlations have been also observed between dimensional anxiety ratings and cerebrospinal fluid neuropeptide Y levels in depressed patients (Heilig and Widerlov 1990). Furthermore, marked reductions in brain tissue concentrations of neuropeptide Y were subsequently reported in suicide victims, with the most dramatic decreases occurring in patients diagnosed with major depression (Widdowson et al. 1992). Preclinical investigations demonstrate the effect of neuropeptide Y in appetitive behaviors. After intracerebroventricular injections, neuropeptide Y provokes excessive eating in mammals (Stanley 1993). After starvation, the hypothalamic paraventricular nucleus concentrations of neuropeptide Y increase; they diminish rapidly to prestarvation levels after food ingestion (Sahu et al. 1988). In humans, increased cerebrospinal fluid concentrations of neuropeptide Y have been detected in underweight amenorrheal anorexic patients and in the same amenorrheal patients within 6 weeks after weight restoration. Furthermore, an inverse relationship between cerebrospinal fluid neuropeptide Y concentration and caloric intake is observed in healthy female volunteers (Kaye et al. 1989, 1990). Whether the symptoms of anorexia are induced by increased neuropeptide Y secretion or whether increased cerebrospinal fluid concentrations of neuropeptide Y result from starvation remains to be determined.

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Efforts toward development of neuropeptide Y receptor–specific agonists and antagonists continue. Neuropeptide Y–ergic medications may have significant benefit in the treatment of affective illness or eating disorders.

Substance P In mammals, members of the rapidly acting peptide tachykinin family are known as neurokinins (Guard and Watson 1991) and include neurokinin A, neurokinin B, and substance P. The most abundant of the neurokinins, the undecapeptide substance P, was discovered in 1931 by von Euler and Gaddum but was not isolated in pure form until 1970 by Chang and Leeman (1970). Substance P binds to the neurokinin 1 receptor, neurokinin A binds to the neurokinin 2 receptor, and neurokinin B binds to the neurokinin 3 receptor. Within the CNS, substance P is localized within in the limbic and stress response areas (amygdala, hypothalamus, periaqueductal gray matter, locus coeruleus, and parabrachial nucleus) (Ku et al. 1998) and exists within norepinephrine- and serotonin-containing cell bodies as well (Bittencourt et al. 1991; Helke and Yang 1996; Magoul et al. 1993; Pelletier et al. 1981). Furthermore, substance P and other tachykinins serve as pain neurotransmitters in primary afferent neurons (J. Culman and Unger 1995) and exert a variety of other peripheral actions, including bronchoconstriction, vasodilatation, salivation, and smooth muscle contraction in the gut (Payan et al. 1984; Pernow 1983). Preclinical studies have provided much of the impetus to continue investigation of the efficacy of substance P receptor antagonism, although these agents have not been effective as analgesics (Nutt 1998). Administration of substance P (or substance P agonist) to animals elicits behavioral and cardiovascular effects resembling the stress response and socalled defense reaction (Helke et al. 1990). Moreover, preclinical studies documented reduction of behavioral and cardiovascular stress responses by administration of substance P receptor antagonists (C. Culman et al. 1997; Kramer et al. 1998). An exciting initial study indicated that the substance P receptor antagonist MK-869 is more effective than placebo and is as effective as paroxetine in patients with moderate to severe symptoms of major depression (Kramer et al. 1998). Future clinical investigations will determine whether brain and cerebrospinal fluid substance P concentrations are altered in patients with major depression (Berrettini et al. 1985; Rimon et al. 1984) and whether there are significant changes in cerebrospinal fluid concentrations of substance P after treatment (Martensson et al. 1989).

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Other Peptides Another neuropeptide that is possibly involved in the pathophysiology of anxiety disorders is diazepam-binding inhibitor (DBI). There has been a great deal of interest in the isolation of endogenous ligands for benzodiazepine recognition sites in the CNS. DBI, an 11-kDa polypeptide, was identified not only in animal brain tissue (Guidotti et al. 1983) but also in human brain tissue (Ferrero et al. 1986; Shoyab et al. 1986). This endogenous peptide, which avidly inhibits the binding of benzodiazepines to brain synaptosomes, is present in high concentrations in the amygdala and hippocampus. DBI is thought to be important in responses to stress, particularly in regulating steroid production in both the CNS and adrenal glands, and it may therefore play a role in modulation of depressive and anxiety symptoms (Ferrarese et al. 1993). Indeed, intracerebroventricular injections of human DBI into animals facilitates behavioral inhibition (Ferrero et al. 1986). Moreover, elevation of cerebrospinal fluid DBI concentrations has been documented in patients with major depression (Barbaccia et al. 1987) and has been positively correlated with cerebrospinal fluid concentrations of CRH (Roy et al. 1989). Clinical investigations will undoubtedly further determine the physiological function of DBI and whether this neuropeptide can be utilized as a biochemical marker indicative of anxiety or affective illness. Delta sleep–inducing peptide (DSIP) may have a role in the pathophysiology of sleep disorders. Isolated in 1977, the nonapeptide DSIP was identified in animals after electrical stimulation of the thalamus to induce sleep (Monnier and Hoesli 1965; Schoenenberger et al. 1978). Circulating forms of DSIP were subsequently recognized by antisera and were referred to as DSIP-LI for DSIP-like immunoreactivity. DSIP-LI has been detected in various brain areas and body fluids, including adenohypophyseal corticotroph/melanotropin cells, where it is co-localized with ACTH (Bjartell et al. 1987; Vallet et al. 1988). DSIP was originally proposed to be a sleep-inducing hormone because of its sleep-inducing qualities after intravenous administration in animals and humans (Schneider-Helmert and Schoenenberger 1983; Schneider-Helmert et al. 1981). DSIP has been utilized in clinical trials with patients with chronic insomnia and narcolepsy, with both positive (Schneider-Helmert 1984a, 1984b) and negative results (Graf and Kastin 1986). In patients with major depression, diminished cerebrospinal fluid DSIP levels have been detected (Lindstrom et al. 1985; Walleus et al. 1985). In depressed patients, CRH stimulation reduces plasma DSIP-LI concentration, in contrast to nondepressed volunteers, in whom intrave-

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nous CRH administration induces increased plasma DSIP-LI concentration (Lesch et al. 1988). Decreased levels of cerebrospinal fluid DSIP have also been detected in drug-free schizophrenic patients in comparison with healthy control subjects (Lindstrom et al. 1985; Van Kammen et al. 1992). Interestingly, prophylactic lithium treatment of patients with mood disorders increases cerebrospinal fluid and plasma concentrations of DSIP (Regnell et al. 1988; Walleus et al. 1985). Obviously, the literature on DBI and DSIP in psychiatric disorders will be further developed and extended. Future efforts will undoubtedly reveal whether agents altering the function of these peptides can be therapeutically effective in patients with anxiety, mood, and sleep disorders.

Clinical Implications The last three decades of neuropsychophysiologic exploration have yielded a plethora of new findings regarding the alterations of CNS neuropeptides and hypothalamic releasing factors in certain psychiatric disorders (Table 3–5). Not only does understanding of these findings require a sophisticated level of psychoneuroendocrine knowledge, but integration of the seemingly disparate data into a conceptual schema must be postponed until further information is gathered. Although the balance of evidence indicates that multiple neuropeptide systems within the CNS are altered in major depression and anorexia nervosa, determination of the activity or dysfunction of these systems within the brain remains relatively difficult. Not only may there be differences between hypothalamic and extrahypothalamic secretion within the brain, but disagreement continues as to which compartment cerebrospinal fluid sampling accesses (or whether it access both compartments). Furthermore, there is discordance between CNS and more peripheral sources of a neuropeptide, such as neurotensin and cholecystokinin. Peripheral plasma concentrations of a neuropeptide or hypothalamic releasing factor are determined not only by the rate of release but also by local metabolic degradation and by redistribution into other extravascular spaces (Linares et al. 1988). For example, plasma CRH concentrations can be measured but may not truly represent CNS secretion because of the CRH contribution by the adrenal medulla and spleen. Nevertheless, the importance of hypothalamic releasing factors in the pathophysiology of psychiatric illness is most evident in the large body of literature indicative of CRH hypersecretion in patients with major depression, although not all studies are in agreement (Geracioti et al.

Neuropeptides and Hypothalamic Releasing Factors TABLE 3–5.

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Alterations of neuropeptides and hypothalamic releasing factors in various psychiatric disorders

Major depression Hyperactivity of the hypothalamic-pituitary-adrenal axis Dysregulation of growth hormone secretion Diminished somatostatin activity Diminished neuropeptide Y secretion Diminished delta sleep–inducing peptide secretion Bipolar disorder—manic phase Hypersecretion of arginine vasopressin Anxiety disorders Increased sensitivity to CCK-4, a preferential CCKB receptor agonist Anorexia nervosa Hyperactivity of the hypothalamic-pituitary-adrenal axis Hypersecretion of neuropeptide Y Schizophrenia Decreased neurotensin secretion Alzheimer’s disease Somatostatin hypoactivity Note.

CCK=cholecystokinin.

1992). Virtually all of the neuropeptide and neuroendocrine axis alterations in patients with major depression thus far studied are state dependent. However, nearly all the studies noted in this chapter are “crosssectional” in design—that is, the psychiatric disorder and the alterations of neuropeptide or hypothalamic releasing factors are determined at approximately the same time. Clinical investigators of the twenty-first century will extend understanding of whether certain neurobiological alterations provide fundamental pathophysiological contributions to the behavioral manifestation of particular psychiatric disorders or are merely epiphenomena, for example, diminished cerebrospinal fluid concentrations of somatostatin in patients with Alzheimer’s dementia. Nevertheless, further cross-sectional studies are necessary to confirm whether DBI peptide systems in depression and endogenous opioid peptide systems in psychiatric disorders with self-mutilatory behaviors are truly disordered. Furthermore, present efforts guided by the neuroendocrine window strategy and the pharmacologic bridge technique may provide information as to whether the secretion of neuropeptides and hypothalamic releasing factors are associated with alterations in the activity of putative neurotransmitters—such as 5-HT, dopamine, and acetylcholine—in particular disease states. More likely, functional brain

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imaging methods, such as positron emission tomography, will provide direct data of alterations in neuropeptide circuits in psychiatric disorders. A clearer understanding of the neuroendocrinology of depression, anxiety, and schizophrenia may well lead to the development of novel pharmacologic agents for the treatment of these major mental disorders. We await confirmation of an initial report documenting the effectiveness of the substance P receptor antagonist, MK-869, in patients with major depression. Early studies of novel CRH receptor antagonists suggest efficacy in the treatment of depression. A selective CCKB antagonist with anxiolytic activity may offer a new psychotropic modality in the treatment of panic disorder. Progress during the last three decades has been nothing short of remarkable, and the future is likely to bring further progress in treating these disorders.

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Tsagarakis S, Rees LH, Besser GM, et al: Neuropeptide Y stimulates CRH-41 release from rat hypothalami in vitro. Brain Res 502:167–170, 1989 Uhl GR, Whitehouse PJ, Price DL, et al: Parkinson’s disease: depletion of substantia nigra neurotensin receptors. Brain Res 308:186–190, 1984 Vaccarino FJ, Rankin J: Nucleus accumbens cholecystokinin (CCK) can either attenuate or potentiate amphetamine-induced locomotor activity: evidence for rostral-caudal differences in accumbens CCK function. Behav Neurosci 103:831–836, 1989 Vale W, Spiess J, Rivier C, et al: Characterization of a 41 residue ovine hypothalamic peptide that stimulates secretion of corticotropin of beta-endorphin. Science 213:1394–1397, 1981 Vallet PG, Charnay Y, Bouras, et al: Distribution and colocalization of delta sleep inducing peptide (DSIP) with corticotropin-like intermediate lobe peptide (CLIP) in the human hypophysis. Neurosci Lett 90:78–82, 1988 Vanderhaeghen JJ, Signeau JC, Gepts LO: New peptide in the vertebrate CNS reacting with gastrin antibodies. Nature 257:604–605, 1975 Van der Woude PF, Goudsmit E, Wierda M, et al: No vasopressin cell loss in the human hypothalamus in aging and Alzheimer’s disease. Neurobiol Aging 16: 11–18, 1995 Van Kammen DP, Waters RN, Gold P: Spinal fluid vasopressin, angiotensin I and II, beta-endorphin and opioid activity in schizophrenia: a preliminary evaluation, in Biological Psychiatry. Edited by Perris C, Strume G, Jansson B. Amsterdam, Elsevier North Holland, 1981, pp 339–344 Van Kammen DP, Widerlov E, Neylan TC, et al: Delta sleep-inducing-peptidelike immunoreactivity (DSIP-LI) and delta sleep in schizophrenic volunteers. Sleep 15:519–525, 1992 van Megen HJ, Den Boer HJGM, Westenberg HGM: Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients. Psychopharmacology 114:449–455, 1994 Van Ree JM, Gaffori O, DeWied D: In rats, the behavioral profile of CCK-8 related peptides resembles that of antipsychotic agents. Eur J Pharmacol 93: 63–78, 1983 van Zwieten EJ, Ravid R, Swaab DF. Differential vasopressin and oxytocin innervation of the human parabrachial nucleus: no changes in Alzheimer’s disease. Brain Res 711:146–152, 1996 Vaughan J, Donaldson C, Bittencourt J, et al: Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378:287–292, 1995 Vecsei L, Widerlov E: Effects of somatostatin-28 and some of its fragments and analogs on open-field behavior, barrel rotation, and shuttle box learning in rats. Psychoneuroendocrinology 15:139–145, 1990 Veith RC, Lewis N, Langohr JI, et al: Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects. Psychiatry Res 46:1–8, 1992

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Verbanck PMP, Lotstra F, Gilles C, et al: Reduced cholecystokinin immunoreactivity in the cerebrospinal fluid of patients with psychiatric disorders. Life Sci 34:67–72, 1984 Vogels OJ, Broere CA, Nieuwenhuys R: Neuronal hypertrophy in the human supraoptic and paraventricular nucleus in aging and Alzheimer’s disease. Neurosci Lett 109:62–67, 1990 Voigt M, Wang RY, Westfall TC: Cholecystokinin octapeptides alter the release of endogenous dopamine from the rat nucleus accumbens in vitro. J Pharmacol Exp Ther 237:147–153, 1986 von Euler US, Gaddum JH: An unidentified depressor substance in certain tissue extracts. Journal of Physiology (London) 72:74–87, 1931 Walleus H, Widerlov E, Ekman R: Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients. Nord J Psychiatry 39 (suppl 11):63–67, 1985 Walsh TJ, Emerich, Winokur A, et al: Intrahippocampal injection of cysteamine depletes somatostatin and produces cognitive impairments in the rat (abstract). Abstr Soc Neurosci 11:621, 1985 Watson M, Makker M, Isackson P, et al: Identification of a polymorphism in the human neurotensin receptor gene. Mayo Clin Proc 68:1043–1048, 1993 Watson SJ, Lopez JF, Young EA, et al: Effects of low dose ovine corticotropinreleasing hormone in humans: endocrine relationships and beta-endorphin/ beta-lipotropin responses. J Clin Endocrinol Metab 66:10–15, 1988 Whitnall MH: Stress selectively activates the vasopressin-containing subset of corticotropin-releasing hormone neurons. Neuroendocrinology 50:702–707, 1989 Widdowson PS, Ordway GA, Halaris AE: Reduced neuropeptide Y concentrations in suicide brain. J Neurochem 59:73–80, 1992 Widerlov E, Lindstrom LH, Besev G, et al: Subnormal CSF levels of neurotensin in a subgroup of schizophrenic patients: normalization after neuroleptic treatment. Am J Psychiatry 139:1122–1126, 1982 Widerlov E, Lindstrom LH, Wahlestedt C, et al: Neuropeptide Y and peptide YY as possible cerebrospinal markers for major depression and schizophrenia, respectively. J Psychiatr Res 22:69–79, 1988 Wolkowitz OM, Rubinow DR, Breier A, et al: Prednisone decreases CSF somatostatin in healthy humans: implications for neuropsychiatric illness. Life Sci 41: 1929–1933, 1987 Wolkowitz OM, Reus VI, Manfredi F, et al: Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 150:810–813, 1993 Wood PL, Etienne P, Lai S, et al: Reduced lumbar CSF somatostatin levels in Alzheimer’s disease. Life Sci 31:2073–2079, 1983 Wynn PC, Aguilera G, Morell J, et al: Properties and regulation of high-affinity pituitary receptors for corticotropin-releasing factor. Biochem Biophys Res Commun 110:602–608, 1983 Wynn PC, Hauger RL, Holmes MC, et al: Brain and pituitary receptors for corticotropin-releasing factor: localization and differential regulation after adrenalectomy. Peptides 5:1077–1084, 1984

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Wynn PC, Harwood JP, Catt KJ, et al: Corticotropin-releasing factor (CRH) induces desensitization of the rat pituitary CRH receptor-adenylate cyclase complex. Endocrinology 122:351–358, 1988 Yehuda R: Sensitization of the hypothalamic-pituitary-adrenal axis in posttraumatic stress disorder. Ann N Y Acad Sci 821:57–75, 1997 Young EA, Watson SJ, Kotun J, et al: Beta-lipotropin–beta-endorphin response to low-dose ovine corticotropin releasing factor in endogenous depression: preliminary studies. Arch Gen Psychiatry 47:449–457, 1990 Zis KD, Zis A: Increased adrenal weight in victims of violent suicide. Am J Psychiatry 144:1214–1215, 1987 Zobel AW, Yassouridis A, Frieboes RM, et al: Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression. Am J Psychiatry 156:949–951, 1999

Chapter 4 Chronobiology and Melatonin Robert L. Sack, M.D. Alfred J. Lewy, M.D., Ph.D. Magda Rittenbaum, M.D. Rod J. Hughes, Ph.D.

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elatonin is a hormone produced at night by the pineal gland. When administered exogenously, its actions are prototypical of a new class of drugs termed chronobiotics (Dawson and Armstrong 1996). Chronobiotics are substances that can therapeutically adjust the timing of circadian rhythms (Simpson 1980); in other words, they can “reset” the biological clock. The prime targets for chronobiotic treatment are the circadian rhythm sleep disorders (American Sleep Disorders Association 1997), which include jet lag and shiftwork maladaptation, as well as some other less common sleep disorders. Certain mood disorders, including winter depression, may also involve circadian rhythm disturbances (Lewy et al. 1987). All of these disorders have a common underlying pathophysiology; that is, a desynchrony between the timing of endogenous circadian rhythms and the timing of the environmental day-night cycle or the timing of the desired sleep-wake schedule (in some cases sleep is desired at an atypical time; for example, during the day in night workers). Chronobiotic drug activity should be distinguished from hypnotic activity. Hypnotic drugs directly induce drowsiness or sleep but do not

An earlier version of this chapter (Sack RL, Lewy AJ, Hughes RJ, et al.: “Melatonin as a Chronobiotic Drug”) was originally published in Drug News and Perspectives 9(6):325–332, 1996. Copyright 1996, Prous Science Publishers. Used with permission.

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necessarily shift circadian rhythms. Chronobiotics are not necessarily hypnotic; instead, they improve sleep by optimizing the alignment between endogenous circadian sleep drive and the desired sleep time. Melatonin may have both chronobiotic and hypnotic actions, especially in higher doses, but it may be possible to tease apart the two actions at lower doses. Perhaps the easiest circadian rhythm disorder to understand is jet lag. After rapid transmeridian travel, there is a period lasting for several days in which endogenous rhythms are out of phase with local time. This state of circadian desynchrony generates symptoms of daytime sleepiness and nighttime insomnia. In addition, there may be intense fatigue, gastrointestinal disturbance, and difficulty maintaining concentration. The symptoms gradually resolve as the internal body clock “catches up” and circadian harmony is restored. A more persistent form of circadian desynchrony underlies night-shift work maladaptation. If the night worker does not reset his or her clock, circadian rhythms will remain desynchronized indefinitely. The night worker’s daytime sleep may be short and unrefreshing. Consequently, a “sleep debt” builds up, and maintaining alertness at night is a struggle. Disorders that may involve misalignment of circadian rhythms are listed in Table 4–1.

TABLE 4–1.

Circadian rhythm disorders

Time zone change syndrome (jet lag) Shift work sleep disorder Irregular sleep-wake pattern Delayed sleep-phase pattern Advanced sleep-phase pattern Non-24-hour sleep-wake disorder

The potential benefits of circadian phase correction have been recognized for some time. Appropriately timed bright light exposure was the first practical treatment method for circadian phase resetting (Lewy et al. 1984) and is currently being applied in a variety of settings. Although bright light exposure is quite potent, it is a relatively inconvenient and timeconsuming treatment compared with a safe and effective drug. Nevertheless, even if chronobiotic drugs are developed, planned light exposure could be used synergistically with pharmacotherapy for the treatment of circadian rhythm disorders. The phase-resetting action of exogenous melatonin administration was discovered quite recently, and the parameters for treatment, such as

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optimal timing and dosage, are currently being worked out. Meanwhile, scientific research on melatonin has been overshadowed by a melatonin fad in the United States, where it is sold in health food stores as a dietary supplement. Although melatonin is not classified as a drug, those who produce it for the health food market make implied claims that it is an effective treatment for insomnia. Proponents of the fad also extend the highly speculative hopes that melatonin has anti-aging effects, bolsters the immune system, and can augment cancer therapy. We do not attempt to review these claims in this chapter; instead we concentrate on the circadian phase-resetting and hypnotic actions of melatonin. The principles discussed will presumably also apply to melatonin analogs and perhaps to other chronobiotics that are under active development.

Circadian Rhythm Physiology The word circadian is derived from the Greek roots circa, meaning “about,” and dies, meaning “day.” Circadian rhythms have evolved as an adaptation to the alternating light-dark cycle caused by the rotation of the earth (for a very readable overview of circadian rhythm physiology, see Moore-Ede et al. 1982). Circadian rhythms are not passive responses but are actively generated by an internal pacemaker that operates to maintain synchrony with the light-dark cycle. The endogenous nature of these rhythms can be demonstrated by placing an organism in an isolated environment and then observing variations in behavior or physiology that continue to oscillate about every 24 hours, even in the absence of any external time cues (zeitgebers, from the German for “time-givers”). The circadian system provides a mechanism for anticipatory adaptation to predictable changes in the environment; for example, core body temperature rises in the second half of the night, presumably preparing an individual for activity on awakening in the morning. In mammals, the circadian clock is located in the hypothalamus within the suprachiasmatic nucleus (SCN) (Klein et al. 1991) (Figure 4–1). The SCN acts as the master circadian pacemaker and controls the timing of most circadian rhythms, including melatonin secretion, sleepiness, core body temperature, and cortisol secretion. If this tiny area of the brain is destroyed in laboratory animals, circadian rhythms in body temperature and hormonal secretion are lost, and sleep occurs in short bouts evenly distributed throughout the 24-hour day. Circadian rhythms can be restored in SCN-lesioned animals by transplanting fetal SCN tissue into the third ventricle of the brain (Ralph 1991). The intrinsic rhythm of the

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FIGURE 4–1. Diagram of the major elements of the pineal interactions with the circadian system. The suprachiasmatic nucleus (SCN) in the hypothalamus receives photic input from the retina via the specialized retinohypothalamic tract (RHT). This pathway is critical for lightmediated entrainment of the circadian pacemaker located in the SCN. Multisynaptic efferents descend from the SCN to the superior cervical ganglion (SCG), and postganglionic b-adrenergic fibers ascend to terminate on the pineal gland. On receiving a signal from the SCN, the pineal gland secretes melatonin. Circulating melatonin interacts with receptors in the SCN, forming a feedback loop. The phase-shifting effects of melatonin administration are most likely mediated by mimicking this arm of the loop. Source. Reprinted from Sack RL, Blood ML, Hughes RJ, et al.: “Circadian Rhythm Sleep Disorders in the Totally Blind.” Journal of Visual Impairment and Blindness 92:145–161, 1998. Used with permission.

SCN is not exactly a 24-hour cycle but ranges from about 23 to 25 hours (in humans, about 24.5 hours). When subjects are isolated from all time cues, circadian rhythms express a cycle that is slightly longer (or shorter) than 24 hours. For circadian rhythms to be synchronized to a precise 24hour day, the circadian clock must be regularly adjusted (reset) by exposure to 24-hour time cues. Thus, circadian phase resetting is a normal, ongoing process; the resynchronization that occurs after a challenge to the system such as transmeridian flight is an extension of an intrinsic process that occurs normally every day in nontravelers. The process of adjustment through interaction with time cues in the environment is called entrainment. In nature the primary time cue is the solar light-dark cycle, although other timing signals may play a role. Light information is delivered directly to the SCN via the retinohypothalamic tract, which is anatomically distinct from the visual imaging circuitry (see Figure 4–1).

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The SCN stimulates the pineal gland to secrete melatonin during the nighttime hours. A functional feedback loop between the pineal and the SCN (see Figure 4–1) is mediated by highly specific melatonin receptors (Reppert et al. 1994, 1995) concentrated in the SCN. This feedback loop appears to regulate the timing, but not the amplitude, of melatonin secretion. Melatonin receptors in the SCN are the probable target for the clock-resetting effects of exogenously administered melatonin.

Melatonin: Basic Biology Melatonin is a phylogenically ancient hormone that is almost ubiquitous in the animal kingdom, including some single-celled organisms (Poeggeler et al. 1991). It is synthesized in the pineal gland from tryptophan via serotonin as an intermediate precursor (Arendt 1995). Melatonin is always produced at night, regardless of whether an animal is active during the day or during the night. Therefore, it is always concomitant with darkness (Arendt 1995) but not necessarily with sleep—nocturnal species are active at night. In nature, melatonin secretion is suppressed by light at dusk and dawn; consequently, the duration of secretion varies with the seasonal changes in the length of the day. It is useful to think of melatonin as a hormonal signal for nocturnal darkness; the message may be used by different species in different ways. For example, the best-established role for melatonin is the regulation of seasonal breeding cycles in some animals (Tamarkin et al. 1985). When melatonin is administered exogenously, it can mimic the effects of the short days and long nights of winter. In hamsters, short days are antigonadal, but in sheep they are progonadal. Thus, the effects of melatonin on reproductive biology are species specific and are mediated through its role as a transducer of day length. It is likely that the phase-resetting effect of exogenous melatonin administration is derived from its role as a signal for nighttime darkness; that is, exogenous melatonin administration is interpreted by melatoninreceptive areas in the hypothalamus as an early dusk or a late dawn, depending on the time it is given, and the circadian pacemaker responds by adjusting its phase accordingly.

Melatonin Phase Response Curves Both the potency and the direction of environmental time cues are dependent on the time of day they are presented. In chronobiology, this

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relationship is described by a phase response curve (PRC) (Moore-Ede et al. 1982). For example, light in the morning (early subjective day) shifts rhythms earlier, whereas light in the afternoon (late subjective day) shifts rhythms later. Light in the middle of the day has no effect. The landmark experiment documenting the entraining effects of melatonin was conducted by Redman, Armstrong, and Ng (1983). They tested the effects of exogenous melatonin administration on rats that were maintained in a constant dim-light environment and that expressed non24-hour, free-running rhythms. Daily injections of melatonin late in the subjective day (1–3 hours before onset of activity) entrained the animals to a normal 24-hour cycle, but placebo treatment at the same time of the day had no effect. The mechanism for entrainment was a daily phase advance (15–45 minutes) sufficient to counteract the free-running rhythms, which were longer than 24 hours. In rodents, melatonin caused advances but not delays. McArthur et al. (1991) provided the first evidence of direct SCN resetting by melatonin using an in vitro brain slice preparation. The dependent measures included the rate of firing in SCN neurons, which typically peaks during midday (8–14 Hz), with slowest rates occurring throughout the night (typically 2–4 Hz). Bath application of physiological melatonin solution applied to rat SCN brain slices induced a phase advance of up to 4 hours in the peak firing rate when delivered late in the day. By monitoring the brain slice for multiple cycles, a permanent resetting of the circadian clock was documented. This observation was remarkably consistent with the behavioral studies of Redman and Armstrong (Armstrong and Chesworth 1987; Redman et al. 1983). There appear to be considerable species differences in the phase-shifting effects of melatonin. For example, in lizards, melatonin injections cause larger shifts than in rodents and can delay as well as advance circadian rhythms, depending on the time of administration (Underwood 1986). On the other hand, hamsters are relatively immune to phase-shifting effects (Hastings et al. 1992). In summary, animal studies have clearly documented the ability of melatonin administration to influence the mammalian circadian system. Presumably, this effect is related to the physiological role of endogenous melatonin.

Melatonin Phase Resetting in Humans In 1987, we reported our initial study of melatonin administration to totally blind subjects (Sack et al. 1987), with additional data reported over

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the next few years (Sack and Lewy 1988; Sack et al. 1990, 1991). The strategy of treatment was based on the animal experiments of Armstrong and co-workers (Armstrong and Chesworth 1987; Redman and Armstrong 1988; Redman et al. 1983). Five totally blind males with consistent free-running (non-24-hour) melatonin rhythms were given exogenous melatonin (5 mg by mouth at bedtime) for up to 3 weeks. Four of the five subjects showed significant cumulative advances (7–16 hours) in the phase of melatonin rhythm compared with phase projections derived from their pretreatment rhythms (Sack et al. 1991). Cortisol rhythms were advanced in parallel with the melatonin rhythms. In blind subjects, the treatment-induced phase advances were unconstrained by the light-dark cycle and therefore accumulated over the 3-week period. In these early studies, we were not able to entrain the subjects’ circadian rhythms to a 24-hour cycle, perhaps because the duration of treatment was limited to 3 weeks. We have readdressed the issue of melatonin treatment of blind people. Using a higher dose (10 mg), we have been able to entrain six of seven subjects treated (Sack et al. 1999, 2000). Placebo treatment had no effect. Figure 4–2 shows representative data from one of the blind subjects. Entrainment of free-running rhythms in blind people is a clear-cut demonstration of the clock-resetting potency of melatonin. Recently, we found that 0.5 mg can be effective in these individuals (Lewy et al. 2001). After our initial demonstration of phase resetting in blind people with free-running rhythms, we proceeded with studies in sighted people. We administered melatonin at all phases of the circadian cycle, evaluating delaying as well as advancing effects, and derived a PRC (Lewy et al. 1992). For each trial, subjects were given a daily 0.5-mg dose of melatonin or placebo at the same time each day for 4 days, and circadian phase was assessed on the fifth day by measuring the timing of endogenous melatonin rhythm (dim light melatonin onset [DLMO]). Sleep times were held relatively constant. The difference in DLMO between active treatment and placebo was used as the measure of phase shift. Figure 4–3 presents the melatonin PRC developed by this strategy. Advance responses (shifts to an earlier time) are most likely to occur after melatonin administration in the late afternoon and evening (just before the onset of endogenous melatonin secretion), whereas delay responses (shifts to a later time) are most likely to occur after melatonin administration in the morning (coincident with the decline in endogenous secretion). The strategy for using melatonin and light to shift circadian rhythms according to their respective PRCs is summarized schematically in Figure 4–4. As shown in the upper panel, melatonin administration in

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Data from entrainment of a totally blind man with freerunning rhythms by melatonin 10 mg given nightly at bedtime.

FIGURE 4–2.

Total blindness is associated with circadian rhythms that run on a non-24-hour, “free-running” cycle (see text). Recurrent insomnia and daytime sleepiness result when endogenous circadian rhythms are out of phase with the desired sleep-wake cycle. The subject is a 57-yearold man who was totally blinded at age 26 from trauma. His 24-hour melatonin profiles were assessed at 2- to 4-week intervals to detect his melatonin onset (MO), the time when concentrations rose above 10 pg/mL. His circadian period (tau) was determined by fitting the MOs to a linear regression. MOs assessed during a diagnostic assessment (open circles) revealed a free-running melatonin rhythm with a tau of 24.6 hours. The tau was unchanged by placebo treatment (open squares). MOs assessed on melatonin treatment days 42 and 52 (closed squares) were at a slightly delayed but consistent phase of 1:00 and 12:45 A.M., 6.8 hours and 13.2 hours (respectively) earlier than predicted by extrapolation of the freerunning rhythm (shown as the dotted line). Source. Reprinted from Sack RL, Brandes RL, deJongh L, et al.: “Melatonin Entrains FreeRunning Circadian Rhythms in a Totally Blind Person.” Sleep 22(suppl):S138–S139, 1999. Used with permission.

the evening (or light in the morning ) will shift circadian rhythms earlier (i.e., cause a phase advance). As shown in the lower panel, melatonin administration in the morning (or light in the evening) will shift the circadian rhythms later (i.e., cause a phase delay). The most critical times for

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FIGURE 4–3.

Melatonin phase response curve (PRC) derived from repeated trials of melatonin administration.

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Advance responses are most likely in the late afternoon and evening (just before the onset of endogenous melatonin secretion), whereas delay responses are most likely to occur in the morning (coincident with the decline in endogenous secretion). Source. Reprinted from Lewy et al. 1998. Used with permission.

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The strategy for using melatonin and light to shift circadian rhythms according to their respective phase response curves (PRCs), shown schematically (see text for details).

FIGURE 4–4.

Source. Reprinted from Lewy AJ, Sack RL: “The Role of Melatonin and Light in the Human Circadian System.” Progress in Brain Research 111(205):205–216, 1996. Copyright 1996, with permission from Elsevier Science.

phase shifting in nature are dawn and dusk. Melatonin given in the middle of the night and light exposure in the middle of the day (so-called dead zones of the PRCs) have minimal phase-shifting effects.

Melatonin Treatment of Night-Shift Workers— Some Research Findings To test the phase-shifting actions of melatonin in the field, we conducted a double-blind clinical trial of melatonin in night-shift workers and have obtained some data indicating therapeutic efficacy (Sack and Lewy 1997). Our subjects were night-shift workers on a “7-70” rotating schedule involving seven consecutive 10-hour shifts (9:30 P.M. to 7:30 A.M) alternating with 7 days off. This schedule is advantageous for circadian rhythm research because subjects have a lengthy opportunity (seven days) to adapt to both their work and off-work schedules, and thus the dynamics of adaptation to the alternating schedules can be investigated. Also, subjects work precisely the same schedule every other week, so that

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repeated measures can be made and the effects of treatments evaluated in a repeated-measures design. The subjects (nurses and hospital clerical personnel) were between ages 21 and 55 and had worked on the 7-70 shift for at least 6 months. All of the subjects participated in a double-blind, crossover study of melatonin administration. For one 2-week block they received melatonin (0.5 mg), and for the other 2-week block they received placebo (cornstarch) formulated in identical gelatin capsules. Subjects were given melatonin (0.5 mg) at their usual bedtimes—that is, between 9:00 and 11:00 P.M. during the off-work weeks and between 8:00 and 10:00 A.M. during work weeks. Subjects were blind to the treatment condition, and the order of treatment was randomized. To monitor circadian phase, weekly assessments of the melatonin profile were obtained so that estimates of the direction and rate of phase shifting could be made. Just before beginning a run of night work, and just after, subjects were admitted to the clinical research center, where blood samples were obtained every hour for 24 hours for determination of the DLMO, which was used as the marker of circadian phase. We have collected data on 24 subjects to date and have formed some conclusions. At the end of their week off, the night workers were in about the same circadian phase as a comparison group of day-active subjects participating in another study. A major question of this study was the magnitude and direction of the circadian phase shifts between the beginning and the end of the 7-night work week without treatment (placebo condition). In brief, we found substantial variability in both the magnitude and the direction of phase shifting (Figure 4–5). Eight subjects showed no shift, four advanced their DLMO, five had partial delays, and eight were delayed 6 hours or more. Laboratory studies indicate that the congruence of sleep with the circadian sleep propensity rhythm is a critical determinant of sleep duration and that correction of an abnormal phase relationship by a variety of strategies can improve sleep. To address this issue, we divided the group into definite “shifters” (more than a 6-hour phase shift) (n=10) and “nonshifters” (less than a 3-hour phase shift) (n=7) and compared wrist actigraphic estimates of sleep during the placebo work and off-work weeks. Between-group comparisons showed that time in bed was an average of 70 minutes longer per day during the work week for shifters than for nonshifters (511±72 minutes vs. 441±83 minutes; P<0.01), and total sleep time was an average of 100 minutes longer (441±64 minutes vs. 341±82 minutes; P<0.01). During the off-work week, there were no significant differences in either time in bed (522±52 minutes vs. 543±24 minutes; P = 0.32) or total sleep time (445 ± 56 minutes vs. 448 ± 58 minutes;

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FIGURE 4–5.

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Variability in phase shifting among “7-70” night-shift

workers. Each pair of bars represents a single subject. For each subject, the dark bar indicates the timing of active melatonin production after a week off work (sleeping at a normal time), and the light bar, after a week at work (sleeping during the day). These data indicate that a night worker may undergo phase advance, have no shift, or undergo phase delay in response to the inversion of his or her sleep-wake schedule.

P=0.90) between the groups. Within-group comparisons showed that on their work week compared with their off-work week, the nonshifters spent almost 2 hours less in bed (406±83 minutes vs. 543±24 minutes; P<0.01) and slept nearly 2 hours less (341±82 minutes vs. 448±58 minutes; P < 0.01); there were no differences between the weeks for the shifters. For the initial analysis of our melatonin treatment trial (the experimental design is described above), we first estimated each subject’s normal DLMO for a day-active schedule (off-work week) and then calculated the magnitude of the phase shift subjects were able to achieve on their night-work, day-sleep schedule, comparing it to the shift they made with placebo or no treatment. Figure 4–6 shows a summary of the results. Subjects 9 through 15 could be considered specific melatonin responders; they had very little or

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FIGURE 4–6. Effect of melatonin treatment on phase shifting in 7-70 workers. Each point represents the timing of a melatonin onset (explained in text). Subject 3 was at a substantially different phase at the end of the off-work week on the two trials, and therefore his baseline is plotted twice). Specific phase-resetting responses to melatonin treatment were observed in night workers who did not shift to placebo treatment alone. Source. Reprinted from Sack RL, Lewy AJ: “Melatonin as a Chronobiotic: Treatment of Circadian Desynchrony in Night Workers and the Blind.” Journal of Biological Rhythms 12(6):595–603, 1997. Used with permission.

no phase shift in their DLMO with the placebo treatment, but they shifted at least 3 hours with melatonin. Subjects 17 through 24 delayed their DLMO substantially with placebo alone, and melatonin did not augment the shift. Subjects 1, 2, and 4 advanced their DLMO equally with melatonin and placebo. Subjects 5–8 had no shift with either treatment. Several subjects seemed to be atypical. For example, subject 3 was at distinctly different phases on two off-week determinations. Perhaps because of his differing starting phase, he advanced on the placebo trial and delayed on his melatonin trial. Subject 16 had a larger delay in her

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DLMO with placebo than with melatonin. In summary, a large proportion of night workers on a 7-70 schedule make substantial phase shifts at the end of a 7-day run without treatment or with placebo; melatonin specifically augmented phase shifts in a subgroup of workers who did not shift with placebo alone. The melatonin treatment trials in this study provide considerable encouragement for pursuing the development of melatonin as a phase-resetting treatment for shift workers. Simulated shiftwork experiments conducted by other investigators have been positive (Sharkey and Eastman 2002).

Direct Sleep-Promoting (Hypnotic) Effects of Melatonin Melatonin may have both chronobiotic and hypnotic actions. Almost from the time of its discovery, there has been a strong interest in the possibility that endogenous melatonin may have sleep-promoting properties, based on the circumstantial evidence that melatonin secretion occurs at night when people are asleep. It is also possible that melatonin may have sedative effects that are not related to its endogenous function. In clinical trials testing its sleep-promoting actions, the formulations and dosages of melatonin and the target populations have varied widely. Therefore, it is difficult to draw firm conclusions from these studies. For example, melatonin has been administered in vastly different doses, ranging from 0.1 to 2,500 mg. Doses that produce blood levels that are substantially higher than 500 pg/mL (from a dose of about 0.5 mg) can be considered “pharmacological,” while doses that mimic endogenous melatonin production (below 0.5 mg) are “physiological.” Physiological-dose trials are presumably more relevant for explaining the action of endogenous melatonin. However, the effects of pharmacologic doses may be explained not only by the higher blood levels but also by the longer duration of circulating levels above a certain threshold. If this is true, then a comparable action may be achieved by a slow-release formulation that maintains blood levels at a steady state over a comparable period of time. The effect of melatonin on sleep is clearly not like those of benzodiazepines or barbiturates. These drugs can induce sleep in a completely alert subject if a high enough dose is given. More refined hypotheses regarding the effects of melatonin on sleep are suggested from the available data. As a general rule, exogenous melatonin may promote sleep mainly (or only) when endogenous levels are low. For example, a hypnotic action has been demonstrated in young healthy subjects when melatonin is given dur-

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ing the day (when endogenous levels are lowest) (Hughes and Badia 1997), but such an effect does not necessarily occur when it is given at night (James et al. 1987). Furthermore, an increase in nocturnal sleep has been reported in elderly persons with insomnia, who may have low endogenous levels (Haimov et al. 1995). Another hypothesis currently undergoing testing is that soporific effects are associated with pharmacologic doses (although some groups insist that physiological doses are equally potent). Several studies illustrate this conclusion: for example, in the initial trials of melatonin with healthy elderly subjects completed to date, a 50-mg dose improved some parameters of sleep (Singer et al. 1995a), whereas a 0.2-mg sustained-release formulation showed no benefit (Singer et al. 1995b). The numbers of subjects were small, and, given the variability of sleep in the elderly, firm conclusions await additional data. In a study of young subjects, Hughes et al. (1995) assessed the hypnotic efficacy of three doses of melatonin (1 mg, 10 mg, and 40 mg) given at 10:00 A.M. before enforced bed rest and a sleep opportunity from 12:00 until 4:00 P.M. Melatonin increased sleep duration during the 4-hour nap, with a suggestion of a dose-response effect. We have attempted to integrate the findings on melatonin and sleep by proposing that melatonin does not produce sleepiness per se; rather, it releases accumulated sleep drive by antagonizing the daytime alerting signal generated by the SCN. This model is schematically portrayed in Figure 4–7. The upper panel illustrates the dynamics of the opponent process of sleep regulation (after Edgar et al. 1993). According to this model, sleep drive builds up during the waking hours and is discharged at night. However, the buildup of daytime sleep drive is usually unexpressed, because it is opposed by an alerting process generated in the SCN. At bedtime there is a rather sudden transition to sleepiness (sometimes referred to as the opening of the sleep gate [Shochat et al. 1997]), which coincides with the abrupt diminution in the SCN-dependent alerting process. The lower panel of Figure 4–7 shows how melatonin might promote sleep by attenuating the SCN-dependent alerting process, thereby releasing the built-up sleep drive. If melatonin is given just before sleep time (A), this action will shorten sleep latency. If given in the middle of the night (B), there will be little effect on sleep because sleep drive is in the process of discharging and the alerting process is quiescent (i.e., the sleep gate is already open). According to the model, melatonin can promote daytime naps (C), depending on the amount of underlying sleep drive. Melatonin appears to have no anxiolytic effects. Therefore, it may be of little benefit to persons with insomnia who cannot sleep because of tension, anxiety, or depression.

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Hypothesized effects of melatonin on the suprachiasmatic nucleus (SCN) alerting process, shown schematically (see text for details).

FIGURE 4–7.

Source. Reprinted from Sack RL, Lewy AJ, Hughes RJ, et al.: “Guidelines for Prescribing Melatonin for Sleep and Circadian Rhythm Disorders.” Annals of Medicine 30:115–121, 1998. Used with permission.

In summary, a soporific effect of melatonin may occur only in certain circumstances, which are currently undergoing definition. Because of its apparent safety (see “Safety Concerns” below), it may be worth trying in individuals who have difficulty sleeping.

Interactions Between the Chronobiotic and Sedative Actions of Melatonin In clinical circumstances, the chronobiotic and hypnotic (if any) actions of melatonin may have synergistic benefits on sleep. For example, in eastward jet travel, there is a need to advance sleep and circadian rhythms. Melatonin taken at local bedtime could both promote sleep and reset the circadian clock to an earlier time. Likewise, for the night worker, mela-

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tonin taken in the morning may promote daytime sleep and also shift the circadian clock to a later time. In clinical practice, a more potent sedative drug might be combined with melatonin. For example, in the treatment of jet lag, it may take several days for the circadian rhythms to synchronize with local time, even if melatonin administration speeds up the adaptive process. During this transition, a hypnotic drug may help to promote sleep. Combining melatonin with a hypnotic agent might be justified in the treatment of other circadian rhythm sleep disorders as a transitional aid. The need for a hypnotic would naturally diminish as rhythms came into alignment with desired sleep times. Treatment recommendations using melatonin, light exposure, and hypnotic medications for jet lag are presented in Table 4–2. A clinical vignette illustrating combination treatment for delayed sleep-phase syndrome is provided below.

TABLE 4–2.

Melatonin to counteract jet lag

To adapt to an eastward flight, the day needs to be shortened and the body clock reset to an earlier time. To adapt to a westward flight, the day needs to be lengthened and the body clock set to a later time. Example: eastward flight from Portland, Oregon, to London Several days before departure, start taking melatonin around 3 P.M. This will start the clock-resetting process. On the day of departure, take melatonin at 3 P.M. On arrival, calculate the time to take melatonin by adding the number of time zones crossed to 3 P.M. London is 8 time zones from Portland, so melatonin should be taken at 11 P.M. local time the first night. For maximum effect, the dose should be taken 1 to 2 hours earlier on the following days. Example: westward flight from Portland, Oregon, to Tokyo Take melatonin at 6 A.M. on the day of departure (to delay the clock). On arrival, calculate the time to take melatonin by subtracting the number of time zones crossed from 6 A.M. Tokyo is 8 time zones from Portland; therefore, melatonin should be taken at 10 P.M. local time the first night. For maximum effect, it can then be taken later each night (e.g., during the first awakening). A safe hypnotic medication can prevent sleep deprivation on a long overseas flight and during the first 3–5 nights after arrival.

A 17-year-old boy was brought to the sleep disorders clinic because he could not wake up in time to get to school. His problems began at puberty. He enjoyed staying up late on the weekends and would sleep in until noon (or later) on Saturday and Sunday. He lived with his mother; she was divorced, worked outside the home, and left early in the morning on weekdays before he was out of bed. On weekdays, he could not fall asleep

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until 2 or 3 A.M. He would set several alarm clocks but would often sleep through the alarms. When he did not wake up in time, he missed his bus, so he stayed home and slept until late morning. Unexcused absences resulted in declining grades and demoralization about school. A diagnosis of delayed sleep-phase syndrome was made. Considerable time was spent with the patient and his mother explaining the circadian system, specifically 1) how the “body clock” tended to run on a longer than 24-hour cycle, especially in teenagers; 2) how sleeping in on the weekend could result in a rhythm that was so delayed that it was not possible to adjust it during the school week; and 3) how appropriately timed light exposure and melatonin administration could be used to reset and stabilize the sleep propensity rhythm. A treatment plan was developed in which a very specific sleep, light exposure, and medication schedule was written out using a computer spreadsheet. The schedule started with the patient’s current preferred wakeup time (10 A.M.). The goal of treatment was to advance wakeup time by 15 minutes every other day. Bedtime was set at 8 hours before wakeup time. The patient was prescribed melatonin 3 mg to take 3 hours before bedtime. If he did not fall asleep within 20 minutes, he was to get up and take zolpidem (a sedative-hypnotic) 10 mg and go back to bed. On arising, he was to go outside in the daylight for at least 15 minutes. He was warned not to advance the schedule any faster than prescribed and to keep on schedule during the weekends. At the end of 3 weeks, the patient was able to wake up in time to make the bus. He stopped taking the zolpidem but continued to take melatonin and to go outside in the morning. He was able to maintain a regular schedule, and with time he was more successful at school, resulting in improved self-esteem.

Although the sedative effect of melatonin may be desirable in certain situations, it can also be undesirable. For example, in westward travel, a morning dose of melatonin would be necessary to delay the clock, but this could increase subsequent daytime sleepiness. In this situation, a low, sustained-release formulation would be ideal.

Melatonin Analogs Melatonin analogs, under development by several pharmaceutical companies for use as chronobiotics, could someday prove to have more potent chronobiotic activity than melatonin itself. For example, animal studies with S20098 have shown effects identical to those of melatonin (Armstrong et al. 1993), and clinical trials with this agent have begun. However, the overall effects of these synthetic agents are more difficult to predict, and therefore greater effort will be required to document safety than for melatonin, which is a more natural treatment—that is, it is not foreign to the body.

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Pharmacokinetics of Melatonin Administration Exogenous melatonin is absorbed rapidly, yielding peak serum levels within 60–150 minutes (Vakkuri et al. 1985). A typical 3-mg melatonin tablet can produce a spike in plasma melatonin level that can be more than 50 times the physiological blood concentration. Oral administration of melatonin incurs significant first-pass hepatic metabolism (Lane and Moss 1985) and is rapidly degraded, with an elimination half-life of 45– 60 minutes (Vakkuri et al. 1985; Waldhauser et al. 1984). Thus, a 3-mg dose is cleared in about 6–10 hours. Melatonin is metabolized by the liver into 6-hydroxymelatonin, a biologically inactive metabolite. A smaller proportion of melatonin is demethylated back into N-acetylserotonin, a precursor of melatonin (Young et al. 1985). The rapid metabolism of melatonin may be related to its function as a hormonal timing signal; that is, it is important for melatonin to clear rapidly once pineal secretion is terminated. For clinical use, the easily available 3-mg dose is appropriate if given before sleep. If sedation is to be minimized, it may be advisable to use a low dose (0.5 mg or less). There may be a role for controlled-release formulations, but these are not readily available at present. Although it has not been extensively investigated, at this time there is no evidence for tolerance.

Safety Concerns Judging from animal studies, melatonin is nontoxic. An early study in mice with doses as high as 800 mg/kg did not reveal a lethal dose (LD50) (Barchas et al. 1967). Studies have also provided reassuring information about the safety of melatonin administration in humans; extremely high blood levels have not produced any acute untoward reactions. Systematic safety studies for long-term administration have not been carried out, but widespread use of melatonin as a dietary supplement has not resulted in any alarming problems. Because melatonin has rather dramatic effects on gonadal function in animals that are seasonal breeders, the question has been raised as to whether reproductive effects occur in humans. In humans, reproductive function does not follow any clear seasonal pattern, so it is quite possible that this action of melatonin is vestigial. Most (perhaps all) melatonin sold in the United States is synthetic, not extracted from pineal gland, so there is little danger of transmitting

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prion disease. Therefore, unregulated use of melatonin for sleep has reminded some clinicians of the experience with tryptophan, in which impurities caused an eosinophilic syndrome; however, there is no evidence for this problem so far with melatonin.

Summary and Conclusions Although it may be an oversimplification, it is very useful to think of melatonin as a hormonal darkness signal. Melatonin can reset the circadian clock and can be thought of as a chronobiotic drug for the treatment of circadian rhythm disorders. Its circadian phase-shifting effects appear to be related to its interactions with receptors in the SCN, the site of the circadian pacemaker. To use melatonin as a chronobiotic, it is critical to consider the timing of administration. Melatonin administration several hours before its endogenous rise will induce phase advances (set the circadian clock earlier), whereas administration around the time of the endogenous decline will induce phase delays (set the circadian clock later). In addition to its chronobiotic activity, melatonin may have some hypnotic activity, which could be an advantage or a disadvantage, depending on the clinical circumstances. We propose that the hypnotic effects are caused by antagonism of an alerting signal generated in the SCN. Melatonin treatment can be synergistically combined with appropriately timed bright light exposure to produce maximal circadian phase resetting. Although melatonin has not gone through the U.S. Food and Drug Administration approval process, current evidence is that it is quite safe.

References American Sleep Disorders Association: International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Edited by Thorpy MJ. Rochester, MN, American Sleep Disorders Association, 1997 Arendt J: The pineal gland: basic physiology and clinical implications, in Endocrinology. Edited by DeGroot LJ, Besser M, Burger HG, et al. Philadelphia, PA, WB Saunders, 1995, pp 432–444 Armstrong SM, Chesworth MJ: Melatonin phase shifts a mammalian circadian clock, in Fundamentals and Clinics in Pineal Research. Edited by Trentini GP, de Gaetani C, Pévet P. New York, Raven, 1987, pp 195–198 Armstrong SM, McNulty OM, Guardiola-Lemaitre B, et al: Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS). Pharmacol Biochem Behav 46(1):45–49, 1993

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Barchas J, Da Costa F, Spector S: Acute pharmacology of melatonin. Nature 214:919–920, 1967 Dawson D, Armstrong SM: Chronobiotics—drugs that shift rhythms. Pharmacol Ther 69:15–36, 1996 Edgar DM, Dement WC, Fuller CA: Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci 13(3):1065–1079, 1993 Haimov I, Lavie P, Laudon M, et al: Melatonin replacement therapy of elderly insomniacs. Sleep 18:598–603, 1995 Hastings MH, Mead SM, Vindlacheruvu RR, et al: Non-photic phase shifting of the circadian activity rhythm of Syrian hamsters: the relative potency of arousal and melatonin. Brain Res 591(1):20–26, 1992 Hughes RJ, Badia P: Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep 20:124–131, 1997 Hughes RJ, Sack RL, Singer CM, et al: A comparison of the hypnotic efficacy of melatonin and temazepam on nocturnal sleep in healthy adults. Sleep Research 24A:124, 1995 James SP, Mendelson WB, Sack DA, et al: The effect of melatonin on normal sleep. Neuropsychopharmacology 1:41–44, 1987 Klein DC, Moore RY, Reppert SM: Suprachiasmatic Nucleus: The Mind’s Clock. New York, Oxford University Press, 1991 Lane EA, Moss HB: Pharmacokinetics of melatonin in man: first pass hepatic metabolism. J Clin Endocrinol Metab 61:1214–1216, 1985 Lewy AJ, Sack RL, Singer CM: Assessment and treatment of chronobiologic disorders using plasma melatonin levels and bright light exposure: the clockgate model and the phase response curve. Psychopharmacol Bull 20(3):561– 565, 1984 Lewy AJ, Sack RL, Miller S, et al: Antidepressant and circadian phase-shifting effects of light. Science 235:352–354, 1987 Lewy AJ, Bauer VK, Ahmed S, et al: The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light.” Chronobiol Int 15: 71–83, 1998 Lewy AJ, Ahmed S, Jackson JML, et al: Melatonin shifts circadian rhythms according to a phase-response curve. Chronobiol Int 9(5):380–392, 1992 Lewy AJ, Bauer VK, Hasler BP, et al: Capturing the circadian rhythms of freerunning blind people with 0.5 mg melatonin. Brain Res 918(1–2):96–100, 2001 McArthur AJ, Gillette MU, Prosser RA: Melatonin directly resets the rat suprachiasmatic circadian clock in vitro. Brain Res 565:158–161, 1991 Moore-Ede MC, Sulzman FM, Fuller CA: The Clocks That Time Us: Physiology of the Circadian Timing System. Cambridge, MA, Harvard University Press, 1982 Poeggeler B, Balzer I, Hardeland R, et al: Pineal hormone melatonin oscillates also in the dinoflagellate Gonyaulax polyedra. Naturwissenschaften 78:268–269, 1991

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Ralph MR: Suprachiasmatic nucleus transplant studies using the tau mutation in golden hamsters, in Suprachiasmatic Nucleus: The Mind’s Clock. Edited by Klein DC, Moore RY, Reppert SM. New York, Oxford University Press, 1991, pp 341–348 Redman JR, Armstrong SM: Re-entrainment of rat circadian activity rhythms: effects of melatonin. J Pineal Res 5:203–215, 1988 Redman JR, Armstrong S, Ng KT: Free-running activity rhythms in the rat: entrainment by melatonin. Science 219:1089–1091, 1983 Reppert SM, Weaver DR, Ebisawa T: Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13:1177–1185, 1994 Reppert SM, Godson C, Mahle CD, et al: Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A 92:8734–8738, 1995 Sack RL, Lewy AJ: Melatonin administration phase advances endogenous rhythms in humans. Sleep Research 17:396, 1988 Sack RL, Lewy AJ: Melatonin as a chronobiotic: treatment of circadian desynchrony in night workers and the blind. J Biol Rhythms 12(6):595–603, 1997 Sack RL, Lewy AJ, Hoban TM: Free-running melatonin rhythms in blind people: phase shifts with melatonin and triazolam administration, in Temporal Disorder in Human Oscillatory Systems. Edited by Rensing L, an der Heiden U, Mackey MC. Heidelberg, Springer-Verlag, 1987, pp 219–224 Sack RL, Stevenson J, Lewy AJ: Entrainment of a previously free-running blind human with melatonin administration. Sleep Research 19:404, 1990 Sack RL, Lewy AJ, Blood ML, et al: Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms 6(3):249–261, 1991 Sack RL, Brandes RW, deJongh L, et al: Melatonin entrains free-running circadian rhythms in a totally blind person. Sleep 22 (suppl):S138–S139, 1999 Sack RL, Brandes RW, Kendall AR, et al: Entrainment of free-running circadian rhythms by melatonin in blind people. New Engl J Med 343:1070–1077, 2000 Sharkey KM, Eastman CI: Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am J Physiol Regul Integr Comp Physiol 282:R454–R463, 2002 Shochat T, Luboshitsky R, Lavie P: Nocturnal melatonin onset is phase locked to the primary sleep gate. Am J Physiol 273:R364–R370, 1997 Simpson HW: Chronobiotics: selected agents of potential value in jet lag and other desynchronisms, in Chronobiology: Principles and Applications to Shifts in Schedules. Edited by Scheving LE, Halberg F. Netherlands, Sijthoff & Noordhoff, 1980, pp 433–446 Singer C, McArthur A, Hughes R, et al: High dose melatonin administration and sleep in the elderly. Sleep Research 24A:151, 1995a Singer C, McArthur A, Hughes R, et al: Physiologic melatonin administration and sleep in the elderly. Sleep Research 24A:152, 1995b Tamarkin L, Baird CJ, Almeida OFX: Melatonin: a coordinating signal for mammalian reproduction? Science 227:714–720, 1985

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Underwood H: Circadian rhythms in lizards: phase response curve for melatonin. J Pineal Res 3:187–196, 1986 Vakkuri O, Lappäluoto J, Kauppila A: Oral administration and distribution of melatonin in human serum, saliva and urine. Life Sci 37:489–495, 1985 Waldhauser F, Weiszenbacher G, Frisch H, et al: Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet i:362–365, 1984 Young IM, Leone RM, Francis P, et al: Melatonin is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man. J Clin Endocrinol Metab 60(1): 114–119, 1985

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Chapter 5 Prolactin, Growth Hormone, Insulin, Glucagon, and Parathyroid Hormone Psychobiological and Clinical Implications Mady Hornig, M.D. Jay D. Amsterdam, M.D.

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lthough it is well known that glucocorticoids, sex steroids, and thyroid hormones are linked to psychiatric disturbances, altered mental states can also result from changes in the anterior pituitary hormones prolactin and growth hormone, the gastropancreatic hormones insulin and glucagon, and parathyroid hormone. Of the endocrine disorders that are associated with psychiatric symptoms, disorders of glucose regulation are the next most frequent cause of altered mental status after disorders of thyroid function. Infrequently, symptoms of mental disorders can also occur as a manifestation of pituitary failure or hypopituitarism. Several of these hormones have been carefully studied in research investigations of the pathobiology of psychiatric disorders. In an effort to assess the responsiveness of distinct hypothalamic-pituitary target organ axes, neuroendocrine stimulation tests have been devised that utilize hormones such as prolactin, growth hormone, glucagon, or insulin as either challenge agents or outcome variables. For example, the so-called insulin tolerance test (ITT), which uses insulin as the challenge agent, has yielded

This work was partly supported by NIMH Neuropsychopharmacology Fellowship PHS Grant MH 14654 (MH), a NARSAD Young Investigator Award (MH), and The Jack Warsaw Fund for Research in Biological Psychiatry of the Depression Research Unit. The authors thank Dr. Elissa Epel for her helpful review and comments.

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important information in several psychiatric conditions. Hormones such as prolactin and growth hormone are more typically used as outcome variables in such investigations; the challenge agent that is administered is typically a pharmaceutical with effects on neurotransmitters that are thought to control or modulate such hormones. For instance, the assessment of prolactin response after administration of a serotonergic agent is based on the knowledge that the central 5-hydroxytryptamine (5-HT) (serotonin) system (in addition to other neurotransmitter systems such as the dopamine system) partly controls prolactin secretion. The importance of prolactin and other hormonal responses in this type of testing is more as a window into central neurotransmitter functioning rather than a direct interest in the hormone level itself. The varied psychiatric presentations associated with disturbances in the levels of these hormones are considered below. The application of these hormones in stimulation tests, with a focus on the biological correlates of psychopathological states, is also briefly reviewed in this chapter.

Prolactin and Psychopathology Psychiatric Effects of Hyperprolactinemia Hyperprolactinemia is most often related to a benign pituitary prolactinoma or to the administration of medications with serotonin agonist or dopamine antagonist effects. The regulation of prolactin is unique among the pituitary hormones in that it is under inhibitory control, primarily by dopamine neurons in the hypothalamus. Other neurotransmitters such as serotonin and acetylcholine promote prolactin secretion, as do thyrotropin-releasing hormone (TRH), estrogens, endogenous opiates, nipple stimulation, and physical or emotional stressors (Rafuls et al. 1987). The only known function of prolactin in humans is to promote milk production, but distress, depression, anxiety, hostility, increased irritability, and decreased libido are frequent symptoms of hyperprolactinemia (Rafuls et al. 1987; Reavley et al. 1997), in addition to the common manifestations of galactorrhea and oligomenorrhea. The role of prolactin in inducing psychiatric symptoms is unclear. Hyperprolactinemic women with no evidence of pituitary microadenoma seen on computed tomographic scans display more anxiety than women with definite microadenomas seen on computed tomography despite similar levels of hyperprolactinemia, raising the possibility of stressrelated or “functional” hyperprolactinemia (Reavley et al. 1997). Major

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depressive disorder (MDD) occurs fairly frequently in hyperprolactinemic females but occurs less commonly in males (Fava et al. 1993); however, the relationship between prolactin excess and the pathogenesis of mood disturbances in these cases is not clear. In amenorrheic women with depression, anxiety, or hostility—especially when associated with additional complaints of decreased libido or galactorrhea—the possibility is great that the MDD-like syndrome may derive from elevated prolactin levels. Such clinical presentations should be promptly pursued with appropriate laboratory tests and subsequent pituitary imaging if elevated serum prolactin levels are persistent and unexplained. Depression associated with hyperprolactinemia often responds specifically to dopamine agonists such as bromocriptine (Fava et al. 1993) (with clinical improvement increasing in parallel with decreases in prolactin levels), but it responds poorly to antidepressants such as amitriptyline (Fava et al. 1987). In contrast, psychotic disturbances occur much more rarely than mood disturbances in patients with hyperprolactinemia (Brambilla 1992). Gender-related effects may mediate certain aspects of hyperprolactinemia-associated symptoms. Women appear to have greater sensitivity than men to dopamine blockade in the tuberoinfundibulum (Szymanski et al. 1995). In male patients, prolactinoma may be more commonly misdiagnosed as an affective disorder because of the low incidence of galactorrhea and gynecomastia in men (Martin et al. 1977). Apathy, asexuality, adiposity, and headache were the most common symptoms among 16 male prolactinoma patients (Cohen et al. 1984). Curiously, in some cases of severe hyperprolactinemia, patients may be asymptomatic. Conversely, there are no known psychiatric or physical correlates of prolactin deficiency other than absence of postpartum lactation. However, reduced basal prolactin level or diminished response to pharmacologic challenge may serve as a biological marker of occult disorders of the hypothalamus and pituitary.

Prolactin Abnormalities Associated With Psychiatric Disorders Prolactin levels are influenced by a variety of physiological and pharmacologic stressors. Hypoglycemic challenges—as with the ITT and TRH and dopamine receptor blockade—are examples of factors that normally increase prolactin. Various studies of prolactin levels at baseline and in response to stimulation by hypoglycemia, TRH, electroconvulsive therapy, serotonin agonists, and dopamine antagonists have been undertaken in psychiatric populations.

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Major Depressive Disorder Most studies indicate a normal basal level of prolactin in patients with MDD, although impaired prolactin responses to insulin (Amsterdam et al. 1987), TRH (Winokur et al. 1983), and intravenous tryptophan (Heninger et al. 1984) have been noted. Basal prolactin levels may be decreased in patients with bipolar disorder in comparison with patients with unipolar MDD (Mitchell et al. 1990). In healthy control subjects, the administration of serotonin agonists such as fenfluramine has been shown to reliably induce increased prolactin levels (Yatham and Steiner 1993). In contrast, administration of serotonin agonist to patients with MDD typically reveals blunted prolactin responses, lending support to the serotonergic hypothesis of depression (O’Keane et al. 1992). This appears to be related to the state of depression and is not a consequence of antidepressant medications (Shapira et al. 1993). Some studies with serotonin type 1A (5-HT1A) agonists (Moeller et al. 1994; Sevincok and Erol 2000), but not all (Meltzer and Maes 1994; Reidel et al. 2002), have found blunted prolactin responses in patients with MDD relative to control subjects. The study by Sevincok and Erol (2000) evaluated subjects with poststroke depression. Pharmacologic specificity and selectivity of the challenge agent at the neurotransmitter receptor in question, dosage administered, and associated damage to neurocircuitry may influence the results of neuroendocrine stimulation tests in different psychiatric populations.

Schizophrenia Although basal prolactin levels are within the normal range in most nonmedicated schizophrenic patients, some studies have shown an inverse relationship between prolactin concentrations and positive symptoms (T.J. Crow et al. 1986). Basal prolactin level in nonmedicated patients with acute schizophrenia is also slightly greater compared with basal levels in patients with chronic schizophrenia or control subjects (Garver 1988). Hyperprolactinemia and associated findings of galactorrhea, menstrual dysfunction, decreased libido, and infertility occur commonly in women responding to typical antipsychotic agents (Canuso et al. 1998). With the exception of risperidone, newer atypical antipsychotic agents appear to avoid elevation of prolactin level (Goodnick et al. 2002; Remington and Kapur 2000). The prolactin-increasing effect is partly related to the potency of blockade at the dopamine type 2 receptor in the tuberoinfundibulum. Although the majority of evidence indicates that such side effects do not appear to interfere with therapeutic response, patient compliance with medication regimens associated with such consequences may be compro-

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mised, increasing risk of relapse (Hamner et al. 1996). Some investigators have attempted to relate endocrine responses to antipsychotic drugs to the risk of tardive dyskinesia in schizophrenic populations, but the evidence for a positive correlation between the severity of antipsychoticrelated tardive dyskinesia and serum prolactin level is inconsistent (Ferrier 1987).

Anxiety Disorders Very little information has been collected regarding changes in prolactin level in simple and social phobia, and most of this information does not show a correlation (Curtis and Glitz 1988). Support for serotonergic hypersensitivity, as evidenced by prolactin hyperresponsiveness to serotonin agonists such as m-chlorophenylpiperazine (mCPP), has been seen in some studies of patients with panic disorder (Klein et al. 1991). However, central serotonergically mediated prolactin responses in obsessivecompulsive disorder (OCD) seem to be more similar to the blunted responses seen in patients with MDD, even after accounting for depressive comorbidity (Lucey et al. 1992), and may correlate with response to intravenous clomipramine treatment in patients with treatment-refractory OCD (Mathew et al. 2001).

Growth Hormone and Psychopathology Psychiatric Effects of Growth Hormone Overproduction Pulsatile secretion of growth hormone (an anterior pituitary hormone) normally occurs in response to decreasing blood glucose levels, exercise, early phases of sleep, stress, and a2-adrenergic agonists and is inhibited by b-adrenergic agonists. The plasma level of growth hormone is regulated by the balance between hypothalamic stimulatory influences such as growth hormone–releasing hormone and inhibitory influences such as somatostatin; the pulsatile secretory pattern and brief half-life (about 20 minutes) of growth hormone result in highly variable plasma levels. Growth hormone acts indirectly to stimulate growth by inducing insulinlike growth factor I (IGF-I). The most common cause of growth hormone excess is pituitary adenoma, which results in gigantism in children and acromegaly in adults. In patients with acromegaly-gigantism, psychiatric symptoms are rare, except in cases where enlargement of a growth hormone–producing adenoma causes mass effects in the sellar space. The most common combination of symptoms is sweating, headache, weakness, and fatigue. A depressive syndrome, sometimes with psychotic fea-

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tures (Fava et al. 1993; Ferrier 1987), or a schizophrenia-like illness (Brambilla 1992) may be seen infrequently. Psychological consequences relating to compromised quality of life may occur (Fava et al. 1993)

Psychiatric Effects of Growth Hormone Deficiency In children, growth failure and short stature resulting from uncorrected relative or absolute growth hormone deficiency may produce psychological sequelae such as impaired self-esteem and distorted body image. Other behavioral and learning problems—including somatic complaints, anxiety, depression, social phobia, and attentional dysfunction—also occur at an increased rate in children with growth hormone deficiency and short stature compared with control children (Stabler et al. 1996a, 1998). Although it is not clear whether growth hormone plays a direct role in inducing these symptoms, the effect does not appear to be directly tied to short stature (Nicholas et al. 1997), and many of these symptoms improve during growth hormone treatment in children (Stabler et al. 1998) and adults (Stabler et al. 1996b). Severe psychosocial stress may also result in functional growth hormone deficiency, known as psychosocial dwarfism, a condition that may be corrected with proper environmental improvements (Fava et al. 1993). More recently, attention has been drawn to the cognitive and psychosocial difficulties associated with growth hormone deficiency in adults, including social isolation, decreased interest and pleasure, fatigue, and irritability (Deijen et al. 1996). Unemployment rates are higher and marriage rates are lower than in the general population (Deijen and van der Veen 1999). The rate of social phobia in adults with childhood-onset growth hormone deficiency is reported to be as high as 38%, far higher than the 10% rate in subjects of short stature without growth hormone deficiency (Nicholas et al. 1997). Improvements in cognitive functioning, depressive symptoms, and quality of life have been reported with administration of recombinant growth hormone in some (Burman et al. 1995; Cuneo et al. 1998; Degerblad et al. 1990; Soares et al. 1999), but not all (Baum et al. 1998), double-blind, placebo-controlled trials in growth hormone–deficient adults. Decreased activation along the growth hormone–IGF-I axis may also be responsible for some of the catabolic changes of normal aging, and some of the psychiatric sequelae. Growth hormone deficiency may be associated not only with reduced muscle mass and decreased exercise tolerance, but possibly also with impaired rapid eye movement (REM) sleep (Steiger et al. 1994; van Cauter et al. 1998) and sense of well-being (Holmes and Shalet 1995). In one study of 41 patients with growth hormone deficiency, a 32% frequency of MDD

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was noted, compared with a frequency of 10% among diabetic patients (Lynch et al. 1994). Specific trials of growth hormone administration in elderly individuals with relative hyposomatotropinemia are associated with reversal of both the neuropsychiatric impairments and the catabolic influences of growth hormone deficiency (Hoffman et al. 1992; Holmes and Shalet 1995). Further studies are needed to determine whether the effects of growth hormone deficiency are related to the absence of actions of growth hormone itself on the central nervous system (CNS), the associated reduction in IGF-I secretion caused by the relative growth hormone deficiency, or impaired functioning of organ systems outside the CNS (Hoffman et al. 1992).

Growth Hormone Abnormalities Associated With Psychiatric Disorders Changes in growth hormone secretion may be evaluated after administration of oral glucose, after administration of the ITT, or in response to a2-adrenergic agonists such as clonidine. Cholinergic mechanisms appear to mediate basal growth hormone levels and the secretion of growth hormone during sleep. Anticholinergic agents can decrease basal growth hormone secretion (Davis et al. 1983) or sleep-dependent growth hormone secretion (Mendelson et al. 1978), whereas cholinergic agonists stimulate growth hormone secretion.

Major Depressive Disorder Basal daytime growth hormone secretion has been reported to be either normal (Antonijevic et al. 1998) or elevated (Mendleweicz et al. 1985) in patients with depression. Decreased cerebrospinal fluid concentration of somatostatin may mediate increases in basal daytime growth hormone level, leading to growth hormone hypersecretion by reducing inhibitory input (Ferrier 1987). Growth hormone secretory patterns can also be disrupted by the hypercortisolemia commonly observed in patients with MDD (Rupprecht et al. 1989; Wiedemann et al. 1991). Despite the finding of increased basal daytime growth hormone level in some studies, growth hormone secretion associated with early phases of sleep may be reduced in depression (Sakkas et al. 1998; Voderholzer et al. 1993). A low nocturnal growth hormone level during adolescence may also be a harbinger of later episodes of depression in the following decade (Coplan et al. 2000). Also, responses of growth hormone to a wide variety of CNS modulators are often reported to be blunted in patients with major

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depression. Growth hormone responses to dexamethasone, for instance, are reported to be subnormal (Dinan 1998; Thakore and Dinan 1994). In addition, growth hormone responses to the a2-adrenergic agonist clonidine are blunted in some (Mitchell et al. 1988) but not all (Gann et al. 1995) studies, suggesting subsensitivity of a2-adrenergic receptors in patients with MDD; such subsensitivity may be reversible with effective antidepressant treatment (Lesch et al. 1990). Disturbances along the hypothalamic-pituitary-somatotropic axis may be further related to the subtype of affective disorder. In one study (Amsterdam and Maislin 1991), although a significantly decreased cumulative growth hormone response was found in hypomanic bipolar patients compared with depressed bipolar patients and healthy control subjects, cumulative growth hormone responses were significantly increased in bipolar patients compared with unipolar depressed patients.

Anxiety Disorders Panic disorder, OCD, and social phobia have been linked to disturbances of the growth hormone system. Basal growth hormone levels are elevated in some studies of patients with panic disorder (Nesse et al. 1984). In addition, blunted growth hormone responses have been consistently observed in patients with panic disorder following administration of a2-adrenergic agonists (Charney and Heninger 1986; Coplan et al. 1995). As with major depression, the reduced growth hormone response to clonidine is thought to reflect reduced sensitivity of a2-adrenergic receptors in the CNS, especially in the hypothalamus. This fits with the hypothesized overactivation of presynaptic noradrenergic neurons in the locus coeruleus in panic disorder, which theoretically contributes to downregulation of postsynaptic a2 receptors (Curtis and Glitz 1988). The assessment of neuroendocrine function in patients with OCD is complicated by frequent comorbidity with depressive disorders. Up to 50% of patients with OCD have coexisting MDD, but neuroendocrine findings, though often similar to those seen in depressed populations, can also occur in patients with OCD uncomplicated by any depressive symptoms. Blunted growth hormone response to clonidine in patients with OCD, a nonspecific finding also occurring in MDD and panic disorder, reflects reduced a2-adrenergic receptor responsiveness (Insel et al. 1984; Siever et al. 1983).

Schizophrenia Although basal growth hormone levels have been noted to be normal in acute and chronic schizophrenia (Ferrier 1987), abnormal responses to

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pharmacologic challenges are noted and may relate to clinical variables. Growth hormone responses to dopamine agonists such as apomorphine are noted by several groups to be blunted in patients with chronic psychosis who were either drug naive or poorly responsive to antipsychotic agents (Pandey et al. 1977; Rotrosen et al. 1976). However, studies of apomorphine-induced growth hormone response in schizophrenic patients with a less chronic course and increased drug responsivity reveal an apparent bimodal response curve, with increased growth hormone response variability in comparison with control subjects (Pandey et al. 1977). Increased growth hormone responses to apomorphine, reflecting heightened sensitivity of hypothalamic dopamine receptors, may have some value in predicting relapse (Brown et al. 1988; Cleghorn et al. 1983; Lieberman 1993).

Alzheimer’s Disease Although two studies of patients with Alzheimer’s disease suggested abnormal growth hormone system functioning (Christie et al. 1987; Thienhaus et al. 1986), the vast majority of studies in this population indicate little change in growth hormone responses (Davidson et al. 1988; Davis et al. 1985; Heuser et al. 1992; McKhann et al. 1984). Effects of gender and severity of illness may account for the few studies in which differences in growth hormone responses to a2-adrenergic or cholinergic agonists were observed between patients with Alzheimer’s disease and control subjects without dementia (Davidson et al. 1988; Heuser et al. 1992).

Insulin and Psychopathology Psychiatric Effects of Hyperglycemia and Diabetes The psychiatric complications of diabetes mellitus, whether related to deficiency of insulin production or impaired sensitivity of insulin receptors, are in large part linked to the well-known neurological consequences of acute and chronic hyperglycemia and hypoglycemia. Surprisingly few systematic studies have been performed regarding the psychiatric comorbidity of diabetes, despite much interest in the role of abnormal glucose regulation in psychiatric disorders in the first half of the twentieth century (Craig 1927; Kooy 1919). Yet it is quite common in psychiatric settings: in a prospective study of psychiatric admissions by Hall et al. (1981), diabetes mellitus was found in 5% of patients, whereas hypoglycemia was evident in 4%. The overall estimated prevalence of diabetes

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in the general population is between 2% and 4% (Andreoli et al. 1986; Harris et al. 1987). In a study of patients with diabetes (both type 1 and type 2), 71% were found to have a lifetime history of at least one criteriadefined psychiatric illness; affective and anxiety disorders were the most common diagnoses in this study (Lustman et al. 1986). The psychological adaptation to life with a serious and chronic illness, the effects of psychosocial stressors on glycemic control, and the possible increased vulnerability of diabetic individuals to disorders of mood and anxiety are important factors mediating the relationship between diabetes and psychiatric symptoms. Early age at onset of diabetes is associated with multiple psychological complications, ranging from dependence on family members, to rebelliousness (often taking the form of noncompliance with insulin regimens or dietary restrictions, especially in adolescents), to hostility (Gath et al. 1980; Sterky 1963; Swift et al. 1967). However, these behavioral manifestations are likely related, at least in part, to the developmental consequences for children and adolescents who are forced to adapt to very significant lifestyle changes imposed on them by their illness. The psychological consequences of adapting to a chronic disease likely play a role in individuals with adult onset of diabetes as well. In addition to necessary restrictive changes in diet and weight control, psychosexual and physical complications (fatigue, peripheral neuropathies, ocular sequelae, and vascular problems) introduce further interference into the lifestyle of the diabetic individual. Impotence and ejaculatory disturbances in diabetic men and anorgasmia in diabetic women occur at high rates (Fairburn et al. 1982; Kolodny 1971; Kolodny et al. 1974). Similarly, moderate to severe problems with fatigue were noted in 20 of 50 patients with insulin-dependent diabetes in one study (Surridge et al. 1984). The older literature has put forward several hypotheses regarding the possible causative influence of physical or emotional stress (Hinkle and Wolf 1952) or personality factors (Treuting 1962) on the initial onset of diabetes. Although stressful circumstances are unlikely to induce an active case of diabetes in an individual who is not biologically vulnerable, psychosocial factors are generally acknowledged to influence the course of latent or established diabetes (Hinkle and Wolf 1952). Such mediation by psychosocial factors may occur indirectly—such as through inattention to dietary restrictions, alcohol consumption, or failure to self-monitor glucose levels or administer insulin regularly when under duress—or through more direct, centrally mediated effects on glucose regulation. Hinkle and Wolf (1952), for instance, found that psychologically stressful topics could induce elevations in glucose excretion and ketones, whereas

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Baker and Barcai (1970) noted a relationship between emotional arousal and ketoacidosis that was thought to reflect an exaggerated response to circulating catecholamines. Thus, regular and close attention to the psychosocial milieu of the person with diabetes may greatly improve control over the disorder. There is evidence of an association of diabetes mellitus with MDD (Goodnick et al. 1995) and other affective syndromes (Cassidy et al. 1999; Lilliker 1980). The relationship appears to be somewhat specific, as the prevalence of diabetes does not appear to be increased in elderly patients with schizophrenia or organic disorders (Adamis and Ball 2000); however, the lifetime history of anxiety disorders may also be increased in the diabetic population (Wells et al. 1989), and children with school refusal and anxiety have been shown to have increased blood glucose levels after an oral glucose tolerance test, with relative suppression of insulin secretion (Iwatani et al. 1997). An increased point prevalence rate of MDD of 8.5%–10.7% has been found in several controlled studies of patients with diabetes (Popkin et al. 1988; Robinson et al. 1988; Wells et al. 1989) compared with a prevalence of 4.8%–8.6% for MDD in the general population, using structured diagnostic techniques. There may also be a particular association between manic-depressive illness and diabetes; in one study, 10% of individuals with bipolar illness also had diabetes, as opposed to only 4% of patients with other psychiatric diagnoses and only 2% of the general population (Lilliker 1980). Similarly, in hospitalized patients with bipolar disorder, the adjusted rate of diabetes mellitus was 9.9%, significantly higher than the expected frequency of 3.5% for an age-, sex-, and race-matched comparison group (Cassidy et al. 1999). Consistent with this specificity of affective and anxiety disorder comorbidity in patients with diabetes, the prevalence of eating disorders does not appear to be increased in diabetic patients in well-controlled studies, although the co-occurrence of eating disorders and diabetes does warrant specific interventions to achieve optimal glycemic control (S.J. Crow et al. 1998). Comorbidity of diabetes with depression may predict a worse psychiatric outcome, with one study estimating an eightfold increase in relapse rate in depressed diabetic patients compared with depressed healthy patients (Lustman et al. 1997a). Similarly, a 5-year follow-up study of diabetic patients previously treated for depression found that 92% of patients had recurrent or persistent depression (Lustman et al. 1997c). Furthermore, depressed diabetic patients may have worse outcomes with regard to their diabetic management. One study found that severity of depression, incidence of physical complaints, and level of hyperglycemia were directly related in patients with type 1 diabetes (Sachs et al. 1991).

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In contrast, glycemic control did not appear to be influenced by a lifetime history of major depression in patients with type 2 diabetes (de Groot et al. 1999). Nevertheless, microvascular and macrovascular complications of diabetes are reported to be increased in non–insulin-dependent diabetic patients with depression (see Leedom et al. 1991; Lustman et al. 1998). Crammer and Gillies (1981) and Kronfol et al. (1981) both report cases of increased insulin requirements in patients with known diabetes during the depressive phase of their bipolar illness. The risk of developing type 2 diabetes also appears to be increased in patients with a history of depression (Eaton et al. 1996; Kawakami et al. 1999; Okamura et al. 1999). Therefore, aggressive management of depressive episodes and maintenance antidepressant treatment in diabetic patients may improve glycemic control and reduce vascular complications (Lustman et al. 1998). For diabetic individuals with comorbid depression, the impact of antidepressants on glucose regulation needs to be considered. In this regard, it is important to note that different neurotransmitter systems may influence glucose levels in different ways. Serotonin may act to decrease plasma glucose, possibly by mechanisms other than insulin release (Erenmemisoglu et al. 1999); furthermore, selective serotonin reuptake inhibitor (SSRI) antidepressants decrease blood glucose by about 20% without affecting plasma insulin levels (Erenmemisoglu et al. 1999; G.A. Wilson and Furman 1982). The hydrazine group present on certain monoamine oxidase inhibitors (MAOIs) such as phenelzine and isocarboxazid has long been known to produce more hypoglycemia than the nonhydrazine MAOIs such as tranylcypromine (Cooper and Ashcroft 1966; Feldman and Chapman 1975). In contrast, drugs with more prominent catecholamine effects, such as the tricyclic antidepressants (TCAs), have considerable stimulatory effects on plasma glucose (Erenmemisoglu et al. 1999; Kaplan et al. 1960; Lustman et al. 1997b) and inhibitory effects on insulin secretion (Aleyassine and Lee 1972; Erenmemisoglu et al. 1999). MAOIs, TCAs, and certain SSRIs (Amsterdam et al. 1997) are associated with the risk of weight gain, which can further interfere with glycemic control. Therefore, specific SSRIs such as fluoxetine, which have beneficial effects in reducing blood glucose but only infrequently cause weight gain in long-term use (Michelson et al. 1999), may be advantageous antidepressant agents for the diabetic population. Sertraline, another SSRI, has been specifically studied in patients with comorbid diabetes and depression and was found to be effective for depressive symptoms as well as reducing levels of glycosylated hemoglobin A1c, indicating better overall glycemic control (Goodnick et al. 1997b). Furthermore, sertraline is capable of improving neuropathy in diabetic patients without depression

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(Goodnick et al. 1997a). Because the effects of other recently introduced antidepressants on glycemic control have not been widely studied, more research is necessary to determine their potential impact. The long-term effects of repeated or prolonged episodes of hyperglycemia or hypoglycemia in the diabetic patient, or the increased propensity to develop atherosclerotic vascular disease, may also produce permanent neurological damage or a dementia-like picture. There is substantial support for the impact of abnormal glucose levels on brain function. Elevated plasma glucose level can result in hyperosmolality with its associated irreversible neuronal damage (Reske-Nielsen and Lundbaek 1963). Several studies have found support for an association of diabetes with intellectual impairment in both children (Ack et al. 1961) and adults (Bale 1973; Wilkinson 1981). Overly tight control over glucose levels in children with type 1 diabetes through intensive management, compared with more conventional treatment, may be detrimental to cognition, with impairments noted in motor speed and in memory tasks relying on medial temporal lobe function (e.g., spatial declarative memory task) (Hershey et al. 1999). A study by Bale (1973) found a significant relationship between test performance on a new word learning task and apparent severity of previous hypoglycemic episodes, but no obvious association with cerebrovascular disease; in fact, 17 of 100 diabetic patients with illness duration of at least 15 years showed test performance in the brain-damaged range; no matched control subjects performed in the same range. In contrast, in another report only 8 of 50 patients with type 1 diabetes had cognitive complaints such as poor concentration and memory; these complaints were of mild severity and had unclear association to current complaints of depressed mood (Surridge et al. 1984). Prospective controlled studies are needed to determine the relationship between control of diabetes and depressive and cognitive symptoms.

Psychiatric Effects of Hypoglycemia or Insulin Overproduction Increased insulin secretion, as occurs with pancreatic beta cell tumors (insulinomas), or conditions that increase glucose utilization (e.g., growth hormone deficiency) or decrease glucose production (e.g., glycogen storage diseases or glucagon insufficiency) can contribute to neuropsychiatric symptoms by inducing hypoglycemia. Other frequent causes of hypoglycemia are poorly regulated diabetes mellitus or reactive hypoglycemia. Idiopathic, reactive forms of hypoglycemia typically produce neuropsychiatric symptoms after ingestion of food (but not after fasting), thus representing an exaggeration of normal physiological responses to

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carbohydrate ingestion. Reactive hypoglycemia is marked by normal insulin secretion but increased insulin sensitivity and reduced glucagon responses to acute hypoglycemia (Leonetti et al. 1996). Symptoms of hypoglycemia that relate to depressed CNS activity in the context of low absolute levels of glucose range from headache, mental dullness, confusion, amnesia, and visual system abnormalities to hypothermia, seizures, and coma. Anxiety, restlessness, lightheadedness, weakness, tremor, tachycardia, palpitations, pallor, perioral and finger tingling, perspiration, irritability, and hunger constitute the adrenergic symptoms of hypoglycemia and may reflect the increased epinephrine secretion induced by an acute drop in glucose levels (Brown 1984; Davidson 1986). There may be varying amnesia for activities during the hypoglycemic episode following recovery (Rafuls et al. 1987). An abnormal oral glucose tolerance test cannot be used to establish the diagnosis; appropriate diagnosis of idiopathic postprandial hypoglycemia instead requires the demonstration of a low plasma glucose concentration and appropriate symptoms occurring in temporal relationship following a mixed meal, with relief of symptoms as plasma glucose concentration rises (J.D. Wilson et al. 1998). In insulinoma, symptoms may be present for years before diagnosis, with up to 20% of cases misdiagnosed as either a neurological or a psychiatric disorder. Although no consistent psychiatric difficulties are seen, there are multiple case reports of bipolar-type symptoms, decreased memory and concentration, psychosis, organic brain syndromes, and dementia in association with insulin overproduction (Body and Cleveland 1967; De Muth and Taft 1964). In one large series of insulinoma cases, 85% of patients experienced weakness, blurry or double vision, sweating, or palpitations; 80% exhibited confusion or abnormal behavior; 53% had periods of amnesia or disturbances of consciousness; and 12% had grand mal seizures (Service 1985). Although the symptoms of acute hypoglycemia are notably similar to the symptoms experienced during panic attacks, several studies have failed to find evidence of a relationship between hypoglycemia and the occurrence of panic attacks in patients with panic disorder (Gorman et al. 1984; Uhde et al. 1984).

Abnormal Insulin Responses in Psychiatric Disorders Insulin is used as a challenge agent in the ITT, during which the resulting hypoglycemia should induce an increase of growth hormone (to >8 mg/ mL) and an increase in cortisol (to twice the baseline value or >18 mg/ dL). Disturbances in growth hormone secretion following insulin chal-

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lenge tests are discussed in the section on growth hormone above. Abnormalities in hypoglycemic responses to insulin tolerance testing in various psychiatric populations are discussed briefly below.

Major Depressive Disorder Blunted hypoglycemic responses to insulin have been reported by numerous investigators studying depressed patients, suggesting a relative insulin receptor subsensitivity in this population (Mueller et al. 1968). Other studies, however, have not confirmed this finding (Amsterdam et al. 1987). In further contrast to findings of hypoglycemic reactions, several groups have found evidence of diminished glucose utilization in depression both at baseline and following an oral glucose tolerance test (van Praag and Leijnse 1965; Winokur et al. 1988). Patients with seasonal affective disorder also demonstrate a more rapid rise in blood glucose and insulin levels during winter depression than when euthymic (Krauchi et al. 1999). Intriguingly, hypothalamic-pituitary-adrenal (HPA) axis responses to insulin challenge appear to be blunted in patients with major depression but not in patients with schizophrenia (Kathol et al. 1992), which is consistent with the hypothesis that the glucocorticoid system abnormalities frequently linked to affective disorder pathophysiology may serve to drive glucoregulatory abnormalities in this population. Whether serotonin system dysfunction further contributes to disturbances of glucose metabolism in affective populations remains to be determined.

Eating Disorders Bulimic patients were found to have increased depression, fatigue, anxiety, and bewilderment as assessed by self-report following glucose challenge in a double-blind, placebo-controlled trial, whereas control subjects did not differ in symptoms reported after glucose challenge. These mood changes were correlated with blood glucose level in the bulimic group but not in the control subjects, although no differences in insulin response could be detected between groups (Blouin et al. 1993).

Personality Disorders and Aggressive Behavior Violent alcoholic criminal offenders were noted to have an increased rate of abnormal hypoglycemic responses following oral glucose tolerance testing in several studies (Benton 1988; Benton et al. 1982; Linnoila and Virkkunen 1992; Roy et al. 1988; Virkkunen et al. 1994). This phenomenon is correlated with depressed concentrations of the serotonin

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metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid (Linnoila and Virkkunen 1992; Virkkunen et al. 1994); it is thought that a “low serotonin syndrome” may impair glucose metabolism. Other studies demonstrated blunted cortisol and prolactin responses following oral glucose loading in substance abusers with antisocial personality disorder and aggressive behavior, but failed to confirm hypoglycemia (Fishbein et al. 1992). A large study of fasting blood glucose and personality factors in psychiatric outpatients confirmed an inverse relationship between blood glucose and extroverted, impulsive, acting-out, and antisocial behavior in men, but found a positive relationship between glucose levels and histrionic personality traits in women (Svanborg et al. 2000). Intriguingly, a recent study has demonstrated that both patients with type 1 diabetes and nondiabetic subjects report more feelings of anger, even in an innocuous context, after insulin-induced hypoglycemia, independent of the degree of hypoglycemia produced (McCrimmon et al. 1999). Thus, the role of glucoregulatory disturbances in the pathogenesis of antisocial and other personality disorders deserves further evaluation in controlled prospective studies.

Glucagon and Psychopathology Severe hyperglucagonemia occurs most commonly in association with glucagon-producing pancreatic alpha cell tumors (typically located in the tail of the pancreas and often malignant), although moderate elevations of glucagon level may occur in conditions such as hepatic cirrhosis and chronic renal failure. The occurrence of psychiatric symptoms in association with glucagonomas is rare and is typically related to the degree of glucose intolerance and hyperglycemia (as reviewed in the section on diabetes above). Glucagon, a product of both pancreas and gut, has a wide spectrum of metabolic effects, such as glycogenolysis, gluconeogenesis, ketogenesis, and lipolysis. Pancreatic glucagon plays an important role in stimulating secretion of water and electrolytes by the small intestine and inhibiting the release of insulin and somatostatin. In glucagonomas, hyperglycemia, gastrointestinal upset, weight loss, fatigue, anemia, and erythematous dermatitis are commonly observed. Glucagonomas may infrequently be found in conjunction with parathyroid adenomas and pituitary tumors (as in multiple endocrine neoplasia [MEN] type I; see section on MEN below). No specific symptoms (either psychiatric or medical) have been reported to occur in association with glucagon deficiency.

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Parathyroid Hormone and Psychopathology Psychiatric Effects of Hyperparathyroidism Parathyroid hormone synthesis and release are stimulated by low levels and inhibited by elevated levels of serum calcium. Additional factors influencing parathyroid hormone secretion include elevated serum phosphorus (as in renal failure), which increases parathyroid hormone release by decreasing serum calcium; a- and b-adrenergic hormones; neurotransmitters; histamine; and prostaglandins. The most common cause of primary hyperparathyroidism is a benign parathyroid adenoma. Parathyroid adenomas can also occur in association with pancreatic and pituitary tumors (as in MEN type I) or in association with pheochromocytoma and thyroid carcinoma (MEN type II; see section on MEN below). Other contributory factors include lithium treatment, which can increase parathyroid hormone secretion and thereby increase serum calcium; vitamin D intoxication; hyperphosphatemia; certain malignancies; acute adrenal insufficiency; and hyperthyroidism. Parathyroid hormone abnormalities can be associated with impressive psychopathology. In one meta-analysis, two of three case-control studies of patients with primary hyperparathyroidism accompanied by mild hypercalcemia found a substantially increased rate of psychiatric disturbances (Okamoto et al. 1997). Other studies indicate that up to twothirds of patients with hyperparathyroidism exhibit some psychiatric symptoms (Petersen 1968). The most common symptoms include depression with anergia (Lishman 1998; Petersen 1968); roughly 10% of patients have evidence of psychosis, whereas an additional 10% have organic mental symptoms (Petersen 1968). Symptoms can range from lack of initiative, memory impairment, lethargy, depression, and personality changes to confusion, aggression, delirium, and unconsciousness, especially in parathyroid crisis, and appear to be most closely linked to the degree of hypercalcemia induced by the elevated parathyroid hormone level, rather than the parathyroid hormone level itself. Elevations of serum calcium are also associated with mania or psychotic agitation (Carman and Wyatt 1979). Whereas impairments of memory and concentration occur infrequently at lower calcium levels, at levels of 16 mg/100 mL or above features consistent with organic delirium appear along with perceptual aberrations, sometimes progressing to coma (Rafuls et al. 1987). This is consistent with the critical role that calcium plays in neurotransmission mechanisms. However, even mild hypercalcemia may cause significant neuropsychiatric changes in susceptible individuals, whereas other individuals may tolerate very high cal-

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cium levels without evidencing any behavioral or physical disturbances. Up to 50% of patients are asymptomatic at diagnosis (Brickman 1986). Diffuse electroencephalographic abnormalities may be seen. Associated physical symptoms include anorexia, nausea, vomiting, headache, anosmia, fatigue, and weakness; gastrointestinal symptoms may be the first signs of the disorder (Rafuls et al. 1987). Bone demineralization, kidney stones, restless leg syndrome, arthralgias, and hypertension are additional findings. Among the most common clinical symptoms are thirst or polyuria (occurring in about a third of patients) and fatigability or back pain (each occurring in about a fifth of patients). Another fifth of patients were asymptomatic (Kobayashi et al. 1997). Thus, in patients who present with depression and fatigue along with symptoms such as thirst, polyuria, or back pain, screening for hyperparathyroid disease might be warranted.

Psychiatric Effects of Hypoparathyroidism Hypoparathyroidism occurs most commonly after inadvertent or unavoidable dissection of the parathyroid glands during thyroidectomy (up to 50% of postthyroidectomy patients). Rare causes include the autoimmune multiple endocrine deficiencies. In addition to its effects on serum calcium, parathyroid hormone deficiency leads to increased reabsorption of inorganic phosphate by the renal tubules; laboratory findings therefore include hypocalcemia and a corresponding hyperphosphatemia. The rate of decrease in serum calcium and the degree of hypocalcemia will influence the symptoms seen. About 70% of hypoparathyroid individuals present with tetany; other clinical signs and symptoms include presenile cataracts, perioral tingling and numbness, muscle spasms, seizures, prolonged QT interval on electrocardiogram, and macrocytic anemia (Brown 1984). Extrapyramidal syndromes may occur, presumably as a result of calcification of the basal ganglia. The seizures resulting from hypoparathyroidism may be misdiagnosed as pseudoseizures because of the nonspecific electroencephalographic changes and their relationship to emotional factors (Rafuls et al. 1987). About half of patients with hypoparathyroidism exhibit psychiatric symptoms (see Denko and Kaelbling 1962; Lishman 1998). Besides carpopedal spasm, psychiatric symptoms may be the only signs of the disorder (Denko and Kaelbling 1962); dementia or delirium may also occur in the absence of tetany or seizures (Haskett and Rose 1981). The hypocalcemia of hypoparathyroidism induces neuronal irritability and is the primary mediator of the brain dysfunction observed. Intellectual impairment occurs in about 30% of individuals with this hor-

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monal abnormality, and organic brain syndromes, emotional lability, anxiety, depression, and irritability occur in another 30%. Depression is thought to be a consistent psychiatric feature (Rafuls et al. 1987). Psychosis was observed in 9% of patients in a series of 267 cases of hypoparathyroidism (Denko and Kaelbling 1962). Obsessions, phobias, derealization, and hyperventilation have also been reported in patients with hypoparathyroidism (Denko and Kaelbling 1962; Fonseca and Calverley 1967). Restoration of eucalcemia usually reverses the neuropsychiatric symptoms; thus, inclusion of serum calcium in the initial evaluation of psychiatric patients is warranted.

Multiple Endocrine Neoplasia Syndromes and Psychopathology Although these diseases are exceedingly rare, the practicing psychiatrist should be aware of the potential for unusual combinations of symptoms due to specific constellations of tumors in patients with one of the autosomal-dominant MEN syndromes. MEN type I and type II are marked by histologic progression from hyperplasia to adenoma (and, in some cases, to carcinoma) in parathyroid, pancreatic, pituitary, adrenal, and thyroid tissues. MEN type I is characterized by the combination of parathyroid, pancreatic islet, and pituitary hyperplasia or neoplasia. The clinical features of MEN type IIA consist of medullary thyroid carcinoma, pheochromocytomas, and, less commonly, parathyroid hyperplasia or adenomatosis. MEN type IIB is characterized by the association of medullary thyroid carcinoma and pheochromocytoma with multiple mucosal neuromas on the tongue, lips, subconjunctivae, and gastrointestinal tract. The first clinical manifestation of MEN type IIB can be colonic obstruction or dilatation or a colic-like childhood syndrome with associated diarrhea resulting from ganglioneuromatosis of the gastrointestinal tract; occasional physical stigmata include a marfanoid body habitus; pectus excavatum; slipped femoral epiphysis; and long, thin extremities. (J.D. Wilson et al. 1998).

Panhypopituitarism and Psychopathology Panhypopituitarism, also known as Simmonds’ disease, is associated with a reduction in all pituitary hormones as well as in hormones usually produced by peripheral glands in response to these pituitary hormones (e.g., thyroid hormones, adrenal corticosteroids). In Sheehan’s syndrome, once

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the most common cause of hypopituitarism, ischemia secondary to postpartum hemorrhage results in pituitary necrosis. Currently, hypopituitarism is more frequently due to an enlarged pituitary adenoma or surgical ablation of the pituitary gland; more unusual causes include craniopharyngioma, head injury with basilar skull fracture, infections (e.g., tuberculosis, syphilis), sarcoidosis, and autoimmune lymphoid hypophysitis (Carlson 1986). Clinical features may include headache and visual field defects; endocrine features depend on the extent of hormone deficiency and the rate at which it develops. Associated psychiatric symptoms can range from organic brain syndromes to reduced memory, severe apathy, confusion, somnolence, depression, mania, or psychosis (Jeffcoate et al. 1979; Kitis 1976). Sheehan and Summers’s (1949) original paper on hypopituitarism noted psychiatric symptoms such as delusions, hallucinations, and depression. Physical symptoms, often nonspecific, may have been present for many years before diagnosis; these include weakness, fatigue, cold sensitivity, decreased libido, amenorrhea, and weight loss. Symptoms characteristic of other end-organ failures such as hypothyroidism, hypoparathyroidism, and Addison’s disease can also be seen in hypopituitarism. Patients can occasionally present with varying degrees of delirium or coma, depending on the rate of onset of the disorder and the degree of pituitary insufficiency, and can be associated with brain damage. Diagnosis typically relies on stimulation tests such as insulin-induced hypoglycemia and growth hormone responses and TRH-induced prolactin secretion. Recovery is typically slow following coma or delirium, but replacement of the end-organ hormones usually results in a good course (Lishman 1998).

Conclusion Aside from diabetes, the endocrine syndromes described in this chapter occur fairly infrequently. In diabetes, mood disturbances are particularly common. However, even in the less commonly occurring endocrinopathies, psychiatric symptoms can often be observed. In a psychiatric setting, concerns regarding possible dysregulation of hormones such as insulin, glucagon, parathyroid hormone, growth hormone, and prolactin may increase when the onset or course of symptoms is unusual or intermittent, somatic complaints are severe, physical or laboratory findings consistent with endocrinopathy are present, or the patient simply does not improve despite seemingly adequate psychopharmacologic treatment.

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When a suspected endocrinopathy is confirmed, definitive treatment should be directed toward correction of the primary hormonal disturbance rather than toward amelioration of the secondary symptoms caused by the endocrine disorder. However, affective, cognitive, and behavioral symptoms associated with an endocrinopathy may not always reverse despite successful treatment of the hormonal disturbance, suggesting either permanent damage from the period of hormonal imbalance or a multifactorial pathophysiology underlying the psychiatric symptoms. The high degree of nonspecific and often inconsistent findings on neuroendocrine stimulation testing as reviewed here in brief suggest that, with few exceptions (as noted), these types of tests should generally be reserved for research into the biological mechanisms underlying psychiatric disorders. Multiple neuroendocrine, neurotransmitter, and neuropeptide systems are likely to interact in extraordinarily complex ways to produce the myriad of clinical presentations seen in association with hormonally influenced psychiatric syndromes; simple hypotheses of hormonal deficiency or overproduction are clearly not adequate to explain the broad spectrum of clinical presentations possible with disturbances of the hormones reviewed here.

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Part III Adrenocortical Hormones

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Chapter 6 The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness Anthony J. Rothschild, M.D.

I

n 1913, Harvey Cushing described the syndrome that bears his name (Cushing 1913), showing the relationship between hyperadrenalism and the presence of sleeplessness, inability to concentrate, visual disturbances, and “fits of unnatural irritability [alternating] with periods of depression” (Cushing 1932, p. 138). (For more on Cushing’s disease see Chapter 7 in this volume.) In 1955, it was observed that the administration of adrenocorticotropic hormone and cortisone was often associated with behavioral changes and in some cases psychosis. It is now generally accepted in medicine that too much (or too little) cortisol can be deleterious and that the brain is both a source and a target of adrenal and other steroid hormone activity (McEwen et al. 1979). And yet today, the role cortisol plays in the pathophysiology of psychiatric disorders remains unclear and is the subject of much debate. The purposes of this chapter are to summarize the evidence for corticosteroid dysregulation in psychiatric illness, to address the question of whether elevated cortisol levels may be harmful to patients regardless of diagnosis, and to discuss interventions that focus on decreasing cortisol levels or blocking cortisol receptors as a treatment strategy.

Measurement Dexamethasone Suppression Test The cortisol response after a challenge with an exogenous glucocorticoid, dexamethasone, distinguishes many psychiatrically ill (particularly de-

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pressed) patients from psychiatrically healthy control subjects. These patients either are unable to suppress their cortisol levels or escape from suppression abnormally early. The most widely used procedure to assess this condition is the dexamethasone suppression test (DST), administered according to the protocol proposed by Carroll (1982; Carroll et al. 1981b): 1.0 mg of dexamethasone is taken at 11:00 P.M. On the day after administration of dexamethasone, blood samples for determination of plasma cortisol concentration are most commonly drawn at 8:00 A.M., 4:00 P.M., and 11:00 P.M. (see Chapter 17 in this volume for more details).

Sampling Times For convenience, often only an afternoon sample is obtained from outpatients, but this does result in a loss of test sensitivity (APA Task Force on Laboratory Tests in Psychiatry 1987; Rush et al. 1996). The combination of 4:00 and 11:00 P.M. samples provides greater sensitivity than the combination of 8:00 A.M. and 4:00 P.M. samples (Rush et al. 1996). The greatest sensitivity is obtained if all three samples are collected (Rush et al. 1996).

Definition of Nonsuppression The criterion level to define normal plasma concentration of cortisol under the test conditions described earlier was defined in Carroll’s 1981 paper (Carroll et al. 1981b) as 5.0 mg/dL, using a modified Murphy competitive protein binding technique (Murphy 1968) (see Chapter 17 in this volume). Rubin and colleagues (1987) suggested a cutoff of 3.5 mg/ dL when using the more specific radioimmunoassay techniques. Others have suggested a cutoff of 4.0 mg/dL, citing data showing that the specificity of the DST is 96% at this threshold (Rush et al. 1996). The APA Task Force on Laboratory Tests in Psychiatry (1987) argued that using a cutoff of 7 mg/dL would enhance the utility of the DST in the clinical setting. In 1982, our group (Rothschild et al. 1982) suggested a threshold of 15 mg/dL might be more specific and predictive for psychotic depression (see below), an observation that has been noted in several other studies (Meyers et al. 1993; J.C. Nelson and Davis 1997). It also remains unclear whether the cortisol abnormality (as determined by the DST) is perhaps better viewed as a spectrum of cortisol levels rather than a binary, all-ornone, nonsuppression versus suppression classification.

Plasma Dexamethasone Concentrations The bioavailability of dexamethasone may be a factor influencing DST results. Postdexamethasone cortisol levels show a significant inverse rela-

The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 141 tionship with plasma dexamethasone concentrations (Arana et al. 1984, 1988; Baumgartner et al. 1986; Carson and Halbreich 1987; Poland et al. 1987; Ritchie et al. 1990; Walsh et al. 1987), and patients with major depression whose DST results show them to be cortisol suppressors have higher plasma dexamethasone concentrations than cortisol nonsuppressors (Carson et al. 1988; Holsboer et al. 1986a). Dexamethasone levels may also rise with treatment (Baumgartner et al. 1986; Devanand et al. 1991; Holsboer et al. 1986a; Maguire et al. 1990). These observations raise the intriguing question of whether psychiatric illness and clinical recovery are associated with changes in dexamethasone metabolism. Holsboer et al. (1986a) suggested a possible induction of hepatic enzymes in response to stress and hypercortisolemia. Other explanations have focused on central nervous system control of hepatic metabolism. Several regions of the brain, including the anterior periventricular hypothalamic areas and the suprachiasmatic nucleus, are involved in hepatic steroid metabolism in male rats (Gustafsson et al. 1980). It has also been hypothesized (Holsboer et al. 1986b) that exaggerated activity of the pituitary-adrenocortical unit may affect the enzymes that metabolize dexamethasone. The importance of dexamethasone plasma levels has prompted some (Johnson et al. 1984; Ritchie et al. 1990) to define dexamethasone plasma “windows” for each postdexamethasone collection point. Only those cortisol values with concurrent dexamethasone plasma levels falling within the defined window are considered valid.

Clinical Use of the Dexamethasone Suppression Test Despite the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis that can be measured by the DST and its importance in research studies, the test has generally not been useful in the clinical setting. However, the DST can be useful in the differential diagnosis of psychotic depression (in which the rate of nonsuppression is high) from schizophrenia (in which the rate of nonsuppression is considerably lower) (APA Task Force on Laboratory Tests in Psychiatry 1987). The differential diagnosis of psychotic depression from schizophrenia can be particularly difficult in a young, first-episode patient who is too psychotic to give an adequate history.

Salivary Cortisol The measurement of salivary cortisol has been shown to provide an accurate and valid measure of biologically active free cortisol (Kirschbaum

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and Hellhammer 1994). The ease of sampling is one of the most obvious advantages of the saliva cortisol test. Although whole saliva sampled in wide disposable containers provides adequate material for analysis, some investigators have used swabs that the subjects chew on to stimulate saliva flow to a rate that provides sufficient material within 30–60 seconds (Kirschbaum and Hellhammer 1994). Salivary cortisol measurements are closely correlated with cortisol levels in serum and plasma before and after administration of exogenous cortisol or dexamethasone (Kirschbaum and Hellhammer 1994). Salivary cortisol levels normally range from 1 to 25 nmol/L. Different cutoff values on the DST for salivary cortisol levels have been used, often leading to conflicting results. Mean salivary cortisol levels at a specific time of day (due to diurnal variation) are usually used when reporting results.

Urinary Free Cortisol Urinary free cortisol (UFC) excretion in a 24-hour urine sample very closely reflects the circulating unbound plasma cortisol production and is a useful indication of adrenal cortical activation (Carroll et al. 1976a). Patients are instructed to collect their urine in containers that are kept on ice during the collection period. After collection, the urine is divided into aliquots and is stored at -70°C for measurement of creatinine and UFC. Results are expressed either as micrograms of UFC per 24 hours or micrograms of UFC per milligram of creatinine. The UFC excretion of normal subjects is approximately 40–50 mg/24 hours; in nonpsychotic depressed patients it rarely exceeds 90 mg/24 hours (Anton 1987) to 100 mg/24 hours (Carroll et al. 1976a).

Other Measures of HPA Axis Activity Several other methods to measure HPA axis activity have been used in research, although all involve greater complexity, making them of less practical use in the clinical setting. Posener and colleagues (2000), using 24-hour monitoring of plasma cortisol in a clinical research center setting, observed distinct profiles of HPA axis dysregulation in psychotic and nonpsychotic depressed patients compared with control subjects. Halbreich et al. (1985) demonstrated that the measurement of plasma cortisol every half hour between 1:00 P.M. and 4:00 P.M. correlates strongly with measurement of plasma cortisol every half hour over 24 hours, making the measurement of plasma cortisol somewhat more practical. Finally, Deuschle and colleagues (1998) observed that the combined

The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 143 dexamethasone–corticotropin-releasing hormone challenge test is more closely associated with activity of the HPA system than the standard DST in nondepressed and depressed subjects. Although each of these tests has important applications in research studies, their complexity makes them difficult to use in the clinical setting. The role of the DST and other tests in the endocrine evaluation of psychiatric patients is further reviewed in Chapter 17 of this book.

Commentary on Cortisol Measurements Measurement of salivary cortisol has been increasingly used in recent years because of its convenience. As discussed above, measurement of salivary cortisol correlates strongly with cortisol levels in plasma and serum. UFC measurements provide the best-integrated sample, but the sample collection method for UFC is the most difficult for the patient to comply with. Some investigators (Rubinow et al. 1984) have observed that neither the DST nor UFC uniformly identified all patients with HPA axis hyperactivity. These studies suggest that postdexamethasone cortisol concentration only partly reflects the endogenous production rate of cortisol over 24 hours. Therefore, the best method for assessment of the HPA axis (particularly for research studies) may be to use more than one modality simultaneously.

Age Several studies have reported increased rates of nonsuppression on the DST with age (Baumgartner et al. 1986; Davis et al. 1984; Halbreich et al. 1984; D.A. Lewis et al. 1984; W.H. Nelson et al. 1984; Stokes et al. 1984; Weiner 1989; Whiteford et al. 1987), whereas others have not observed a relationship (Aguilar et al. 1984; Carroll et al. 1981b; Ferrier et al. 1988; Greden et al. 1986; Schweitzer et al. 1991; Tourigny-Rivard et al. 1981). Rush and colleagues (1996) suggested that the apparent increase in DST nonsuppression in depressed patients older than age 69 (or younger than age 20) may be due to a higher proportion of endogenous patients in this age range. However, in healthy older subjects an association between advancing age and higher cortisol levels on the DST has been observed (O’Brien et al. 1994). Age may play a key role in the effects of cortisol hypersecretion on cognitive functioning. Rubinow and colleagues (1984) observed a significant relationship between performance on the Halstead Category Test and mean UFC excretion in depressed patients but not in control subjects. Although an even more robust correlation was observed between

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age and test errors in the depressed patients, it appeared that age and depression interacted to produce severe cognitive impairment. Other studies (e.g., Lupien et al. 1997) have reported significant relationships between stress-induced declarative memory impairment and cortisol in healthy elderly subjects.

Mood Disorders There is substantial evidence for cortisol hypersecretion in patients with mood disorders (Carroll et al. 1976b, 1976c; Ettigi and Brown 1977; Rubin 1989; Sachar et al. 1970). There is less agreement about whether the DST separates endogenous from nonendogenous patients. Several studies have observed higher rates of nonsuppression on the DST in endogenously depressed patients compared with nonendogenously depressed patients (Brown and Shuey 1980; Calloway et al. 1984; Carroll et al. 1976b, 1976c, 1980, 1981b; Davidson et al. 1984; Kumar et al. 1986; Rush et al. 1996). However, many of these studies included patients with psychotic depression, who are known to have high levels of cortisol (see below). In a meta-analysis (J.C. Nelson and Davis 1997) evaluating the four studies that explicitly excluded psychotic patients (all inpatient studies), rates of nonsuppression did not differ significantly in the 103 patients with endogenous depression (39%) and the 140 with nonendogenous depression (36%).

Psychotic Depression It is in patients with psychotic depression (PD) that one of the most replicable findings in the HPA axis literature exists: high rate of DST nonsuppression, markedly elevated postdexamethasone cortisol levels, and high levels of 24-hour UFC. In 1983, our group (Schatzberg et al. 1983) reported that patients with major depression and very high plasma cortisol levels (15 mg/dL or more at 4:00 P.M.) had a propensity for exhibiting mood-congruent psychotic features at the time of study. For example, of the 9 patients with major depression who had plasma cortisol levels of 15 mg/dL or more, 7 showed psychotic features, and all 6 with plasma cortisol levels of 17 mg/dL or more at 4:00 P.M. were psychotic. In contrast, of the remaining 36 patients with major depression whose plasma cortisol levels were less than 15 mg/dL, only 7 showed psychotic features (c2 =11.4; df=1; P<0.001). (Schatzberg et al. 1983). In this study the frequency of nonsuppression (10 of 14, or 71.4%) was higher in the PD

The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 145 patients than in the nonpsychotic patients with major depression (18 of 31, or 58.1%) (Schatzberg et al. 1983). We then compared these PD patients with a group of schizophrenic patients to ascertain whether the high postdexamethasone cortisol levels in the patients with PD reflected a nonspecific effect due to psychosis (Rothschild et al. 1982). Eight of the 14 psychotic patients with major depressive illness had a 4:00 P.M. postdexamethasone cortisol level above 14 mg/dL. In contrast, none of the psychotic schizophrenic patients had a 4:00 P.M. postdexamethasone cortisol level above 14 mg/dL (Rothschild et al. 1982). The mean postdexamethasone cortisol level for the unipolar psychotic depressed patients (13.0±8.1 mg/dL) was significantly higher than that for the psychotic schizophrenic patients (2.4±2.8 mg/dL; P<0.05) (Rothschild et al. 1982). We concluded that the high cortisol levels seen in our patients with unipolar psychotic depression was not due to the psychosis per se, but rather to the presence of psychosis in the context of an affective disorder. Since these early reports, the vast majority of studies point to significantly greater HPA axis activity in PD than in nonpsychotic depression, although not all studies agree (Schatzberg and Rothschild 1992). The literature does not support the notion that the greater HPA activity seen in patients with PD is merely the result of greater severity of depression or the presence of endogenous features (Schatzberg and Rothschild 1992). A meta-analysis of 14 studies that compared DST results in psychotic and nonpsychotic depression (Nelson and Davis 1997) found the nonsuppression rate to be substantially higher in patients with PD (64%) than in nonpsychotic patients (41%) (c2 =47.43; df=1; P<0.001). The differences between psychotic and nonpsychotic depressed patients in rates of nonsuppression on the DST could not be explained by severity (Nelson and Davis 1997). Our group (Schatzberg and Rothschild 1988; Schatzberg et al. 1985) hypothesized that hypercortisolemia may enhance dopamine activity in some depressed patients, leading to the development of psychosis.

Bipolar Disorder, Manic Phase The reported frequencies of nonsuppression on the DST in mania have ranged from 0% to 70% (Cassidy et al. 1998). Comparisons of these studies are complicated by many methodological differences, including dose of dexamethasone and time of blood sampling. In addition, few studies have reported the percentage of patients in mixed and pure manic states, which may also explain differences in reported rates of nonsuppression.

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Evans and Nemeroff (1983) studied 7 patients who met DSM-III (American Psychiatric Association 1980) criteria for mixed bipolar disorder and 3 patients who met criteria for manic bipolar disorder. All 7 of the patients with mixed bipolar disorder were nonsuppressors, whereas the 3 patients with manic bipolar disorder were suppressors. Krishnan and colleagues (1983) described 10 bipolar patients with depressive features who were all nonsuppressors. Godwin (1984) reported a nonsuppression rate of 60% for 35 subjects who met DSM-III criteria for manic bipolar disorder and 5 subjects who met DSM-III criteria for mixed bipolar disorder. Swann and colleagues (1992) reported that 3 of 9 medication-free patients with mania and 5 of 7 medication-free patients with mixed mania were nonsuppressors at 8:30 A.M. after a 1-mg dose of dexamethasone. Cassidy and colleagues (1998) reported that dexamethasone plasma levels were lower and cortisol levels higher in patients who were diagnosed with mixed bipolar disorder compared with patients with manic bipolar disorder. When subjects were retested after remission, dexamethasone levels were higher and cortisol levels lower than during the manic and mixed states.

Dysthymic Disorder Several studies have investigated the rate of nonsuppression on the DST in dysthymic disorder. Generally, the rate of DST nonsuppression is less than in major depression and is similar to what is observed in control subjects without dysthymic disorder. For example, in a meta-analysis of 10 studies that used DSM-III criteria comparing DST results in dysthymic disorder, major depression, and other psychiatric disorders in adults (Howland and Thase 1991), the rate of nonsuppression on the DST in subjects with dysthymic disorder (14%) was found to be lower than in subjects with major depression (59%) and not significantly different from the rate in psychiatrically healthy control subjects (6%). In a more recent study (Ravindran et al. 1994), primary dysthymic patients had a rate of nonsuppression on the DST of 7%. In contrast, another study (Rihmer and Szadoczky 1993) reported a 50% rate of abnormal response on the DST in patients with dysthymic disorder, similar to that reported in patients with major depression. Our group reported a rate of DST nonsuppression in patients with either dysthymic disorder or borderline personality of 16% compared with a rate of DST nonsuppression of 61% in the major depression group (Schatzberg et al. 1983). We also found that the mean (±SD) 4:00 P.M. postdexamethasone cortisol level for patients with major depression (8.8±6.7 mg/dL) was significantly higher than that seen in the dysthymic disorder–borderline personality group

The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 147 (2.9±1.0 mg/dL; P<0.05). We did not observe any significant differences between the dysthymic disorder–borderline personality group and the control group on mean (±SD) 4:00 P.M. postdexamethasone cortisol levels (Schatzberg et al. 1983). However, at least one group (Rihmer et al. 1983) reported both a high incidence of DST nonsuppression in dysthymic patients and a correlation between nonsuppression on the DST and treatment response (Rihmer et al. 1983). In a study by Ravindran and colleagues (1994), patients with dysthymic disorder who were responders to fluoxetine treatment showed significantly higher postdexamethasone cortisol levels than did nonresponders. Although nonsuppression on the DST may not be useful for predicting antidepressant response in dysthymic disorder, it may be that the actual plasma cortisol levels following dexamethasone administration are useful in identifying subgroups of patients with dysthymic disorder who may be good responders to antidepressant treatment (Ravindran et al. 1994).

Posttraumatic Stress Disorder Numerous studies have demonstrated that male combat veterans with posttraumatic stress disorder (PTSD) have differences in HPA axis functioning compared with healthy control subjects. Combat veterans with PTSD have been shown to have lower 24-hour urinary cortisol excretion (Mason et al. 1986; Yehuda et al. 1990) and lower plasma cortisol levels in the morning (Boscarino 1996) and at several points throughout the circadian cycle (Yehuda et al. 1994). Combat veterans also exhibit greater suppression of plasma cortisol in response to low doses of dexamethasone (Yehuda et al. 1993b, 1995a). Similarly, male and female Holocaust survivors with PTSD have been shown to have lower 24-hour urinary cortisol levels (Yehuda et al. 1995c). These observations have led Yehuda and colleagues (1993a, 1995b) to propose that enhanced negative-feedback regulation of cortisol is an important feature of the pathophysiology of PTSD. Yehuda (1993b, 1995a) has hypothesized an increased density of glucocorticoid receptors in patients with PTSD. Evidence in support of this hypothesis is the observation that combat veterans with PTSD (Yehuda et al. 1991, 1995a) and adult women with a history of childhood sexual abuse (Stein et al. 1997) have a greater density of glucocorticoid binding sites on lymphocyte membranes than psychologically healthy control subjects. These studies suggest that abnormalities in HPA axis activity in patients with PTSD are the opposite of those observed in patients with

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major depression, raising interesting questions for future research. For example, would there be an HPA axis abnormality (and of what type?) in patients who concurrently have major depression and PTSD or major depression with psychotic features and PTSD? In the clinical setting, there are often patients in whom the specific diagnosis is unclear. For example, some patients have major depression with psychotic features and also have a history of abuse or trauma. Should they be considered PTSD patients who exhibit psychotic symptoms, or should they be treated as patients with major depression with psychotic features who happen to have a history of trauma? The low-dose DST (i.e., 0.5 mg instead of 1.0 mg) may be a potentially useful clinical and research tool for distinguishing what is primarily a PTSD disorder from major depression with psychotic features.

Schizophrenia Studies of the DST in schizophrenia have yielded rates of nonsuppression ranging from 0% to 73% (Yeragani 1990). Higher rates of DST nonsuppression in schizophrenia have been associated with depressive symptomatology (Munro et al. 1984; Sawyer and Jeffries 1984), negative symptoms (Coppen et al. 1983; Shima et al. 1986; Tandon et al. 1989, 1991), and the nonparanoid subtype (Banki et al. 1984). Reviews of the DST literature in patients with schizophrenia suggest that variances in DST results may be due to the phase of the illness and the medication status of the patient when the test is performed (Tandon et al. 1991). Several groups (Herz et al. 1985; Holsboer-Trachsler et al. 1987; Moller et al. 1986; Tandon et al. 1989, 1991; Wik et al. 1986) have observed reductions in the rates of DST nonsuppression in patients with schizophrenia after 3–4 weeks of neuroleptic treatment. Furthermore, rates of DST nonsuppression are higher in drug-free schizophrenic patients than in medicated schizophrenic patients (Tandon et al. 1991). Although antipsychotic medications are believed to have no effect on the DST (Carroll et al. 1981b), other groups (Devanand et al. 1984; Kraus et al. 1988) have suggested that withdrawal of neuroleptics and anticholinergics may produce DST nonsuppression lasting up to 21 days. The pathophysiology of the hypercortisolemia in schizophrenia is unclear. Some investigators have suggested that concurrent depression is the major determinant of DST nonsuppression in schizophrenia (Addington and Addington 1990). Depression is common in schizophrenia, affecting approximately one-third of patients (Roy 1981), and suicide accounts for

The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 149 10% of deaths in this population (Miles 1977). Jones and colleagues (1994) found that nonsuppression on the DST may be related to suicidal behavior in a sample of 57 patients with schizophrenia; specifically, nonsuppression on the DST differentiated between those who had attempted suicide and those who had not. However, other studies have not been able to replicate this observation (C.F. Lewis et al. 1996). Some studies have reported higher rates of nonsupression on the DST in depressed schizophrenic patients (Addington and Addington 1990; Munro et al. 1984; Sawyer and Jeffries 1984). However, other investigators have found no differences in the rate of nonsuppression between depressed and nondepressed schizophrenic patients when the depression is measured using the Hamilton Rating Scale for Depression (Ham-D) (Mina et al. 1990; Whiteford et al. 1988; Yeragani 1990). The possibility that nonsuppression is associated with negative symptoms of schizophrenia has also been studied. Coppen and colleagues (1983) reported that DST nonsuppression was associated with negative symptoms. In another study (Saffer et al. 1985), the same researchers found that a higher proportion of patients with Crow’s type II schizophrenia (patients with affective flattening, poverty of speech, loss of drive, and often evidence of cognitive impairment) had abnormal DST results. However, neither study measured depression. Altamura and colleagues (1989) also reported higher rates of nonsuppression on the DST in patients with schizophrenia with higher scores on the Scale for Assessment of Negative Symptoms (SANS), but again depression was not measured. McGauley and colleagues (1989) observed that mean postdexamethasone cortisol level correlated with the SANS score, whereas depression as measured by the Ham-D did not. In a study of 21 medication-free patients with schizophrenia, Newcomer and colleagues (1991) observed significant correlations between postdexamethasone cortisol levels and both negative symptoms (as measured by the Brief Psychiatric Rating Scale [BPRS] subscale) and cognitive deficits. However, several studies did not demonstrate a relationship between SANS score and nonsuppression on the DST (Addington and Addington 1990; Mina et al. 1990; Whiteford et al. 1988). Interpretation of DST studies in schizophrenia is complicated by the fact that negative symptoms and depression may not be mutually exclusive (Andreasen 1982). In one study (Ismail et al. 1998) involving 64 patients with schizophrenia diagnosed according to DSM-IV criteria (American Psychiatric Association 1994), postdexamethasone cortisol levels correlated significantly with Ham-D and BPRS scores but not with SANS scores. Overall, the rate of nonsuppression in the patients with schizophrenia was very low (less than 2%). In an interesting study by

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Goldman and colleagues (1993) comparing DST results of polydipsic and nonpolydipsic patients with chronic schizophrenia who were stabilized on psychotropic regimens, it was found that those with polydipsia had a higher rate of DST nonsuppression (38%) than those without polydipsia (5%). The authors hypothesize that hippocampal dysfunction could cause both the polydipsia and cortisol dysregulation in these patients.

Hypercortisolemia and Specific Symptoms Most studies using the DST have focused on the frequency of nonsuppression within a specific diagnostic category. Certainly within a specific diagnosis some patients exhibit hypercortisolemia and some do not, leading to confusion as to the relevance of the elevated cortisol levels to the pathophysiology of the illness. And yet, why do some patients have this measurable abnormality? Using an interesting approach to this question, Reus (1982) examined whether suppression and nonsuppression on the DST was associated with specific behavioral symptom clusters independent of diagnosis. Nonsuppressors on the DST exhibited an increase in classic endogenous signs of depression—including increased symptoms of anxiety, sleep disturbance, attentional difficulty, and anergy—compared with suppressors on the DST (Reus 1982). In patients with schizophrenia (as discussed above), higher cortisol levels were associated with a greater frequency of negative and depressive symptoms in most studies.

Hypercortisolemia and Its Relationship to Outcome Because it has been known for many years that endogenous hypercortisolemia or the administration of exogenous glucocorticoids can be deleterious for animals and human beings, one would expect that chronic hypercortisolemia may play a role in the pathophysiology and outcome of psychiatric illness. Prolonged elevation of cortisol levels in depressed patients, as evidenced by failure to convert to normal suppression on the DST (even after an apparently adequate initial clinical response to treatment), has been reported in many studies to be a warning sign of increased risk for relapse (Ribeiro et al. 1993). In a meta-analysis of studies of the long-term outcome of depressed patients who were nonsuppressors of cortisol on the DST at posttreatment evaluation, a significantly poorer outcome was observed in the nonsuppressors compared with the suppressors (c2 =32.54; df=1; P<0.0001) (Ribeiro et al. 1993). We have

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observed significant correlations between measures of cortisol activity (DST, UFC) at 1 year and measures of social and occupational functioning at 1 year (Rothschild et al. 1993). Patients with UFC values greater than 100 mg/24 hours at 1 year had significantly poorer functioning, as measured by total score on the self-report version of the Social Adjustment Scale (Weissman et al. 1978), than did patients with UFC values less than 100 mg/24 hours at 1 year. A similar relationship was observed between DST nonsuppressor status at 1 year and poorer social and occupational functioning at 1 year (Rothschild et al. 1993). We have hypothesized that the association between higher levels of cortisol at 1 year and poorer social and occupational functioning is secondary to subtle cognitive deficits caused by the higher cortisol levels seen in depressed patients (Rothschild et al. 1993). Our hypothesis is based on observations that increased HPA axis activity in depressed patients is associated with larger ventricle-to-brain ratios (Kellner et al. 1983; Rao et al. 1989; Rothschild et al. 1989) and cognitive disturbances (Brown and Qualls 1981; Demeter et al. 1986; Reus 1982; Rothschild et al. 1989; Rubinow et al. 1984; Sikes et al. 1989; Winokur et al. 1987; Wolkowitz et al. 1990, 1997). Sheline and colleagues (1996) reported that patients with a history of major depression had significantly smaller left and right hippocampal volumes than did nondepressed control subjects, although no differences in cerebral volumes were observed. The degree of hippocampal volume reduction correlated with the total duration of major depression. Taken together, these studies suggest possible associations among cognitive disturbances, cortisol hypersecretion, enlarged ventricles, and hippocampal atrophy. Similar observations of relationships between cortisol and outcome have been reported in patients with schizophrenia. Tandon and colleagues (1991) reported that persistent DST nonsuppression in patients with schizophrenia was associated with greater negative symptom severity at 4 weeks and poorer outcome at 1 year. Conversely, conversion of DST nonsuppression at baseline to normal suppression after 4 weeks of neuroleptic treatment was associated with significantly greater improvement in both negative symptoms and global severity at 4 weeks. This observation is consistent with previous reports by the same group (Tandon et al. 1989) and others (Holsboer-Trachsler et al. 1987). Analogous to observations by our group in patients with depression (Rothschild et al. 1989), persistent DST nonsuppression in patients with schizophrenia was associated with greater ventricle-to-brain ratios and poorer 1-year outcome (Tandon et al. 1991). These observations of an association between chronic hypercortisolemia and poorer outcome in patients with psychiatric disorders is of con-

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cern in light of animal studies that have demonstrated the neurotoxic effects of corticosteroids. Throughout the animal literature, there is a consistent finding across the mammalian species that the hippocampus is the principal target for neurosteroidal activity (McEwen 1991; Sapolsky 1992; Uno et al. 1994). Lesions in this area produce severe memory and attention deficits with serious affective and behavioral disturbances (Cohen and Eichenbaum 1993; Milner 1972; Papez 1937). Chronically elevated glucocorticoid levels have been shown to be associated with loss of neurons in the hippocampi of mammals such as rats and monkeys (Sapolsky 1992; Sapolsky et al. 1985, 1990). Hippocampal volume has also been found to be reduced in Cushing’s syndrome (Sapolsky 1992; Starkman 1992) (see Chapter 7 in this volume). Further studies are needed to explore, in a systematic way, the relationships among increased HPA activity, cognition, brain scan abnormalities, and social and occupational functioning in patients with depression, schizophrenia, and other psychiatric disorders. It may be that elevated cortisol levels, which were once thought to be simply a biological marker or an epiphenomenon, may be playing a key role in the pathophysiology and long-term outcome of several serious psychiatric disorders.

Antiglucocorticoid Strategies Several years ago our group hypothesized that the development of delusions in depressed patients is secondary to the effects of hypercortisolemia (Schatzberg et al. 1985) and that acute improvement in psychotic symptoms in major depression with psychotic features may occur after cortisol levels are lowered or the effects are blocked with cortisol receptor antagonists in the brain (Schatzberg and Rothschild 1988). The hypothesis that endogenous hypercortisolemia may play a role in the pathophysiology of psychiatric illness can be tested by the administration of antiglucocorticoid medication. Several studies (Amsterdam et al. 1994; Anand et al. 1995; Arana et al. 1995; Chouinard et al. 1996; Ghadirian et al. 1995; Iizuka et al. 1996; Murphy 1991; Murphy and Wolkowitz 1993; O’Dwyer et al. 1995; Raven et al. 1996; Sovner and Fogelman 1996; Thakore and Dinan 1995; Wolkowitz et al. 1992, 1996a, 1996b) have reported antidepressant effects in some patients when antiglucocorticoid medication was administered. Antiglucocorticoid medications used in these studies include the cortisol synthesis inhibitors aminoglutethimide, metyrapone, and ketoconazole. The use of antiglucocorticoid strategies in the treatment of depression have been superbly

The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 153 reviewed by Murphy and Wolkowitz (1993) and Wolkowitz and Reus (1999). Wolkowitz and colleagues (1999) reported on a sample of depressed patients treated with ketoconazole in a double-blind, placebocontrolled paradigm. Ketoconazole was found to be superior to placebo in alleviating depressive symptoms in patients with hypercortisolemia but not in eucortisolemic patients. Another interesting strategy is the progesterone receptor antagonist mifepristone (RU 486), which at high concentrations is an effective antagonist of glucocorticoid action in vivo and in vitro (Lamberts et al. 1984; Proux-Ferland et al. 1982). Mifepristone has been observed to be useful in rapidly reversing psychotic depression secondary to Cushing’s syndrome (Nieman et al. 1985; Van Der Lely et al. 1991) and in patients with psychotic major depression (Belanoff et al. 2001; Rothschild and Belanoff 2000). Studies of mifepristone for the treatment of psychotic major depression using a double-blind, placebo-controlled paradigm are currently in progress at our center and several others across the country. In addition to studies of antiglucocorticoid medications in depression, other investigators have examined the use of these medications in other psychiatric illnesses. Ravaris and colleagues (1994) reported the successful treatment of a patient with previously refractory bipolar II depression by adding ketoconazole to the existing regimen of lithium and phenelzine. Improvement was correlated with decreases in UFC levels, and discontinuation of the ketoconazole resulted in relapse, which was preceded by increasing UFC levels. Chouinard and colleagues (1996) described a case of severe refractory obsessive-compulsive disorder that was successfully treated by adding aminoglutethimide to the previously ineffective fluoxetine. Finally, Wolkowitz and colleagues (1996b) studied ketoconazole augmentation of neuroleptics in patients with schizophrenia and schizoaffective disorder in a double-blind paradigm. Although ketoconazole had no effect on psychotic symptoms, it was associated with a highly significant antidepressant effect consistent with the hypothesis (Reus 1982) that corticosteroid activity may moderate depressive symptoms across psychiatric diagnoses.

Conclusion The DST, as one of the first laboratory tests introduced in psychiatry, represents an important milestone in the history of psychiatry. The rate of nonsuppression of cortisol following dexamethasone administration is dependent on diagnosis and also on certain symptoms (anxiety, sleep dis-

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turbance, attentional difficulty, anergy) that cut across diagnostic groups, as well as many technical and physiological factors. Although the use of the DST in the clinical setting is not common, the test may have utility in certain situations such as the differentiation of major depression with psychotic features (high nonsuppression rate) from schizophrenia (low nonsuppression rate)—a diagnosis that can be clinically difficult, particularly in a young person with a first episode of psychosis. The DST may also be of use in predicting likelihood of relapse. Attempts to correlate abnormalities observed on administration of the DST with specific psychiatric disorders (with the exception of psychotic depression) has met with limited success. However, it is important to remember that diagnostic classification systems undergo frequent update and revision. If results on measurements of HPA axis activity do not precisely match up with the current diagnostic criteria, it does not necessarily mean that the biological test does not have validity. There must be some reason why many patients with psychiatric disorders have hypercortisolemia, and it may be important for the treatment and outcome of these patients that the hypercortisolemia be monitored and treated. At present, we are left with the observation that many psychiatric patients have these abnormalities on measurements of HPA axis activity and with the knowledge that cortisol is just one of the 100 different adrenal steroid hormones and hormone metabolites that may have pathophysiological or diagnostic significance. By further exploring the reasons for and the consequences of HPA axis abnormalities, we hope to learn more about the pathophysiology and treatment of many psychiatric disorders.

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The Hypothalamic-Pituitary-Adrenal Axis and Psychiatric Illness 155 Amsterdam J, Mosley PD, Rosenzweig M: Assessment of adrenocortical activity in refractory depression: steroid suppression with ketoconazole, in Refractory Depression. Edited by Nolan W, Zohar J, Roose S, et al. Chichester, England, Wiley, 1994, pp 199–210 Anand A, Malison R, McDougle CJ, et al: Antiglucocorticoid treatment of refractory depression with ketoconazole: a case report. Biol Psychiatry 37:338– 340, 1995 Andreasen NC: Negative symptoms in schizophrenia: definition and reliability. Arch Gen Psychiatry 39:784–788, 1982 Anton RF: Urinary free cortisol in psychotic depression. Biol Psychiatry 22(1): 24–34, 1987 APA Task Force on Laboratory Tests in Psychiatry: The dexamethasone suppression test: an overview of its current status in psychiatry. Am J Psychiatry 144: 1253–1262, 1987 Arana GW, Workman RJ, Baldessarini RJ: Association between low plasma levels of dexamethasone and elevated levels of cortisol in psychiatric patients given dexamethasone. Am J Psychiatry 141:1619–1620, 1984 Arana GW, Reichlin S, Workman R, et al: The dexamethasone suppression index: enhancement of DST diagnostic utility for depression by expressing serum cortisol as a function of serum dexamethasone. Am J Psychiatry 145:707–711, 1988 Arana GW, Santos AB, Laraia MT, et al: Dexamethasone for the treatment of depression: a randomized, placebo-controlled, double-blind trial. Am J Psychiatry 152:265–267, 1995 Banki CM, Arato M, Rihmer Z: Neuroendocrine differences among subtypes of schizophrenic disorder. Neuropsychobiology 11:174–177, 1984 Baumgartner A, Haack D, Vecsei P: Serial dexamethasone suppression tests in psychiatric illness, III: the influence of intervening variables. Psychiatry Res 18:45–64, 1986 Belanoff JK, Flores BH, Kalezhan M, et al: Rapid reversal of psychotic major depression with mifepristone. J Clin Psychopharmacol 21:516–521, 2001 Boscarino JA: Posttraumatic stress disorder, exposure to combat, and lower plasma cortisol among Vietnam veterans—findings and clinical implications. J Consult Clin Psychol 64:191–201, 1996 Brown WA, Qualls CB: Pituitary-adrenal disinhibition in depression: marker of a subtype with characteristic clinical features and response to treatment? Psychiatry Res 4:115–128, 1981 Brown WA, Shuey I: Response to dexamethasone and subtype of depression. Arch Gen Psychiatry 37:747–751, 1980 Calloway SP, Dolan RJ, Fonagy P, et al: Endocrine changes and clinical profiles in depression, I: the dexamethasone suppression test. Psychol Med 14:749– 758, 1984 Carroll BJ: The dexamethasone suppression test for melancholia. Br J Psychiatry 140:292–304, 1982 Carroll BJ, Curtis GC, Davies BM, et al: Urinary free cortisol excretion in depression. Psychol Med 6(1):43–50, 1976a

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Chapter 7 Psychiatric Manifestations of Hyperadrenocorticism and Hypoadrenocorticism (Cushing’s and Addison’s Diseases) Monica N. Starkman, M.D., M.S.

A

substantial percentage of patients with major depressive disorder (MDD) secrete excessive amounts of cortisol, and many escape early from the normal feedback inhibition by administered steroids such as dexamethasone. Thus, hypercortisolemia and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis have become of major interest in psychiatry (see Chapter 6 in this volume for further discussion). Cushing’s disease, the major type of spontaneous Cushing’s syndrome, is the classic endocrine disease characterized by hypersecretion of cortisol and diminished suppression of cortisol by dexamethasone. Intriguingly, emotional disturbances were already recognized as a feature of the disease in Harvey Cushing’s original description (Cushing 1932). This association was later confirmed by retrospective chart reviews (Trethowan and Cobb 1952). More recently, evaluations of patients with Cushing’s syndrome before treatment have shown that the majority manifest many of the clinical features seen in patients with a primary depressive disorder, such as depressed mood, irritability, decreased concentration, decreased libido, and middle and late insomnia (Cohen 1980; Starkman et

This chapter was adapted from Starkman MN: “The HPA Axis and Psychopathology: Cushing’s Syndrome.” Psychiatric Annals, 23:691–701, 1993. Used with permission.

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al. 1981). In fact, the majority of patients with Cushing’s syndrome were found to meet DSM-III (American Psychiatric Association 1980) criteria for MDD (except for the exclusion of an organic mental disorder) (Haskett 1985; Starkman et al. 1981). From a theoretical point of view, defining and exploring the clinical and biochemical similarities between patients with spontaneous Cushing’s syndrome and patients with primary depression provides a unique opportunity to examine in greater detail the relationship between HPA axis dysregulation and abnormalities in mood and cognition. For the clinician, however, these similarities may lead to a problem in differential diagnosis, particularly early in the course of Cushing’s syndrome when the characteristic physical stigmata are less prominent. Similarly, the converse condition exists: primary adrenal insufficiency (Addison’s disease) also produces behavioral symptoms that can lead to difficulties in distinguishing this condition from primary psychiatric illness. This chapter examines the behavioral effects of abnormalities in adrenal steroid secretion and points out parameters that may assist in differential diagnosis.

HPA Axis Physiology Under normal conditions, the secretion of cortisol from the adrenal gland is regulated by a system extraordinarily sensitive to changes within the organism and changes in its environment. Hypothalamic neurosecretory cells produce corticotropin-releasing hormone (CRH), and neurotransmitter pathways modulate its release. CRH, in turn, acts on the adrenocorticotropic hormone (ACTH)–producing cells of the anterior pituitary, and ACTH is secreted into the systemic circulation acting on the adrenal cortex to elicit the secretion of corticosteroids, including cortisol. (Regulation of the HPA axis is discussed in greater detail in Chapter 3.) Regulatory mechanisms are present at various levels along the axis. Cortisol feedback occurs at pituitary, hypothalamic, and suprahypothalamic brain levels. An endogenous timer superimposes a circadian and ultradian pattern on CRH, and thereby on ACTH and cortisol secretion. The suprachiasmatic nucleus is a major anatomical component of the timer, regulating the periodicity of other physiological functions such as body temperature, eating, drinking, and activity. In addition, central nervous system centers regulate CRH release in response to environmental and endogenous inputs such as emotional and physical stress, infection, and the metabolic milieu.

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Plasma ACTH and cortisol concentrations fluctuate over the 24-hour period. Highest concentrations are present just before and at the time of awakening, whereas the lowest ones occur before and during the early part of sleep. With a normal sleep cycle, cortisol secretion is virtually absent between midnight and 4:00 A.M. This is followed by a period of increasing HPA activity in the form of seven to nine short secretory episodes until around 9:00 A.M. (Krieger 1979) b-Endorphin, an opiate-like peptide, is also secreted by the pituitary gland. Pro-opiomelanocortin (POMC), the precursor of ACTH, contains the entire sequence of both ACTH and b-lipotropin, from which b-endorphin is derived. When an ACTH-releasing stimulus is given, both ACTH and b-endorphin are secreted concomitantly (Guillemin et al. 1977).

Addison’s Disease Etiology Insufficient secretion of corticosteroids may arise in two different ways. Secondary adrenal insufficiency results when ACTH secretion by the pituitary is inadequate, and the normal adrenal gland responds by decreasing its secretion accordingly. Primary adrenocortical insufficiency, referred to as Addison’s disease, results from destruction of the adrenal gland. In the past, tuberculosis was the most frequent cause of this disorder. Currently, 80% of new cases are idiopathic, and most are thought to arise from autoimmune destruction of the adrenal gland. Many such patients also manifest autoimmune attack on other endocrine glands as well, leading to multiple endocrine deficiencies such as hypothyroidism, hypoparathyroidism, and premature ovarian failure. Additional causes of adrenal insufficiency include fungal disease (such as histoplasmosis), blood-borne bacterial infections, disorders such as sarcoidosis, and adrenal hemorrhage due to anticoagulant treatment. Patients with acquired immunodeficiency syndrome (AIDS) can also develop primary adrenal insufficiency, possibly as a result of cytomegalic virus infection of the adrenal gland. In contrast to Cushing’s disease, which occurs primarily in women, men and women are equally affected with Addison’s disease.

Somatic Effects of Insufficient Adrenal Hormones Because the entire adrenal cortex is affected, there is a deficiency of cortisol, aldosterone, and androgens. As a consequence of the aldosterone

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deficiency, patients develop hyponatremia, hyperkalemia, and volume depletion with orthostatic hypotension and dizziness. The cortisol deficiency leads to fasting hypoglycemia. Profound generalized weakness and fatigue are cardinal symptoms. Patients develop loss of appetite, together with an intense craving for salt. They have nausea, vomiting, abdominal pain, and weight loss. Joint and muscle aches are often present, and loss of body hair occurs. In primary adrenal insufficiency, patients develop skin color changes, ranging from mild pigmentation to marked bronzing. This occurs because the normal pituitary responds to insufficient cortisol production by increasing synthesis of POMC; cleavage of POMC yields a and b melanocyte-stimulating hormone (MSH), both of which stimulate skin melanocytes and cause pigmentation. Because the disease symptoms are nonspecific and insidious, an acute presentation after a relatively minor infection, or loss of consciousness due to hypoglycemia, is frequently the event that leads to diagnosis. Full addisonian crisis is a medical emergency. It can occur either in undiagnosed patients as the degree of adrenal insufficiency increases or in diagnosed patients during an acute stress such as systemic illness or injury that raises the need for corticosteroids. Patients in addisonian crisis have severe hypotension, pallor, cyanosis, a rapid and weak pulse, and tachypnea. Delirium may occur, with disorientation, confusion, and psychotic thinking. Without immediate medical assistance, death will occur.

Neuropsychiatric Symptoms and Problems of Differential Diagnosis There is a paucity of recent research on the behavioral manifestations of Addison’s disease. Most existing studies predate contemporary criteria for the description and diagnosis of psychiatric disorders and are retrospective reviews rather than prospective studies (Cleghorn 1951; Engel and Margolin 1942). However, there is a consensus that the major defining behavioral features of the disease are lethargy and apathy. Other behavioral manifestations include irritability, crying, and impaired sleep. Cognitive difficulties, particularly problems with memory, decreased concentration, and episodic confusion, may occur. The course of the disease is often insidious, and the patient shows vague and nonspecific signs and symptoms that wax and wane over an extended period of time; therefore accurate diagnosis is often delayed. Because periods of stress exacerbate symptoms as the adrenal gland is called on to increase secretion, and symptoms decrease when the stress abates, the undiagnosed patient is often considered to have a psychiatric condition. The combination of anorexia, weight loss, and lethargy can lead to

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a diagnosis of depressive disorder. Tachycardia, dizziness, and trembling legs may be seen as signs of an anxiety disorder, as may the description addisonian patients give that their muscles feel leaden. (Muscle weakness and heaviness are often described by patients with anxiety; in fact, this is a good symptom to use in discriminating between patients with pheochromocytoma and those with anxiety [Starkman et al. 1985]). Addisonian patients have also been diagnosed with hypochondriasis, conversion disorder, and anorexia nervosa. Although many of the symptoms of Addison’s disease are nonspecific, the salt craving, the increased pigmentation of the skin, and the loss of body hair are major clues pointing to the correct diagnosis.

Diagnosis Once Addison’s disease is suspected, diagnosis is readily established. Laboratory abnormalities include hyponatremia and hyperkalemia, although these may be normal in the earlier phase of the disease. Hypercalcemia occurs in 10%–20% of patients. Patients with adrenal insufficiency secondary to primary hypothalamic or pituitary abnormalities do not exhibit hyperkalemia. The diagnosis is supported by a low 8:00 A.M. serum cortisol concentration and by decreased 24-hour excretion of urinary free cortisol or 17-hydroxysteroids. The diagnosis is further strengthened by using exogenous synthetic ACTH to stimulate the adrenal glands. A normal response to a rapid stimulation by ACTH excludes the diagnosis of primary or secondary adrenal insufficiency. An abnormal response must be confirmed by a more extended ACTH infusion. Radioimmunoassays for ACTH are now commercially available. These assays can document the elevated serum ACTH levels that exist in primary adrenal insufficiency. (A detailed description of tests of HPA axis function is provided in Chapter 17 of this volume.)

Treatment Correction of the electrolyte imbalance alone does not alter psychiatric symptoms appreciably. Treatment requires replacement of both glucocorticoids and mineralocorticoids. Recently, it has been shown that replacement of dehydroepiandrosterone (which is also low in patients with untreated Addison’s disease) confers added benefit, improving wellbeing, mood, energy, and libido in women (Arlt et al. 1999). Because patients remain extremely sensitive to declines in blood levels of steroids, multidose administration of steroids throughout the day is preferable to

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single-dose administration. Patients respond with improvements in symptoms within a period of days. Treated patients are at risk of becoming relatively adrenal insufficient with stress, particularly when taking medications that cause hypotension or volume depletion. Therefore, if psychotropic medications are required for treating a psychiatric disorder in addisonian patients, neuroleptics and antidepressants that are less likely to lower blood pressure (such as selective serotonin reuptake inhibitors) are preferable.

Cushing’s Syndrome and Cushing’s Disease In spontaneous Cushing’s syndrome, adrenocortical hyperfunction develops in one of two ways: 1) excessive ACTH is secreted, which then stimulates the adrenal gland; or 2) pathology, such as a neoplasm, exists in the adrenal gland, leading directly to the overproduction of cortisol. Thus, Cushing’s syndrome is divided into two types: ACTH dependent and ACTH independent. In the most common form of ACTH-dependent illness (Cushing’s disease), excessive ACTH is produced by the pituitary gland. In addition to excessive secretion of ACTH, the normal circadian rhythm of ACTH release is blunted, and the sensitivity of the feedback control system to levels of circulating cortisol is diminished. Much more rarely, ACTH-dependent Cushing’s syndrome is caused by an ectopic CRH- or ACTH-producing tumor such as a bronchial carcinoid, a malignant thymoma, or a small-cell carcinoma of the lung. These nonpituitary neoplasms have the capacity to synthesize and release peptides resembling CRH and ACTH that are physiologically active. The ACTH produced by the tumor leads to excessive stimulation of cortisol secretion by the adrenal cortex, which appropriately suppress ACTH release from the normal pituitary gland. Thus, the high ACTH levels in these patients come from the neoplasm and not from the patient’s own pituitary gland. Small-cell carcinoma of the lung is the most common of these neoplasms. Patients with excessive ACTH secretion derived from either the pituitary or an ectopic tumor may also secrete sufficient amounts of a-MSH as well as b-MSH, both of which have melanotropic activity, leading to hyperpigmentation of the skin and mucous membranes. ACTH-independent Cushing’s syndrome occurs when a tumor develops in the adrenal cortex with a capacity to secrete cortisol in an autonomous fashion. The elevated cortisol concentration suppresses ACTH

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secretion by the normal pituitary gland. Adrenocortical tumors leading to Cushing’s syndrome may be benign adenomas or malignant carcinomas. In comparison with pituitary ACTH-dependent disease, adrenal adenomas and carcinomas are quite rare.

Etiology of Cushing’s Disease The etiology—or etiologies—of spontaneous pituitary ACTH-dependent Cushing’s syndrome, known as Cushing’s disease, is still controversial. There are currently several major hypotheses: • The primary disorder is in the neoplastic pituitary cells that constitute the pituitary microadenoma seen in a large percentage of patients with Cushing’s disease. The exaggerated ACTH secretory response of many of these patients to stimulation by administered CRH (Gold et al. 1984) is consistent with this hypothesis. • The primary disorder is in the central nervous system. Abnormality in the limbic system, in particular, may lead to an overproduction of hypothalamic CRH, which drives the pituitary to increased secretion of ACTH and thence drives the adrenal gland to secrete cortisol (Krieger 1972, 1975). The disordered circadian periodicity of ACTH, growth hormone, and prolactin secretion and the remission of a small percentage of patients treated with cyproheptadine, a serotonergic blocking agent, are considered consistent with this view. • There may be two forms of Cushing’s disease, one involving CRH hypersecretion and one not. Studies analyzing episodic cortisol secretion support this hypothesis (Van Cauter and Refetoff 1985). • The idea of a continuum of HPA axis abnormalities has been proposed in which Cushing’s disease and MDD lie on one endocrinologic spectrum, separated by an overlapping “gray zone” (Krystal et al. 1990). • Decades ago, a psychosomatic hypothesis was proposed: namely, Cushing’s disease is a pathophysiological reaction to bereavement that occurs in predisposed individuals with lifelong disturbances in personality structure, homeostatic self-regulation, and neuroendocrine responsiveness (Gifford and Gunderson 1970). More recently, the occurrence of a greater number of stressful life events in the year before onset of Cushing’s syndrome has been reported, suggesting that such stress may be part of a multifactorial model of pathogenesis (Sonino et al. 1988). Other investigators have not found a greater frequency of adverse life events within the 2 years preceding the onset of Cushing’s disease than that seen in patients with pituitary adenomas secreting growth hormone or prolactin (Kelly 1996).

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Somatic Effects of Excess Glucocorticoids in Patients With Cushing’s Syndrome Glucocorticoids have catabolic and antianabolic effects on protein. There is loss of protein from tissues such as skin, muscles, blood vessels, and bone. Clinically, the skin atrophies and breaks down easily, and wounds heal slowly. Rupture of elastic fibers in the skin causes purple stretch marks, or striae. Muscles atrophy and become weak. Thinning of blood vessel walls and weakening of perivascular supporting tissue result in easy bruising. The protein matrix of bone becomes weak, causing osteoporosis. Bones become brittle and develop pathological fractures. Osteoporosis occurs most frequently in the spine, leading to vertebral collapse with back pain and loss of height. Carbohydrate metabolism is affected by abnormally high levels of glucocorticoids. Glucocorticoids stimulate gluconeogenesis and interfere with the action of insulin in peripheral cells. Although some Cushing’s syndrome patients compensate by increasing insulin secretion and subsequently normalizing glucose tolerance, others with diminished insulinsecreting capacity (diagnosed as prediabetic or subclinical diabetic) develop abnormal glucose tolerance, fasting hyperglycemia, and clinical manifestations of overt diabetes. Excessive glucocorticoid levels affect the distribution of adipose tissue that accumulates in the central areas of the body. Patients develop truncal obesity, round face (moon facies), supraclavicular fossa fullness, and cervicodorsal hump (buffalo hump). Truncal obesity occurs together with thinning of the upper and lower extremities as a result of muscular atrophy. Although glucocorticoids normally have minimal effects on serum electrolytes, in very large concentrations they may cause sodium retention and potassium loss, leading to edema, hypokalemia, and metabolic alkalosis. Glucocorticoids inhibit the immune response. They impair humoral antibody production and the induction and proliferation of immunocompetent lymphocytes. They also suppress delayed hypersensitivity reactions, so the skin tests for tuberculosis may convert from positive to negative. Clinically, these patients have an increased susceptibility to infectious disease.

Diagnosis of Cushing’s Syndrome The diagnosis of Cushing’s syndrome is confirmed by the measurement of abnormally high levels of cortisol in plasma and urine, impairment of a sensitive feedback control mechanism, and diminution or absence of

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circadian rhythm of cortisol secretion (see Chapter 17 of this volume). Not all patients demonstrate the full picture of these abnormalities, however. Diminished or absent sensitivity of the feedback control system is demonstrated by lack of suppression of cortisol following administration of the synthetic steroid dexamethasone. To define the subtype of Cushing’s syndrome, metyrapone, an inhibitor of adrenal corticosteroid synthesis that lowers cortisol levels, can be used to test hypothalamicpituitary responsiveness to the removal of the strong inhibitory feedback exerted by cortisol. More recently, CRH has been used to demonstrate the exaggerated secretion of ACTH seen in patients with Cushing’s disease. (A detailed description of tests of HPA axis function is provided in Chapter 17 of this volume.)

Neuropsychiatric Symptoms in Patients With Spontaneous Untreated Cushing’s Syndrome The majority of patients with spontaneous Cushing’s syndrome do not have very severe neuropsychiatric disturbances of a psychotic or confusional nature, as patients receiving exogenous corticosteroids sometimes may. Less than 10% of patients with Cushing’s syndrome manifest a thought disorder or confusional state that may present as depression or mania with paranoid ideation (Starkman et al. 1981). This observation can be understood by considering that patients with spontaneous Cushing’s syndrome differ from those receiving high-dose exogenous steroids in several respects. The level of circulating cortisol in the former is not as high as the equivalent amount of steroid administered to the latter. The mean cortisol secretion rate of 35 Cushing’s syndrome patients studied was 73 mg/day, an amount equivalent to 20 mg of prednisone (Starkman and Schteingart 1981). The Boston Collaborative Drug Surveillance Program, reporting on administration of high doses of prednisone to hospitalized patients, noted a dose-response relationship between prednisone and acute major psychiatric reaction (psychoses or euphoria). This correlation was not present for other adverse reactions such as gastrointestinal side effects (Boston Collaborative Drug Surveillance Program 1972). The probability of developing an acute psychotic reaction to steroids is highest when dosages of more than 40 mg/ day of prednisone or its equivalent are administered (Hall et al. 1979). It is of interest that patients with Cushing’s syndrome who did have a very severe psychiatric disability with delusional or confusional symptoms had a mean cortisol secretion rate of 157 mg/day, an amount that is equivalent to 40 mg/day of prednisone (Starkman and Schteingart 1981). Patients with Cushing’s syndrome also differ from those receiving exog-

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enous steroids in that they are exposed to sustained elevated cortisol levels for months to years and are less subject to sudden acute shifts and rapid rates of change of steroid levels that occur during short-term treatment with high-dose corticosteroids. (Neuropsychiatric effects of prednisone and other exogenous glucocorticoids are further discussed in Chapter 8.) What patients with Cushing’s syndrome do manifest is a consistent constellation of symptoms that includes impairments in affect (irritability and depressed mood), vegetative functions (decreased libido and middle insomnia), and cognitive functions (decreased concentration and memory) (Starkman et al. 1981). Some authors view the symptom profile as being characteristic of endogenous depression (Haskett 1985), whereas others consider that the profile represents atypical depression (Dorn et al. 1995).

Mood and Affect Irritability, a very frequent symptom seen in close to 90% of patients, is often the earliest behavioral symptom to appear (Starkman et al. 1981). It begins close to the onset of weight gain and before the appearance of other physical manifestations of Cushing’s syndrome. Patients describe themselves as having become overly sensitive and unable to ignore minor irritations and feeling impatient with or pressured by others. Because some patients reported that external noises bothered them excessively, this may reflect a generalized hypersensitivity to stimuli. In addition, an overreactivity and easy development of anger were reported. Patients described feeling that they were often on the verge of an emotional explosion and that the intensity of anger experienced was also increased. Although most could restrain themselves, patients were frightened by their irritability and potential for verbal or physical loss of control. They described being on guard for a flare-up of anger and fleeing from confrontations to avoid a feared loss of control. Depressed mood is reported by 60%–80% of patients (Cohen 1980; Haskett 1985; Starkman et al. 1981). There is a range in the intensity of depressed mood. Some patients describe short spells of sadness; others experience feelings of hopelessness and giving up. Suicide attempts are infrequent but may occur. Some patients describe hypersensitivity and oversentimentality as determinants leading to crying spells. For some, crying is experienced as their only available behavioral response to anger, frustration, and feeling unable to respond effectively. Patients also experience spontaneous onset of depressed mood or crying in the absence of any preceding upsetting thought or event.

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The time course of the mood disturbances is noteworthy. Most patients report that their mood disturbances are intermittent rather than sustained (Starkman et al. 1981). Sometimes they wake up depressed and remain depressed throughout the day and perhaps the next day as well. Alternatively, the onset of depressed mood or crying might occur during the day, sometimes suddenly, with a rapid shift. Although there are intervals when they might not experience pleasure, these patients did not describe persistent anhedonia. That is, most do not experience the unrelenting, unremitting inability to experience pleasure that is characteristic of patients with endogenous major depressive illness (Starkman et al. 1981). There are intervals when they retain the capacity for pleasure and could still find enjoyment in hobbies and interpersonal relationships. At times, some patients find it difficult to initiate such activities, although once others mobilize them, they enjoy them. The duration of each depressive episode is usually 1–2 days and is rarely longer than 3 days at a time. A frequent weekly total of dysphoria is reported as being 3 days. There is no regular cyclicity, however, so that patients cannot predict when a depressive day would occur. Some patients do have constant depressed mood. Social withdrawal is often related to shame because of physical appearance, as well as a decreased sense of focus, alertness, and clarity in unstructured group settings. Most patients report an increased desire to have contact with significant family members. However, sporadic withdrawal might occur because of the patient’s need to remove himself or herself from a situation of overstimulation that elicits the fear of impending emotional dyscontrol. Guilt is infrequent, if present, and is not excessive, self-accusatory, or irrational. Instead, it is related primarily to remorse about the uncontrollable angry outbursts and inability to function well at work and in the family. Hopelessness, if present, is attributed to the existence of a chronic illness with increasing physical and emotional disability that so far had proved undiagnosable and untreatable. A minority of patients experience episodes of elation-hyperactivity early in the course of the disease (Starkman et al. 1981). As the disease progresses and new physical signs of Cushing’s syndrome begin to appear, this type of episode becomes rare or disappears entirely. The quality of these episodes of elation is described as a “high.” Patients are more ambitious than usual and might attempt to do more than their ability and training make reasonable. Increased motor activity is present, with restlessness and rapidly performed activities. Patients report embarrassment that their speech is both loud and rapid. In an unusually severe presentation, one patient with ectopic ACTH-secreting thymoma presented with

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a typical full-blown manic syndrome, with increased pressure of speech, rhyming of words, and paranoid ideation. A substantial percentage of patients report generalized anxiety (Starkman et al. 1981). New-onset panic disorder has also been observed in patients with Cushing’s syndrome (Loosen et al. 1992). In addition, even patients who do not experience psychic anxiety describe episodic symptoms of autonomic activation such as shaking, palpitations, and sweating.

Biological Drives Abnormalities in four areas of basic biological vegetative drives are present: • Fatigue. This is reported by 100% of patients. • Libido. A decrease in libido was very frequent, and was reported by close to 70% of patients (Starkman et al. 1981). In fact, this is one of the earliest manifestations of Cushing’s disease, beginning when the patient is experiencing the first onset of weight gain. • Appetite and eating behavior. More than 50% of patients have an alteration in their appetite: In 34%, appetite is increased; in 20%, it is decreased (Starkman et al. 1981). • Sleep and dreams. Difficulty with sleep, particularly middle insomnia and late insomnia (early-morning awakening), is found in more than 50% of patients (Starkman et al. 1981). Difficulty with early insomnia (not falling asleep at bedtime) is not as frequent. One-third of patients report an alteration in the frequency or quality of their dreams: increased in their frequency, intense, bizarre, and very vivid. Some patients report they have lost the ability to wake themselves out of a nightmare.

Cognition Cognitive symptoms are a prominent part of the clinical picture. Inattention, distractibility, difficulty with concentration, and shortened attention span are reported by most patients (Starkman et al. 1981). Difficulty with reasoning ability, comprehension, and processing of new information is often reported. Some patients report episodes of rapid scattered thinking, whereas others complain of slow and ponderous thinking. Thought blocking may occur in more severe instances. Patients complain of using incorrect words while speaking and of misspelling simple words. Impairment of memory is one of the most frequent symptoms, reported by 80% of patients (Starkman et al. 1981). Patients report prob-

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lems with registration of new information, which could be related in part to impaired concentration. They commonly repeat themselves in ongoing conversations. They easily forget items such as appointments, names of people, and location of objects. Difficulty occurs with recall of important dates in their personal or medical histories. On mental status evaluation, difficulties with serial 7 subtractions and recall of presidents are seen in close to 50% of patients, and difficulty with recall of three cities is seen in more than 30% of patients (Starkman et al. 1981). Despite this, the great majority of these patients have no disorientation or overt clouding of consciousness, and the electroencephalographs of only 5% are characteristic of delirium (Tucker et al. 1978). Detailed neuropsychological studies reveal that individuals vary in the severity or degree of cognitive dysfunction, ranging from minimal to moderate and extending to the severe deficits in a wide variety of subtests seen in close to one-third of patients (Whelan et al. 1980). Verbal learning and other verbal functions seem more vulnerable than do visuospatial functions (Starkman et al. 2001). Magnetic resonance brain imaging revealed that lower scores on verbal learning and memory tests are associated with reduced volume of the hippocampal formation, a brain region key to learning and memory, which has an abundant concentration of glucocorticoid binding sites (Starkman et al. 1992). Volume of the hippocampal formation was also negatively correlated with serum cortisol level.

Pathogenesis of Psychiatric Symptoms Overall, the psychiatric symptoms that develop in Cushing’s syndrome and their quality argue for a pathogenesis over and above a nonspecific response to severe physical illness. Irritability and decreased libido occur early, often before patients are aware that they have any physical problems other than a steady increase in weight. Later in the course, when depressed mood makes its appearance, it is experienced not simply as the demoralization common to patients with medical illness, but as episodic sadness and crying, sometimes occurring in the absence of depressive thought content. The difficulties with memory and concentration seen in these patients appear in the absence of disorientation or overt clouding of consciousness, and the electroencephalographs in almost all cases are not characteristic of delirium (Starkman et al. 1981; Tucker et al. 1978). The incidence of depressive disorders is greater than in comparison groups of patients with other types of pituitary tumors (66% versus 8%; Kelly et al. 1980) or with Graves’ disease (62% versus 23%; Sonino et al. 1993).

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Cushing’s Syndrome After Treatment: Improvement in Neuropsychiatric Symptoms Cushing’s syndrome is treated in a variety of ways. In patients with pituitary ACTH-dependent disease, a transsphenoidal resection is usually performed after a magnetic resonance imaging study of the pituitary has revealed a defined pituitary microadenoma. If there is evidence of pituitary hyperfunction but such a microadenoma tumor is not found or completely removed, cobalt irradiation of the pituitary gland is performed, although several years may pass before an effect on ACTH secretion is seen. Until such an effect on ACTH occurs, cortisol increase can be controlled by chemical agents capable of blocking (such as ketoconazole) or of blocking and destroying (such as mitotane) the cortisolsecreting adrenocortical cells. Adrenal adenomas and carcinomas are treated by surgical removal, followed by chemotherapy in patients with carcinoma. In patients with Cushing’s syndrome due to nonmalignant causes, improvement in hypertension occurs promptly after treatment. Remission of other physical signs and symptoms takes place over a period of 6–12 months. Similarly, in patients with adrenal adenomas (Haskett 1985) or pituitary ACTH-dependent Cushing’s syndrome (Starkman et al. 1986), certain neuropsychiatric symptoms such as irritability improve rapidly, whereas other symptoms such as lowered libido require a delay of months to years from the correction of elevated cortisol levels for remission or improvement. In treated patients, improvements in depressed mood are manifested by a decrease in the frequency of days when the patient feels depressed. In addition, each episode lasts a shorter period of time, perhaps only a few hours instead of 1 or 2 days. The patients also describe a change in the quality of the depressive mood: they no longer experience total depression or such a deep or all-encompassing depression. They also no longer feel depressed without some external precipitating reason. A mood change comes on gradually and abates gradually, rather than appearing suddenly as before. Crying becomes less frequent, is less easily elicited by environmental upsets, occurs only with some identifiable external precipitant, and is of shorter duration (Starkman et al. 1986). Rating scales for depression improve significantly (Kelly et al. 1996). Patients also report improvements in cognitive function. The degree of improvement in concentration is significantly associated with the degree of decrease in cortisol level (Starkman et al. 1986). After treatment, the volume of the hippocampal formation increases, and this increase is

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significantly associated with the magnitude of decrease in urinary free cortisol (Starkman et al. 1999). The time course of improvement in depressed mood compared to improvement in other neurovegetative symptoms is of interest. In patients with Cushing’s disease who manifest depressed mood at initial evaluation and are subsequently studied during the first 12 months after treatment, improvement in symptoms other than depressed mood occurs before improvement in depressed mood (Starkman et al. 1986). Depressed mood is less likely than irritability and sleep, for example, to be among the first cluster of symptoms to improve. Interestingly, this lag is similar to that seen in patients with major depressive episodes treated with antidepressants, in whom improvements in sleep and psychomotor activity often occur before improvement in depressed mood. Antidepressant medications, particularly the tricyclics, produce little or no improvement in the depressive syndrome when administered to patients with active, untreated Cushing’s syndrome (Sonino et al. 1993). There is less experience with the newer selective serotonin reuptake inhibitors, which can be administered safely (if not necessarily effectively). After treatment, antidepressants may prove helpful when depressed mood lingers after treatment has lowered cortisol levels or is exacerbated because steroid levels have declined rapidly and sharply.

Relationship of Hormone Levels and Depression The association between pretreatment cortisol levels and the degree of severity of depressive symptoms is complex and has not yet been fully clarified. On the one hand, individuals with greatly elevated urinary free cortisol levels (1,000 mg/day and above) have been shown to have the highest depression severity score, using a modified version of the Hamilton Rating Scale for Depression (Ham-D; Hamilton 1967), a standard measure of the multiple components of the depressive syndrome. On the other hand, depression severity scores in several series of patients show either no correlation or only a trend for correlation with urinary free cortisol levels. For example, scatter plots show that at the higher levels of 24-hour urinary free cortisol, higher scores on the Ham-D occur more consistently, but at lesser levels of 24-hour urinary free cortisol elevation, Ham-D scores can be either high or low (Starkman et al. 1986). In the milieu of elevated cortisol levels before treatment, low or normal ACTH levels are associated with mild rather than pronounced depressed mood, whereas moderately to highly elevated ACTH levels are equally likely to be associated with mild or pronounced depressed mood (Starkman et al. 1981).

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Because patients with adrenal adenoma constitute the major proportion of Cushing’s syndrome patients with low ACTH levels, it is informative to examine them as a separate group. Results of such studies, however, do not provide a uniform answer, partly because this condition is extremely rare, and therefore sample sizes are often small. Some studies report no difference in incidence or severity of depressive symptoms compared with pituitary ACTH-dependent Cushing’s disease (Kelly 1996; Sonino et al. 1993). Other studies do report such differences. In a series examining 29 patients with Cushing’s syndrome, of the 4 who were “mentally unaffected,” 3 had adrenal tumors (Cohen 1980). In another study, of 5 patients with adrenal tumors, 4 were only mildly depressed (Jeffcoate et al. 1979). In a retrospective review of 78 cases of Cushing’s syndrome reported in the literature, although two-thirds of patients with pituitary ACTH disturbance had a problem with depression, one-fourth of patients with Cushing’s syndrome secondary to an adrenal tumor had depression, a highly statistically significant difference (Carroll 1972). These latter studies, taken together, would suggest that elevated cortisol levels in the absence of elevated ACTH levels in patients with adrenal adenomas may be less frequently associated with severe depressed mood. Several studies have investigated the relationship of improvement in depression with the decrease in cortisol level induced by treatment. Significant improvement in Ham-D scores clearly occurs after treatment produces decreases in cortisol levels (Kelly et al. 1983; Starkman et al. 1986). In fact, normalizing cortisol levels can improve depressed mood and the depressive syndrome despite the continuation of elevated ACTH levels. In one study, 23 patients with Cushing’s disease were treated with mitotane, an adrenal gland inhibitor that reduces cortisol levels without reducing (and even increasing) ACTH levels. More than 60% of Cushing’s disease patients with depressed mood before treatment who subsequently achieved normal cortisol levels but continued to have elevated ACTH levels showed improvement in scores evaluating depressed mood despite the continuing elevation of ACTH levels (Starkman et al. 1986). Other investigators, using different treatments that lower cortisol but not ACTH (bilateral adrenalectomy or metyrapone), also observed improvements in depression subsequent to cortisol normalization (Cohen 1980; Jeffcoate et al. 1979). In summary, the data from these studies indicate that patients with elevation of ACTH alone (as in mitotane-treated patients) are less likely to have severe depressed mood. In contrast, patients with elevation of both cortisol and ACTH levels may be more at risk for developing and sustaining severe depressed mood. If so, one hypothesis suggested is that abnormally elevated cortisol levels destabilize important psychoneuro-

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physiological systems and make the central nervous system more vulnerable to the effects of increases in ACTH and other neuroactive substances (Starkman 1987). Currently, evidence indicates that relevant neuroactive substances include excitatory amino acids such as glutamic acid (Sapolsky 1990).

Behavioral Effects of ACTH and Cortisol The studies reviewed above lend support to the hypothesis that the neuropsychiatric changes seen in Cushing’s syndrome are related, at least in part, to the effect of elevated levels of cortisol. Further support for the role of cortisol in eliciting neuropsychiatric abnormalities comes from research with patients with primary MDD, as reviewed in Chapter 6 of this volume. Studies in patients with primary psychiatric disorders also indicate that increased cortisol levels are associated with behavioral abnormalities. Psychiatric inpatients with high 8:00 A.M. values of plasma cortisol, regardless of whether they had primary endogenous depression or some other psychiatric diagnosis, were more symptomatic on admission, and on discharge had more symptoms of sleep disturbance and decreased ability to think, than patients with normal values of plasma cortisol (Reus 1982). Several investigators have reported extremely high urinary free cortisol levels in subgroups of depressed patients who subsequently attempted suicide (Bunney et al. 1969; Ostroff et al. 1982). Cerebrospinal fluid cortisol levels are elevated in depressed patients compared with nondepressed subjects, and there is a correlation between cerebrospinal fluid cortisol level and the severity of depression (Gerner and Wilkins 1983). Possible mechanisms for the effect of cortisol on behavior include a direct effect of the steroid on the cells of the central nervous system; on neurotransmitter synthesis or function; on glucose and electrolytes, and on increasing the sensitivity of the brain to other neuroactive substances. Cortisol has effects on a wide variety of enzymes important in neurochemistry, and one mechanism of its action may be to induce alterations of mood-regulating neurotransmitter systems within the brain. For example, glucocorticoids increase liver tryptophan pyrrolase, with a subsequent decrease in brain tryptophan and serotonin (Green and Curzon 1968). In tissue culture, hydrocortisone and dexamethasone stimulate tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, and inhibit choline acetyltransferase, markedly inhibiting the synthesis of acetylcholine (Schubert et al. 1980). In rat brain, corticosteroids altered the sensitivity to norepinephrine of the norepinephrine receptor– coupled adenylate cyclase system (Mobley and Sulser 1980). Cortico-

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steroids also interact with the g-aminobutyric acid (GABA) receptor complex, altering neuronal excitability (Majewska 1987). Exposure to increased glucocorticoids increases intracellular calcium and extracellular excitatory amino acids (glutamate) (McEwen 1997) and inhibits glucose utilization of the brain, particularly in the hippocampus (Brunetti et al. 1998; de Leon et al. 1997; Kadekaro et al. 1988). ACTH, too, has potent behavioral effects. ACTH fragment 4-10 increases the state of arousal in limbic midbrain structures (DeWied 1977). Microinjection of ACTH fragment 1-24 into the periaqueductal gray matter of rats produces a syndrome of fearful hyperactivity in which the animals shriek shrilly and jump repetitively on exposure to mild auditory and visual stimuli that are normally neutral to the rat (Jacquet 1983). Interestingly, microinjection of b-endorphin elicits the opposite effect: sedated immobility. Because normal levels of ACTH and b-endorphin apparently do not cross the blood-brain barrier, it is currently unclear how the increased ACTH and b-endorphin produced by the pituitary in patients with Cushing’s disease directly affect the brain. There are areas of the brain where the blood-brain barrier, in fact, does not exist. Alternatively, the increased levels of pituitary ACTH and b-endorphin produced by the pituitary may diffuse by retrograde flow back up the portal vein to the hypothalamus and thus regulate the brain’s production of its own b-endorphin, which occurs in the hypothalamus. Immunoreactive CRH levels in cerebrospinal fluid are significantly lower in patients with Cushing’s disease than in patients with MDD and in healthy subjects (Kling et al. 1991; Tomori et al. 1983). CRH has behavioral effects in animals, being primarily anxiogenic. Its role in human behavior is still insufficiently understood. It is important to note that this discussion has focused primarily on a single adrenal steroid, cortisol, and a single pituitary peptide, ACTH. This reflects the current state of knowledge. However, other adrenal glucocorticoids as well as sex steroids produced by the adrenal gland, such as testosterone, are also often increased in patients with Cushing’s disease (Schoneshofer et al. 1986), as are the pituitary peptides b-lipotropin and its product, b-endorphin. These substances likely contribute to the psychopathology of Cushing’s disease—and possibly to the psychopathologies of primary psychiatric disorders such as MDD—and remain to be studied.

Problems of Differential Diagnosis Differentiation of patients with Cushing’s syndrome from other patients with a cluster of similar physical signs and symptoms (obesity, hirsutism,

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menstrual irregularities, hypertension, diabetes mellitus) is difficult in the early stages of the disease. Manifestations of protein catabolism (muscle weakness and atrophy, thinning of skin, and easy bruising) are the clinical features of greatest discriminatory value in distinguishing these patients from those with obesity. Deciding whether a patient with hypercortisolemia has primary depression or early Cushing’s syndrome may be difficult. (In fact, there is some evidence for somatic effects of glucocorticoid excess even in patients with MDD when Cushing’s disease is not a possible alternate diagnosis; MDD patients who were abnormal responders on the dexamethasone suppression test showed hematologic and blood chemistry findings consistent with the effects of hypercortisolemia [Reus and Miner 1985] and had significantly more hypertension [Pfohl et al. 1991] than patients who suppressed normally.) Some patients who eventually have a full-blown picture of Cushing’s syndrome begin with only intermittent elevations of cortisol level and symptoms of a major affective disorder (Gold et al. 1984). Conversely, patients have been reported in whom the physical presentation and hypercortisolemia are suggestive of Cushing’s disease, yet the clinical course and response to psychotropic medication favor primary psychiatric illness (Krystal et al. 1990). Although it is similar in many respects to the major depressive disorders, the depression seen in Cushing’s syndrome does have certain distinguishing clinical characteristics that may aid in differential diagnosis. To summarize these characteristics, irritability is a prominent and consistent feature, as are symptoms of autonomic activation such as shaking, palpitations, and sweating. Depressed affect is often intermittent, with episodes of 1–3 days’ duration, recurring very frequently at irregular intervals. Patients usually feel their best, not their worst, in the morning. Psychomotor retardation, although present in many patients, is usually not so pronounced as to be clinically obvious and is usually apparent only in retrospect after improvement with treatment. The majority of these patients are not withdrawn, monosyllabic, unspontaneous, or hopeless. Their guilt, when present, is not irrational or self-accusatory and is primarily related to their realistic inability to function effectively. Significant cognitive impairment, including disorders of concentration and memory, is a consistent and prominent clinical feature of patients with Cushing’s syndrome. Are there any procedures currently available that may aid in the differential diagnosis? Sleep electroencephalographic studies indicate that there are many similarities between patients with Cushing’s disease and patients with MDD, which is theoretically interesting but makes such studies not diagnostically helpful. Both groups showed a significantly

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longer sleep latency, less total sleep time, and lower sleep efficiency than did the healthy subjects. In both Cushing’s disease patients and MDD patients, rapid eye movement (REM) latency was significantly shortened, and REM density in the first REM period was significantly increased compared with control subjects (Shipley et al. 1992a, 1992b). One procedure that holds some promise as a possible tool for helping to distinguish between patients with Cushing’s disease and those with MDD is the administration of CRH to stimulate ACTH secretion (Gold et al. 1986). (See also Chapter 17 in this volume.) At present, however, there is still a substantial overlap in the ACTH secretory responses between the two groups, impairing the clinical utility of the test. Further refinements will be required. One modification includes taking both the pre-CRH plasma cortisol level and the peak ACTH response to CRH into account (Gold et al. 1987). Further improvement in diagnostic accuracy is achieved when CRH is administered 2 hours after completion of the classic endocrine 2-day low-dose dexamethasone suppression test (Yanovski et al. 1993). As research continues to provide greater understanding of HPA axis pathophysiology and its associations with the depressive syndromes, the development of better tools to provide the discriminatory power necessary can be anticipated. Some patients with MDD continue to have an abnormal overnight 1-mg dexamethasone suppression test after treatment. Although this may reflect an increased risk of poor outcome or relapse, if any clinical manifestations consistent with Cushing’s disease develop, such patients should receive endocrine evaluation, including the standard 2-mg and 8-mg dexamethasone suppression tests (Schlechte et al. 1986).

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980 Arlt W, Callies F, van Vlijmen JC, et al: Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 341:1013–1020, 1999 Boston Collaborative Drug Surveillance Program: Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol Ther 13:694–698, 1972 Brunetti A, Fulham MJ, Aloj L, et al: Decreased brain glucose utilization in patients with Cushing’s disease. J Nucl Med 39(5):786–790, 1998 Bunney WE Jr, Fawcett JA, Davis JM, et al: Further evaluation of urinary 17-hydroxycorticosteroids in suicidal patients. Arch Gen Psychiatry 21:138– 150, 1969

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Carroll BJ: Psychiatric disorders and steroids, in Neuroregulators and Psychiatric Disorders. Edited by Usdin E, Hamburg DA, Barchas JD. New York, Oxford University Press, 1972 Cleghorn RA: Adrenal cortical insufficiency: psychological and neurologic observations. Can Med Assoc J 65:449–454, 1951 Cohen SI: Cushing’s syndrome: a psychiatric study of 29 patients. Br J Psychiatry 136:120–124, 1980 Cushing H: The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 50:137–195, 1932 de Leon MJ, McRae T, Rusinek H, et al: Cortisol reduced hippocampal glucose metabolism in normal elderly, but not in Alzheimer’s disease. J Clin Endocrinol Metab 82:3251–3259, 1997 DeWied D: Pituitary adrenal system hormones and behavior. Acta Endocrinol (Copenh) 85 (suppl):9–18, 1977 Dorn LD, Burgess ES, Dubbert B, et al: Psychopathology in patients with endogenous Cushing’s syndrome: “atypical” or melancholic features. Clin Endocrinol (Oxf) 43(4):433–442, 1995 Engel GL, Margolin SG: Neuropsychiatric disturbances in internal medicine. Arch Intern Med 70:236, 1942 Gerner RH, Wilkins JN: CSF cortisol in patients with depression, mania, or anorexia nervosa and in normal subjects. Am J Psychiatry 140:92–94, 1983 Gifford S, Gunderson JG: Cushing’s disease as a psychosomatic disorder: a selective review of the clinical and experimental literature and a report of ten cases. Perspect Biol Med 13:169–221, 1970 Gold PW, Chrousos G, Kellner C, et al: Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 141:619– 627, 1984 Gold PW, Loriaux DL, Roy A, et al: Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. N Engl J Med 314:1329–1335, 1986 Gold PW, Kling MA, Calabrese JR, et al: Corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease—reply (letter). N Engl J Med 316:218–219, 1987 Green AR, Curzon G: Decrease of 5-hydroxytryptamine in the brain provoked by hydrocortisone and its prevention by allopurinol. Nature 220:1095– 1097, 1968 Guillemin R, Vargo T, Rossier J, et al: Beta-endorphin and adrenocorticotropin are secreted concomitantly by the pituitary gland. Science 197(4311):1367– 1369, 1977 Hall RC, Popkin MK, Stickney SK, et al: Presentation of the steroid psychoses. J Nerv Ment Dis 167:229–236, 1979 Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278–296, 1967 Haskett RF: Diagnostic categorization of psychiatric disturbance in Cushing’s syndrome. Am J Psychiatry 142:911–916, 1985

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Jacquet YF: Dual action of morphine on the central nervous system: parallel actions of beta-endorphin and ACTH. Ann N Y Acad Sci 398:272–290, 1983 Jeffcoate WJ, Silverstone JT, Edwards CR, et al: Psychiatric manifestations of Cushing’s syndrome: response to lowering of plasma cortisol. Q J Med 48:465–472, 1979 Kadekaro M, Ito M, Gross PM: Local cerebral glucose utilization is increased in acutely adrenalectomized rats. Neuroendocrinology 47:329–334, 1988 Kelly WF: Psychiatric aspects of Cushing’s syndrome. Q J Med 89(7):543–551, 1996 Kelly WF, Checkley SA, Bender DA: Cushing’s syndrome, tryptophan and depression. Br J Psychiatry 136:125–132, 1980 Kelly WF, Checkley SA, Bender DA, et al: Cushing’s syndrome and depression— a prospective study of 26 patients. Br J Psychiatry 142:16–19, 1983 Kelly WF, Kelly MJ, Faragher B: A prospective study of psychiatric and psychological aspects of Cushing’s syndrome. Clin Endocrinol (Oxf) 45(6):715– 720, 1996 Kling MA, Roy A, Doran AR, et al: Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing’s disease and major depression: potential clinical implications. J Clin Endocrinol Metab 72(2):260–271, 1991 Krieger DT: The central nervous system and Cushing’s syndrome. Mt Sinai J Med 39:416–428, 1972 Krieger DT: Cyproheptadine-induced remission of Cushing’s disease. N Engl J Med 293:893–896, 1975 Krieger DT: Rhythms in CRF, ACTH and corticosteroids, in Endocrine Rhythms. Edited by Krieger DT. New York, Raven, 1979 Krystal A, Krishnan KR, Raitiere M, et al: Differential diagnosis and pathophysiology of Cushing’s syndrome and primary affective disorder. J Neuropsychiatry Clin Neurosci 2:34–43, 1990 Loosen PT, Chambliss B, DeBold CR, et al: Psychiatric phenomenology in Cushing’s disease. Pharmacopsychiatry 25:192–198, 1992 Majewska M: Actions of steroids on neuron: role in personality, mood, stress and disease. Integrative Psychiatry 5:258–273, 1987 McEwen BS: Possible mechanisms for atrophy of the human hippocampus. Mol Psychiatry 2:255–262, 1997 Mobley PL, Sulser F: Adrenal corticoids regulate sensitivity of noradrenaline receptor-coupled adenylate cyclase in brain. Nature 286:608–609, 1980 Ostroff R, Giller E, Bonese K, et al: Neuroendocrine risk factors of suicidal behavior. Am J Psychiatry 139:1323–1325, 1982 Pfohl B, Rederer M, Coryell W, et al: Association between post-dexamethasone cortisol level and blood pressure in depressed inpatients. J Nerv Ment Dis 179:44–47, 1991 Reus VI: Pituitary-adrenal disinhibition as the independent variable in the assessment of behavioral symptoms. Biol Psychiatry 17:317–326, 1982 Reus VI, Miner C: Evidence for physiologic effects of hyper-cortisolemia in psychiatric patients. Psychiatry Res 14:47–55, 1985

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Sapolsky R: Glucocorticoids, hippocampal damage and the glutamatergic synapse. Prog Brain Res 86:13–23, 1990 Schlechte JA, Sherman B, Pfohl B: A comparison of adrenal cortical functions in patients with depressive illness and Cushing’s disease. Horm Res 23:1–8, 1986 Schoneshofer M, Weber B, Oelkers W, et al: Urinary excretion rates of 15 free steroids: potential utility in differential diagnosis of Cushing’s syndrome. Clin Chem 32:93–96, 1986 Schubert D, LaCorbiere M, Klier FG, et al: The modulation of neurotransmitter synthesis by steroid hormones and insulin. Brain Res 190:67–79, 1980 Shipley JE, Schteingart DE, Tandon R, et al: EEG sleep in Cushing’s disease and Cushing’s syndrome: comparison with patients with major depressive disorder. Biol Psychiatry 32:146–155, 1992a Shipley JE, Schteingart DE, Tandon R, et al: Sleep architecture and sleep apnea in patients with Cushing’s disease. Sleep 15:514–518, 1992b Sonino N, Fava GA, Grandi S, et al: Stressful life events in the pathogenesis of Cushing’s syndrome. Clin Endocrinol (Oxf) 29:617–623, 1988 Sonino N, Fava GA, Belluardo P, et al: Course of depression in Cushing’s syndrome: response to treatment and comparison with Graves’ disease. Horm Res 39:202–206, 1993 Starkman MN: Commentary on Majewska M: Actions of steroids on neuron: role in personality, mood, stress and disease. Integrative Psychiatry 5:258–273, 1987 Starkman MN, Schteingart DE: Neuropsychiatric manifestations of patients with Cushing’s syndrome. Relationship to cortisol and adrenocorticotropic hormone levels. Arch Intern Med 141:215–219, 1981 Starkman MN, Schteingart DE, Schork MA: Depressed mood and other psychiatric manifestations of Cushing’s syndrome: relationship to hormone levels. Psychosom Med 43:3–18, 1981 Starkman MN, Zelnik TC, Nesse RM, et al: Anxiety in patients with pheochromocytomas. Arch Intern Med 145:248–252, 1985 Starkman MN, Schteingart DE, Schork MA: Cushing’s syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome. Psychiatry Res 17:177–188, 1986 Starkman MN, Gebarski SS, Berent S, et al: Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765, 1992 Starkman MN, Giordani B, Gebarski SS, et al: Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol Psychiatry 46:1595–1602, 1999 Starkman MN, Giordani B, Berent S, et al: Elevated cortisol levels in Cushing’s disease are associated with cognitive decrements. Psychosom Med 63:985– 993, 2001 Tomori N, Suda T, Tozawa F, et al: Immunoreactive corticotropin-releasing factor concentrations in cerebrospinal fluid from patients with hypothalamic-pituitary-adrenal disorders. J Clin Endocrinol Metab 57(6):1305–1307, 1983

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Trethowan WH, Cobb S: Neuropsychiatric aspects of Cushing’s syndrome. Archives of Neurology and Psychiatry 67:283–309, 1952 Tucker RP, Weinstein HE, Schteingart DE, et al: EEG changes and serum cortisol levels in Cushing’s syndrome. Clin Electroencephalogr 9:32–37, 1978 Van Cauter E, Refetoff S: Evidence for two subtypes of Cushing’s disease based on the analysis of episodic cortisol secretion. N Engl J Med 312:1343–1349, 1985 Whelan TB, Schteingart DE, Starkman MN, et al: Neuropsychological deficits in Cushing’s syndrome. J Nerv Ment Dis 168:753–757, 1980 Yanovski JA, Cutler GB, Chrousos GP, et al: Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA 269(17):2232–2238, 1993

Chapter 8 Psychiatric Effects of Glucocorticoid Hormone Medications Victor I. Reus, M.D. Owen M. Wolkowitz, M.D.

T

he introduction of corticosteroids to medical treatment in 1949 was accompanied almost immediately by an awareness of their possible behavioral side effects (Clark et al. 1952; Fox and Gifford 1953; Freyberg et al. 1951; Ritchie 1952; Rome and Braceland 1952). By 1956, even the general public appreciated the potential liabilities of the new “wonder drug” through Hollywood director Nicolas Ray’s movie Bigger Than Life, in which James Mason portrayed a family man progressing into paranoia and mania because of his addiction to cortisone. Although the dosages employed have markedly decreased over time, drug-induced changes in mood and cognition are still observed, perhaps at a lower incidence, although definitive epidemiological data are lacking. Remarkably, considering the time that has elapsed, the state of knowledge continues to be based principally on retrospective case series, anecdotal reports, and a few prospective investigations that differ from each other in their rigor and approach to behavioral assessment (Reus and Wolkowitz 1993; Wolkowitz et al. 1997).

Frequency and Character of Behavioral Symptoms The majority of individuals receiving corticosteroids will experience a change in their behavior, most commonly in the direction of a shortlived, mild euphoria or anxiety state. Subtle changes in sleeping pattern and sensory and thought processes may also become apparent. Although

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such effects are generally regarded as unwanted, some investigators have suggested that glucocorticoids should be investigated as possible therapeutic antidepressants (Arana 1991; Arana et al. 1995; Beale and Arana 1995; DeBattista et al. 2000; Dinan et al. 1997; Goodwin et al. 1992; Mitchell 1996; Plihal et al. 1996). In a minority of patients, more profound alterations in mood, ranging from frank mania to paranoid psychosis, may emerge, whereas in others the initial elevation in mood can progress to a sustained major depression over a period of weeks (Cameron et al. 1985; Dawson and Carter 1998; Kershner and Wang-Cheng 1989; Ling et al. 1981; Naber et al. 1996; Plihal et al. 1996; Reckart and Eisendrath 1990). Suicidality can emerge in rare cases (Braunig et al. 1989; Wolkowitz 1990). However, there is no pathognomonic symptom complex or progression in symptoms, and precipitation of obsessivecompulsive behavior, fugue states, catatonia, and frank dementia-like states have been linked to corticosteroid treatment in individual case reports (Bick 1983; Gifford et al. 1976–1977; Quarton et al. 1955; Varney et al. 1984; Wolkowitz et al. 1997). Estimates of the actual incidence of the more severe behavioral changes vary and depend in large part on the nature of the population studied, the approach to behavioral assessment, and the length and intensity of treatment provided (Pies 1995). In the largest study to date, the Boston Collaborative Drug Surveillance Program (1972), 718 consecutively hospitalized medical patients who received prednisone were studied. Twenty-one of these patients, receiving an average of 60 mg/day of prednisone, developed what were termed “acute psychiatric reactions,” defined by the investigators as either psychosis or inappropriate euphoria. This undoubtedly represented an underestimate of risk, because patients who were considered to be emotionally unstable before treatment were excluded from the study. Furthermore, of patients prescribed 80 mg/day of prednisone in that study, 18.4% developed steroid psychosis (Boston Collaborative Drug Surveillance Program 1972). Surveys of steroid treatment in more defined populations have generally reported significantly higher incidences of mental disturbance (Bobele and Bodensteiner 1994; Gift et al. 1989; Soliday et al. 1999), the highest figures (around 50%) occurring in patients with systemic lupus erythematosus who received prednisone (Cade et al. 1973; Goolker and Schein 1953; Sergent et al. 1975). Interpretation of this finding, however, is complicated by the use of extremely high doses of steroids (up to 500 mg/day) and by the central nervous system changes associated with the disease process itself (Denburg et al. 1994; Kohen et al. 1993). Differentiation of lupus cerebritis from iatrogenic steroid-induced changes may be aided by the observation of high levels of P ribosomal protein

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antibodies in the former, but in general the differential diagnosis rests on the timing and duration of the mental changes observed and on the response to increases or decreases in the steroid dose (Kohen et al. 1993; Tincani et al. 1996; Wolkowitz et al. 1997). Reviews of glucocorticoid treatment in general have concluded an overall incidence of serious psychiatric symptoms of approximately 6%, although many more patients will experience mild, but perhaps disturbing, behavioral change (Cameron et al. 1985; Reckart and Eisendrath 1990; Stiefel et al. 1989). In one of the few prospective clinical trials using structured ratings, Naber et al. (1996) noted a 26%–34% incidence of hypomanic reactions and a 10%– 12% incidence of depressive reactions in ophthalmologic patients receiving moderate to high short-term doses of corticosteroids. Hall and colleagues (1979), in addition to describing more classic syndromes, also underscored transient emotional lability, distractibility, memory impairment, and alteration in sensory perception, particularly an increase in sensory intensity, which they termed “sensory flooding.” Subjectively rated increases in sensory intensity were confirmed in a prospective double-blind trial of prednisone in healthy volunteers (Wolkowitz et al. 1990a). The feeling of being overwhelmed by sensory stimuli had previously been observed in some of the original case reports provided by Glaser (1953), Goolker and Schein (1953), and Clark et al. (1952), but it deserves emphasis in light of the otherwise undifferentiated symptom picture and clinical experience that reduction in sensory stimulation helps alleviate symptoms of steroid psychosis (Ducore et al. 1983). The memory-impairing effects of corticosteroid medication in medically ill patients are reviewed in Wolkowitz et al. (1997). Attempts to identify reliable clinical predictors of risk have met with mixed success. Several investigators have identified female gender as one possible factor, although this may be an artifact of the marked gender disparity in the prevalence of autoimmune diseases that are commonly treated by corticosteroids, and a prospective study did not confirm a differential gender susceptibility (Naber et al. 1996). Evidence for a doseresponse effect is more clear-cut. Investigators in the Boston Collaborative Drug Surveillance Program (1972) found a statistically significant increase in incidence with increase in daily dose, a finding that has been supported by many of the case series and reports that have followed (Carroll 1977), but not by all (Drigan et al. 1992). Lewis and Smith (1983), for example, found that only 23% of patients who experienced psychiatric symptoms received less than 40 mg/day of prednisone. Corticosteroid dosage does not, however, seem to predict onset, intensity, or character of steroid-induced behavioral symptoms (Hall et al. 1979; Ling et al. 1981). Low dosages may precipitate unusual behavioral

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responses. In one case a 21-year-old woman became psychotic on a regimen of 7.5 mg of prednisolone a day in divided doses (Greeves 1984), whereas in another otherwise stable patient mania was apparently precipitated by short-term usage of a steroid nasal spray (Goldstein and Preskorn 1989). In some patients even one-time administration of doses as low as 1 mg of dexamethasone may provoke “amphetamine-like” reactions (Sovner 1983). Several studies have shown that older patients tend to be overrepresented, but this again is confounded by the age penetrance of the diseases studied. Keenan et al. (1996), however, did find an increased incidence of steroid-related cognitive difficulties in older but not in younger patients with arthritis. Previous history of psychiatric disorder has likewise not been shown to reliably relate to corticosteroid-induced mental change, although it is quite possible that it contributes to shaping the symptom picture once a drug-induced effect occurs (Hall et al. 1979; Ling et al. 1981). However, Minden et al. (1988) reported that past history or family history of major depression did predict the development of manic or hypomanic symptoms in patients with multiple sclerosis treated with adrenocorticotropic hormone (ACTH) or prednisone. It is still not clear whether a history of mood change or psychosis following a previous course of corticosteroids predisposes an individual to similar experiences on retreatment later. The average time for onset and overall duration of symptoms has been reported to vary widely. Lewis and Smith (1983) noted a mean duration of symptoms of 21 days in their sample and compared it to a range of 1–150 days in their survey of the literature. Symptoms usually present within days of the introduction of treatment or of the increase in dosage and usually remit promptly with appropriate diagnosis and discontinuation of drug, but delayed onset (after 4 weeks) and more prolonged and progressive courses have also been reported (Pies 1981; Wolkowitz et al. 1997). In one published case report, a 28-year-old woman developed depression, and then mania, after a single course of corticosteroids and went on to have repetitive, autonomous cycles of mood change despite discontinuation of the corticosteroid therapy (Pies 1981). Particularly clear-cut evidence for a cause-and-effect relationship between corticosteroid therapy and behavioral abnormalities may be evident in patients who undergo long-term alternate-day steroid regimens. Sharfstein and colleagues (1982) reported several patients whose mood fluctuated on a regular basis in a manner akin to rapid mood cycling, becoming more euphoric and hyperverbal on the day of dose increase and more withdrawn, lethargic, and psychomotorically impaired on the day of dose decrease. The mood-altering effects of corticosteroids may sometimes lead to their intentional abuse by patients (Flavin et al. 1983). In several cases

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reported by Goldberg and Wise (1986–1987), patients reported experiencing an unusual sense of well-being even on low doses of prednisone (10 mg) and a rather rapid decrease in mood when they attempted to lower the dose below this point. A history of substance abuse was not apparent, but each of the subjects had a history suggestive of prior depressive episodes. Accordingly, clinicians should be aware of the potential for drug dependence in patients whose medical symptoms do not correlate with physical or laboratory examination and should use a protocol for tapered withdrawal in all patients who have been maintained on corticosteroids for a significant length of time (Dixon and Christy 1980; Kimball 1971; Stelzner et al. 1990). In patients who experience incipient depressive symptoms on attempted withdrawal from steroid therapy, antidepressants may prove useful (Goldberg and Wise 1986–1987). It is not generally appreciated that the cognitive effects of corticosteroids may result in as much dysfunction as their mood-altering properties (Wolkowitz et al. 1997, 2001). Such cognitive disturbances can occur in the presence of an otherwise clear sensorium (Naber et al. 1996; Varney et al. 1984) and are not necessarily correlated with the severity of the affective changes (Naber et al. 1996). In one particularly well-controlled study, 32 children with chronic severe asthma were studied through a course of short-term alternating-dose prednisone treatment (Bender et al. 1991). During their high-dose (61.4 mg) days, children reported increased anxiety and depression and demonstrated decreased verbal memory, in comparison to their low-dose (6.97 mg) days. Clinical effects on cognition have been verified in empirical paradigms. Keenan et al. (1996) found that medically ill patients treated with prednisone displayed significant impairments in explicit memory function, while Wolkowitz and colleagues (1990b) showed that healthy volunteers given a single 1-mg dose of dexamethasone—or alternatively, 80 mg of prednisone daily for 5 days—made significantly more errors on verbal memory tasks than did subjects who received placebo. Similar results have been obtained by Newcomer et al. (1994, 1999), who reported that synthetic glucocorticoids as well as hydrocortisone (in stress-level doses for 4 days) impaired verbal declarative memory performance in healthy subjects. Acutely administered hydrocortisone, however, was not found to impair memory in healthy subjects (Beckwith et al. 1986). The types of memory function that seem most susceptible to corticosteroid impairment are the ones dependent on the hippocampus, such as explicit and declarative memory; procedural and implicit memory function, which are largely independent of hippocampal activity, do not seem to be similarly affected (Keenan et al. 1996; Naber et al. 1996; Wolkowitz 1994; Wolkowitz et al. 1990b). Executive function and working mem-

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ory, which are mediated by the frontal cortex, may also be affected by steroid treatment (Lupien et al. 1999). In rare cases, steroid-induced cognitive impairment can be so severe as to mimic a stupor or dementia-like syndrome (Doherty et al. 1991) and can be a source of considerable morbidity (Reckart and Eisendrath 1990; Wolkowitz and Rapaport 1989; Wolkowitz et al. 1997, 2001). In six patients studied by Varney et al. (1984), the steroid-induced dementia was characterized by deficits in memory retention, attention, concentration, mental speed and efficiency, IQ, and occupational performance.

Steroid Withdrawal Syndrome Apart from the acute behavioral reactions seen during steroid treatment, a “steroid withdrawal syndrome,” during steroid withdrawal or after discontinuation of steroid treatment, has been described in approximately 21% of patients (Freyberg et al. 1951). This syndrome may occur even in the absence of biochemical evidence of deficient adrenal secretion (Miller and Tyrell 1995). Symptoms of this syndrome may include lowered sense of well-being, discouragement, depression, irritability, lethargy, malaise, anorexia and weight loss, nausea, arthralgias and myalgias, skin desquamation, headache, fever, depersonalization, confusion, poor concentration, and impaired memory (Freyberg et al. 1951; Glaser 1953; Hassanyeh et al. 1991; Judd et al. 1983; Miller and Tyrell 1995; Wolkowitz and Rapaport 1989; Wolkowitz et al. 1997, 2001). Vomiting, postural hypotension, psychosis, obsessiveness, and suicidality also occur, but less commonly. In medically ill patients, it is important to differentiate such symptoms from a recurrence of the condition for which the steroids were being prescribed and from symptoms of frank adrenal insufficiency. Although prolonged adrenal insufficiency lasting more than a few days is rare after short-term steroid treatment, long-term or high-dose steroid treatment may impair adrenal function for months to a year or longer. Persistent adrenal suppression is often discernible with the ACTH stimulation test. An excellent clinical and laboratory approach to the diagnosis and treatment of adrenal insufficiency is presented by Miller and Tyrell (1995). The causes of the steroid withdrawal syndrome are unknown (Wolkowitz and Rapaport 1989). Steroid withdrawal–related symptoms typically resolve by 6–8 weeks (Freyberg et al. 1951; Wolkowitz and Rapaport 1989), but they may persist for considerably longer periods in some

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patients (Lewis and Smith 1983; Wolkowitz et al. 1997, 2001). If withdrawal-related symptoms do not spontaneously subside, it may be necessary to reintroduce the steroid and withdraw it more gradually (Hassanyeh et al. 1991; Miller and Tyrell 1995). Pharmacotherapy and electroconvulsive therapy have also been used (Glaser 1953; Judd et al. 1983).

Treatment of Steroid-Induced Psychopathology Decrease in corticosteroid dosage or discontinuation of treatment is usually sufficient to result in remission of steroid-induced adverse behavioral symptoms; specific protocols for steroid taper are described by Miller and Tyrell (1995). Psychopharmacologic intervention is sometimes required, however (Seifritz et al. 1994). Both tricyclic antidepressants and electroconvulsive therapy have been used to treat steroid-precipitated behavioral syndromes. However, in one series, tricyclic agents exacerbated the psychopathology even more, precipitating visual and accusatory auditory hallucinations that remitted only with discontinuation of the antidepressant and the addition of a phenothiazine (Hall et al. 1978; Sutor et al. 1996). Antidepressants may be of greater utility in the more rare pure depressive reactions (Stiefel et al. 1989). It is unknown how serotonin-specific antidepressants compare to tricyclics in the treatment of steroid psychosis, but one case report has suggested efficacy (Beshay and Pumariega 1998). Phenothiazines have also been used with apparent success prophylactically in situations where patients have had prior psychotic experiences on high-dose glucocorticoid regimens (Ahmad and Rasul 1999; Bloch et al. 1994), although, as mentioned above, it is unknown if such patients would have developed psychotic reactions on retreatment with steroids. Anecdotal clinical reports suggest the possible usefulness of the atypical antipsychotic olanzapine in treating steroid psychosis. The fact that steroid-induced mood changes are reminiscent of those naturally occurring in bipolar mood disorder has led to the empirical usage of lithium carbonate, both acutely and prophylactically. In an initial report, Siegel (1978) found that lithium ameliorated part of the symptomatology associated with corticosteroid usage in a patient who carried diagnoses of both bipolar disorder and non-Hodgkin’s lymphoma. Additional reports since have been supportive of the potential utility of lithium (Alcena and Alexopoulos 1985; Reus et al. 1991; Terao et al. 1994, 1997). In a controlled study, Falk et al. (1979) found that lithium pre-

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vented the development of psychotic symptoms in patients who were receiving ACTH therapy for treatment of multiple sclerosis. The serum lithium levels found to be effective are equivalent to those used routinely in the treatment of bipolar disorder (i.e., 0.8–1.2 mEq/L). Lithium has been found to blunt the circadian fluctuation of serum cortisol in humans, possibly by altering the secretory pattern of ACTH (Halmi et al. 1972), and has been found to block corticosterone-induced increases in brain dopamine activity in rat brain (Reus et al. 1991). In a similar vein, although less well documented, other mood stabilizers such as valproic acid and lamotrigine may provide prophylaxis against steroid psychosis (Abbas and Styra 1994; Preda et al. 1999). The use of mood stabilizers in medically complicated patients has been reviewed by Greenberg et al. (1993) and Stiefel et al. (1989). Last, small-scale trials suggest that administration of another adrenal corticosteroid, dehydroepiandrosterone, may allow tapering of the prednisone dosage in some patients with systemic lupus erythematosus (van Vollenhoven et al. 1994) and bronchial asthma (Koo et al. 1987) without worsening the overall medical conditions. Anecdotally, such cotreatment may enhance energy and memory in prednisone-treated patients. The clinical place of this strategy, if any, remains to be determined. There are no convincing studies that clearly discriminate among available steroid compounds in terms of their risk of inducing behavioral change. There are some suggestions that methylprednisolone may be associated with less risk (Coirini et al. 1994) or that changing from prednisone to hydrocortisone plus fludrocortisone may be useful (Seifritz et al. 1994). These strategies have not been adequately tested, however.

Potential Etiologic Mechanisms The parallels between corticosteroid-induced behavioral changes and those observed naturally in the course of primary psychiatric and endocrine disorders associated with pituitary-adrenal dysfunction have led to increasing consideration of the roles of corticosteroids in central nervous system function (Kawata 1995; Wolkowitz 1994; Wolkowitz et al. 2001). McEwen (1992) has outlined how adrenal steroid hormones may mediate the ways in which environment shapes the structure and function of the brain during early development, as well as during active adult life and in aging. The hormonal effects may be both immediate and transient when mediated at the membrane level, or they may be longer lasting through modulating genomic transcription.

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Steroids can have particularly prominent effects as well on neuronal function (Landfield 1994). The highest density of corticosteroid receptors in the central nervous system is found in the hippocampus, an area critically involved in memory and behavioral learning (Joels and de Kloet 1992). Corticosteroids have effects on neurotransmitter and peptide receptors, second messengers, ion transport, G proteins, neurotrophin activity, and membrane integrity (Lesch and Lerer 1991; Sapolsky 1996), and any or all of these may be relevant to the drugs’ effects on behavior. Administration of high doses of corticosteroids to healthy human volunteers is associated with changes in brain electrical activity, particularly increases in theta waves, and with decreases in cerebrospinal fluid levels of corticotropin, norepinephrine, b-endorphin, b-lipoprotein, and somatostatin (Wolkowitz 1994; Wolkowitz et al. 1990b, 1993). No significant prednisone-induced changes in the cerebrospinal fluid levels of metabolites of dopamine or serotonin were found by Wolkowitz et al. (1990a), but levels of 3-methoxy-4-hydroxyphenylglycol, the norepinephrine metabolite, significantly decreased. Other human and animal studies have shown that dexamethasone increases plasma free dopamine and plasma homovanillic acid in healthy volunteers (Rothschild et al. 1984, 1985; Wolkowitz et al. 1986). In animal studies, corticosteroid administration has been found to produce significant changes in a variety of neurotransmitter systems, enhancing acetylcholine release, reducing dopamine reuptake, and modulating g-aminobutyric acid (GABA) receptor activity (Gilad et al. 1987; Nausieda et al. 1982). The hippocampus is particularly rich in 5-hydroxytryptamine (serotonin) type 1A (5-HT1A) receptors, and there is evidence that corticosterone modulates 5-HT1A receptor binding density and messenger RNA levels in the CA1 region (Beck et al. 1996; Farabollini et al. 1986). Because most antidepressants modulate serotonergic transmission by selectively regulating 5HT1A receptors, it is possible that the mood changes observed in clinical usage of corticosteroids are mediated through these pathways (Meijer and de Kloet 1998). Several studies have also suggested an alteration of 5-HT activity via additional mechanisms (Biegon 1990; Chauloff 1993; Joseph et al. 1984; Lesch and Lerer 1991; McEwen 1987). Neuronal atrophy (especially in the hippocampus) or neuronal endangerment has been seen in some animal models employing long-term exposure to high levels of corticosteroids (Sapolsky 1996). Such effects may be secondary to intracellular glucose deprivation (with subsequent elevations in intracellular calcium levels and excitotoxicity) (Sapolsky 1996) or to steroid-induced decreases in levels of brain-derived neurotrophic factor (Duman et al. 2001). Such effects remain to be definitively proved in humans, however. Some of the alterations brought about

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by corticosteroids may be reversible, whereas others represent potentially permanent changes in neural circuitry. In a recent study, Lucassen et al. (2001) found that a small proportion of steroid-treated patients showed signs of hippocampal neuronal apoptosis as well as heat shock protein 70 staining (an index of response to oxidative damage and cellular stress) at autopsy.

Conclusion Any patient receiving a course of corticosteroids should be informed of the risk of behavioral side effects. Major psychiatric side effects are relatively uncommon; however, mild hypomanic-like activating or sleep-disrupting side effects and difficulties with concentration or memory are quite common. In the absence of reliable predictors of risk, patient and family education and close objective monitoring of the patient emerge as central components of treatment. If significantly adverse behavioral symptoms occur, dosage reduction or discontinuation of treatment should be considered, although rapid withdrawal is generally ill advised, because symptoms may be exacerbated. In situations where complete discontinuation is infeasible, and with patients who have developed serious mental changes during previous courses of corticosteroids (or, perhaps, with patients who have strong histories of affective illness), prophylactic treatment with either lithium carbonate or low doses of an antipsychotic may be useful. Tricyclic antidepressants should be used only with caution, and there is preliminary evidence that selective serotonin reuptake inhibitors and mood-stabilizing anticonvulsants may be effective in certain cases.

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Chapter 9 Dehydroepiandrosterone in Psychoneuroendocrinology Owen M. Wolkowitz, M.D. Victor I. Reus, M.D.

Whether diandrone [dehydroepiandrosterone] turns out to be of therapeutic value in psychiatric practice remains to be seen. . . . However, we appear to have at our disposal a chemical agent that can exert a direct and prolonged action on the mental state. Strauss and Stevenson (1955)

D

ehydroepiandrosterone (DHEA) is an abundantly produced adrenal steroid hormone (Figure 9–1) whose physiological role remains a mystery. Nonetheless, it has been evaluated as a treatment for psychiatric disorders for nearly half a century (Sands and Chamberlain 1952; Strauss et al. 1952). Several positive uncontrolled reports were published in the 1950s (Strauss and Stevenson 1955; Strauss et al. 1952), but large-scale interest in this potential therapy languished until the early 1990s. At that time, a rapidly expanding body of preclinical data, plus

We gratefully acknowledge the following individuals who provided stimulating discussions and ideas about the role of DHEA in human illness, although the ideas presented in this article do not necessarily reflect their own: Eugene Roberts, Ph.D.; Louann Brizendine, M.D.; William Regelson, M.D.; Joe Herbert, M.D.; Kristine Yaffe, M.D.; Joel Kramer, Psy.D.; Ray Sahelian, M.D.; David Rubinow, M.D.; and Steven M. Paul, M.D. This research was partially funded by grants to O.M.W. from the National Alliance for Research in Schizophrenia and Affective Disorders, the Stanley Foundation, the Alzheimer’s Association (Grant 1 1RG-95–174), and the National Institute on Aging (Grant R41-AG13334–01).

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FIGURE 9–1.

Biosynthetic pathway of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S).

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the first adequately controlled clinical trial (Morales et al. 1994), fostered the hope that DHEA might increase well-being in humans and the hope (or the wish) that it could extend life, protect the brain, and retard the ravages of aging. Coincident with this burst of scientific activity, consumer interest in DHEA was enlivened by the passage, in the United States, of the Dietary Supplement Health and Education Act of 1994 (P.L. 103-417), which allowed the marketing and sale of DHEA as a “food supplement” (not subject to the usual U.S. Food and Drug Administration regulations) rather than as a hormonal medication. Shortly thereafter, popular mass-market books began promoting DHEA with titles such as The DHEA Breakthrough: Look Younger, Live Longer, Feel Better (Cherniske 1998) and DHEA: The Miracle Hormone That Can Help You Boost Immunity, Increase Energy, Lighten Your Mood, Improve Your Sex Drive, and Lengthen Your Lifespan (Callahan 1997). Such claims, as well as the widespread unregulated use of DHEA, have concerned many medical investigators and practitioners, because preclinical data may not readily extrapolate to clinical situations, and because the full risk-benefit ratio of long-term DHEA usage remains unknown (Katz and Morales 1998; van Vollenhoven 1997). The purpose of this chapter is to put into scientific context the possible role of DHEA as a psychotropic agent and to review clinical data regarding its use in neuropsychiatric illnesses. The main focus is on clinical efficacy, feasibility, and safety in neuropsychiatric conditions. More extensive discussions of pertinent preclinical studies are available elsewhere (Baulieu 1997; Baulieu and Robel 1996, 1998; Majewska 1992, 1995; Regelson and Kalimi 1994; Regelson et al. 1990; Roberts 1990; Roberts et al. 1987; Svec 1997; Svec and Porter 1998; Wolkowitz and Reus 2000; Wolkowitz et al. 2000, 2001), as are reviews of the possible uses of DHEA in nonpsychiatric conditions (Arlt et al. 1999; Katz and Morales 1998; van Vollenhoven 1997) and in healthy aging individuals (Barnhart et al. 1999; Flynn et al. 1999; Hinson and Raven 1999; Kroboth et al. 1999).

DHEA as a Neurosteroid DHEA and its metabolite DHEA sulfate (DHEA-S) are the most plentiful adrenal corticosteroids in humans, yet their physiological roles remain uncertain. Important actions in the central nervous system, however, have been inferred from the fact that DHEA and DHEA-S are synthesized in situ in the brain; indeed, it has been termed a neurosteroid for this reason

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(Baulieu 1997; Zwain and Yen 1999). Highlighting the potential importance of DHEA and DHEA-S for brain functioning, accumulation of DHEA and DHEA-S in rat brain is largely independent of adrenal and gonadal synthesis, remaining constant after gonadectomy, adrenalectomy, and dexamethasone administration and increasing in response to acute stress independently of changes in plasma levels (Corpechot et al. 1981a; Robel and Baulieu 1995).

Decreases in DHEA and DHEA-S Levels as a Function of Aging, Chronic Stress, and Illness Perhaps the most remarkable and well-replicated observation about DHEA and DHEA-S in humans is that their circulating levels (in both plasma and cerebrospinal fluid) peak in the mid-20s and then progressively decline with age, approaching a nadir (about 20% of peak levels) at approximately 65–70 years, the age at which the incidence of many age-related illnesses steeply increases (Azuma et al. 1993; Guazzo et al. 1996; Regelson and Kalimi 1994). Levels of DHEA and DHEA-S also decrease with chronic stress and medical illness (Nishikaze 1998; Ozasa et al. 1990; Parker et al. 1985; Spratt et al. 1993; Wolkowitz et al. 2001). Glucocorticoids do not show a similar pattern of decrease with age, illness, or stress. In fact, cortisol levels typically rise or do not change in these conditions, and there is a highly significant decrease in plasma ratios of DHEA and DHEA-S to cortisol with age and chronic stress (Fava et al. 1989; Goodyer et al. 1998; Guazzo et al. 1996; Hechter et al. 1997; Leblhuber et al. 1992, 1993; McKenna et al. 1997; Nishikaze 1998; Oberbeck et al. 1998; Ozasa et al. 1990; Parker et al. 1985; Reus et al. 1993; Wolkowitz et al. 1992, 2001). Because DHEA and DHEA-S may physiologically buffer the deleterious effects of excessive glucocorticoid exposure (see the later section “Neurotrophic Potential of DHEA and DHEA-S”), decreasing ratios of DHEA and DHEA-S to cortisol may prove especially problematic in hypercortisolemic states, including aging, depression, dementia, and other conditions (Dubrovsky 1997; Ferrari et al. 2001; Hechter et al. 1997; Herbert 1998; Leblhuber et al. 1992, 1993; Wolkowitz et al. 2001). Indeed, Lupien et al. (personal communication, 1995) noted greater cognitive deterioration in elderly men and women who showed larger decreases in ratios of DHEAS to cortisol over a 2-year period, whereas changes in DHEA-S levels alone were not significantly correlated with cognitive change.

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Behavioral Effects of DHEA and DHEA-S in Animals By necessity, much of the data about the effects of DHEA and DHEA-S derive from animal or tissue culture–based studies. Species typically studied, such as rats and mice, have significant concentrations of brain DHEA and DHEA-S, but minimal peripheral (adrenally derived) levels, challenging the relevance of such preclinical data to effects in humans. Nonetheless, such studies have provided valuable leads for designing clinical trials and have suggested possible mechanisms of the behavioral effects of DHEA and DHEA-S. DHEA and DHEA-S generally have memory-enhancing effects in animals. They can restore learning performance in old male mice and rats to the levels seen in young animals (Flood and Roberts 1988; Tejkalova et al. 1998) and can reverse pharmacologically induced amnesia in mice (Flood et al. 1988; Melchior and Ritzmann 1996; Roberts 1990). DHEAS can reverse amnesia induced by scopolamine, an anticholinergic drug, and by anisomysin, a protein synthesis inhibitor (Flood et al. 1988; Roberts 1990). DHEA-S also has antidepressant-like effects in mice tested in the Porsolt forced swim test, significantly decreasing immobility time (Reddy et al. 1998). The nonsulfated parent compound, DHEA, also has antidepressant effects in this test, but interestingly, only in high-anxiety rats (Prasad et al. 1997). Anti-anxiety effects of DHEA and DHEA-S have also been demonstrated in mice using the elevated plus maze test (Melchior and Ritzmann 1994). However, whereas DHEA augments the anxiolytic effect of ethanol in this model, DHEA-S blocks it (Melchior and Ritzmann 1994). Consistent with possibly different effects of DHEA versus DHEA-S in animal models of anxiety, DHEA-S has been found to be anxiogenic in the mirrored chamber test, another test of anxiety in mice (Reddy and Kulkarni 1997). Administration of DHEA, but not DHEA-S, also decreases mouse aggressive behavior in certain paradigms (e.g., the attack by group-housed triads of castrated male mice on lactating female mouse intruders) (Robel and Baulieu 1995). The specificity of DHEA versus DHEA-S in these models of depression, anxiety, and aggression may be related to differential effects of the two hormones at brain g-aminobutyric acid A (GABA-A) receptors (with DHEA-S having a stronger antagonist or inverse agonist effect) (Corpechot et al. 1981b; Demirgoren et al. 1991; Robel and Baulieu 1995), although, physiologically, DHEA and DHEA-S are readily interconvertible in the circulation. DHEA-S also affects eating behavior, producing hypophagia in fooddeprived male mice (Reddy and Kulkarni 1998). This effect may, at least

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partly, involve an N-methyl-D-aspartic acid (NMDA) receptor mechanism, because it is blocked by dizocilpine, a NMDA receptor antagonist (Reddy and Kulkarni 1998). DHEA also decreases feeding in obese Zucker rats; this effect may be related to DHEA-induced increases in hypothalamic serotonin or dopamine activity (Abadie et al. 1993; Porter et al. 1995).

Neurotrophic Potential of DHEA and DHEA-S Several studies have suggested that DHEA and DHEA-S have neurotrophic potential. For example, DHEA and DHEA-S enhance neuronal and glial survival and differentiation in dissociated cultures of mouse embryo brain (Bologa et al. 1987; Roberts et al. 1987) and induce the formation of hypertrophic cells in hippocampal slice cultures derived from orchiectomized adult male rats (Del Cerro et al. 1995). These hypertrophic cells appear similar to the reactive astroglia that may be involved in restorative events following brain injury (Del Cerro et al. 1995). DHEA and DHEA-S also modulate the astrogliosis that usually accompanies myelin breakdown, lessening the formation of astroglial scar (Muntwyler and Bologa 1989). DHEA and DHEA-S have also been shown to prevent or reduce hippocampal neurotoxicity induced by the glutamate agonist NMDA (Kimonides et al. 1998), by corticosterone (Kimonides et al. 1999), by the oxidative stressors hydrogen peroxide and sodium nitroprusside (Bastianetto et al. 1999), and by transient but severe forebrain ischemia (Li et al. 2001). In a provocative recent study using explants of adult human cortical brain tissue (obtained from neurosurgical samples), DHEA-S, in synergy with recombinant fibroblast growth factor, significantly improved neuronal survival (Brewer et al. 2001). It is possible that decreased levels of DHEA and DHEA-S contribute to the increased vulnerability of the aging or stressed human brain to neurotoxic damage, because 1) glutamate release has been implicated in neural damage resulting from cerebral ischemia and other neuronal insults; 2) excessive corticosterone exposure has been linked to hippocampal atrophy; and 3) oxidative stress has been implicated in degenerative changes in the hippocampus (Bastianetto et al. 1999; Hechter et al. 1997; Herbert 1997, 1998; Kimonides et al. 1998, 1999; Leblhuber et al. 1992; Wolkowitz et al. 1992). Such effects may be related to the observations that in normal aging and in Alzheimer’s disease, hippocampal perfusion (Murialdo et al. 2000b) and volume (Magri et al. 2000) are positively related to serum levels of DHEA and DHEA-S and to the ratios of DHEA and DHEA-S to cortisol.

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Correlation of DHEA and DHEA-S Levels With Mood, Memory, and Functional Abilities in Humans Correlational studies have provided indirect evidence of an effect of DHEA on mood, memory, and functional abilities in humans, but it is important to consider numerous caveats (outlined more fully elsewhere; see Wolkowitz et al. 2000) before ascribing causality in these relationships. For example, DHEA and DHEA-S levels often decrease nonspecifically with chronic illness. This may confound studies examining differences in DHEA and DHEA-S levels in clinical populations, because the lowered hormone levels may reflect chronic illness, stress, or incapacity rather than having diagnostic specificity or direct pathophysiological significance (Kroboth et al. 1999). Many, but not all, studies have reported lowered levels of DHEA and DHEA-S in patients with depression, poor life satisfaction, psychosocial stress, and functional limitations (Barrett-Connor et al. 1999b; Berr et al. 1996; Furuya et al. 1998; Legrain et al. 1995; Nagata et al. 2000; Scott et al. 1999; Tode et al. 1999; Yaffe et al. 1998a). In one of the largest cross-sectional, population-based studies, Barrett-Connor and colleagues (1999b) assessed depression ratings in relation to plasma levels of several steroid hormones (total and bioavailable estradiol, testosterone, estrone, androstenedione, cortisol, DHEA, and DHEA-S) in 699 non-estrogenusing, community-dwelling, postmenopausal women (ages 50–90 years). These researchers found that only DHEA-S levels were significantly and inversely correlated with ratings of depressed mood; this association was independent of age, physical activity, and weight change. Furthermore, women in that study with categorical diagnoses of depression had significantly lower DHEA-S levels compared with age-matched nondepressed women. In another study, partially or completely remitted depressed patients had DHEA levels intermediate between the currently depressed patients and control subjects, and, in the currently depressed patients, morning DHEA levels were inversely related to depression ratings (Michael et al. 2000). Low DHEA levels have also been reported in child and adolescent patients with depression (Goodyer et al. 1996). Several groups have found that ratios of DHEA to cortisol more accurately discriminate between depressed and nondepressed individuals than do levels of either hormone alone (Ferrari et al. 1997; Osran et al. 1993; Michael et al. 2000), with lower morning ratios seen in the depressive individuals (Michael et al. 2000; Osran et al. 1993). Goodyer et al. (1996) found that morning DHEA hyposecretion and evening cortisol

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hypersecretion were significantly and independently associated with major depression in 8- to 16-year-olds, and that patients who remained depressed several months after the initial assessment had lower ratios of DHEA to cortisol at baseline (Goodyer et al. 1998). The authors speculated that, in the presence of adequate DHEA concentrations, high cortisol concentrations alone may not inhibit recovery (Goodyer et al. 1998). In assessing whether premorbid steroid levels predicted the subsequent development of major depression, these researchers found that high DHEA levels predicted its development in high-risk adolescents of both genders (Goodyer et al. 2000a, 2000b) but not in adult women (T. O. Harris et al. 2000). They suggested that contribution of DHEA to the onset of depression may be different from its contribution to current or persistent depression (Goodyer et al. 2000a). Low levels of DHEA and DHEA-S have also been associated with higher ratings of perceived stress (Labbate et al. 1995), trait anxiety (P. Diamond et al. 1989), and Type A behavior, cynicism, and hostility (Fava et al. 1987, 1992; Littman et al. 1993; R.H. Schneider et al. 1989), whereas higher levels of DHEA and DHEA-S have been associated with greater amount, frequency, and enjoyment of leisure activities (Fava et al. 1992); greater sexual gratification and frequency of masturbation (in females) (Persky et al. 1982; van Goozen et al. 1997); healthier psychological profiles (Fava et al. 1992); more “expansive” personality ratings (characterized by self-centeredness, high activity drive, and high capacity for work) (Hermida et al. 1985); and greater “sensation-seeking” and “monotony avoidance” attributes (Klinteberg et al. 1992). However, “disruptive behavior” ratings were found to be directly correlated with DHEA-S levels in children with conduct disorder (Dmitrieva et al. 2001). Buckwalter and colleagues (1999) examined hormonal correlates of mood and cognitive function in pregnancy and in the postpartum period. They reported a very consistent pattern of associations of plasma DHEA levels with mood and memory. During pregnancy and after delivery, higher DHEA levels were correlated with lower ratings of depression, interpersonal sensitivity, and tension and anxiety and with better executive control processes and free recall. The authors proposed that DHEA endogenously regulates mood and cognitive function during pregnancy, and that postpartum depression may be exacerbated by declines in DHEA level. As such, they suggested that DHEA supplementation might be a viable option for treating postpartum mood disturbances (Buckwalter et al. 1999), although this remains to be empirically tested. Perhaps in a related vein, postmenopausal women experiencing a climacteric syndrome (including symptoms of anxiety, depression, fatigue, and insomnia) have

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half the circulating DHEA-S levels of matched postmenopausal women without such symptoms and have significantly higher cortisol to DHEA-S ratios (Tode et al. 1999). The remaining literature examining endogenous serum or urinary DHEA and DHEA-S levels in major depression is inconsistent, with reports of increased (Hansen et al. 1982; Heuser et al. 1998; Maayan et al. 2000; Takebayashi et al. 1998; Tollefson et al. 1990), decreased (Ferguson et al. 1964), and unaltered (Fava et al. 1989; Reus et al. 1993; Shulman et al. 1992) levels. The reasons for this disparity are unclear. In one of the studies showing high DHEA-S levels in depressed patients, the levels were positively correlated with depression severity ratings (Tollefson et al. 1990), but in another study (Takebayashi et al. 1998) hormone levels tended to be inversely correlated with depression severity ratings (P<0.10). Finally, in one of the studies showing increased DHEA and DHEA-S levels in depressed patients, markedly elevated basal DHEA-S levels predicted poor response to electroconvulsive therapy (ECT); ECTresponsive patients had relatively lower levels at baseline, and therapeutic responses to ECT were associated with significant treatment-associated increases in DHEA-S levels (Maayan et al. 2000). DHEA and DHEA-S levels have also been examined in other psychiatric illnesses. Increased, rather than decreased, ratios of DHEA-S to cortisol have been reported in patients with panic disorder (Fava et al. 1989). Possibly consistent with this, Herbert and colleagues (1996)—the same group that reported low morning DHEA levels in depressed adolescents (Goodyer et al. 1996)—found that depressed adolescents with comorbid panic or phobic disorder did not show low morning DHEA levels. Patients with anorexia nervosa reportedly have low DHEA and DHEA-S levels (Gordon et al. 1999; Winterer et al. 1985) as well as very low ratios of DHEA to cortisol (Zumoff et al. 1983). These abnormalities revert to normal with partial clinical recovery (Zumoff et al. 1983). However, women without anorexia nervosa who are self-described “smalleaters” have significantly higher DHEA-S levels than do women who are self-described “large-eaters” (Clark et al. 1995). Patients with schizophrenia reportedly have low serum levels of DHEA (Dilbaz et al. 1998; Erb et al. 1981; Oertel et al. 1974; Tourney and Erb 1979), but levels of DHEA-S (which has been examined less frequently than DHEA in this disorder) may be elevated (Oades and Schepker 1994). In a small study comparing 13 patients who had acutely exacerbated paranoid schizophrenia with matched control subjects, low DHEA and high DHEA-S levels were observed in the schizophrenic group, but these differences were not statistically significant (Brophy et al. 1983). However, in accord with a diagnostic cutoff DHEA level of

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470 ng/dL, proposed by Erb and colleagues (1981), Brophy and colleagues determined the mean serum DHEA level in their sample of schizophrenic patients to be 405 ng/dL compared with 506 ng/dL in their sample of control subjects. In a recently completed study, D. S. Harris and colleagues (in press) noted that morning serum DHEA levels and ratios of DHEA to cortisol were directly correlated with aspects of memory performance and were inversely correlated with ratings of psychosis and parkinsonian movements in medicated, institutionalized patients with chronic schizophrenia. These findings cumulatively raise the possibility that low DHEA levels (or low ratios of DHEA to cortisol) identify a particularly impaired subgroup of chronic schizophrenic patients. Three recent studies have also demonstrated low basal or stimulated DHEA and DHEA-S levels in patients with chronic fatigue syndrome (CFS) (De Becker et al. 1999; Kuratsune et al. 1998; Salahuddin et al. 1997). De Becker et al. (1999) found no basal difference in DHEA levels in CFS patients but found a blunted DHEA response to intravenous injection of adrenocorticotropic hormone (ACTH). Scott et al. (2000) found no difference in DHEA response to a low-dose ACTH stimulation test but found evidence for a divergence in DHEA versus cortisol responses in comparison with a control group. Kuratsune and colleagues (1998) speculated that decreases in DHEA and DHEA-S levels are directly responsible for the neuropsychiatric aspects of this condition. Such a hypothesis would be consistent with reports that exogenous DHEA administration alleviates fatigue in healthy subjects (Morales et al. 1994) as well as in medically ill patients (Calabrese et al. 1990). To our knowledge, DHEA has not been formally tested as a treatment for CFS, although infusions of DHEA along with high doses of vitamin C have been reported to alleviate CFS in a series of uncontrolled studies in Japan (Kodama et al. 1996a, 1996b). Many studies have also assessed the relationship of DHEA and DHEA-S levels to overall well-being and cognitive and general functioning. In many population-based studies, cognitive and general functional abilities have been shown to be positively correlated with DHEA and DHEA-S levels in elderly persons (Abbasi et al. 1998; Berkman et al. 1993; Berr et al. 1996; Cawood and Bancroft 1996; Kalmijn et al. 1998; Morrison et al. 1998; Ravaglia et al. 1996, 1997; Reus et al. 1993; Rudman et al. 1990) as well as in the young (Klinteberg et al. 1992), but in some studies, the relationships were gender specific. Based on the data in elderly populations, some investigators have proposed that DHEA and DHEA-S play a role in “successful aging” (Ravaglia et al. 1996, 1997) as well as in “brain aging” (Magri et al. 2000).

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Other studies, however, have reported no significant relationship between DHEA-S levels and cognitive performance in women (Yaffe et al. 1998a) or have reported inverse relationships between DHEA and DHEA-S levels and cognitive test performance in men and women with Alzheimer’s disease (Miller et al. 1998) and in female (but not male) nursing home residents (Morrison et al. 1998). The latter authors concluded that contradictory relationships exist between DHEA-S levels and neuropsychiatric function and that these relationships may be gender specific (i.e., direct relationships in men and inverse or no relationships in women). Adding to the uncertain nature of the relationship of DHEA and DHEA-S to cognitive function in demented individuals, patients with Alzheimer’s disease or multi-infarct dementia have been variously reported to exhibit DHEA and DHEA-S levels that are decreased (Azuma et al. 1999; Bernardi et al. 2000; Ferrari et al. 2000; Murialdo et al. 2000a; Nasman et al. 1991; Solerte et al. 1999; Sunderland et al. 1989; Yanase et al. 1996), increased, or unchanged (Birkenhager-Gillesse et al. 1994; Cuckle et al. 1990; Ferrario et al. 1999; Legrain et al. 1995; L. S. Schneider et al. 1992; Spath-Schwalbe et al. 1990). As with depression, Alzheimer’s disease may be characterized more strongly by decreases in DHEA-S to cortisol ratios than by decreases in DHEA-S levels alone (Ferrari et al. 2001; Leblhuber et al. 1992, 1993). Other studies have evaluated whether low DHEA and DHEA-S levels at an index time point predict the subsequent development (BarrettConnor and Edelstein 1994; Berr et al. 1996; Yaffe et al. 1998a) or progression (Miller et al. 1998) of dementia or cognitive decline. Two of these studies failed to ascertain a significant predictive relationship, although the studies may have had methodological limitations (BarrettConnor and Edelstein 1994; Miller et al. 1998; see Wolkowitz et al. 2000 for discussion). One prospective study with sufficient control for confounding factors did note significantly lower plasma DHEA-S levels in healthy elderly patients who developed Alzheimer’s disease over the ensuing 3 years compared with those who did not (Hillen et al. 2000). Cumulatively, then, the descriptive and epidemiological data in humans raise the possibility of a direct relationship between DHEA and DHEA-S levels and functional abilities, memory, mood, and sense of well-being, although direct correlations may be stronger in men than in women, and many inconsistencies exist in the literature. Furthermore, abnormalities in patients with depression and dementia have not been uniformly replicated. Nonetheless, even if endogenous DHEA and DHEA-S levels are not decreased in depression and dementia, it is possible that pharmacologic increases in their levels may have mood- and memoryenhancing effects. This possibility is reviewed in the next section.

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Effects of DHEA Treatment on Well-Being, Mood, and Memory in Humans In early clinical trials, DHEA was found to rapidly improve energy, insight, self-confidence, emotionality, vitality, adjustment to the environment, and school and occupational performance and to decrease anxiety, depression, apathy, and withdrawal in patients with schizophrenia, inadequate personality, or emotional immaturity (Sands 1954; Sands and Chamberlain 1952; Strauss and Stevenson 1955; Strauss et al. 1952) and in patients with phobic-obsessive psychoneuroses, neuropsychasthenia, psychopathic personality, involutive syndromes, and depressive psychoses (Pelliccioni et al. 1981; Scali et al. 1980; Serra 1953). Although these studies were largely uncontrolled, in several cases the improvements dissipated on single-blind crossover to placebo and returned with singleblind crossover back to DHEA. In the first double-blind, placebocontrolled clinical trial of DHEA, eight patients with depression, anxiety, social phobia, shyness, lack of confidence, hyposexuality, and so forth (classified by the authors as having vulnerable personalities) showed slightly more global positive assessments and slightly fewer negative global assessments when taking DHEA compared with placebo, but these improvements were not interpreted as being significant by the authors (Forrest et al. 1960). After a 30- to 40-year hiatus, clinical trials with DHEA resumed. Patients with multiple sclerosis and systemic lupus erythematosus, for example, showed increased energy, libido, and sense of well-being in open-label trials (Calabrese et al. 1990; Roberts and Fauble 1990; van Vollenhoven et al. 1994). In another study, DHEA was administered to healthy middle-aged and elderly subjects in a randomized, placebocontrolled, double-blind crossover study (Morales et al. 1994). Subjects, ages 40–70 years old, received 50 mg of DHEA or placebo every evening for 3 months. This dosing schedule restored DHEA and DHEA-S levels to youthful levels within 2 weeks, and levels were sustained for the entire 3-month period. DHEA-treated subjects showed significant increases in perceived physical and psychological well-being with no change in libido. Reported improvements included increased energy, deeper sleep, improved mood, feeling more relaxed, and having enhanced ability to handle stressful events. These results generated considerable interest in the possible behavioral effects of DHEA, but the global subjective measure used to assess behavioral change in this study was relatively crude.

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Labrie and Diamond and colleagues (P. Diamond et al. 1996; Labrie et al. 1997) treated women ages 60–70 with daily percutaneous applications of a 10% DHEA cream for 12 months. This was preceded or followed by 6 months of placebo cream, although it is not stated if the protocol was open label, single blind, or double blind. These researchers noted, as did Morales and colleagues (1994), that 80% of the women reported improved “well-being and an increase in energy” during DHEA treatment. Unfortunately, these behavioral changes were assessed via nonstandardized daily diaries. Vogiatzi and colleagues (1996) administered micronized DHEA (40 mg) or placebo twice daily sublingually in a double-blind manner to 13 morbidly obese adolescents. The researchers reported no change in sense of well-being in these subjects, but their assessment method was not specified, and the sample size was too small to meaningfully gauge this effect. Piketty and colleagues (1998) administered DHEA, 50 mg/day for 4 months, to patients with advanced HIV disease in a randomized, controlled study. They found significant improvement in ratings of mental function in the DHEA-treated patients compared with the placebo-treated patients. An additional double-blind study examined the effects of 2 weeks’ treatment with DHEA, 50 mg/ day, compared with 2 weeks of placebo in healthy elderly men and women (Kudielka et al. 1998; Wolf et al. 1997b). Only women tended to report an increase in well-being (P=0.11) and mood (P=0.10), as assessed with questionnaires. They also showed better performance in one of six cognitive tests (picture memory) after DHEA treatment. However, after post hoc correction for multiple comparisons, this difference was no longer significant. No such trends were observed in the male subjects (P>0.20). This study employed reliable neuropsychological test instruments and had an adequate sample size, but the duration of treatment was likely too short for behavioral changes to be manifested (Polleri et al. 1998). Most recently, Baulieu and colleagues (2000) reported preliminary results of a 1-year double-blind trial of DHEA (50 mg/day) versus placebo in a large group of healthy elderly patients recruited from a geriatric clinic. Most of these patients were being seen for problems such as mild anxiety, memory complaints, pain, and asthenia but did not qualify for diagnoses of major depressive or dementing disorders. Significant improvements in libido, sexual function, and sexual satisfaction were noted in the women but not in the men; effects were more prominent after 12 months of treatment compared with 6 months of treatment. Data from this study on changes in cognitive performance and quality of life had not been presented at the time of this writing. In another recent study, perimenopausal women with complaints of “altered mood and well-being”

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were treated with DHEA (50 mg/day) or placebo in a blind manner for 3 months (Barnhart et al. 1999). DHEA had no significant effects on perimenopausal symptoms, mood, dysphoria, libido, cognition, memory, or well-being, but, as suggested by Baulieu et al. (2000), such effects may progressively develop over more extended periods of time. Consistent with this possibility, a recent study in which postmenopausal women were treated with DHEA (50 mg/day) for 6 months found significant improvements in a measure of psychological and vasomotor symptoms (Stomati et al. 2000). Perhaps the strongest evidence to date of an improvement in wellbeing with DHEA replacement (at least in individuals with pathologically low levels of DHEA and DHEA-S at baseline) comes from a study utilizing well-validated psychological outcome measures in women with adrenal insufficiency secondary to Addison’s disease (Arlt et al. 1999). Twenty-four patients were treated daily with DHEA (50 mg orally) or placebo for 4 months in a double-blind crossover study. Treatment with DHEA, but not placebo, resulted in significant improvements in wellbeing, mood, anxiety, obsessive-compulsive traits, hostility, and exhaustion. These improvements were seen after 4 months of treatment but not after 1 month, supporting assertions that the psychological effects of DHEA may take several months to develop (Baulieu et al. 2000; Polleri et al. 1998). In a similar study, men and women with Addison’s disease showed significant improvements in self-esteem, mood, and fatigue, but not in cognitive function, with 3 months of DHEA treatment (Hunt et al. 2000). Other studies have specifically assessed the effect of DHEA on mood in depressed or dysthymic subjects. In an initial small-scale (N=6) openlabel pilot study, Wolkowitz and colleagues (1997) reported antidepressant effects of DHEA in middle-aged and elderly patients with major depression. Dosages of DHEA were individually adjusted between 30 and 90 mg/day for 4 weeks to achieve circulating DHEA and DHEA-S levels in the mid-to-high normal range for healthy young adults. Subjects demonstrated highly significant improvements in scores on the Hamilton Rating Scale for Depression (Ham-D) and the Hopkins Symptom Checklist–90 and showed a significant improvement in “automatic” cognitive processing at week 3 of DHEA treatment. Mood improvements were significantly related to increases in circulating levels of DHEA and DHEA-S and to their ratios with cortisol; changes in cortisol concentrations alone were not correlated with behavioral changes. One subject from this study, an elderly woman with previously treatment-resistant depression, received extended open-label treatment with DHEA (60 mg/day for 4 months followed by 90 mg/day for an additional 2 months). Her

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depression ratings improved by approximately 50% and her access to semantic memory improved by 63% during DHEA treatment and returned to pretreatment levels after discontinuation of DHEA treatment. Increases in DHEA-S levels over time in this patient were also directly correlated with improvements in depression ratings and with improvements in recognition memory (Wolkowitz et al. 1997). These open-label studies were followed by a double-blind, placebocontrolled trial in which 22 depressed patients received either DHEA (60–90 mg/day) or placebo for 6 weeks (Wolkowitz et al. 1999). Some patients were free of medication at the time of entering the study; others remained depressed despite being prestabilized (more than 6 weeks) on antidepressant medication. In the former group, DHEA or placebo was used alone; in the latter group, DHEA or placebo was added to the stabilized antidepressant regimen. In the group as a whole, DHEA, compared with placebo, was associated with significant antidepressant responses; 5 of 11 DHEA-treated patients showed more than 50% improvement in depression ratings and had end-point Ham-D scores below 10, compared with none of the 11 placebo-treated patients. These results remain to be replicated in larger studies, but they raise the possibility that DHEA, used alone or as an adjunct to antidepressant medication in patients with refractory depression, has significant antidepressant effects in some patients. Bloch and colleagues (1999) conducted a 12-week double-blind, placebo-controlled study in unmedicated patients with midlife dysthymia (one patient concurrently had major depression). Subjects received, in randomized order, DHEA (90 mg/day for 3 weeks, followed by 450 mg/ day for 3 weeks) or placebo for 6 weeks. Compared with placebo, DHEA produced a robust antidepressant response at both dosages. No changes were noted in cognitive function. Gordon and colleagues (1999) treated young women with anorexia nervosa with DHEA (50, 100, or 200 mg/day for 3 months). Although the specific DHEA dosage group assignment was double blind, there was no placebo control group. The researchers noted that, despite patients having significant levels of depression and anxiety at baseline, DHEA treatment had no significant effects on self-ratings of either symptom. This study should be interpreted cautiously because there was no placebo control group, the sample size was small, the subjects may have been sporadically noncompliant with the study drug regimens (per the authors’ estimation), and the psychological measures employed were all selfratings. Self-ratings in patients with anorexia nervosa may be less reliable than corresponding observer ratings (Johnson-Sabine et al. 1984; Kennedy et al. 1990).

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Another important area of clinical investigation is the possible cognition-enhancing effects of DHEA. In 1990, a single case was reported of a 47-year-old woman with low serum DHEA and DHEA-S levels and with a 20-year history of treatment-refractory learning and memory dysfunction. She was treated openly with very high daily doses of DHEA ranging from 12.5 mg/kg to 37 mg/kg for 2 years, and she demonstrated improved verbal recall and recognition along with a normalization in electroencephalography and P300 brain electrophysiology (Bonnet and Brown 1990). A recent small-scale study also suggested benefits in cognitive function in patients with systemic lupus erythematosus treated with DHEA, 200 mg/day, for 7–12 months (van Vollenhoven 2002). Recent studies by Wolf and others in Germany (Kudielka et al. 1998; Wolf et al. 1997a, 1997b, 1998a, 1998b) have failed to detect major cognitive effects of short-term DHEA administration in healthy volunteers, although conclusions are limited by the short duration of DHEA administration used in those studies (Polleri et al. 1998). Single-dose DHEA administration (300 mg dissolved in 5 mL of ethanol) to healthy young adults failed to alter memory performance, despite significantly lowering cortisol levels (Wolf et al. 1997a). In another study (Wolf et al. 1997b) (described above), 2 weeks of double-blind DHEA administration to healthy elderly control subjects produced only a trend toward improvement in picture memory in women, but this was not significant after adjusting for the number of tests administered. Event-related potentials (ERPs) were assessed in the male subjects but not in the female subjects in this treatment paradigm (Wolf et al. 1998b). Certain significant ERP changes were induced by DHEA treatment, indicating changes in central nervous system stimulus processing, but these changes were apparently insufficient to significantly alter memory performance in these men (Wolf et al. 1998b). If DHEA exerts memory-enhancing effects via antiglucocorticoid actions, such benefits might be apparent only under conditions of hypercortisolemia or stress. To test this hypothesis, the same group of investigators tested cognitive performance before and after a laboratory stressor in subjects treated with either DHEA or placebo. DHEA treatment yielded opposing effects on memory performance: it decreased the poststress recall of visual material learned before the stressor, but it enhanced poststress attentional performance (Wolf et al. 1998a). DHEA has also been studied as a possible memory enhancer in patients with Alzheimer’s disease and other dementias. A great deal of excitement followed the initial reports of low serum DHEA and DHEA-S levels in patients with Alzheimer’s disease (Sunderland et al. 1989) and multi-infarct dementia (Azuma et al. 1999; Yanase et al. 1996). Although

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these reports were only inconsistently replicated (as reviewed above), they raised the possibility that increasing DHEA and DHEA-S levels in such patients to the physiological levels seen in healthy young adults might have salutary cognitive effects. An initial small-scale study addressing this possibility yielded negative findings. Dukoff et al. (1998) reported that DHEA (1,600 mg/day orally for 4 weeks) had no significant cognitive or mood effects in demented or nondemented elderly individuals. This negative report should be interpreted cautiously, however, because the sample size was small, the demented population was heterogeneous, and the trial duration may have been too short to see cognitive change in this population. Furthermore, very high doses of DHEA were used; these may have exceeded a therapeutic window, as suggested by prior preclinical and clinical data (Bologa et al. 1987; Lee et al. 1994; Roberts and Fauble 1990; Roberts et al. 1987; Svec and Porter 1998). Wolkowitz and colleagues (in press) recently treated 58 unmedicated patients with Alzheimer’s disease with either DHEA (50 mg orally twice daily) or placebo for 6 months in a between-groups design. At these doses, DHEA treatment restored serum DHEA and DHEA-S levels to (or slightly above) levels seen in healthy young adults. Relative to placebo, DHEA treatment was not associated with significant improvement on the cognitive scale of the Alzheimer’s Disease Assessment Scale (ADASCog), a cognitive performance test, at month 6 (P=0.10). Transient improvement was noted at month 3 (P=0.014), but this was not statistically significant after correction for multiple comparisons. No significant difference between treatments was seen on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus), a global rating measure, at either time point. Finally, Azuma et al. (1999) reported that open-label administration of DHEA-S (200 mg/day intravenously for 4 weeks) improved psychometric test performance in four of seven patients with multi-infarct dementia. In three of these cases, the improvements were judged to be clinically significant, and in two cases, electroencephalographic patterns showed improvement with DHEA-S treatment. Review of the DHEA treatment literature cumulatively suggests that, in certain situations, DHEA administration enhances mood, energy, sleep, sense of well-being, functional capabilities, and memory. Such effects may be more likely in elderly, depressed, or infirm patients or in patients with markedly low DHEA levels (e.g., patients with Addison’s disease or adrenal insufficiency) than in young, healthy individuals. They may also be more likely to emerge after 1 or more months of treatment, and they may continue to evolve over 6 months or longer (Baulieu et al. 2000; van Vollenhoven et al. 1998; Wolkowitz et al., in press). Effects in individuals

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with dementia have not been consistently demonstrated, and larger-scale double-blind trials are required in these patients. Cognitive and mood effects in healthy individuals after short-duration treatment (2 weeks or less) seem unlikely or else are quite mild. In any event, the findings reviewed here await larger-scale, placebo-controlled replication.

Possible Mechanisms of the Neuropsychiatric Effects of DHEA A full review of the postulated mechanisms underlying the neuropsychiatric effects of DHEA (see Wolkowitz and Reus 2000, 2001; Wolkowitz et al. 2000, in press) is beyond the scope of this chapter, but the most salient possibilities are listed in Table 9–1 and are briefly reviewed here. Although DHEA or its metabolites may regulate gene transcription (Bruder et al. 1997; Nephew et al. 1998; Rupprecht 1997), most research has focused on its nongenomic, membrane receptor–based effects. Electrophysiological and neurochemical data suggest that DHEA and DHEA-S have GABA-A receptor antagonistic (Friess et al. 1995; Majewska 1992; Spivak 1994; Steffensen 1995; Yoo et al. 1996) and NMDA and s receptor potentiating (Bergeron et al. 1996; Monnet et al. 1995; Urani et al. 1998) properties. DHEA-S has stronger GABA-A receptor antagonist or inverse agonist effects than does DHEA; the latter may even secondarily increase levels of certain GABA agonist neurosteroids (Friess et al. 1995; Majewska 1992). Excitatory effects of DHEA and DHEA-S may facilitate memory function via enhancement of neuronal depolarization and excitation (Carette and Poulain 1984; D.M. Diamond et al. 1995; Meyer and Gruol 1994; Spivak 1994). DHEA-S treatment elicits excitatory postsynaptic potentials in rat dentate gyrus and can fully counteract the decrements in long-term potentiation caused by corticosterone in that structure, consistent with its “antiglucocorticoid” effect (Kaminska et al. 2000). Importantly, DHEA-S also increases hippocampal cholinergic function (Rhodes et al. 1996, 1997). DHEA and DHEA-S could have antidepressant effects by increasing brain serotonin and dopamine activity (Abadie et al. 1993; Murray and Gillies 1997; Porter et al. 1995), as well as by potentiating NMDA-induced hippocampal norepinephrine release (Majewska 1995; Monnet et al. 1995), but direct effects of DHEA administration on biogenic amine levels in humans have yet to be assessed. Actions on the hypothalamic-pituitary-adrenal axis are also likely to be involved in the mood and other neuropsychiatric effects of DHEA and DHEA-S (Dubrovsky 1997; Her-

Dehydroepiandrosterone in Psychoneuroendocrinology TABLE 9–1.

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Some possible mechanisms of the neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S)

g-Aminobutyric acid–A receptor antagonistic (and perhaps weakly agonistic) effects N-Methyl-D-aspartic acid and s receptor potentiating effects Increased brain regional serotonin and dopamine activity Increased hippocampal primed burst potentiation and cholinergic function Metabolized to testosterone and estrogen Antiglucocorticoid activity Protection against excitatory neurotoxicity Increased production and release of amyloid precursor protein and secretion of nonamyloidogenic isoforms (which are neuroprotective) and decreased production and deposition of amyloid b protein Inhibited production of proinflammatory cytokines, interleukin-1a, interleukin-6, and tumor necrosis factor a and scavenging of free radicals Increased levels and bioavailability of insulin-like growth factor I Note.

References are cited in the text.

bert 1997; Holsboer et al. 1994; Leblhuber et al. 1992; Svec and Lopez 1989; Wolkowitz et al. 1992, 1997). Antagonism of glucocorticoid effects by DHEA or by certain of its metabolites has been demonstrated in multiple model systems in peripheral tissue (Attal-Khemis et al. 1998; Ben-Nathan and Feuerstein 1990; Blauer et al. 1991; Browne et al. 1992; Fleshner et al. 1997; Loria 1997; Morfin and Chmielewski 1997; Padgett et al. 1997; Riley et al. 1990; Svec and Lopez 1989) and in brain (Kimonides et al. 1999). Antiglucocorticoid effects could, in theory, account for both antidepressant (Dubrovsky 1997; Goodyer et al. 1998; Hechter et al. 1997; Herbert 1997; Murphy and Wolkowitz 1993; Reus et al. 1997; Wolkowitz et al. 2001) and neuroprotective (Herbert 1998; Kimonides et al. 1999; Leblhuber et al. 1992; Sapolsky 1986; Wolkowitz et al. 1992) effects of DHEA. Miscellaneous other mechanisms that could contribute to the neuropsychiatric effects of DHEA include increased serum levels and bioavailability of insulin-like growth factor I (Morales et al. 1994); inhibition of the formation of proinflammatory brain cytokines (e.g., interleukin-1, interleukin-6, and tumor necrosis factor a) and free radicals, which have been implicated in neurodegeneration (Aragno et al. 1997; Danenberg et al. 1992; Daynes et al. 1993; Griffin et al. 1989; Solerte et al. 1999; Straub et al. 1998; Tamagno et al. 1998); elevation of a kB-dependent transcription factor (which has been associated with neuroprotection) (Mao and Barger 1998); and increases in brain calcium-ATPase activity

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(Zylinska et al. 1999), leading to lower intraneuronal calcium concentrations. Finally, of course, DHEA could have neuropsychiatric effects secondary to its conversion to estradiol and testosterone, both which have significant behavioral and central nervous system actions (Barrett-Connor et al. 1999a; Morrison 1997; Yaffe et al. 1998b).

Side Effects of DHEA With news of the effects of DHEA entering the lay media and with the ready availability of commercial DHEA in health food stores nationwide, many consumers are already purchasing and self-prescribing this hormone. Many medical authorities and researchers in this field, including ourselves, believe this enthusiasm remains premature until more is learned about the benefit-risk ratio of long-term DHEA supplementation (Goldberg 1998; Katz and Morales 1998; Svec 1997; van Vollenhoven 1997). This admonition may change as additional studies emerge in the near future. Human studies to date—typically involving 6–12 months or less of treatment with DHEA—suggest that DHEA treatment is generally well tolerated and not associated with significant group mean changes in physical examination; hepatic, thyroid and hematologic tests; urinalysis and prostate-specific antigen levels; or prostatic or urinary function (Baulieu et al. 2000; Morales et al. 1994; Reiter et al. 1999; van Vollenhoven 1997; Wolkowitz et al., in press). Long-term and other unforeseen side effects remain possible, however, and DHEA cannot yet be recommended for clinical use (van Vollenhoven 1997), with the possible exceptions of treating Addison’s disease (Arlt et al. 1999; Hunt et al. 2000) or systemic lupus erythematosus (van Vollenhoven et al. 1998) or as an adjunctive therapy in certain patients receiving long-term glucocorticoid therapy (Straub et al. 2000). Relatively common minor side effects that are seen with DHEA treatment (even with treatment periods less than 6 months) include acne, oily skin, nasal congestion, and headache. Less commonly reported side effects include insomnia, overactivation (including disinhibition, aggression, mania, or psychosis), hirsutism, increased body odor, itching, irregular menstrual cycles, and voice deepening (Dean 2000; Strauss et al. 1952; van Vollenhoven 1997; Wolkowitz et al., in press). Proarrhythmogenic and antiarrhythmogenic effects (Sahelian and Borken 1998) have also been reported, as have (in animal models) pro-tumor and antitumor effects. Tumorigenic effects in humans remain controversial

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(McNeil 1997), but because DHEA may be converted to testosterone and estradiol, individuals with hormone-sensitive tumors should probably not receive this hormone. It would also seem prudent for any individuals taking DHEA for a long period to have regular physical and laboratory examinations, including (as appropriate) liver function tests, prostate-specific antigen, digital prostate examination, Pap smear, uterine ultrasound, mammography, blood tests for levels of DHEA-S, bioavailable (free) testosterone and estradiol, and possibly electrocardiography (van Vollenhoven 1997).

Clinical Considerations For patients who are interested in trying DHEA, and for physicians interested in prescribing it, despite the cautions just listed, the following recommendations seem prudent; additional recommendations are outlined by van Vollenhoven (1997). Most of the following recommendations are derived from an informed reading of the scientific literature and from common sense and anecdotal experience rather than from empirical clinical studies: • The current state of knowledge about the effects of DHEA and about its potential side effects should be reviewed with patients, with particular emphasis on diminishing any unrealistic expectations about its anti-aging effects. • Patients should be monitored for the occasional development of hypomanic, aggressive, psychotic, or disinhibited behavior (Dean 2000; Howard 1992; Markowitz et al. 1999; Strauss and Stevenson 1955; Strauss et al. 1952; Wolkowitz et al., in press). • Patients at increased risk for hormonally sensitive tumors (e.g., cancer of the breast, ovary, uterus, cervix, or prostate or malignant melanoma) should be advised not to take DHEA (until more is known about its potential risks), although certain antitumor as well as protumor effects have been reported in animal studies (Comstock et al. 1993; Dorgan et al. 1997; Goldberg 1998; Jones et al. 1997; McNeil 1997; Schwartz et al. 1986). For other patients, baseline and follow-up assessments, such as prostate-specific antigen measurements (Goldberg 1998), mammograms, uterine ultrasounds, and Pap smears, may be prudent (van Vollenhoven 1997). For nonhysterectomized women contemplating long-term DHEA treatment (e.g., more than 3 months), periodic progesterone treatment aimed at shedding the uterine lining

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(which may have hypertrophied under the estrogenic influence of DHEA) may also be a prudent precaution. Periodic assays of serum testosterone (in particular, bioavailable or free testosterone) and estradiol levels should be performed to preclude excessive increases in levels of either. Baseline serum levels of DHEA-S should be measured to assess the relative appropriateness of DHEA “replacement” and to establish a baseline against which the treatment-induced increases can be compared, although it is unknown if baseline levels predict clinical response. Although few clear relationships have yet been demonstrated between exogenously augmented serum DHEA and DHEA-S levels and therapeutic outcome (van Vollenhoven 1997; Wolkowitz et al., in press), it seems reasonable on purely theoretical grounds to assay serum DHEA-S levels after each dosage adjustment to guide the achievement of levels in the normal or high-normal range for young adults (although for some disease conditions, supraphysiological levels may be more efficacious [Barry et al. 1998; Svec 1997; Svec and Porter 1998]). It remains to be determined if, as suggested by preclinical and some clinical studies, certain of the biological and clinical effects of DHEA bear an inverted-U-shaped relationship to DHEA and DHEA-S concentrations (Bologa et al. 1987; Flood and Roberts 1988; Flood et al. 1988; Kroboth et al. 1999; Lee et al. 1994; Roberts 1990; Svec and Porter 1998), raising the possibility of a therapeutic window. Dosages for most of the neuropsychiatric conditions reviewed here have been in the general range of 25–100 mg/day, although there have been few studies that have systematically compared the efficacy and tolerability of differing doses. Indeed, clinical trials have used dosages as low as 5 mg/day to as high as several grams/day. Due to the relatively short half-lives of DHEA-S and, especially, DHEA, we have generally divided the total daily doses into twice-daily or three-timesdaily dosing in our studies, with the larger portion of the dose being given in the morning to mimic the endogenous circadian rhythm (Svec 1997). Doses given late in the evening (e.g., after 6:00 or 8:00 P.M.) may be overly activating and may cause insomnia in some patients. However, a study demonstrating positive effects on well-being employed only nightly dosing (Morales et al. 1994). If no benefit is observed after approximately 3–6 months of treatment, it seems unlikely that additional benefit will accrue, and discontinuation of DHEA seems appropriate. Few studies have investigated the effects of abrupt DHEA withdrawal, but after prolonged DHEA administration, gradual tapering of the dose may be prudent.

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• As noted, DHEA can be procured widely without prescription in the United States. There is no federal regulatory control over the purity and bioavailability of these uncontrolled commercial preparations, and the actual DHEA content of over-the-counter preparations reportedly varies from 0% to 150% of the claimed content (Parasrampuria et al. 1998). In particular, preparations advertising “natural DHEA” derived from Mexican wild mountain yams are composed of diosgenin, a manufactured source of steroid products that is, by itself, ineffective in vivo (Araghiniknam et al. 1996). Pharmaceutical-grade DHEA is available by prescription in the United States from various compounding pharmacies.

Conclusion Despite the meteoric rise in research in DHEA and DHEA-S in recent years, their role in human neuropsychiatric diseases and their possible place in clinical therapeutics remain uncertain. It is to be hoped that this situation will be remedied in the near future. The provocative clinical and preclinical leads reviewed in this chapter should bolster enthusiasm for exploring the neuropsychotropic potential of DHEA and DHEA-S. In our opinion, DHEA supplementation is not yet ready for unsupervised clinical use, because its benefits and safety with long-term use, as well as the optimum parameters for its administration, have yet to be clearly established. Individuals wishing to undertake DHEA supplementation, nonetheless, should obtain DHEA from a reputable source and take it under medical supervision, with appropriate laboratory and clinical monitoring.

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Part IV Gonadal Hormones

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Chapter 10 Menstrual Cycle–Related and Perimenopause-Related Affective Disorders David R. Rubinow, M.D. Peter J. Schmidt, M.D.

A

s part of a growing recognition of the impact of gonadal steroids on central nervous system function, increased attention has been paid recently to the possible role of the menstrual cycle and the perimenopause in disorders of mood and behavior. This increased attention represents the latest expression of a continuing discussion between those observing mood disturbances during these periods of reproductive endocrine change and those cautioning against unwarranted statements about causality. For centuries medical observers have reported that the changes in reproductive hormones occurring during the normal menstrual cycle or the perimenopause may influence mood and behavior. In fact, some early reports suggested that changes in reproductive hormones not only could modulate behavior but could actually result in the de novo appearance of disturbances in mood and behavior. In keeping with this early suggestion that reproductive endocrine function might affect mood in various ways, it is important to understand that although the behavioral effects of gonadal steroids are not uniform, this fact does not imply that these hormones are irrelevant to behavior. In this chapter we focus on two conditions that suggest a possible relationship between changing gonadal steroid levels and changes in mood and behavior: menstrually related mood disorders and perimenopauserelated depression. After briefly describing the endocrinologic characteristics of the normal menstrual cycle and of the perimenopause, we discuss

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each of these conditions separately and pose questions that help define the possible relationships between mood changes, the menstrual cycle, and the perimenopause. Finally, for each condition, we provide several recommendations for evaluation and treatment.

Normal Cycling The first day of menstruation is, by convention, the first day of the menstrual cycle. Gonadotropin-releasing hormone (GnRH) is secreted in a pulsatile fashion from the hypothalamus and stimulates the secretion of follicle-stimulating hormone (FSH) from the pituitary. FSH stimulates the secretion of estrogen from the ovarian follicles, resulting in the proliferation of the uterine lining. At the end of the first menstrual cycle week, one follicle is selected and becomes the predominant follicle. That follicle undergoes maturation and secretes increasing amounts of estrogen. The release of the egg from the follicle, ovulation, marks the end of the follicular phase. After ovulation and under the influence of luteinizing hormone (LH) stimulation, the corpus luteum (the remains of the ovarian follicle) secretes large amounts of progesterone (P4) and, to a smaller extent, estradiol (E2). This phase of the menstrual cycle is the luteal phase. If fertilization and implantation of the egg do not take place, the corpus luteum atrophies. Progesterone levels precipitously decline, and that decline initiates the shedding of the uterine lining—menstruation—within approximately 14 days of ovulation.

Perimenopause and Menopause The menopause has been defined as the permanent cessation of menstruation resulting from loss of ovarian activity and is characterized endocrinologically by tonically increased gonadotropin (FSH, LH) secretion, persistently low levels of ovarian steroids (estradiol and progesterone), and relatively low (50% decrease compared with younger age groups) androgen secretion (see Figure 10–1) (Adashi 1994). The perimenopause has been defined as the transitional period from reproductive to nonreproductive life (Reame 1997; Seifer and Naftolin 1998). As the perimenopause progresses, ovarian follicular depletion occurs, the ovary becomes less sensitive to gonadotropin stimulation, and a state of relative hypoestrogenism occurs; gonadotropin secretion is increased across the men-

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Levels of the ovarian steroids estradiol (E2) and progesterone (Prog) and the pituitary gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH) at three phases of reproductive life.

FIGURE 10–1.

The illustrated hormonal patterns for the climacteric do not reflect intraindividual and interindividual variability in frequency of ovulation and length of menstrual cycle during this phase. Ov=ovulation; M=menses. Source. Reprinted from Schmidt PJ, Rubinow DR: “Menopause-Related Affective Disorders: A Justification for Further Study.” American Journal of Psychiatry 148:844–952, 1991. Copyright 1991, American Psychiatric Association. Used with permission.

strual cycle, ovulatory cycles are fewer, and menstrual cycle irregularity ensues (Judd and Fournet 1994). However, in contrast to the postmenopause, episodic (not tonic) gonadotropin secretion is present and both ovulation and normal (or at times increased) estradiol secretion may occur (Burger et al. 1995; Santoro et al. 1996). The late perimenopause is characterized endocrinologically by persistent elevations of plasma FSH levels, sustained menstrual cycle irregularity with periods of amenorrhea, and hypoestrogenism. However, the levels of several other hormones that may impact mood and behavior also decrease with aging (concomitant with changes in reproductive function): androgens (testosterone and androstenedione) (Adashi 1994; Burger et al. 1995; Davis and Burger 1996); dehydroepiandrosterone (Morley et al. 1997); and insulin-like growth factors and binding proteins (Klein et al. 1996; Morley et al. 1997).

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Menstrual Cycle–Related Mood Disorders (MRMD) MRMD refers to cyclic mood disorders with symptoms (e.g., irritability, sadness, mood swings, anxiety) that interfere with daily function and that are confined to the luteal phase of the menstrual cycle, with symptom remission occurring within a few days of the onset of menses. The term MRMD was chosen to emphasize the affective symptomatology in the cyclic disorder that is otherwise most commonly called premenstrual syndrome (PMS). More recently the term premenstrual dysphoric disorder (Table 10–1) has been applied to women in whom the affective and behavioral symptoms are prominent and are a source of impairment. As such, women with premenstrual dysphoric disorder can be viewed as a subset of the women identified as having PMS by the criteria of the International Classification of Diseases, 9th Revision (World Health Organization 1977), or as the equivalent of women with MRMD or PMS as operationally defined in a variety of publications (Freeman et al. 1990; Mortola et al. 1991; Schmidt et al. 1998) (i.e., affective symptoms confined to the luteal phase and causing impairment). A representative case of a woman presenting with PMS follows: A 30-year-old married mother of four was referred to the National Institute of Mental Health for a cyclic mood disorder. She noted that during the preceding 7 years she had experienced mood and somatic symptoms that were seemingly related to her menstrual cycle. Approximately 9 days before her menses, she would become sad and cry, want to be alone, and experience sensitivity to rejection, guilt, self-criticism, and occasional suicidal ideation. These symptoms were not responsive to expressed concern from others. Rather, she attempted to isolate herself because she became profoundly irritable around others and demonstrated anger, impatience, “meanness,” overreactivity, and verbal outbursts. Her verbal loss of control caused problems at work and in her relationships with her family. Other symptoms included a decrease in her general level of interest and energy; an inability to initiate activities or to experience pleasure; fatigue; disturbed sleep; distractibility; indecisiveness; and increased appetite and food intake with cravings for chocolate and carbohydrates. Somatic symptoms included swelling of the hands, abdomen, and breasts. Symptoms gradually increased in intensity during the 9 days before her menses but disappeared “within minutes” at or immediately following its onset. The patient had attempted a number of treatments—including magnesium, B vitamins, diuretics, and progesterone suppositories—without success. On standardized diagnostic interview, she did not meet the criteria for current or past psychiatric disorder.

Menstrual Cycle–Related Affective Disorders TABLE 10–1.

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Research diagnostic criteria for premenstrual dysphoric disorder

A. In most menstrual cycles during the past year, five (or more) of the following symptoms were present for most of the time during the last week of the luteal phase, began to remit within a few days after the onset of the follicular phase, and were absent in the week postmenses, with at least one of the symptoms being either (1), (2), (3), or (4): (1) markedly depressed mood, feelings of hopelessness, or selfdeprecating thoughts (2) marked anxiety, tension, feelings of being “keyed up,” or “on edge” (3) marked affective lability (e.g., feeling suddenly sad or tearful or increased sensitivity to rejection) (4) persistent and marked anger or irritability or increased interpersonal conflicts (5) decreased interest in usual activities (e.g., work, school, friends, hobbies) (6) subjective sense of difficulty in concentrating (7) lethargy, easy fatigability, or marked lack of energy (8) marked change in appetite, overeating, or specific food cravings (9) hypersomnia or insomnia (10) a subjective sense of being overwhelmed or out of control (11) other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of “bloating,” weight gain Note: In menstruating females, the luteal phase corresponds to the period between ovulation and the onset of menses, and the follicular phase begins with menses. In nonmenstruating females (e.g., those who have had a hysterectomy), the timing of luteal and follicular phases may require measurement of circulating reproductive hormones. B. The disturbance markedly interferes with work or school or with usual social activities and relationships with others (e.g., avoidance of social activities, decreased productivity and efficiency at work or school). C. The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of these disorders). D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles. (The diagnosis may be made provisionally prior to this confirmation.) Source. Reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). Washington, DC, American Psychiatric Association, 2000. Copyright 2000, American Psychiatric Association. Used with permission.

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Defining Questions Are There Luteal Phase–Specific Mood Disturbances? If women’s daily moods are studied over three or more cycles, a subgroup can be identified in which mood clearly varies in a menstrual cycle– dependent fashion, with increasing symptoms during the luteal phase and elimination of symptoms at or soon after the onset of menses. (See Figure 10–2 for three examples of women’s self-ratings.) The fact that fewer than 50% of women presenting with a history of PMS will show a cycle-dependent pattern, however, illustrates the need to obtain longitudinal ratings in addition to a history of PMS before making a diagnosis. This requirement for prospective ratings has been incorporated into both sets of diagnostic guidelines for PMS: those for premenstrual dysphoric disorder, a diagnosis appearing in Appendix B of DSM-IV-TR (American Psychiatric Association 2000) (Table 10–1), and those of the National Institute of Mental Health (NIMH Premenstrual Syndrome Research Workshop Guidelines. Rockville, MD, National Institute of Mental Health, unpublished, 1983). According to these criteria (which also contain an impairment requirement), about 5% of women of reproductive age would be diagnosed with PMS (Rivera-Tovar and Frank 1990). In an attempt to operationalize the definition of PMS, the National Institute of Mental Health PMS Research Workshop (in Rockville, MD, 1983) specified the degree of change (30%) in symptom severity during the luteal phase required for a syndromal diagnosis. These and other operational criteria for PMS are reviewed and compared by Schnurr (1989). For our studies, PMS is operationally defined as follows: Each woman has an increase of at least 30% (relative to the range of the scale employed) in her mean self-ratings of negative moods (depression, anxiety, and irritability) in the 7 days before menses, compared with the ratings for the 7 days afterward, in at least two of three cycles during the 3-month baseline. As described by Schnurr (1988, 1989), this method correlates highly with the effect-size method used to establish that severity criteria for PMS have been met. Women are excluded from the study if they have mood symptoms during the follicular phase of the cycle, that is, postmenstrual mean mood ratings beyond the midpoint of the rating scale. All women with PMS come to our clinic or are referred by their personal physician because their PMS symptoms interfere with daily function. Additional criteria include the following: regular menstrual cycles (e.g., 22–34 days), normal gynecologic examinations, and do not meet criteria for a current DSM-IV Axis I diagnosis. Approximately 30% of the women presenting to our clinic with symptoms of PMS meet these diagnostic criteria.

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FIGURE 10–2.

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Depression self-ratings of three women with premenstru-

al syndrome. Source. Reprinted from Rubinow DR, Roy-Byrne PP, Hoban MC, et al.: “Prospective Assessment of Menstrually Related Mood Disorders.” American Journal of Psychiatry 141:684– 686, 1984. Copyright 1984, American Psychiatric Association. Used with permission.

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Are These Mood Disturbances Associated With Abnormal Physiological Events? Once women with PMS are identified, the question is whether menstrual cycle–related mood changes are accompanied by abnormal physiological events. For obvious reasons, attention has been focused largely on the reproductive endocrine system. Despite many investigations of basal hormone levels in patients with PMS compared with control subjects, no diagnosis-related differences in gonadal steroids, gonadotropins, or sex hormone–binding globulin have been consistently observed. Therefore, both the levels of reproductive endocrine hormones (including estradiol, progesterone, FSH, LH, and ovarian and adrenal androgens) and their pattern of secretion over the menstrual cycle do not appear to be disturbed in PMS (Figure 10–3). Similarly, most (Bicikova et al. 1998; Schmidt et al. 1994; Wang et al. 1996), but not all (Rapkin et al. 1997), examinations of the levels of the progesterone metabolites (and neurosteroids) allopregnanolone and pregnanolone, which modulate the activity of the receptor for the neurotransmitter g-aminobutyric acid (GABA), have found no differences between women with PMS and controls. Because much of the regulatory information of the endocrine system is conveyed by the pattern of pulsatile secretion, dynamic elements of the hypothalamic-pituitary-ovarian axis have been studied. In a study of 15 patients with PMS and 15 control subjects, the FSH and LH responses to GnRH were similar (P.J. Schmidt, MD, et al., unpublished data, May 1993). Data from LH pulsatility studies are conflicting: some studies show no differences in pulsatility (Reame et al. 1992), and others demonstrate increased frequency and decreased amplitude of pulses (Facchinetti et al. 1990) in patients with PMS compared with control subjects. In sum, there is no consistent or convincing evidence that PMS is related to abnormal circulating levels of gonadal steroids or gonadotropins. Even if group differences in gonadal steroid–related factors were identified, the following questions posed by Reid (1986) would have to be addressed before any biochemical abnormality is accepted as etiologically relevant in PMS: What percentage of patients and control subjects show such a premenstrual alteration? What degree of alteration constitutes evidence for PMS? Is the alteration reproducible in patients from month to month? Does the severity of PMS correlate with premenstrual change observed in a circulating factor? Are changes in a factor pathognomonic of the premenstrual mood state or epiphenomenal to depressive states in general?

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Several nonreproductive endocrine factors have also been examined. Although there is no consistent evidence for abnormal levels or patterns of secretion of any hormone in PMS, it is striking that recently reported (Rubinow and Schmidt 1999) diagnosis-related differences in biological factors (which remain to be confirmed) are not confined to the luteal phase but rather appear in both follicular and luteal phases. These biological differences include increased prevalence of abnormal thyroid-stimulating hormone responses to thyrotropin-releasing hormone (Roy-Byrne et al. 1987), decreased slow-wave sleep (Lee et al. 1990), phase-advanced temperature minima and cessation of melatonin secretion (Parry et al. 1989, 1990), decreased red blood cell magnesium concentration (Rosenstein et al. 1994; Sherwood et al. 1986), blunted growth hormone and cortisol responses to L-tryptophan (Bancroft et al. 1991), and increased cortisol response to corticotropin-releasing hormone infusion (Rabin et al. 1990). If any of these findings are relevant, they must be related to the susceptibility to PMS symptoms, but they cannot by themselves explain this cyclic phenomenon. Luteal phase decreases in both plasma b-endorphin (Chuong et al. 1985; Facchinetti et al. 1987) and platelet serotonin uptake (Ashby et al. 1988; Taylor et al. 1984) have been reported in PMS, although neither the diagnostic group–related decreases nor their confinement to the luteal phase is consistently observed (Bloch et al. 1998; Hamilton and Gallant 1988; Malmgren et al. 1987; Tulenheimo et al. 1987; Veeninga and Westenberg 1992).

Is the Luteal Phase Necessary for the Occurrence of PMS? If there are no basal or stimulated reproductive endocrine abnormalities or luteal phase–specific biological abnormalities in PMS, is the luteal phase even necessary for its expression? This question was answered in a study by Schmidt et al. (1991), in which women with prospectively confirmed PMS were blinded to menstrual cycle phase by administering the progesterone receptor antagonist mifepristone (RU 486) in combination with either human chorionic gonadotropin (hCG) or placebo. Seven days after the LH surge, women with PMS were randomly administered placebo or mifepristone, a progesterone receptor blocker that causes a sudden decrease in plasma progesterone and the onset of menses within 48–72 hours. Patients also received hCG or placebo. Patients receiving mifepristone and hCG had menses within 48–72 hours, but normal luteal phase progesterone levels were maintained by the stimulatory effects of hCG on the ovary, and a second menses occurred about 9 days later with involution of the corpus luteum. Thus, hCG preserved the luteal phase despite the induction of menses by mifepristone. Alternatively, patients

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No significant diagnosis-related effects were observed. Data presented are group means plus standard deviation. Source. Reprinted from Rubinow DR, Hoban MC, Grover GN, et al.: “Changes in Plasma Hormones Across the Menstrual Cycle in Patients With Menstrually Related Mood Disorder and in Control Subjects.” American Journal of Obstetrics and Gynecology 158:5–11, 1988. Used with permission.

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Menstrual cycle–related changes in levels of estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone in patients with premenstrual syndrome and in control subjects.

FIGURE 10–3.

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receiving mifepristone and placebo entered the follicular phase after the mifepristone-induced menses. Results demonstrated that women with prospectively confirmed PMS experienced their characteristic premenstrual mood state after the mifepristone-induced menses, at a time when the peripheral endocrine profile was that of the early follicular phase (Figures 10–4 and 10–5). The observation that, as a group, women with prospectively confirmed PMS showed no alterations of their symptoms despite the resetting of the menstrual cycle could support either of two conclusions. Premenstrual syndrome may represent an autonomous, cyclic disorder that is linked to, but can be dissociated or desynchronized from, the menstrual cycle. Alternatively, symptoms may be triggered by hormonal events before the late luteal phase, consistent with reports that the suppression of ovulation results in a remission of PMS symptoms (Casson et al. 1990). To test the latter possibility, we suppressed ovarian steroid production and created a temporary, reversible menopause by administering the GnRH superagonist leuprolide acetate (Lupron). Suppression of the ovarian cycle prevented the appearance of PMS symptoms, a finding that was also observed in other studies (Bancroft et al. 1987; Muse et al. 1984). To determine whether gonadal steroids were the factors that when removed resulted in the elimination of PMS, we added back estradiol and progesterone separately to women who continued to take leuprolide and for whom leuprolide alone successfully eliminated symptoms of PMS. Both estradiol and progesterone were associated with the return of symptoms typical of PMS (Schmidt et al. 1998) (Figure 10–6). It does appear, therefore, that gonadal steroids can trigger symptoms of PMS, an observation that at first glance appears discordant with the lack of differences in gonadal steroid levels between women with PMS and control subjects. In the second part of this study, women with confirmed absence of PMS received the same protocol of leuprolide and hormone addback. The control women showed no perturbation of mood during leuprolide-induced hypogonadism and, significantly, no perturbation of mood during hormone addback with either progesterone or estradiol, despite achieving hormone levels comparable to those seen in the women with PMS. Women with PMS, therefore, are differentially sensitive to gonadal steroids such that they experience mood destabilization with levels or changes in gonadal steroids that are absolutely without effect on mood in women lacking a history of PMS. These results indicate that gonadal steroids are necessary but not sufficient for PMS. They can trigger PMS, but only in women, who, for undetermined reasons, are otherwise vulnerable to experiencing mood state destabilization (Schmidt et al. 1998).

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Absence of the effect of truncation of the late luteal phase with RU 486 on the appearance of premenstrual syndrome symptoms.

FIGURE 10–4.

Data show group means plus standard deviation. Analysis of variance with repeated measures showed significant increases in anxiety symptoms from day 5 through day 11 after the administration of RU-486 or placebo (open bars) compared with the ratings from the 7 days before the luteinizing hormone (LH) surge (the follicular phase) (shaded bars). No significant effects in the treatment group were observed. hCG=human chorionic gonadotropin. Source. Reprinted from Schmidt PJ, Nieman LK, Grover GN, et al.: “Lack of Effect of Induced Menses on Symptoms in Women With Premenstrual Syndrome.” New England Journal of Medicine 324:1174–1179, 1991. Copyright 1991, Massachusetts Medical Society. Used with permission.

258 Appearance of premenstrual syndrome (PMS) symptoms during an RU 486–induced follicular phase in one

Sadness ratings ranged from 1 (none) to 6 (extreme). After the administration of RU 486, the woman had typical PMS symptoms during the drug-induced follicular phase of the menstrual cycle, confirmed by the plasma levels of gonadal steroids shown. LH=luteinizing hormone. Source. Reprinted from Schmidt PJ, Nieman LK, Grover GN, et al.: “Lack of Effect of Induced Menses on Symptoms in Women With Premenstrual Syndrome.” New England Journal of Medicine 324:1174–1179, 1991. Copyright 1991, Massachusetts Medical Society. Used with permission.

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FIGURE 10–5. woman.

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Premenstrual syndrome, then, may represent a behavioral state that is triggered by an undefined biological stimulus related to the menstrual cycle in those who may be rendered susceptible to changes in behavioral state by antecedent experiential events (e.g., history of physical or sexual abuse) (Paddison et al. 1990) or biological conditions (e.g., hypothyroidism) (Schmidt et al. 1990). This hypothesis would be consistent with data from studies showing the successful treatment of PMS with surgical or medical oophorectomy (Casper and Hearn 1990; Muse et al. 1984) (addressing the trigger) as well as with nonreproductive modalities (e.g., fluoxetine) (Steiner et al. 1995; Stone et al. 1990) that may address the underlying susceptibility.

The Menstrual Cycle and Psychiatric Disorders There are various ways in which the menstrual cycle may modulate mood and behavior disturbances independent of the presence of PMS: 1) the menstrual cycle may modify the severity of appearance of certain psychiatric illnesses; 2) the menstrual cycle may trigger the recrudescence of a previously experienced psychiatric illness. In general, these phenomena may be readily distinguished from PMS during longitudinal confirmation of the diagnosis.

Menstrual Cycle–Related Events May Modulate Preexisting Psychopathology A series of observations have suggested that normal menstrual cycle function may influence or alter the expression of the symptoms of primary psychiatric disorders. First, phase-related symptom exacerbation has been noted, with several reports of psychiatric patients (with mania or schizophrenia) whose symptoms increased in severity before menses and improved after menses. For example, Malikian et al. (1989) reported the premenstrual worsening of the symptoms of depression in a sample of women with chronic depressive illness. Second, the potential influence of the menstrual cycle on the expression of the symptoms of psychiatric illness has been inferred from numerous reports of the disproportionate occurrence of suicide attempts and psychiatric admissions during the premenstrual phase (Dalton 1959; Janowsky et al. 1969; Mandell and Mandell 1967; Tonks et al. 1968). However, a postmortem study employing endometrial biopsies as a method of dating menstrual cycle phase found no increased proportion of suicides occurring during the premenstruum (Vanezis 1990).

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In contrast, women with premenstrual syndrome but not the control subjects had a significant increase in sadness during administration of either estradiol (E2) or progesterone (P4). Histograms represent the mean (± standard error) of the seven daily scores on the Daily Rating Form Sadness Scale for each of the 8 weeks preceding hormone replacement (leuprolide alone) and during the 4 weeks of estradiol (plus leuprolide) and progesterone (plus leuprolide) replacement. A score of 1 indicates that the symptom was not present, and a score of 6 indicates that it was present in the extreme.

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Sadness ratings for 10 women with premenstrual syndrome (upper panel) and 15 control subjects (lower panel), showing minimal mood and behavioral symptoms during administration of leuprolide.

FIGURE 10–6.

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In contrast, the menstrual cycle may be associated with the episodic improvement of a coexisting psychiatric illness. Figure 10–7 illustrates the pattern of dysphoric symptoms in a woman initially presenting to our clinic with PMS and who had the diagnosis of PMS confirmed prospectively. After the onset of menstrual cycle irregularity, she developed a pattern of chronic dysphoria punctuated by symptom-free intervals during the menstrual and postmenstrual phases of the menstrual cycle. Thus, instead of PMS, it appeared that this patient experienced a brief, postmenstrualrelated remission of the symptoms of a chronic affective disorder. Menstrual cycle phase may influence the appearance (as opposed to the severity) of symptoms of a concurrent psychiatric disorder. Sutherland (1892) noted that 99 of 162 women with mania characteristically experienced their mania during (88 women) or within 1 day to 1 week before (11 women) their menses. The episodic symptoms of certain psychiatric disorders (e.g., bulimia and panic disorder) have been reported anecdotally as being disproportionately frequent during the premenstrual phase. Although several authors have noted premenstrual increases in food cravings and appetite in women with and without PMS (Both-Orthman et al. 1988; Cohen et al. 1987; Fankhauser et al. 1989; Smith and Sauder 1969), no consistent premenstrual increase in bulimic episodes has been observed. Similarly, studies have failed to identify a menstrual cycle phase–related exacerbation or clustering of the symptoms of panic or anxiety in patients with panic disorder (Cameron et al. 1988; Cook et al. 1990; Stein et al. 1989).

Menstrual Cycle–Related Events May Trigger the Recrudescence of Previously Experienced Psychiatric Illness The menstrual cycle may also influence the reappearance of characteristic symptoms of a psychiatric disorder that otherwise appears to be in remission. In 1868 Isaac Ray stated that “in female patients, the menstrual period may produce an abnormal excitement after convalescence appeared to be firmly established” (Evans 1893). Brockington et al. (1988) reported this phenomenon in three cases of postpartum psychosis in which a remission was disturbed by a time-limited recrudescence of the original symptoms during the premenstruum. This relationship between the menstrual cycle and postpartum illness is of particular interest given the reports of a higher-than-expected prevalence of a history of postpartum depression in some patients with PMS (Warner et al. 1991). These reports suggest that hormonal changes such as those seen during the postpartum period and the premenstrual phase of the normal menstrual cycle may trigger the recurrence of a previously experienced mood or behavioral disturbance.

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FIGURE 10–7.

Daily self-ratings of sadness in a woman with prospectively confirmed PMS.

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After the onset of menstrual cycle irregularity (hatched histogram), the patient’s ostensible premenstrual dysphoria became a chronic dysphoria punctuated by symptom-free intervals during the menstrual and postmenstrual phase of her infrequently occurring menstrual cycles.

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Treatment Approaches Until recently, the ability of medical professionals to help women with PMS was limited and for the most part was confined to unproven therapies (e.g., progesterone) or to lifestyle and dietary manipulations. Some nutritional, behavioral, and cognitive approaches—such as the initiation of regular exercising, restriction of caffeine consumption, and education regarding sleep hygiene—may benefit some women. Our approach to treatment is founded on the principle that the cornerstone of effective treatment is a careful evaluation. A complete medical and psychiatric history and review of systems is required to rule out medical disorders (e.g., hypothyroidism) that may masquerade as an episodic mood disorder as well as psychiatric disorders, the symptoms of which may or may not vary according to the phase of the menstrual cycle. The patient is then told that, both for purposes of evaluation and to establish a baseline against which the efficacy of treatment can be measured, it will be necessary for her to rate the intensity of her symptoms on a daily basis for the next few cycles. Either 100-mm line scales or sixpoint severity scales can be used to track the appearance and intensity of commonly experienced symptoms or of symptoms that the patient identifies as most characteristic of her syndrome. For practical purposes, the Daily Rating Form (Endicott and Halbreich 1982) permits the patient and physician to determine at a glance the relationship between symptom appearance and menstrual cycle phase. These daily ratings serve several functions. First, they establish whether symptoms appear during the luteal phase and are confined to that phase, whether they occur chronically with premenstrual exacerbation, or whether they lack menstrual cycle–related variation (e.g., depression or recurrent brief depression). Second, they provide considerable information about the life and symptom determinants of the patient, irrespective of the diagnosis. Third, they provide considerable therapeutic benefit: the patient not only develops self-observational skills that can assist her treatment but additionally may experience relief in response to the validation, predictability, and control that are conferred by the rating process. For most women with PMS (as defined in this chapter), manipulations of lifestyle are not sufficient, and some form of medication is usually prescribed. A multitude of vitamins and minerals—such as pyridoxine (vitamin B6), vitamin E, vitamin A, magnesium, and calcium—have been studied as treatment modalities for PMS. All of these agents have shown inconsistent results and have not been proved to be superior to placebo. Other agents—such as diuretics, b-blockers, prostaglandin inhibitors, and

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prolactin inhibitors—may have some beneficial effects for specific symptoms but are not overall effective treatments for PMS (Altshuler et al. 1995; Rausch and Parry 1993; Rubinow and Schmidt 1995; Steiner et al. 1995; Yonkers et al. 1997). However, the two options that at this time are associated with replicable efficacy are the selective serotonin reuptake inhibitors (SSRIs) (Steiner et al. 1995; Stone et al. 1991; Su et al. 1997; Sundblad et al. 1992; Wood et al. 1992; Yonkers et al. 1997) and ovarian suppression (Bancroft et al. 1987; C.S. Brown et al. 1994; Freeman et al. 1993; Hammarback and Backstrom 1988; Hussain et al. 1992; Mezrow et al. 1994; Mortola et al. 1991; Muse et al. 1984; West and Hillier 1994). As such, one can easily justify a trial of an SSRI in someone with PMS, with either continuous therapy or the intermittent administration of medication from (approximately) ovulation until the onset of menses. SSRIs are effective in only 50%–60% of patients with PMS, with predictors of efficacy currently undetermined. In most studies the effective dose of an SSRI in PMS is lower than that required for the treatment of major depression and may additionally require adjustment of dosage (up or down) or time of administration (morning or evening) to assess efficacy or manage side effects (particularly sleep disturbance). For those who are unresponsive or for whom side effects (e.g., sexual dysfunction) may limit treatment, any of the other putative therapeutic agents may be employed, albeit with even less of a guarantee of success. Use of ovarian suppression should be reserved for women with severe PMS and for whom oophorectomy would be a potential option (i.e., women who will not wish to have additional children). Although they require application of both the art and the science of medicine, menstrual cycle–related mood disorders are treatable conditions.

Perimenopause-Related Depression Defining Questions How Is the Perimenopause Defined and Characterized? In the past, several different criteria have been employed to define the reproductive status of women participating in studies of the relationship between menopause and mood. First, an age window of 45–55 years has been used to select perimenopausal subjects. Although the average age of the menopause is 51 years, there is considerable individual variation in the age at onset of the menopause, ranging from the early 40s to the late 50s. Adopting an age window as the sole selection criteria will inevitably result in the selection of a heterogeneous sample of women in different

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phases of reproductive life: some premenopausal, some perimenopausal, and some postmenopausal. Second, investigators have employed age combined with retrospective or prospective self-reports of menstrual cycle history and have defined the menopause as 6 months to 1 year of amenorrhea and the perimenopause as menstrual cycle irregularity. However, self-reports of menstrual cycle irregularity cannot be used to reliably define reproductive status. Treolar (1981) observed that menstrual cycle irregularity is not confined to the perimenopause and may occur frequently during other periods of reproductive life. Moreover, Kaufert et al. (1987) observed that, among a sample of middle-aged women with menstrual cycle irregularity, as many women returned to normal menstrual cycle function as entered the menopause (defined by 6 months of amenorrhea) during a 3-year period of follow-up. The third criterion commonly used to define reproductive status has been the presence of elevated plasma gonadotropin levels in the context of low plasma estradiol levels. However, perimenopause-related elevations in gonadotropins may be reversible, and, again, the sole reliance on elevated gonadotropin levels may result in the selection of heterogeneous samples of women unless gonadotropin levels are subsequently measured to prospectively confirm group assignment. For example, we have observed several women who presented with a history of either menstrual cycle irregularity or amenorrhea and with elevated gonadotropin levels but whose mood symptoms and hot flushes improved over a 2-month period associated with a resumption of normal estrogen production and a return of plasma gonadotropin levels to the premenopausal range (Daly et al., unpublished data, June 1992). Thus, a combination of both menstrual cycle history and elevated gonadotropin levels may be the best method for selecting and characterizing the reproductive status of perimenopausal women, but it is not necessarily predictive of future reproductive function.

Do Disturbances of Mood Occur During the Perimenopause? Studies attempting to determine whether mood disturbances are associated with the perimenopause have been complicated by several methodologic issues. First, problems have arisen when investigators attempted to measure specific depressive symptoms by using rating scales designed to measure the severity of depressive syndromes and which may, therefore, fail to sample relevant symptoms or be sufficiently sensitive to changes in target symptoms. A second problem in studies examining the possible occurrence of depression during the perimenopause has been the failure to distinguish between instruments designed to measure the severity of an

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affective syndrome (a rating scale) and those established to diagnose an affective syndrome (a structured diagnostic interview). A third methodological problem, present in most investigations of the linkage between the perimenopause and disturbances in mood and behavior, has been the overly restrictive supposition on the part of investigators about the nature of the mood disturbance. Debates over the phenomenology of perimenopausal affective disorders date back more than a century. In a paper by William Conklin (1889), a form of neurasthenia or mixed anxiety–depressive illness was described in relation to the perimenopause. In addition to case reports verifying Conklin’s description of neurasthenia-like disorders during the perimenopause, medical observers such as Maudsley in England (Merson 1876) and Kraepelin in Germany (Kraepelin 1896/1975) also suggested that a special form of melancholia occurred during the perimenopause, commencing a controversy in psychiatry that continues to date and has overshadowed attempts to further explore other perimenopause-related affective syndromes. Several influential studies have not confirmed the existence of involutional melancholia (Weissman 1979; Winokur and Cadoret 1975), and some studies have not identified an increased prevalence of major depressive disorder during the perimenopause. Perimenopause-related depression, in contrast to postpartum depression, is therefore not recognized as a distinct condition in DSM-IV-TR. Nonetheless, studies have not disproved a relationship between depression and the perimenopause in women who experience depression in this context. In particular, the occurrence of a neurasthenia or atypical depression associated with the menopause, described in early case reports, has been largely ignored. In fact, the symptoms of 40 women presenting to our clinic with depression associated with the perimenopause were consistent with minor depression (as determined by the Schedule for Affective Disorders and Schizophrenia [Spitzer et al. 1978]), with an increased frequency of symptoms such as irritability, tearfulness, anxiety, disturbed sleep, difficulty concentrating, and food cravings (Table 10–2). Furthermore, some studies suggest that the perimenopause in some women may interact with and alter the course of primary affective disorder (Angst 1978; Kukopulos et al. 1980).

What Are the Possible Relationships Between Mood Disturbances and the Perimenopause? Several possible relationships exist between the onset of disturbances of mood and behavior and the perimenopause. First, several investigators

268 TABLE 10–2.

PSYCHONEUROENDOCRINOLOGY Presenting symptoms of depression during the perimenopause (N=40)

Symptom Irritability Tearfulness Excessive worry Anxiety Mood more fragile; easily upset by life events Depressed mood Mood instability Increased appetite, cravings Unmotivated Decreased energy Poor concentration Early-morning waking Interrupted sleep Emotionally detached from important people in life

Percentage showing symptom 70 70 67 67 64 61 61 58 56 53 53 50 50 50

Note. Subjects met criteria for major or minor depression after administration of the Structured Clinical Interview for DSM-IV (Spitzer et al. 1990) and the modified Schedule for Affective Disorders and Schizophrenia—Lifetime Version (Spitzer et al. 1978), respectively.

have suggested that it is a purely coincidental relationship and that there is no specific etiologic connection between reproductive endocrine events and the experience of a change in mood and behavior during this phase of a person’s life. Second, the perimenopause may act as a nonspecific stress related to midlife and the vicissitudes of aging, whereby a change or a loss of self-esteem (or depression) is precipitated in response to stressful life events in someone who is predisposed to experience these symptoms. Third, the perimenopause causes specific somatic symptoms such as hot flushes, which may produce a secondary sleep disturbance that is sufficient to result in daytime somnolence, decreased energy, and other mood and behavioral symptoms. Certainly, some women with severe nocturnal hot flushes may present with disturbances of mood and behavior; however, hot flushes by themselves are neither necessary nor sufficient for the production of mood and behavioral disturbances in perimenopausal women. A fourth possible relationship is that the perimenopause may result in the de novo appearance of mood and behavioral symptoms or may modulate mood and behavioral disorders. This relationship implies that the endocrine-related events of the perimenopause may alter candidate neurotransmitter systems associated

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with psychiatric illness. This possibility suggests the potential importance of either estrogen withdrawal/deprivation or perimenopause-related unopposed estrogen exposure (due to more frequent anovulatory cycles) in the development of mood and behavioral disturbances in the perimenopause.

The Perimenopause and Affective Disorders Causal Relationship The manifold interactions between gonadal hormones and neurotransmitters and neuromodulators suggest a possible neurobiological basis for the effect of alterations in reproductive hormone activity on mood and behavior. The extent to which interactions between gonadal hormones, gonadotropins, catecholamines, neuropeptides, and neurosteroids actually influence the development of climacteric-related and menopauserelated mood and behavioral disorders is purely a matter for speculation (McEwen and Alves 1999; Roca et al. 1999; Rubinow et al. 1998). Nonetheless, it seems clear that changes in reproductive endocrine function would be accompanied by discrete alterations in central nervous system neurotransmitter activity that may constitute relevant mechanisms in the pathophysiology of mood disorders. Furthermore, the rate of hormonal changes may be an important regulatory variable, perhaps conveying a differential behavioral sensitivity to sudden (surgically induced menopause) versus gradual (natural menopause) decline of ovarian function (Kaufert et al. 1992; Kritz-Silverstein et al. 1993). Despite the inferred potential of perimenopausal changes in gonadal steroids to alter human behavior, several epidemiological studies have suggested that in fact there is no relationship between the onset of depression and changes in reproductive function during the perimenopause. In general, the types of evidence that have been adduced to refute the existence of involutional melancholia are epidemiological and phenomenological. Weissman (1979) studied a sample of 422 women consecutively admitted as outpatients with diagnoses of major nonbipolar depression. Using an age criterion of 45–55 years for defining menopausal status, Weissman found no difference in symptom patterns and number of previous depressive episodes between the 347 women younger than age 45 (presumed premenopausal) and the 75 women older than age 45 (presumed menopausal or postmenopausal). Weissman concluded there was not sufficient evidence to consider involutional-onset depression as a distinct entity. In agreement with Weissman’s findings,

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studies have not demonstrated an increased risk of suicide or psychiatric hospitalization in women during the perimenopause or postmenopause years. Furthermore, despite a generally higher prevalence rate of depression in females compared with males, several studies reported a slightly lower 6-month prevalence rate of depression during the presumed menopausal-climacteric years than in younger age groups (Weissman et al. 1988). However, this evidence is far from conclusive in refuting the existence of a perimenopause-related affective syndrome. Despite similar or lower point prevalence rates and similar clinical presentations of depression during the menopause and at other times of life, one cannot infer that these syndromes share identical etiologies. At least two investigators reported involutional-onset depression to be associated with a lower family history of depression than that observed in patients with early-onset depression (R.P. Brown et al. 1984; Stenstedt 1959). Thus, while perimenopausal major depression (as opposed to minor depression) does not appear to be phenomenologically distinct, there is some evidence suggesting that it may differ from earlier-onset depression with respect to family history and age at index depressive episode (R.P. Brown et al. 1984). It is not unusual in medicine for phenomenologically similar disorders to have different precipitants or causes; for example, meningitis in both the neonate and the infant may present with fever, vomiting, and drowsiness, yet different pathogenic organisms are typically involved with each age group. Some epidemiological studies have suggested, in contrast to the conclusions described above, that the perimenopause may be a period of life that increases the vulnerability of a woman to experience depression (Kessler et al. 1993). For example, some studies report that during midlife, compared with other periods of reproductive life, the sex ratio for depression increases from 2:1 to 3–4:1 (female to male) (Kessler et al. 1993; Myers and Weissman 1980). In addition, although Winokur (1973) concluded that his data did not support the idea of menopause as an important precipitating factor in episodes of affective disorder, he observed that the postmenopausal women in his sample described a high frequency of symptoms of depression (38%) and nervousness (75%); consequently, he elected to use more stringent diagnostic criteria for depression (e.g., need for hospitalization) during the 3 years after menopause. Thus, although Winokur concluded that there is no increase in risk of depression during the 3 years after the menopause, his risk rates were decreased spuriously by employing more stringent diagnostic criteria for depression during the 3 years after the menopause compared with depression during other periods of life. Similarly, studies have reported a

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high prevalence of mood and behavioral symptoms in women after oophorectomy (Oldenhave et al. 1993), which in some studies exceeds the prevalence of symptoms reported by women after natural menopause (Kritz-Silverstein et al. 1993). In multinational preliminary data, Weissman et al. (unpublished data, May 1995) observed an increased hazard rate for onset of depression in their older cohort of women (but not men) during ages 45–50. Finally, some clinic-based treatment trials report the improvement of mood and behavioral symptoms in perimenopausal women with estrogen replacement, suggesting a potential role for ovarian steroids in the treatment and possibly the development of depression during the perimenopause (Brincat et al. 1984; Montgomery et al. 1987; Schmidt et al. 2000; Soares et al. 2001). Thus, although the perimenopause is not associated with the development of depression in the majority of women, the endocrine changes during this phase of life may be related to the onset of depression in some women.

Treatment Recommendations The management of mood and behavioral disturbances during the perimenopause requires the determination of the symptoms experienced and the hormonal context in which they appear. As a complement to the usual dicta regarding careful neuropsychiatric evaluation, longitudinal monitoring of symptoms on a daily basis may provide invaluable information about the severity, stability, and pattern of symptom experience. Both affective and relevant somatic symptoms (e.g., vaginal dryness, hot flushes) should be followed up. If it was not previously done, the presence of the perimenopause and hypoestrogenism should be documented with FSH and estradiol measures. As part of our operational criteria, we have required three of four serial FSH levels to be greater than 20 IU/L (depending on the laboratory) for the perimenopause and greater than 40 IU/L for the menopause. Although estradiol levels below 60 pg/mL are consistent with decreased ovarian function, levels above 60 pg/mL may nonetheless appear in the presence of markedly elevated FSH levels that suggest ovarian insensitivity. The therapy selected for a major depressive disorder during the perimenopause will depend on the nature and severity of the somatic symptoms and the presence (or absence) and type of hormone replacement therapy. In perimenopausal women presenting with depression, the presence of distressing signs of estrogen deficiency such as vaginal dryness and hot flushes should lead to consideration of a trial of estrogen therapy, unless contraindications to estrogen treatment exist (e.g., history of breast cancer). Alternatively, if perimenopausal somatic symptoms are mild or

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minimal, despite laboratory evidence of perimenopausal reproductive status, and moderate to severe mood symptoms are present, then the choice of hormone versus antidepressant therapy may be best informed by such factors as personal history of depression, family history of affective disorder, severity of affective symptoms, or the presence of contraindications to estrogen therapy. The relationship between the onset of mood symptoms and the initiation of hormone therapy should be determined for at least two reasons. First, mood and behavioral symptoms may appear with inadequate estrogen replacement and can remit with appropriate dosage adjustments or with a change to an alternative form of estrogen therapy. Adjustment of hormone therapy is therefore recommended before considering adjunctive psychopharmacotherapy. Second, mood and behavioral symptoms may directly result from the hormone therapy. Specifically, cyclic mood and behavioral symptoms have been reported in association with sequential hormone replacement in some (Hammarback et al. 1985; Magos et al. 1986), but not all (Kirkham et al. 1991; Prior et al. 1994), studies and may remit with a change in the replacement regimen from sequential to continuous combination therapy. Alternatively, if addition of progesterone consistently precipitates adverse mood changes, estrogen therapy alone may be attempted if it is accompanied by appropriate monitoring of the endometrium. Symptoms of depression and loss of libido consequent to ovarian failure may nonetheless be responsive to antidepressant therapy, and this option should not be ruled out irrespective of the strength of the association between ovarian dysfunction and affective disorder. Potential roles for testosterone (Sherwin 1988; Sherwin and Gelfand 1985, 1987; Sherwin et al. 1985) or dehydroepiandrosterone (Bloch et al. 1999; Wolkowitz et al. 1999) in the treatment of perimenopause- or midlife-associated sexual dysfunction or depression have also been proposed. The value of these proposed treatments awaits determination.

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Vanezis P: Deaths in women of reproductive age and relationship with menstrual cycle phase. An autopsy study of cases reported to the coroner. Forensic Sci Int 47:39–57, 1990 Veeninga AT, Westenberg HGM: Serotonergic function and late luteal phase dysphoric disorder. Psychopharmacology 108:153–158, 1992 Wang G-J, Volkow ND, Overall J, et al: Reproducibility of regional brain metabolic responses to lorazepam. J Nucl Med 37:1609–1613, 1996 Warner P, Bancroft J, Dixson A, et al: The relationship between perimenstrual depressive mood and depressive illness. J Affect Disord 23:9–23, 1991 Weissman MM: The myth of involutional melancholia. JAMA 242:742–744, 1979 Weissman MM, Leaf PJ, Tischler GL, et al: Affective disorders in five United States communities. Psychol Med 18:141–153, 1988 West CP, Hillier H: Ovarian suppression with the gonadotrophin-releasing hormone agonist goserelin (Zoladex) in management of the premenstrual tension syndrome. Hum Reprod 9:1058–1063, 1994 Winokur G: Depression in the menopause. Am J Psychiatry 130:92–93, 1973 Winokur G, Cadoret R: The irrelevance of the menopause to depressive disease, in Topics in Psychoendocrinology. Edited by Sachar EJ. New York, Grune & Stratton, 1975, pp 59–66 Wolkowitz OM, Reus VI, Keebler A, et al: Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 156:646–649, 1999 Wood SH, Mortola JF, Chan Y-F, et al: Treatment of premenstrual syndrome with fluoxetine: a double-blind, placebo-controlled, crossover study. Obstet Gynecol 80:339–344, 1992 World Health Organization: International Classification of Diseases, 9th Revision. Geneva, World Health Organization, 1977 Yonkers KA, Halbreich U, Freeman E, et al: Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment: a randomized controlled trial. JAMA 278:983–988, 1997

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Chapter 11 Endogenous Gonadal Hormones in Postpartum Psychiatric Disorders Lisa S. Weinstock, M.D. Lee S. Cohen, M.D.

D

escriptions of postpartum mood disturbance date back to the time of ancient Greece. The Greeks attributed postpartum illness to a “wandering uterus.” Despite the evolving understanding of brain function, the knowledge of what factors mediate the pathophysiology of postpartum psychiatric illness remains limited. Psychiatric symptoms that manifest at particular points across the female life cycle—such as the premenstrual period, pregnancy, or the puerperium—have frequently been attributed to changes in female reproductive physiology. This has been the case despite an absence of systematically derived data from well-studied populations of women that might support the association between depressive symptoms, for example, and specific changes in hormonal status. Factors such as personal or family history of mood disorder and psychosocial support appear to be more consistently associated with risk for affective disorder at certain points in the female life cycle. This chapter describes the spectrum of postpartum psychiatric disorders. Epidemiology and etiology are reviewed. Risk factors for postpartum psychiatric illness as well as evaluation and treatment approaches are also discussed. Particular attention is given to the potential role of endogenous gonadal hormones in the modulation of postpartum psychiatric disorders. Postpartum affective disorders are frequently classified into three categories: postpartum blues, postpartum depression, and postpartum psychosis. In this chapter we describe these syndromes with respect to epidemiology, risk factors, etiology, pathophysiology, and strategies for evaluation and treatment.

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Overview of Postpartum Psychiatric Disorders Postpartum Blues Postpartum blues, also known as maternity blues, are the least severe forms of postpartum psychiatric disorder. They are a commonly experienced phenomenon, with an estimated prevalence ranging from 26% to 85% (O’Hara 1991). Blues occur typically in the first week after delivery. Common features include crying spells, anxiety, mood lability, confusion, sleep and appetite disturbance, irritability, and depressed mood. Symptoms usually appear between postpartum days 3 and 7 (Kendell et al. 1981), although they can be seen as early as postpartum day 1 (Yalom et al. 1968). Symptoms typically remit by postpartum day 10.

Postpartum Depression Postpartum depression represents a more severe form of puerperal mood disturbance. Unlike blues, symptoms emerge slowly during the first few weeks after delivery. Symptoms include those characteristic of other major depressive episodes: dysphoric mood, loss of interest, decreased energy and appetite, sleep changes, guilt, change in psychomotor activity, diminished concentration, and potential suicidality. Because some symptoms of depression—such as sleep disturbance, fatigue, and appetite changes—can be normative during the postpartum period, it may be difficult to distinguish such vegetative symptoms of depression from those more characteristic of a depressive episode. The severity of postpartum depression ranges from mild to severe. Postpartum mood disturbance may also be classified as psychotic or nonpsychotic. Prevalence rates of nonpsychotic postpartum major depression are estimated between 6.8% (Gotlib et al. 1989) and 16.5% (Whiffin 1988). The extent to which pregnancy and the postpartum period constitute a period of increased risk for affective disorder has been addressed in several studies, with inconsistent results. Several studies have shown that the risk of depression after delivery is higher than the risk of depression during pregnancy (Kumar and Robson 1984; Watson et al. 1984). However, studies that compare rates of depression during the postpartum period to rates of depression in nonpuerperal women have not consistently shown a significant difference in rates of mood disturbance (O’Hara 1986; O’Hara et al. 1991). Although rates of postpartum mood disturbance may not vary from those seen in a matched control group, other data sug-

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gest that women with histories of depression are at significantly increased risk for postpartum major depression (O’Hara 1995; O’Hara et al. 1983). In addition, depression during pregnancy appears to be a strong predictor of postpartum depression (O’Hara et al. 1991). Postpartum depression typically lasts between 3 and 6 months, although many women report episodes lasting more than 1 year (Cox et al. 1982). Proposed risk factors for postpartum depression are listed in Table 11–1.

TABLE 11–1.

Risk factors for postpartum depression

History of prior episode of postpartum depression Depression during pregnancy History of nonpuerperal depression Family history of depression Marital discord Stressful life events Stressful newborn-related events Source. Altshuler L, Hendrick V, Cohen L: “Course of Mood and Anxiety Disorders During Pregnancy and the Postpartum Period.” Journal of Clinical Psychiatry 59 (suppl 2):29– 33, 1998.

Postpartum Psychosis Postpartum psychosis is the most severe form of postpartum mood disturbance. Typical symptoms include hallucinations or delusions, confusion, and (occasionally) severely depressed mood. The incidence is estimated at approximately 1 in 1,000 to 4 in 1,000 births (Brockington et al. 1982). Although nonpsychotic postpartum depressive episodes may typically emerge during the first 4 weeks after delivery, puerperal psychotic episodes begin earlier in the immediate postpartum period—very often within the first few days after delivery. Several studies suggest that the first 30 days postpartum represent a period of increased risk for newonset psychosis (Kendell et al. 1987; McNeil 1987; Nott 1982). In a frequently cited study by Kendell et al. (1987), it was described that the number of psychiatric admissions in women during the first 30 days after delivery was much higher than in a 30-day nonchildbearing period during pregnancy or after 30 days postpartum. Whether postpartum psychoses are distinct from psychotic episodes that occur at other times has been debated. Many have suggested that most postpartum psychosis is a form of affective disorder, specifically bipolar disorder. For example, a study by Brockington et al. (1981) determined that women with postpartum psychosis experienced higher levels

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of euphoria, activity, incompetence, and confusion than women with nonpuerperal psychosis. However, the women in the postpartum psychosis group were primarily women with depression or mania, whereas the women in the other group were primarily diagnosed with schizophrenia or schizoaffective disorder. Kendell’s epidemiological study revealed that women with histories of manic-depressive illness were at the highest risk for psychiatric admissions during the postpartum period (Kendell et al. 1987). Many researchers believe that postpartum psychosis represents a form of bipolar disorder, and women with histories of bipolar disorder appear to be at increased risk for postpartum psychotic episodes (Dean et al. 1989).

Etiology of Postpartum Psychiatric Disorders: Endocrine Factors A number of potential causes of postpartum psychiatric syndromes have been investigated. These include both biological and psychosocial factors that may contribute to affective worsening in the postpartum period. In this section we describe the endocrine changes that take place during pregnancy.

Endocrine Changes in Pregnancy and the Puerperium Given the significant and rapid changes in the reproductive environment characteristic of the postpartum period, a considerable focus has been placed on the role of hormones in the etiology of postpartum affective syndromes. Pregnancy and the puerperium are a time of significant endocrinologic change. Hormones that undergo changes during pregnancy include peptide hormones—such as human chorionic gonadotropin (hCG), human placental lactogen (hPL), prolactin, gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and b-endorphins—as well as steroid hormones such as progesterone, estrogens, androgens, and glucocorticoids. Significant changes in the thyroid system occur during pregnancy as well. What follows is a brief description of the major hormonal changes seen during pregnancy and the postpartum period, and a review of effects these hormones have on the neural systems associated with psychiatric disorders. How these hormonal changes (and their impact on neuromodulating systems in the brain) affect pregnancy and the puerperium has yet to be adequately delineated.

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Human Chorionic Gonadotropin A glucoprotein produced by the placenta, hCG functions to maintain pregnancy. Levels of hCG begin to rise 8 days after ovulation and peak between days 60 and 90. The concentration of hormone then falls to a constant level during the period between 100 and 130 days of pregnancy (Cantazarite et al. 1987). Concentrations of hCG fall precipitously during the first 48–96 hours postpartum. We know of no studies investigating the relationship between hCG and the neurotransmitter systems associated with psychiatric disorders.

Human Placental Lactogen hPL is a single-chain polypeptide similar to pituitary growth hormone and prolactin. Maternal serum concentrations rise throughout gestation and are at maximum levels in the last month of pregnancy. hPL has a half-life of 20 minutes, and the concentration of this hormone falls precipitously after delivery, becoming undetectable by postpartum day 2. As is the case with hCG, there is no evidence that hPL affects neurotransmitter systems associated with psychiatric disorders.

Gonadotropin-Releasing Hormone GnRH is a decapeptide produced by the hypothalamus and is responsible for synthesis and release of LH and FSH from the pituitary. In nongravid women, GnRH is released in a pulsatile fashion. Hypothalamic release of GnRH is suppressed during pregnancy and early in the puerperium. The relationship between GnRH and behavior has not been well studied. In animals, central administration of GnRH has been shown to enhance sexual behavior (Moss and McCann 1973). In humans, GnRH cannot be easily measured in the systemic circulation. The extent to which GnRH dysregulation might contribute to puerperal psychiatric disorders has not been explored.

Follicle-Stimulating Hormone and Luteinizing Hormone Serum concentrations of FSH and LH are low in all women during the first 10–12 days postpartum. Levels then increase and reach follicularphase concentrations by postpartum week 3. Low levels of postpartum LH and FSH are believed to be due to decreased GnRH secretion during pregnancy and the early puerperium. Pituitary gonadotropins have no known central nervous system actions on neurotransmitter systems asso-

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ciated with psychiatric disorders; there is no evidence that changes in levels of either FSH or LH are related to postpartum psychiatric illness.

b-Endorphin Circulating levels of b-endorphins increase during late pregnancy and reach very high levels during delivery. Levels then drop rapidly during the first few hours after delivery (Newnham et al. 1984). However, serum b-endorphin does not cross the blood-brain barrier and does not reflect central nervous system concentration of b-endorphin.

Prolactin Prolactin is a peptide hormone, made in the anterior pituitary (see Chapter 5, this volume). Plasma concentrations in nonpregnant women are approximately 10 ng/mL. During pregnancy, maternal blood levels rise to concentrations of 200 ng/mL. In nonlactating women, levels decline postpartum over a period of approximately 2 weeks. In women who breastfeed, levels remain above the nongravid range and increase in response to suckling. If breastfeeding occurs 1–3 times a day, prolactin returns to nongravid levels within 6 months; if breastfeeding occurs more than 6 times a day, levels can remain high for up to 1 year postpartum (Novy 1987). In the hypothalamus, increasing concentrations of prolactin lead to increases in dopamine release, which then inhibits further prolactin release. Studies of the effects of prolactin on other dopamine systems of the brain have not consistently shown any specific effects of prolactin on dopamine binding sites. One study showed hyperprolactinemia increasing striatal dopamine receptor binding sites (Hruska et al. 1982), but another series of studies failed to show an effect of hyperprolactinemia on dopamine receptor binding sites in the striatum (Simpson et al. 1986). In nonchildbearing women, hyperprolactinemia has been associated with depression, anxiety, and hostility (Simpson et al. 1986).

Estrogen Estrogens are produced by both the placenta and the fetus during pregnancy. Estrone and estradiol are produced by the placenta through conversion of the androgen dehydroepiandrosterone sulfate (DHEA-S), which is produced by fetal and maternal adrenal glands. Estriol is also synthesized by the placenta, but from the precursor 16a-hydroxy DHEA-S, produced by the fetal liver from adrenal DHEA-S (Campbell and Winoker 1985). Plasma levels of estrogens rise dramatically throughout preg-

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nancy, increasing in an almost linear fashion in late pregnancy (Carsten 1986). After delivery, plasma levels of estrogens decline very rapidly. Within 3 hours after removal of the placenta, plasma concentrations of estradiol fall to 10% of the antepartum value (Cantazarite et al. 1987). Within 24 hours after delivery, estradiol levels in the maternal circulation are less than 2% of prepartum levels. Estrone and estriol levels fall at similar rates (Filer 1992). The lowest levels of estrogens are reached by 1 week postpartum, and levels do not climb back to follicular-phase levels until approximately 3 weeks postpartum in nonlactating women. In lactating women levels remain low anywhere from 60 to 180 days postpartum, depending on the timing of the return of menses (Novy 1987). In addition to their role in the feedback mechanisms associated with control of the menstrual cycle, estrogens appear to have effects on neurotransmitter systems implicated in the etiology of mood and anxiety disorders. Estrogens have been shown to have neuroleptic-like effects on dopamine systems in animals. For example, estradiol administration has been shown to cause changes in dopaminergic receptor function in rat striatal tissue (Hruska and Silbergeld 1980; Levesque and DiPaolo 1993). Administration of estrogens leads to an increase in dopaminergic receptor density (Hruska and Silbergeld 1980), and long-term administration of estrogen leads to an effect similar to that seen with long-term administration of antipsychotics, producing dopamine supersensitivity on withdrawal of estrogen (Gordon et al. 1980). It has also been reported that elevated estrogen levels decrease tyrosine hydroxylase activity, thereby decreasing dopamine synthesis (Blum et al. 1987). Resultant reduction in synaptic dopamine after estrogen administration is hypothesized to lead to dopamine supersensitivity (Snyder 1977). These animal findings are consistent with the theory that the large increases in estrogen levels seen during pregnancy, followed by rapid withdrawal of estrogen postpartum, may cause dopamine supersensitivity. It has been theorized that this dopamine supersensitivity may lead to increased vulnerability to psychosis or affective instability in certain women (Kumar et al. 1993). Exogenous estradiol has also been associated with changes in serotonin and noradrenaline receptor function in the brains of animals (Kendall et al. 1981; Wagner et al. 1979). Studies have shown that estrogen treatment decreased b-adrenoreceptor binding in rat cerebral cortex (Wagner et al. 1979). Kendall et al. (1981) reported that ovariectomy prevents antidepressant-induced downregulation of the 5-hydroxytryptamine (serotonin) type 2 (5-HT2) receptor, and that this effect is reversed with estradiol administration. It is unclear how the rapid withdrawal of estrogen seen in the early postpartum period may impact the serotonergic

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and noradrenergic systems implicated in the etiology of depressive disorders.

Progesterone Progesterone is produced by the ovary during the first 6–7 weeks of pregnancy, and then production shifts to the placenta. At term, serum progesterone levels are approximately 170 times higher than levels seen in the follicular phase of the menstrual cycle (Filer 1992). Levels fall precipitously after delivery, and the half-life of progesterone is calculated in minutes (Novy 1987). As the corpus luteum of pregnancy continues to produce small amounts of progesterone during the first few days postpartum, levels do not fall as precipitously as do estrogen levels (Filer 1992). However, by postpartum day 3, plasma levels are lower than those observed in the luteal phase of the menstrual cycle, and by the end of postpartum week 1, levels are as low as those seen in the follicular phase (Filer 1992). A progesterone metabolite, 3a-hydroxy-5a-dihydroxyprogesterone (allopregnanolone) has been shown to bind to g-aminobutyric acid type A (GABA-A) receptors in rat brain, mimicking the GABA-mediated inhibition produced by benzodiazepines and barbiturates (Majewska et al. 1986). Administration of micronized progesterone has been associated with sedative and hypnotic effects similar to those seen with benzodiazepines (Arafat et al. 1988; Freeman et al. 1992).

Androgens Serum levels of testosterone increase throughout pregnancy and are significantly elevated in the third trimester. The increase is due to the increase in estrogen, which causes an increase in the liver-synthesized binding protein that binds both estrogen and testosterone. Although total testosterone levels increase throughout pregnancy, free testosterone concentrations remain stable. At delivery, testosterone levels drop secondary to the drop in binding protein, but free levels again remain stable. Levels of DHEA and DHEA-S decrease during pregnancy because they are utilized to produce the large amounts of estrogens synthesized by the placenta. After delivery there is a gradual return of DHEA and DHEA-S to baseline levels (Filer 1992).

Thyroid Hormones Rapid fluctuations in thyroid indices occur in the immediate postpartum period. During pregnancy, there is an increase in total thyroxine (T4) and

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triiodothyronine (T3) levels secondary to increased liver production of thyroid-binding globulin. However, levels of free T3 and T4 remain constant. During the postpartum period, total T3 and T4 levels drop, but free levels do not change (Filer 1992). Thyroid-stimulating hormone levels do not differ significantly between the nonpregnant, pregnant, and postpartum states (Novy 1987). Thyroid dysfunction, particularly blunted thyroid-stimulating hormone response to thyrotropin-releasing hormone, has been associated with many psychiatric disorders, and thyroid dysfunction is often associated with affective symptoms (Cohen 1997) (see Chapters 14 and 15, this volume).

Corticosteroids Plasma concentrations of both free and bound cortisol rise during late pregnancy and peak during labor. Postpartum levels rapidly fall to those seen in late pregnancy, and then gradually return to pregravid concentrations (O’Hara 1991). By postpartum day 1, levels have returned to the antepartum range. Return of both cortisol and 17-hydroxycorticosteroid to nonpregnant levels occurs by the end of the first postpartum week (Novy 1987). Hypercortisolemia and nonsuppression with dexamethasone have been associated with depression (see Chapter 6, this volume). In addition, a reduced metabolite of deoxycorticosterone, 3a-5a-tetrahydrodeoxycorticosterone, has been shown to modulate the GABA-A receptor complex, interacting at a site close to or identical with that of barbiturates (Majewska et al. 1986).

Endocrine Changes and Postpartum Psychiatric Disorders Given the rapid fluctuations of the hormonal environment noted in the postpartum period, and evidence suggesting that many of these hormones may affect the neurotransmission systems implicated in the pathophysiology of psychiatric disorders, it has been hypothesized that these postpartum endocrine changes may catalyze the onset of psychiatric symptoms in some women during the postpartum period. However, there are no consistent data suggesting a particular relationship between concentrations of most of these hormones and what is seen clinically in women who suffer from psychiatric disorders.

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Postpartum Blues Etiology Endocrine factors. Systematic study of the relationship between endocrine factors and postpartum blues has yielded conflicting and inconclusive results. Nott et al. measured levels of LH, FSH, estrogen and progesterone in women during the six weeks postpartum. They found no consistent evidence of an association between specific changes in hormone levels and changes in mood. However, a correlation was noted between irritability and antepartum estrogen levels (Nott 1982). Feksi et al. (1984) describe a relationship between maternity blues and elevated concentrations of salivary progesterone and estrogen. A study by Heidrich et al. (1994), however, failed to show significant differences in free hormone levels of estradiol and progesterone between women with and without postpartum blues. Gard et al. (1986) also found no difference in estrogen or progesterone in the first 5 days postpartum between women with or without maternity blues. No consistent relationship between cortisol levels and postpartum blues has been found. A few studies have looked at b-endorphin levels and postpartum mood, but results have been inconsistent. One investigation noted a relationship between low levels of b-endorphin at 36 weeks gestation and severe symptoms of blues (Newnham et al. 1984). Another study showed no association between b-endorphin levels and blues (Brinsmead et al. 1985). Nonendocrine factors. Biological factors which have been investigated as potential causes of postpartum blues include plasma tryptophan levels, platelet monoamine oxidase (MAO), and platelet alpha receptors. Two studies have noted an absence of normal increase in plasma tryptophan seen typically in the first 2 days postpartum in association with postpartum blues (Gard et al. 1986; Handley et al. 1980). However, tryptophan supplementation during the first 10 days postpartum did not reduce the incidence of blues. One study showed that women with postpartum blues had more platelet alpha 2 receptors than women without blues (Metz et al. 1983). Psychosocial and demographic factors have been investigated in the etiology of postpartum blues. First pregnancy and past history of PMS appear to be risk factors for postpartum blues (Nott et al. 1976; Yalom et al. 1968).

Treatment Postpartum blues are generally considered to be a transient, self-limited, and normal consequence of pregnancy. There is some evidence that blues

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may predict risk for later postpartum depression. However, the majority of women with postpartum blues recover without any negative sequelae (O’Hara 1987). Appropriate treatment includes anticipation, support, reassurance, and follow-up to ensure that symptoms have in fact remitted by 2 weeks postpartum. Symptoms that continue beyond this time frame may reflect an evolving mood disturbance.

Consequences There have been no studies suggesting that postpartum blues has any long-term negative effects on mother or child.

Postpartum Depression Etiology Endocrine factors. As is the case for postpartum blues, there is little consistent evidence suggesting that a specific hormonal imbalance or abnormality is the cause of postpartum depression. Pedersen et al. (1993) found higher cortisol levels during the puerperium in women with postpartum dysphoria. O’Hara et al. (1991) did not find any difference in plasma or urinary cortisol levels between depressed and nondepressed women in the early postpartum period. Studies of dexamethasone suppression have not shown a distinction between postpartum depressed and nondepressed women in the early postpartum period (Greenwood and Parker 1984; Singh et al. 1986). O’Hara et al. (1991) did find significantly lower levels of estradiol at gestation week 36 and postpartum day 2 among postpartum depressed women. Studies examining the relationship between postpartum depression and progesterone levels have failed to show a consistent relationship between level of depression and levels of progesterone (Ballinger et al. 1982; Kuevi et al. 1983). A study by Harris et al. (1989) reported lower levels of progesterone in depressed breastfeeding women than in nondepressed breastfeeding women, with the opposite effect seen in bottlefeeding women. A study by Buckwalter et al. (1999) found that although mood disturbances during pregnancy were associated with higher levels of progesterone and lower levels of DHEA, in the postpartum period elevated testosterone levels were associated with greater mood disturbance. Studies of thyroid function and postpartum mood have produced inconsistent results as well. One study failed to show evidence of thyroid disturbance associated with postpartum mood disturbance (Grimmel and Larsen 1965). Two more recent studies did show an association between thyroid dysfunction and postpartum mood disturbance (Harris

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et al. 1989; Pop et al. 1991). Pedersen et al. (1993) found that women with higher levels of postpartum dysphoria had lower free T4 levels and higher T3 uptake at 38 weeks of pregnancy. Nonendocrine factors. A number of studies describe risk factors that appear to increase risk for postpartum depression. However, these studies tend not to be particularly consistent. No data suggest that age, parity, or marital status are consistently associated with increased risk for postpartum depression. The extent to which certain psychosocial factors have been implicated in the etiology of (or contribute risk for) postpartum depression has also been explored. Some studies have noted an association between negative or stressful life events during pregnancy or during the postpartum period and increased probability of postpartum depression. For example, poor marital relationships have been associated with depression during the postpartum period in some but not all studies (Blair et al. 1970; Feggetter and Gath 1981; Hopkins et al. 1987; O’Hara 1986; O’Hara et al. 1983). In contrast, poor social support has been associated quite consistently with increased risk for postpartum depression (O’Hara et al. 1983; Paykel et al. 1980). Most studies have suggested that history of depression is a risk factor for postpartum depression (Martin 1977; Nilsson and Almgren 1970; O’Hara 1986; O’Hara et al. 1983, 1991; Paykel et al. 1980; Playfair and Gowers 1981; Tod 1964; Uddenberg 1974; Watson et al. 1984). In addition, family history of depression also appears to be a risk factor for postpartum depression (Nilsson and Almgren 1970; O’Hara et al. 1984; Watson et al. 1984). Although history or family history of mood disorder appears to be highly associated with postpartum depression, a small number of studies have failed to demonstrate this association (Blair et al. 1970; Dalton 1971; Kumar and Robson 1984; O’Hara et al. 1991; Pitt 1968). No factor has been identified as singularly driving the risk for postpartum depression. However, history of depression and family history of depression appear to increase the risk of postpartum depression most consistently in studies that have examined this issue. In addition, depression during pregnancy and poor psychosocial support do appear to consistently increase the risk of postpartum depression (O’Hara 1986; O’Hara et al. 1991).

Treatment There are few treatment studies of postpartum depression. Research into prevention of postpartum depression has shown that prenatal education

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(including relaxation training and advice to avoid stressors and seek support) may decrease postpartum distress. Because women with histories of depression appear to be at increased risk for postpartum depression, prophylactic strategies to reduce the risk of postpartum depression are indicated. In women with histories of chronic or recurrent depression, consideration of continuation of pharmacotherapy during pregnancy and the postpartum period is appropriate. Given evidence that depression during pregnancy is a strong predictor of postpartum depression, avoidance of recurrence of depression during pregnancy may decrease the likelihood of a postpartum depressive episode. Women must be informed of the risks to the fetus of pharmacotherapy during pregnancy, and a careful weighing of risks to the fetus against risks of untreated depression in the mother must be undertaken to come up with appropriate treatment strategies for individual patients. Risks to the fetus associated with use of pharmacotherapy during pregnancy may include specific risks of certain congenital anomalies when specific medications are used during the first trimester, unknown risks of neurodevelopmental problems associated with exposing the developing fetal brain to psychotropic medications throughout the pregnancy, and potential risks of toxicity and withdrawal associated with maternal use of medications at time of delivery (Altshuler et al. 1996). Appropriate treatment of postpartum depression is like treatment of depression in other settings. Patients who have profound depression with suicidality, or those who are unable to take care of themselves, benefit in almost all cases from hospitalization. Evaluation to rule out medical causes of depression, such as Sheehan’s syndrome or postpartum thyroid dysfunction, is important. Treatment of postpartum depression may include pharmacotherapy in conjunction with psychotherapy and other support when necessary. Only a few studies of the treatment of postpartum depression with specific agents have been published. These agents include antidepressants such as sertraline, venlafaxine, and fluoxetine, all of which have demonstrated efficacy (Appelby et al. 1997; Cohen et al. 2001; Stowe et al. 1995). Estrogen, administered either transdermally or sublingually, has been reported to have a small effect on improvement of postpartum depressive symptoms (Ahokas et al. 1998; Gregoire et al. 1996). However, in the study of transdermal estrogen (Gregoire et al. 1996), many subjects received antidepressants in conjunction with estrogen, thus calling into question the effect of estrogen alone. Further investigation is needed into the possible use of estrogen in the treatment of postpartum depression before it can be considered a first-line therapy. Both cognitive-behavioral therapy and interpersonal therapy have been shown to be helpful in the treatment of postpartum depression

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(Appelby et al. 1997; Stuart et al. 1995). Services such as home health aides or visiting nurses who can help with baby care, thus allowing mothers to catch up on rest, are often quite helpful. Enlisting family members to take over some of the numerous chores involved with care of a new baby also may allow a mother with depression to recover more quickly. If pharmacotherapy is initiated, safety of breastfeeding may be raised as an issue of concern. The use of lithium is generally contraindicated during breastfeeding, as breast milk levels of this drug are relatively consistent and may reach 50% of serum levels (Llewellyn and Stowe 1998; Schou and Amdisen 1973). Other psychotropic medications may be secreted into breast milk; however, the amount may be small or unmeasurable by standard laboratory tests. Mothers should be advised that if they wish to breastfeed when using psychotropic medications, the baby’s serum should be measured for presence of drug approximately 2 weeks after medication is initiated. If medication is not detected in the infant’s plasma, then mothers may elect to continue to breastfeed. However, they should be cautioned that standard laboratory assays may not be sufficiently sensitive to detect trace amount of drug. On the other hand mothers may be reassured that the likelihood of neonatal toxicity in the setting of a nondetectable infant plasma level of drug is extremely small (Birnbaum et al. 1999; Stowe et al. 1997).

Consequences Follow-up studies of women who have experienced postpartum depression have shown that women with postpartum depression often continue to experience depression up to 3.5 years after delivery (O’Hara et al. 1991). Risk for recurrent postpartum depression has been estimated to be 50%, and risk for recurrent nonpostpartum depression is also elevated (O’Hara 1995). Studies of children of mothers who have had postpartum depression have shown more problems in these children than in children of nondepressed mothers, including behavior problems, poorer cognitive performance as toddlers, and patterns of insecure attachment with mothers (Cogill et al. 1986).

Postpartum Psychosis Etiology Endocrine factors. There has been little research concerning the relationship between endocrine status and postpartum psychosis. A study by Kumar et al. (1993) found that women with histories of bipolar or schizoaffective disorder who went on to have a postpartum recurrence of illness

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exhibited an enhanced growth hormone response to the apomorphine challenge test compared with both women who remained well and control subjects. The enhanced growth hormone reflected increased dopamine receptor supersensitivity in the hypothalamus in the women who experienced a recurrence postpartum (Kumar et al. 1993). These authors hypothesized that the dopamine supersensitivity may have been related to an impairment in downregulation of dopamine receptors consequent to estrogen withdrawal postpartum, although estrogen levels were not reported in the study. Meakin et al. (1995) investigated the relationship between development of puerperal psychosis, growth hormone response to apomorphine, and levels of other hormones (including progesterone, estrogen, and thyroid hormones) and were not able to identify any markers for the development of puerperal psychosis. Nonendocrine factors. Primiparous women appear to be at increased risk for postpartum psychosis. The risk of postpartum psychosis in a first pregnancy appears to be twice as high as that in multiparous women (Kendell 1985). Women with a history of bipolar disorder also appear to be at increased risk of developing postpartum psychosis. The increase in risk has been estimated as high as 50% (Reich and Winokur 1970). Family history of psychosis also appears to be a risk factor for postpartum psychosis (Brockington et al. 1982; Kendell 1985; Tetlow 1955).

Treatment Few studies of treatment of postpartum psychosis have been reported. Postpartum psychosis should be considered a psychiatric and obstetric emergency. Postpartum psychosis has been associated with infanticide (O’Hara 1995). Treatment should include hospitalization, and accepted somatic treatments have included antipsychotic medications and mood stabilizers, as well as electroconvulsive therapy. In the United Kingdom, specialized mother-baby units have been established that allow psychotic mothers to be hospitalized along with the infant. This allows the mother to continue to take as much responsibility as she is able for care of the infant while she is undergoing treatment. Children hospitalized with their psychotic mothers do not appear to be at increased risk of physical injury (Margison and Brockington 1982).

Consequences Women who experience a postpartum psychotic episode appear to be at increased risk for subsequent episodes of both nonpuerperal and postpartum psychosis. Estimates of risk of postpartum psychotic episodes in sub-

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sequent pregnancies have ranged from 21% (Brockington et al. 1982) to as high as 75% (O’Hara 1995). Studies examining the long-term effects of postpartum psychosis on children have suggested that children of psychotic mothers are at increased risk for attentional and behavior problems, as well as childhood depression (Cohler et al. 1977; Emery et al. 1982; Harvey et al. 1981; McKnew et al. 1979; Weintraub et al. 1978; Welner et al. 1977; Winters et al. 1981).

Conclusion Postpartum psychiatric disorders affect a large number of women worldwide. Clinicians should be aware of the risk factors that make certain women more vulnerable to developing psychiatric symptoms in the postpartum period, and careful screening for symptoms of mood disorder should take place both before and after pregnancy to ensure that women with mood symptoms can receive treatment. Endogenous gonadal hormones affect neurotransmitter systems implicated in the etiology of mood disorders; however, the precise role these hormones may have in the etiology of postpartum mood disorders is not well understood. Further research into the potential effects of postpartum hormonal changes on mood is necessary.

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O’Hara MW: Social support, life events, and depression during pregnancy and the puerperium. Arch Gen Psychiatry 43:569–573, 1986 O’Hara MW: Postpartum blues, depression, and psychosis: a review. J Psychosom Obstet Gynaecol 7:205–227, 1987 O’Hara MW: Postpartum mental disorders, in Gynecology and Obstetrics, Vol 6, Chapter 84. Edited by Sciarra JJ. Philadelphia, PA, Harper & Row, 1991 O’Hara MW: Postpartum Depression: Causes and Consequences. New York, Springer-Verlag, 1995 O’Hara MW, Rehm LP, Campbell SB: Postpartum depression: a role for social network and life stress variables. J Nerv Ment Dis 171:336–341, 1983 O’Hara MW, Neunaber DJ, Zekoski EM: A prospective study of postpartum depression: prevalence, course, and predictive factors. J Abnorm Psychol 93: 158–171, 1984 O’Hara MW, Schlechte JA, Lewis DA, et al: Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal factors. J Abnorm Psychol 100:63–73, 1991 Paykel ES, Emms EM, Fletcher J: Life events and social support in puerperal depression. Br J Psychiatry 136:339–346, 1980 Pedersen CA, Stern RA, Pate J, et al: Thyroid and adrenal measures during late pregnancy and the puerperium in women who have been major depressed or who become dysphoric postpartum. J Affect Disord 29:201–211, 1993 Pitt B: “Atypical” depression following childbirth. Br J Psychiatry 114:1325– 1335, 1968 Playfair HR, Gowers JI: Depression following childbirth—a search for predictive signs. J R Coll Gen Pract 31:201–208, 1981 Pop VJM, de Rooy HAM, Vader HL, et al: Postpartum thyroid dysfunction and depression in an unselected population. N Engl J Med 324:1815–1816, 1991 Reich T, Winokur G: Postpartum psychosis in patients with manic depressive disease. J Nerv Ment Dis 151:60–68, 1970 Schou M, Amdisen A: Lithium and pregnancy, III: lithium ingestion by children breast-fed by women on lithium treatment. Br Med J 2:138, 1973 Simpson MD, Jenner P, Mardson CD: Hyperprolactinaemia does not alter specific striatal 3H-spiperone binding in the rat. Biochem Pharmacol 35:3203– 3208, 1986 Singh B, Gilhotra M, Smith R, et al: Postpartum psychoses and the dexamethasone suppression test. J Affect Disord 11:173–177, 1986 Snyder SH: The dopamine hypothesis of schizophrenia: focus on a dopamine receptor. Am J Psychiatry 134:138–143, 1977 Stowe ZN, Casarella J, Landrey J, et al: Sertraline in the treatment of women with postpartum major depression. Depression 3:49–55, 1995 Stowe ZN, Owens MJ, Landry JC, et al: Sertraline and desmethylsertraline in human breast milk and nursing infants. Am J Psychiatry 154:1255–1260, 1997 Tetlow C: Psychoses of childbearing. Journal of Mental Science 101:629–639, 1955 Tod EDM: Puerperal depression: a prospective epidemiological study. Lancet 2: 1264–1266, 1964

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Uddenberg N: Reproductive adaptation in mother and daughter. A study of personality development and adaptation to motherhood. Acta Psychiatr Scand Suppl 254:1–115, 1974 Wagner HR, Crutcher KA, Davis JN: Chronic estrogen treatment decreases betaadrenergic responses in rat cerebral cortex. Brain Res 171:147–151, 1979 Watson JP, Elliott SA, Rugg AJ, et al: Psychiatric disorders in pregnancy and the first postnatal year. Br J Psychiatry 144:453–462, 1984 Weintraub S, Prinz RJ, Neale JM: Peer evaluations of the competence of children vulnerable to psychopathology. J Abnorm Child Psychol 6:641–673, 1978 Welner Z, Welner A, McCrary MD, et al: Psychopathology in children of inpatients with depression: a controlled study. J Nerv Ment Dis 164:408–413, 1977 Whiffin VE: Vulnerability to postpartum depression: a prospective multivariate study. J Abnorm Psychol 97:467–474, 1988 Winters KS, Stone AA, Weintraub S, et al: Cognitive and attentional deficits in children vulnerable to psychopathology. J Abnorm Child Psychol 9:435– 453, 1981 Yalom ID, Lunde DT, Moos RH, et al: “Postpartum blues” syndrome. Arch Gen Psychiatry 18:16–27, 1968

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Chapter 12 Clinical Psychotropic Effects of Gonadal Hormone Medications in Women Uriel Halbreich, M.D. Steven J. Wamback, B.S. Linda S. Kahn, Ph.D.

T

he female gonadal hormones, estrogen and progesterone, play a major role in the regulation of fertility and sexuality in women. The emphasis in studies of these hormones, as well as in their clinical applications, has been on their use in gynecological clinics and in situations that are associated with women’s reproductive life cycle and menopause. Since antiquity, however, it has been very well known that some of the events during a woman’s life cycle are closely associated with changes in mood and behavior. These events include puberty, the menstrual cycle, pregnancy, the postpartum period, and menopause. In modern times, the use of contraceptive pills, amenorrhea, ovariectomy, infertility treatments, hormonal replacement therapy, and other situations were added. All of these periods, events, and changes are associated with changes in levels of gonadal hormones. Therefore, it has become quite plausible that these hormones might be responsible for behavioral and mood changes. Furthermore, for more than 60 years, it has been suggested that exogenous administration of these hormones might be beneficial for treatment of dysphoric disorders. In this chapter we selectively review the clinically relevant literature on the effects of estrogen and progesterone on mood and behavior. The emphasis in the discussion concerning estrogen is on its most frequent use, namely as hormone replacement therapy (HRT) for postmenopausal women. The emphasis in the discussion of progesterone is on its role as a

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protective counterbalance to estrogen in HRT as well as on its role as an oral contraceptive. The suggested actions of estrogen are further examined with a comparison of the effects of the estrogen mixed antagonist tamoxifen, which is widely used for treatment of women with breast cancer. Some of the distinctions between hormone-related effects and sex-related determinations may be examined by the study of hormonal effects in male-to-female transsexuals, even though most clinicians do not see very many transsexuals in their daily practice.

Interaction Between Gonadal Hormones, Brain, and Behavior The secretion and activity of gonadal hormones are regulated via the hypothalamic-pituitary-gonadal (HPG) system. Inputs and circuits from the cortex and several internal brain regions influence the hypothalamus, which secretes gonadotropin-releasing hormone (GnRH) in a pulsatile fashion. GnRH causes the secretion of the pituitary hormones, folliclestimulating hormone (FSH) and luteinizing hormone (LH), which are involved in the process leading to ovulation and which regulate the female gonadal hormones estrogen and progesterone. A series of feedback mechanisms maintain a very delicate homeostasis of the HPG system and its interactions with other hormonal and biological systems. This homeostasis can be impaired in response to environmental stimuli, pharmacologic interventions, and a variety of physical and mental disorders. The interaction between the brain and gonadal hormones is bidirectional. The peripheral gonadal hormones exert two main types of actions on the central nervous system: organizational/genomic effects and activational/nongenomic effects (McEwen 1991). The organizational/genomic effects are trophic and occur early during development of the brain. They are permanent and control neural architecture and future activity. Among other influences, organizational effects of gonadal hormones or their absence are responsible for gender differences in brain and behavior. Activational/nongenomic effects of gonadal hormones occur mostly during postnatal life and throughout the entire life cycle. They are reversible and include alterations of normal electrical and biochemical functions and structure. They can add to, and support, gender-differentiated brain functions. Activational/nongenomic effects include many functions that are considered to be involved in the continuous regulation of behavior and mood, are putatively impaired in mental disorders, and are influenced by psychotropic medications. These activities include receptor

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potentiation by direct or modulatory effects, enzyme induction or inhibition, potentiation of intracellular second-messenger processes, and other transitory effects. Receptors and binding sites for gonadal hormones are selectively distributed in the brain and in connection to different neurotransmitter systems. Therefore, their effect cannot be generalized. Another caveat in the evaluation of effects of gonadal hormones is that different metabolic or synthetic analogs might cause opposing behavioral effects. For example, several progesterone metabolites and progestins are anxiolytic, whereas some others are anxiogenic. Timing is also of importance. Priming with estrogen might change the effects of progesterone, and cyclic administration might cause different effects than continuous use.

Estrogen Replacement Therapy for Menopausal Women: Effects on Mood and Cognition HRT for menopausal women is quite prevalent. It is estimated that up to 30% of women receive HRT after menopause. The main menopausal change is the discontinuation of ovulation and menstrual cycling, which is accompanied by constant increased levels of LH and FSH, low levels of estrogen, and negligible levels of progesterone. These low levels of estrogen result in accelerated decrease in bone mineral density and osteoporosis, increased vulnerability to cardiovascular disorders, and atrophy of the gonadal-urinary tract. HRT is approved by the U.S. Food and Drug Administration for prevention of decreased bone mineral density (e.g., Lindsay 1991), as well as for prevention and treatment of menopausal genitourinary atrophy. However, shortly after the proposed “use of folliculin in involutional stress” (Sevringhaus 1933), there were initial attempts to use estrogen for treatment of postmenopausal depression (Wiesbader and Kurzrok 1938). Mostly animal studies, but also some human trials (e.g., Best et al. 1992; Ditkoff et al. 1991; Halbreich et al. 1995; Limouzin-Lamothe et al. 1994) suggest that estrogen should have antidepressant properties. It increases serotonergic functions as well as norepinephrine synthesis and activity on receptor levels. In addition, it decreases metabolism of monoamines by inhibiting the activity of the enzymes monoamine oxidase and catechol O-methyltransferase. It also increases g-aminobutyric acid (GABA) activity. Its effect on some other systems like the cholinergic one is mixed. Estrogen shows a modulatory effect on dopaminergic systems, which might be important for gender differences in schizophrenia, as

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well as adverse effects of antipsychotic medications, which are not discussed in detail here (McEwen et al. 1997). Nonetheless, the few reports on studies of the efficacy of estrogen for treatment of depressed postmenopausal women were consistently negative and disappointing (Coope 1981; Coope et al. 1975; Oppenheim 1986; M.A. Schneider et al. 1977; Shapira et al. 1985). Yet a recent study by Whooley et al. (2000), comparing current estrogen users and nonusers among 6,602 postmenopausal women, found that current use of unopposed estrogen was associated with a decreased risk of depressive symptoms. There are also clinical observations and suggestions that estrogen might be used effectively as an adjunct therapy for postmenopausal women who have not responded to treatment with tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). Several post hoc analyses of postmenopausal women with and without HRT who participated in clinical trials suggest that women receiving HRT respond better to antidepressants (L. Schneider et al. 1997). Regretfully, we are unaware of double-blind, placebo-controlled prospective reports of estrogen efficacy in these situations, but personal communications and discussions at scientific meetings are quite numerous. Certainly, there is a need for a well-designed scientific confirmation of this notion (which, on a theoretical basis, would be expected to be positive). The combination of an SSRI and estrogen might be expected to be more beneficial than a TCA-estrogen combination because of amplification of the side effects of TCAs (e.g., cholinergic effects) by estrogen. Estrogen probably complements and supplements SSRI activity by its inhibitory effect on monoamine oxidase, its postsynaptic effect on serotonin receptors, its enhancement of norepinephrine activity, and its positive effect on intracellular signal transduction. It is of interest that the clinically reported effects of estrogen as an adjunct therapy in depressed women is similar to the reported effects of thyroid hormones in the same group of patients. Because of the similarities between thyroid and estrogen receptors and receptor-mediated activities, the clinical similarities are of great heuristic and practical interest. It is to be hoped that further studies will clarify these issues. As opposed to the negative results of using estrogen as an independent antidepressant for depressed women, there were more than a dozen reports of clinical trials showing that the administration of estrogen replacement to healthy, nondepressed postmenopausal women improves their mood and general feeling of well-being (Aylward 1976; Aylward et al. 1974; Best et al. 1992; Daly et al. 1993; Ditkoff et al. 1991; FedorFreybergh 1977; Furuhjelm and Carlstrom 1977; Furuhjelm and FedorFreybergh 1976; Limouzin-Lamothe et al. 1994; Michael et al. 1970;

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Palinkas and Barrett-Connor 1992; M.A. Schneider et al. 1977). In addition, there are numerous case studies and uncontrolled clinical reports of increased well-being; increased energy and libido; and improved sexual performance, desire, and affection in elderly women who have received HRT for long periods of time. The influence of HRT on cognitive functions of postmenopausal women is still under investigation. Since the early 1950s, it has been suggested that this influence might be diversified and may depend on the cognitive construct studied (Caldwell and Watson 1952). In most cases, when various tests of memory were studied, a positive effect of estrogen was reported (e.g., Campbell and Whitehead 1977; Fedor-Freybergh 1977; Furuhjelm and Carlstrom 1977; Hackman and Galbraith 1976; Halbreich et al. 1995; Kampen and Sherwin 1994; Phillips and Sherwin 1992; M.A. Schneider et al. 1977). However, this improvement is not generalized. For example, some women who had improved immediate recall and association learning in response to estradiol administration (Phillips and Sherwin 1992) did not show improvement of delayed recall, visual reproduction, or digit span. In another large survey (Barrett-Connor and Kritz-Silverstein 1993) of 800 women who either were or were not taking estrogen (mostly Premarin), verbal and visual memory were not improved by estrogen use. In a study by Sherwin’s group (Kampen and Sherwin 1994), selective reminding and paragraph recall (verbal memory) were improved, whereas spatial ability and attention span were not. Our own studies (Halbreich 1997; Halbreich et al. 1993, 1995), with an extensive battery of cognitive tests, showed improvement on complex integrative cognitive tasks that require integration of several cognitive constructs, such as recognition, interpretation, decision making, eyehand coordination, and reaction. These integrative tasks are reported to be impaired in conditions that involve generalized brain impairment (such as concussion or generalized brain trauma) and might involve damage to brain circuitry. We also found positive effects of estrogen on several short-term memory functions. A rapidly developing area of interest is the possible positive effect of estrogen in women with Alzheimer’s-type dementia. It has been reported that among women receiving estrogen replacement therapy the incidence of Alzheimer’s disease tended to be lower and the deterioration in those who did develop Alzheimer’s disease was less severe than in women of the same age who did not receive HRT (Birge 1997; Henderson 1997; Paganini-Hill 1994). Several studies have reported improvement of dementia in women who were treated with conjugated estrogen (e.g., Honjo et al. 1989, 1995; Mortel and Meyer 1994, 1995; Ohkura et al. 1994, 1995). It is of interest that in several studies (Asthana et al.

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1999; Ohkura et al. 1994, 1995) termination of treatment resulted in a worsening of cognitive functions. However, a recent study by Mulnard et al. (2000) did not find evidence that estrogen replacement therapy for 1 year enhances cognitive function or slows the progression of Alzheimer’s dementia. It is also known that the addition of progesterone to HRT regimens reduces the effect of HRT on depressed mood (Zweifel and O’Brien 1997). The involvement of estrogen in Alzheimer’s dementia is being unfolded at present. It is still undetermined whether estrogen replacement therapy might be a preventive measure or whether it might also be used as treatment for improvement of dementia and other cognitive impairments once they already exist. The importance of the lack of estrogen as a risk factor for Alzheimer’s disease and the magnitude of its contribution to the variance of dementia is also still unknown. Considering the intensified interest in the interaction between estrogen and Alzheimer’s dementia, it might be expected that answers to these questions are not far ahead. With the advent of a new class of drugs, selective estrogen receptor modulators, which have differential site-specific estrogenic or antiestrogenic effects in different target tissues, HRT will undergo a sea of change in the coming years.

Common Estrogen Preparations and Dosages In premenopausal women, the most significant estrogen is estradiol, which is secreted from the ovaries and is their most potent hormone. After menopause, women still have small amounts of estrogen in the form of estrone, which is derived from the adrenals by metabolism of androstenedione. Estradiol is also metabolized (oxidized) to estrone and then to estriol. Pharmacologically, the two most prevalent estrogen products are estradiol and conjugated estrogens, even though several other preparations are available. Estradiol is probably the most potent estrogen, but when given in equipotent dosages, all estrogens probably show similar effects on bone mineral density and the cardiovascular system. Their effect on lipids might be different. It is still unknown whether they differ in their effects on mood and cognition because we are not aware of any direct comparison studies to this effect. Hence, we address only issues that might be related to mood and behavior in consideration of preparations that are widely and commonly used. Oral conjugated estrogens are sulfate esters mostly of estrone and equilin. The usual daily dosage for HRT is 0.625 mg. Because of preliminary findings that positive effects of estrogen on cognitive functions might be related to plasma levels of estrogen (Drake et al. 2000; Sherwin

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2000), it might eventually be found that for improved cognition and well-being, 1.25 mg/day is actually needed. According to the American Medical Association’s Drug Evaluations Annual (American Medical Association 1995), “There have been problems with bioequivalence of generic preparations; new manufacturing specifications to ensure conformity of generic products to Premarin are being developed." Our own studies initially involved estradiol delivered via a transdermal patch to postmenopausal women. The combination of this preparation and mode of delivery appears to be preferable because it is readily absorbed; it is only minimally metabolized in the skin; and it results in a close-to-physiological situation of high estradiol-to-estrone ratio compared with the high estrone levels of oral preparations. Transdermal administration also entirely bypasses the liver and therefore produces less binding to sex hormone–binding globulin and other binding proteins (less protein binding as well as less first-pass extraction by the liver). Therefore, higher available estrogen levels are coupled with steady continuous plasma levels of estrogen (estradiol) delivery; and, provided that the assumption that higher levels of steady estrogen might be needed to produce favorable cognitive effects is true, transdermal patches might be preferable to oral conjugated preparations. In our studies of postmenopausal women, we used 0.1-mg patches twice weekly. Because of the finding of a positive correlation between plasma levels of estradiol and cognitive performance in some tests, it is still unclear whether the lowerdose 0.05-mg patch would be sufficient, even though it provides the usual recommended dose for HRT. Transdermal patches are prescribed for change twice weekly and should be rotated on the trunk or buttocks. Some women prefer to apply them on the upper thigh. An additional side effect of transdermal patches is irritation and redness at the application site, which in many cases is transitory. An interesting variation of oral estrogens is a combination of esterified estrogen (0.625 or 1.25 mg) and methyl testosterone (1.25–2.5 mg). For purposes of mood, cognition, and libido, this combination of estrogen and androgen should be quite effective because of the addition of the androgen, which might have a positive effect on mood and cognition in its own right. This suggestion is strengthened by the reports here (Rako 1999). After hysterectomy and subsequent ovarian failure (a consequence of loss of the blood supply provided by the uterine artery) or after oophorectomy, symptoms of estrogen deficiency and testosterone deficiency are present. Symptoms of loss of libido and sexual response, lack of general energy, and a diminished sense of well-being can be attributed to testosterone deficiency. Too often these symptoms are misdiagnosed, and many women are prescribed antidepressants (Rako 1999). At present,

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however, there are few studies showing any direct comparison of effects on well-being and cognition of esterified estrogen or estradiol with and without methyl testosterone (Sherwin and Gelfand 1985). In fact, this preparation might cause some androgenic side effects.

Regimens of Hormone Replacement Therapy: Pros and Cons Most clinicians prescribe HRT in a cyclic fashion—cyclic or continual estrogen with a cyclic addition of progesterone. However, several other options should be taken into consideration: estrogen only, cyclic estrogen with no addition of progesterone, continual administration of estrogen and progesterone combination, and cyclic or continual administration of an estrogen-androgen combination. Evaluation of the mood and behavioral effects of progesterone per se is discussed separately. In this section we focus on the merits and disadvantages of the addition of progesterone as part of HRT. Progesterone is recommended as part of HRT to induce endometrial shedding and bleeding, to avoid estrogen-induced endometrial hyperplasia, and to decrease the risk of endometrial cancer. In women who have had hysterectomy, progesterone is not needed, and unopposed continual estrogen can be prescribed (Williams and Moley 1994). Most clinicians prescribe progesterone in a cyclic sequential fashion of HRT in women who have attained natural menopause, as well as for oral contraception. In this way, estrogen (usually Premarin or Estraderm) is taken for 25 days and a progesterone, usually medroxyprogesterone acetate (Provera) (5–10 mg), is added during days 15–25. This is usually followed by withdrawal bleeding, and the cyclic hormonal regimen is resumed within 5 days, even if no bleeding occurs. Negative mood effects in this regimen are quite prevalent. They appear during the period in which progestogens are added or shortly thereafter. Actually, this sequential addition of progestogen has been used as a model for simulating premenstrual syndrome (PMS) and its cyclicity (Hammerback et al. 1983). The negative mood effects of this HRT regimen might be dose related and may be more severe with increased dosage of the progestogen (Magos et al. 1984, 1986a, 1986b). It has been suggested (Halbreich 1996), though not yet confirmed, that women who had PMS during their reproductive life might be more vulnerable to the development of mood side effects from sequential cyclic HRT. The mood effects of continual administration of estrogen with cyclic progestogen are probably similar. Symptoms might be less severe because of no cyclic withdrawal of estrogen (see Lobo et al. 1984), but

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we are unaware of actual studies to this effect. Continual administration of combined estrogen and progesterone in low dosages produces fewer mood and behavioral side effects than the cyclic regimen and therefore may be a preferential HRT modality. Clinical experience is that mood side effects might be milder or dependent on the progestogen used. A recent study by Bjorn et al. (2000) compared side effects of medroxyprogesterone acetate and norethindrone acetate among postmenopausal women with and without a history of PMS. Researchers found that women with a history of PMS had significantly more negative mood symptoms during medroxyprogesterone treatment and had more negative daily life effects while taking norethindrone compared with women with no history of PMS. Among women with no history of PMS, medroxyprogesterone was associated with more positive mood symptoms compared with norethindrone. Because pyridoxine deficiency may be a contributing factor to depression, especially among users of oral contraceptives, 25–30 mg/day of pyridoxine is recommended (Coukell and Balfour 1998). Patients experiencing depression should be advised to discontinue the medication to determine if the symptom is drug related. In patients with a history of depressive disorder, oral contraceptives are to be discontinued if depression recurs to a severe degree. Our experience is that cyclic administration of estradiol patches with no progesterone produces withdrawal bleeding within a few days after discontinuation of the estrogen. We used this regimen for research purposes for periods up to 60 days. Several other groups gave continual estrogen for longer periods. As is the case with other regimens, there might be increased irritability, tension, and anxiety during the first 2 weeks of estrogen administration, but these initial side effects usually disappear with continuation of treatment. The reported mood side effects that are observed with HRT regimens that include progestogens are not observed with this pattern. For routine clinical purposes, however, the relative risk should be evaluated by the individual clinician.

Contraindications and Adverse Effects of Estrogen The contraindications for the prescription of estrogens are listed in Table 12–1. In addition, close supervision is required in cases of severe hypertension, diabetes mellitus, asthma, migraine, epilepsy, cardiac or renal dysfunction (due to possible exacerbation or because of water retention), and liver diseases (due to a possibility of decreased metabolism of exogenous estrogen) (Drug Facts and Comparisons 2000; “Estrogens” 2000). Adverse effects of estrogen are listed in Table 12–2. It should be

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TABLE 12–1.

Contraindications for the use of estrogen

Breast cancer (with a possible exception of localized receptor-negative breast cancer) Estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding Active thrombophlebitis or thromboembolic disorders History of thrombophlebitis, thrombosis, or thromboembolic disorders during previous estrogen use Known or suspected pregnancy Source.

Information adapted from “Estrogens” 2000.

TABLE 12–2.

Adverse effects of estrogens

Increased risk of endometrial carcinoma Increased risk of breast cancer ?? Increased risk of gallbladder disease Breakthrough bleeding Thrombophlebitis Nausea, vomiting, abdominal cramps Bloating, water retention Breast tenderness, enlargement, or secretion Headache, dizziness, convulsions During initial 2 weeks: anxiety, depression, and irritability With Estraderm: irritation or rash at application site Intolerance to contact lenses Changes in libido Teratogenic effects

emphasized that some of the side effects—such as anxiety, depression, and irritability—might be very acute and usually disappear or improve within 2 weeks. Therefore, if the patient complains of these side effects immediately after initiation of treatment, their transitory nature should be explained to her and she should be encouraged to continue medication. Some of the other adverse effects—for example, nausea, vomiting, and weight changes—might also decline with time, although frequently they might persist.

Hormonal Treatment of Premenstrual Syndrome: Effects of Ovulation Suppression With GnRH Analogs and Estrogen Premenstrual syndromes are quite prevalent and might affect up to 40% of women of reproductive age (Andersch et al. 1986; Woods et al. 1982a,

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1982b). Three to eight percent of women meet criteria for severe dysphoric PMS or premenstrual dysphoric disorder (American Psychiatric Association 2000); such diagnoses require impaired functioning and warrant treatment (American College of Obstetricians and Gynecologists 1989; Rivera-Tovar and Frank 1990). Even though the exact etiology and pathobiology of PMS are still obscure, most researchers in the field believe that gonadal hormones play a major role in the disorder. It is suggested that the etiology of PMS involves a compilation of vulnerability factors; environmental, social, and personality inputs; and biological determinants. The biological determinants probably involve an interplay between steroids, gonadal hormones, other hormonal systems, neurotransmitters, and intraneural mechanisms (Gold and Severino 1994; Halbreich 1995, 1996, 1999; Halbreich and Endicott 1985; Halbreich et al. 1986, 1988, 1995; Smith and Schiff 1993). The role of ovulation or ovulation-related mechanisms and processes in the pathophysiology of PMS is underscored by reports that women with PMS did not have symptoms during anovulatory menstrual cycles (Backstrom et al. 1983, 1989). Hysterectomy and ovariectomy were shown to eliminate PMS, whereas symptoms continued when hysterectomy alone was performed (Backstrom et al. 1983; Casper and Hearn 1990; Casson et al. 1990). Indeed, one of the most effective treatments for PMS is elimination of ovulation with GnRH analogs or with danazol (Bancroft et al. 1985, 1987; Halbreich et al. 1991; Muse et al. 1984). Suppression of ovulation interferes with multiple processes as well as with their cyclicity, and even though the main change is probably in the decreased levels and elimination of cyclicity of gonadal hormones, the influence of other parameters cannot be ignored. This is also the case when GnRH analogs or other ovulation suppressants are administered as treatment for other disorders (e.g., endometriosis or polycyclic ovaries). Ovulation might be suppressed by danazol (Danocrine), which is a synthetic derivative of 17a-ethinyl testosterone. It inhibits the midcycle gonadotropin surge. It has been shown (Day 1979; Gillomere et al. 1985) to be effective for treatment of PMS in a marginal dosage of 200 mg/day. It is effective only when ovulation is suppressed (Halbreich et al. 1991). Even though it has been reported that danazol is also effective when given following ovulation at the beginning of the luteal phase, this has probably not been confirmed. Danazol might cause a myriad of side effects, mostly androgenic, and is not well tolerated by many women. Ovulation suppression by several GnRH analogs (e.g., buserelin) has been widely shown to be effective in treatment of a wide range of premenstrual syndromes, including dysphoric PMS (Bancroft et al. 1985, 1987; Hammerback and Backstrom 1988). The most convenient way to sup-

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press ovulation and treat PMS is by administration of leuprolide acetate (Lupron), which is injected intramuscularly (3.75 mg) once a month. However, leuprolide is quite expensive, and in the current market it is not reimbursable for the indication of PMS by most third-party payers. Administration of leuprolide and other GnRH analogs produces a lack of estrogen and progesterone and therefore a “pharmacologic menopause” with possible initial menopausal symptoms. If taken without any estrogen supplement, leuprolide and other GnRH analogs produce long-term effects. This state can be overcome with the addition of continual estrogen or cyclic estrogen. If progesterone is added in a sequential cyclic regimen, the advantages of GnRH analogs are overcome because this cyclicity induces symptoms that mimic PMS (Mortola et al. 1991). Suppression of ovulation, elimination of cyclicity, and fluctuation of gonadal hormones can actually be achieved by sustained high levels of estrogens. Crystalline estradiol subcutaneous implants (100 mg in the anterior abdominal wall) have been shown to be superior to placebo for treatment of PMS (Magos et al. 1984, 1986a, 1986b) in long-term (10month) treatment. Two points are of interest regarding this regimen: first, very high placebo response (94%) was noticed during the first 2 months, but it disappeared 4 months into the study. Second, to counteract the endometrial building effect of estrogen and to induce bleeding, progestin (Norethisterone) (5 mg) was administered sequentially, which produced PMS-like effects during the progestin period, although to a lesser degree and in a smaller number of patients. A substantial group of women have been treated with this regimen of continual estrogen and cyclic progestin for many years (more than 8–10 years) with sustained relief from PMS (Watson and Studd 1993; Watson et al. 1989, 1990). A relatively convenient and less intensive modality of sustained estrogen administration is transdermal estrogen patches (Estraderm and Systen), which in high dosages of 0.2 mg twice weekly suppress ovulation. This treatment is highly effective for PMS (Watson et al. 1989, 1990), is sustainable, does not induce menopause-like symptoms, and is relatively cost-effective. When given in combination with a sequential cyclic progestogen, some of its therapeutic efficacy is lost. However, estrogen withdrawal usually induces bleeding within a few days, and therefore with adequate long-term follow-up, cyclic (up to 60 days) administration of transdermal estradiol patches with no addition of progesterone should be effective and safe for long periods of time. We are unaware, however, of any published controlled studies of the long-term efficacy and safety of this regimen in the United States (nor of any other sustained regimen except estrogen implants); hence this recommendation should be taken very cautiously.

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A very reliable and less dramatic alternative is symptomatic treatment. In women with dysphoric PMS, several antidepressants, especially SSRIs, have been shown to be highly effective (see reviews by Gold and Severino 1994; Halbreich 1996). Their evaluation, however, is beyond the scope of this chapter. The effects of progesterone and contraceptive pills on menstrually related mood and behavioral changes, as well as their side effects, are discussed under “Mood and Behavioral Effects of Contraceptive Hormones” below.

Mood and Behavioral Effects of Contraceptive Hormones Oral contraceptives are used very widely. Many products are available on the market, and generalization of their effects on mood and behavior would be misleading because they have different steroids, different combinations, and various modes of administration; most of them can markedly affect the regulation of mood and behavior. Hormonal contraceptives are marketed mainly as oral pills. However, there is increasing use of longacting depot preparations and intravaginal rings, which are discussed briefly at the end of this section. Oral contraceptives are usually a combination of synthetic estrogen and a progestin or, in a few cases, progestin-only “minipills.” The combination pills are supplied in three main modes of administration: 1) monophasic, in which constant amounts of low-dose estrogen and progestin are taken for 21 days with a 7-day withdrawal period (during which bleeding usually occurs); 2) biphasic, in which a constant low dose of estrogen is combined with a low dose of a progestin for 10 days, then the progestin is increased for 11 days, after which both hormones are withdrawn; and 3) triphasic, in which the progestin is alternately increased and decreased every 7 days with a constant dose of estrogen. There are also triphasic preparations in which the levels of both estrogen and the progestin change. It is of interest that even though mood side effects of oral contraceptives were already reported a generation ago (Cullberg 1972) and up to 30% of women discontinue oral contraceptive use because of mental side effects (Milsom et al. 1991), the knowledge about the diversified mood and behavior affects of oral contraceptives is far from satisfactory. The report that 30% of women discontinue oral contraceptive use because of mental effect is quite consistent with other reports that 30% of women taking oral contraceptives develop negative mood changes (Clare 1985a, 1985b; Cullberg 1972). The mood and behavioral side effects of oral contraceptives are probably due mostly to the progestin component. As mentioned above, the different progestin compounds used might be responsible for conflicting

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reports in this field. This possibility was demonstrated by Backstrom (1992), who found that levonorgestrel induced more mental side effects than desogestrel. The schedule of administration might also be of importance. It has been documented (Bancroft et al. 1985, 1987, 1993) that triphasic oral contraceptives induced more mental side effects than monophasic oral contraceptives, even though the monophasic pills had higher progestin dosages. This observation is in accord with the notion that menstrually related symptoms might be associated with the cyclic fluctuation of gonadal hormones, mostly progesterone, and not necessarily with their absolute levels. The triphasic preparations simulate and amplify the hormonal fluctuations, and according to the hypothesis described above would be expected to induce higher rates of side effects. Vulnerability to depression might play an important role in the development of mood side effects to oral contraceptives. It has been suggested that women who have a history of dysphoric PMS, which has been shown to be associated with major depressive disorder and other affective disorders (Halbreich and Endicott 1985), are more prone to dysphoric mood side effects of oral contraceptives (Backstrom 1996; Backstrom et al. 1985; Cullberg 1972; Graham and Sherwin 1987; Hammerback and Backstrom 1988). This issue is still not entirely clear, because it has been reported that women with moderate to severe PMS were more likely to develop negative mood symptoms while taking oral contraceptives, compared with women with mild PMS who had positive mood changes when taking oral contraceptives (Backstrom 1992). As implied by Backstrom (1996), the latter effect might be due to a placebo effect that might be more influential on women with mild PMS, whereas the actual drugrelated side effects are more apparent in women with severe PMS—who might also be the women who are more vulnerable or are at higher risk of developing affective disorders in general. The mood effects of minipills, which contain only progestin and are taken continually, are not well studied. They are less favorable than combination pills, mainly due to menstrual irregularities and a lower degree of contraceptive effectiveness. Dysphoria might be expected, especially in vulnerable women, but this has not been extensively studied. The depot contraceptives are very widely used, mostly depot medroxyprogesterone (Depo-Provera) and, more recently, levonorgestrel (Norplant). The mental side effects of these drugs remain unclear. Several controlled studies have reported some mood side effects (Haugen et al. 1996; Kirkman et al. 1999; Sivin et al. 1998), as have two case reports (Wagner 1996; Wagner and Berenson 1994). Westhoff and colleagues (1998a, 1998b) undertook a prospective multicenter study to evaluate

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the relationship between contraceptives and depression, focusing on Norplant and Depo-Provera. With both Norplant and Depo-Provera, relationship satisfaction was the greatest predictor of depression symptom scores. Other multicenter studies assessing the impact of long-acting contraceptives like Depo-Provera and Norplant show that there is no increase in depressive symptoms (Kaunitz 1999).

Mood and Behavior Effects of Tamoxifen and Other Estrogen Antagonists Tamoxifen is a synthetic steroidal compound that was introduced as an antiestrogen for treatment of breast cancer in women (Richardson 1988). It is also used as a prevention maintenance therapy for healthy women who are at high risk to develop breast cancer (National Surgical Adjuvant Breast and Bowel Project 1992) and is therefore administered to quite a large population of women. It is currently acknowledged that tamoxifen is actually a mixed estrogenic-antiestrogenic compound, and in some species and in some tissues its estrogen-like activity prevails. Such is the case with bone tissue, in which tamoxifen was shown to delay decreased bone mineral density. Its activity on the central nervous system and biological processes that are putatively involved in regulation of brain and behavior has not yet been fully documented. Implications from animal studies of the behavioral effects of tamoxifen should be viewed cautiously due to the species variability of its effects. Tamoxifen prevents lordosis in female rats (Etgen 1979), as well as prepartum onset of maternal behavior (Ahdieh et al. 1987). It reduces offensive behavior in rats (Brain et al. 1988) and aggressive behavior in mice (Hasan et al. 1988). Tamoxifen increases estrogen-related anxiety behavior in female rats (i.e., it acted as an estrogen antagonist) (Pellow et al. 1985). Short-term administration of tamoxifen to ovariectomized female rats causes decreases in food intake, body weight, and adipose tissue (Bowman et al. 1983), whereas longer-term administration transiently increases food intake and body weight (Gray et al. 1993) in a way similar to that of estrogen. Information on the mood and behavior effects of tamoxifen in humans is still limited. The evaluation of the role of drug-related depression is complicated by the fact that most patients who receive this medication are women with breast cancer, who might be depressed due to their primary illness. In women with breast cancer, 15% of those taking tamoxifen developed depressive symptoms, compared with 3% of women who did not receive tamoxifen. Symptoms improved following discontinuation of treatment (Cathcart et al. 1993). Similar observations were reported by

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another group (Shariff et al. 1995), which found that 12% of breast cancer patients taking tamoxifen had moderately elevated scores for anxiety and dysthymia. When given as a chemopreventive therapy to healthy women, only 2% (3/141) reported depression, a rate that was quite similar to that of placebo (2/138) (Powles et al. 1990). In a small study of males taking tamoxifen, 4 of 24 patients reported depression (Anelli et al. 1994). Our own impression is that tamoxifen does not usually cause depression by itself. However, if a woman with a lifetime history of a major depressive disorder becomes depressed again as part of her usual pattern while taking tamoxifen, her response to antidepressants might be altered. She might not respond to medications to which she responded well in the past, or she might need higher dosages of these medications. It is intriguing (and distressing) that despite the relatively extensive use of other antiestrogens, such as clomiphene (which is used for stimulation of secretion of gonadotropins and induction of ovulation) (American Medical Association 1994) and recently raloxifene (which is used for HRT and breast cancer), the effects of these medications on the central nervous system, mood, and behavior have not yet been properly studied. However, alertness to possible alteration of mood in women treated with these medications is advisable.

Mood and Behavior Effects of Progesterone and Progestins Many clinically relevant aspects of progesterone and progestins (synthetic preparations with progesterone-like activity) are described earlier in the sections “Regimens of Hormone Replacement Therapy,” “Hormonal Treatment of Premenstrual Syndrome,” and “Mood and Behavioral Effects of Contraceptive Hormones.” In this section we briefly draw some implications from previously discussed clinical observations and added aspects that might be related to dysphoric mood in general. Natural progesterone is mainly available for parenteral administration and is being used as vaginal or rectal suppositories; synthetic progesterones are generally administered orally. They might be derived from the testosterone molecule or from 17-hydroxyprogesterone. They vary greatly in their potency, progestational and androgenic effects and in their mood and behavioral effects. The diversity of biological and pathobiological effects is further emphasized by the expanded knowledge on the different effects of various progesterone metabolites. Progesterone and its metabolites enter the central nervous system. Levels of progesterone in the brain change throughout the menstrual cycle, and they are not evenly distributed; they are

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higher in the cerebral cortex, hypothalamus, and limbic regions. One of the first indications that the brain is a target organ for progesterone was the finding of progesterone receptors in selected mood-related and cognition-related areas of the brain (Luine et al. 1975; Pfaff and McEwen 1983). Progesterone binding sites have been identified (in selected areas) on neuron cell membranes as well as on its nucleus. Progesterone and other steroids may also be metabolized in the brain itself as well as in the periphery. Various metabolites might have opposite effects on mood; therefore, the metabolic pathway might determine the overall effect. The A-ring reduced metabolites of progesterone, allopregnanolone (3a-hydroxy5a-pregnane-20-one) and pregnanolone (3a-hydroxy-5b-pregnan-20-one), have been shown to be potent agonists of the brain GABA-A receptor (Paul and Purdy 1992), and as such they have anxiolytic (antianxiety) properties. However, as GABA-A agonists with barbiturate-like modulation, these metabolites might also show effects similar to those of benzodiazepines on several cognitive functions. This was actually discovered when progesterone was administered to healthy women (Freeman et al. 1990, 1993), who experienced increased fatigue and confusion and decreased performance on immediate recall and symbolic copying (a measure of motor performance) tasks—results that are similar to the cognitive effects of benzodiazepines. The cognitive impairment was dose related. Similar anesthetic, anxiolytic, and antiepileptic effects of pregnanolone and allopregnanolone, which are related to the agonist effect on GABA-A receptors, were consistently reported by other groups (Carl et al. 1990; Finn and Gee 1993a, 1993b, 1994; Gee 1988; Landgren et al. 1982; Majewska 1992; Majewska and Schwartz 1987; Majewska et al. 1986; Norberg et al. 1987). Clinically, the memory and other cognitive impairments induced by these progesterone metabolites might explain the observations that the cognitive side effects of benzodiazepines are amplified by progesterone and some other progestogens. This should be taken into consideration in the selection and administration of specific HRT regimens or oral contraceptives simultaneously with anxiolytics. A non-GABAergic anxiolytic might be preferable, especially in women who are taking progesterone. The interaction between GABA, benzodiazepine, and progesterone led to the speculation that progesterone might also be beneficial to attenuate withdrawal symptoms of benzodiazepine-dependent patients (Schweizer et al. 1995). As opposed to allopregnanolone and pregnanolone, some other progestogens, such as pregnenolone sulfate, and some androgen metabolites show anxiogenic effects (Paul and Purdy 1992) and act on the GABA-A receptor’s benzodiazepine site as “inverse agonists.”

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A recent study of women with PMS (Wang et al. 1996) showed a significant menstrually related cyclic variation of pregnenolone and pregnenolone sulfate, which was correlated with progesterone levels and variation. These authors found that higher luteal-phase levels of 5a-pregnane-3,20-dione (5a-dihydroprogesterone [5a-DHP]) and 3a-hydroxy5a-pregnan-20-one (3a,5a-tetrahydroprogesterone [3a,5a-THP]) were associated with improved PMS symptoms, whereas higher levels of pregnanolone sulfate and pregnanolone (as well as estradiol) were associated with worsened negative dysphoric symptoms. This might suggest that different metabolic pathways of progesterone might exist in different women and in different situations, resulting in different anxiolytic or anxiogenic effects. In women with dysphoric PMS, or any other dysphoric state, the dominant pathway is the one leading to the anxiogenic metabolites. It is of interest whether these not-yet-confirmed hypotheses are also pertinent to the central nervous system. Another interesting and generalizable finding of the same study (Wang et al. 1996) is that dysphoric symptoms correlate with plasma levels of progesterone, pregnenolone, 5a-DHP and 3a,5a-THP, with a delay of 3–4 days between hormonal peaks and symptoms formation. This finding confirms previous reports by Halbreich et al. (1986) and Redei and Freeman (1995) and might have implications for the understanding of the clinical timeline of progestogens as well as for the elucidation of their pathophysiology.

Effects of Female Hormones on Male-to-Female Transsexuals Even though the prevalence of transsexualism is quite low (probably 1 in 30,000 men) (Meyer-Bahlburg 1994), and the likelihood of the average clinician actually treating transsexuals or addressing their side effects is remote, transsexualism is of interest because it provides an excellent model for the study and understanding of the effects of gonadal hormones. This is a useful model for several reasons: 1) Genetically male subjects receive female hormones, and therefore the gender, biological, and behavioral effects can be distinguished from gonadal hormonal effects in the same subject. 2) The same people can be studied before hormonal treatment, while their hormonal milieu is predominantly that of the male gonadal hormones, and then after treatment, while they are predominantly influenced by female hormones. They can also be studied before and after surgical castration. 3) At baseline, before hormonal treatment, people with transgender identities (whether or not it is defined as a disorder) (American Psychiatric Association 2000) can be compared to men

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and women in behavioral as well as hormonal and other biological parameters, as part of the search for biological underpinnings of gender and sex. Nevertheless, transsexuals are not a perfect model for the influences of exogenous gonadal hormones on biology and behavior. First, many of them are homosexuals, and as such, they might have inherent biological differences from heterosexual men (Dorner et al. 1991, 1993). The wish for gender and sex transformation might distinguish them even further from other homosexual men who do not wish to change their sex (Dorner et al. 1991, 1993). Another caveat for generalizations from this work is that male-tofemale transsexuals receive estrogen dosages that are far higher than those used for HRT and other indications in women. The usual dosage of conjugated estrogen administered to transsexuals is 7.5–10.0 mg/day, which is 10 times higher than the dosage normally given to postmenopausal women (Meyer et al. 1986). Up to 2 years of estrogen treatment at this high dose is necessary to achieve maximum breast development. The effects of estrogen and antiandrogens (cyproterone acetate) on the behavior of genetic XY transsexuals are quite pronounced (Van Goozen et al. 1995). Anger, aggression proneness, sexual arousability, and cognitive spatial ability decreased after estrogen treatment, whereas verbal fluency improved, indicating that these behaviors and cognitive functions are influenced by activational effects and are not entirely or essentially sex-specific organizational functions. Because of their antiandrogenic effects, progestins are sometimes coadministered (continually or cyclically) with estrogen therapy to male-to-female transsexuals, although we are not aware of any studies that have measured the behavioral effects of such progestin treatment. Synthetic progestins such as medroxyprogesterone acetate and cyproterone acetate, however, have been shown to suppress self-initiated aggressive sexual activity and libido for extended periods of time in male felony sex offenders, even though when given in appropriate doses normal sexual responsiveness is maintained in these patients (Cooper 1986). Behavioral studies on the response of transsexuals to administration of female hormones are currently quite scarce. They should be evaluated cautiously, because double-blind, placebo-controlled studies are difficult to conduct with this population. The very high resolve of transsexual patients to change their appearance and behavior might affect their responses to self-reporting on female behavior and feelings, which might be exaggerated. Objective tests of research might suggest that not all changes are subjective, but further rigorous research is needed in this area.

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Summary and Conclusion The female gonadal hormones estrogen and progesterone, as well as their metabolites and other gonadal hormone agonists and antagonists, have an extensive and significant impact on the brain and its related mood, cognition, and behavioral processes. There is a substantial, growing body of data suggesting that estrogens might be indicated for treatment and prevention of Alzheimer’s dementia, as well as for protection against deterioration of cognitive function in postmenopausal women and improvement of their well-being. Even though estrogen alone probably does not improve the mood of depressed postmenopausal women, estrogen administration might augment the effectiveness of SSRIs among those diagnosed with depression (Amsterdam et al. 1999; L. Schneider et al. 1997, 1998). Estrogen might also be effective in the treatment of PMS. Progesterone often counteracts the effects of estrogen, and some of its metabolites appear to act as anxiolytic agents, whereas others are anxiogenic. A woman’s mental health history should be considered before administering longacting depot contraceptives (i.e., Depo-Provera and Norplant) until more is known about the specific mood effects of the progestins depot medroxyprogesterone and levonorgestrel.

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Chapter 13 Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids Harrison G. Pope Jr., M.D. David L. Katz, M.D., J.D.

The anabolic-androgenic steroids (AASs) are a family of

hormones that includes the natural male hormone, testosterone, together with a large number of synthetic analogs of testosterone that have been synthesized over the course of the last 40 years. In the body, natural testosterone is synthesized from cholesterol; its four-ring chemical structure resembles that of cholesterol. Testosterone binds to androgen receptors in the cytoplasm of cells; the steroid-receptor complex is then transported to the cell nucleus, where it stimulates gene transcription and hence new protein synthesis. Synthetic AASs generally represent small modifications to the testosterone molecule, such as addition of an alkyl group at the 17a position of the molecule, or formation of an ester at the 17b hydroxyl group; the mechanism of action of these synthetic compounds is essentially identical to that of testosterone itself. Both testosterone and synthetic AASs produce a combination of anabolic and androgenic effects. The anabolic effects—which are the effects generally sought by illicit users of these drugs—include increased protein synthesis, decreased nitrogen excretion, and consequent gains in muscle size and strength. The androgenic effects are the masculinizing effects of the drugs, such as growth of male hair patterns and male sexual characteristics. The androgenic effects of natural testosterone are largely attributable to its metabolite dihydrotestosterone, which displays about 10 times the androgenic potency of testosterone itself. However, testosterone is also partly metabolized to the estrogenic compound estradiol. Synthetic AASs are similarly metabolized in part to estrogenic compounds, which may produce such effects as gynecomastia in some illicit users of

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AASs. Although various AASs may differ in their relative degree of anabolic versus androgenic effects, no AAS even approaches being purely anabolic or purely androgenic. Since the 1970s, AASs have come into widespread use, first among elite athletes, and subsequently among amateur bodybuilders, football players, and other athletes seeking gains in muscle mass and strength. However, research suggests that many men who use these drugs illicitly do not have any particular athletic aspirations at all, but simply wish to improve their physical appearance (Pope et al. 1988, 2000a). Epidemiological studies in the United States suggest that more than 1 million Americans have used AASs at some time in their lives (Buckley et al. 1988; Durant et al. 1993; Faigenbaum et al. 1998; Johnston et al. 2002; Pope et al. 2000a; Radokovich et al. 1993; Yesalis et al. 1990, 1993, 1997). Partially in recognition of the magnitude of this problem, the U.S. Congress has reclassified AASs as schedule III substances (Anabolic Steroids Control Act of 1990 [P.L. 101-647]; U.S. Senate 1990). AASs are well known to produce important physiological side effects in addition to their anabolic properties. These include, for example, acne, hypertension, gynecomastia (as mentioned above), testicular atrophy, and unfavorable alterations in the ratio of total cholesterol to highdensity lipoproteins (Brower 2002; Catlin 1998; Friedl and Yesalis 1989; Glazer 1991; Haupt and Rovere 1984; Kouri et al. 1996; Lenders et al. 1988; Lombardo and Sickles 1992; Yesalis 2000). These effects have been well documented in the literature and are not reviewed here. Less extensively studied, however, are the psychiatric effects of AASs; it has only recently been recognized that AASs may produce prominent psychiatric changes in some illicit users and that these effects may represent a public health problem. In this chapter, we review studies that have examined the psychiatric effects of AASs and offer some general impressions to assist the clinician who may encounter patients who exhibit these effects. Studies that have examined the psychiatric effects of AASs include 1) clinical studies of AASs in the treatment of psychiatric or medical disorders, 2) laboratory studies of the effects of AASs in normal volunteers, and 3) naturalistic field studies of athletes using AASs illicitly.

Clinical Studies Soon after the isolation of testosterone in 1935 (David et al. 1935; Wettstein 1935), a number of investigators assessed the possible psy-

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 333 chiatric benefits of this hormone, in doses ranging from 10 mg/week to as much as 100 mg/day, in various populations of patients (Altschule and Tillotson 1948; Barahal 1938; Danziger et al. 1944; Davidoff and Goodstone 1942; Guirdham 1940; Zeifert 1942). These studies most frequently examined middle-aged men with melancholic depression, and they generally documented a modest antidepressant effect with AAS administration. However, with the advent of electroconvulsive therapy and the tricyclic antidepressants, AASs rapidly lost favor as antidepressant agents. As recently as 1985, however, a double-blind study of the AAS mesterolone versus amitriptyline noted a clear antidepressant effect of the former drug (Vogel et al. 1985). Few adverse effects were noted in most of these studies, even after many weeks of treatment, but one investigation found that four of five men receiving imipramine for treatment of depression developed paranoid delusions when methyltestosterone was added to their regimen (Wilson et al. 1974). Several recent studies have renewed interest in the possible antidepressant effects of testosterone. Seidman and colleagues (1998) recruited five men who remained depressed despite adequate treatment with selective serotonin reuptake inhibitors (SSRIs) and added intramuscular testosterone to their antidepressant regimen. All five men improved; four of these subjects then underwent discontinuation of testosterone, and three of the four relapsed within a few weeks. In a subsequent doubleblind study, Seidman and colleagues (2001) assigned 30 depressed men to intramuscular testosterone or placebo; in this study, however, testosterone was administered alone rather than in conjunction with an existing antidepressant. No significant difference was found between treatment groups at 6 weeks on either the Hamilton Rating Scale for Depression (Ham-D) or the Beck Depression Inventory. Most recently, Pope and colleagues (in press) conducted a placebo-controlled, double-blind study in which testosterone transdermal gel or equivalent placebo gel was added to the antidepressant regimen of 22 men who remain depressed in spite of adequate antidepressant treatment. At 8 weeks, the subjects assigned to adjunctive testosterone gel exhibited significantly greater improvement on the Ham-D and the Clinical Global Inventory than did subjects assigned to placebo. AASs have also been used to treat various medical conditions, such as certain anemias (Blumberg and Keller 1971; Fried et al. 1973; Shahidi and Diamond 1961) and muscular dystrophy (Barwick et al. 1963; Bekeny et al. 1960; Dowben and Perlstein 1961; Griggs et al. 1989). Most of these studies employed only physiological or modestly supraphysiological doses of AASs (equivalent to 50–200 mg of testosterone per week)

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and did not specifically assess psychiatric symptoms in their subjects. However, in studies of replacement therapy with AASs in hypogonadal men, psychiatric effects have been more systematically documented. Findings in these studies have varied, with some investigations finding increased irritability, improved mood, and increased energy in hypogonadal men receiving testosterone (Luisi and Franchi 1980; O’Carroll et al. 1985; Skakkebaek et al. 1981; Wang et al. 1996) and other groups failing to observe such effects (Davidson et al. 1979; O’Carroll and Bancroft 1984; Salmimies et al. 1982). However, since these studies generally employed only physiological replacement doses of testosterone, their results probably do not generalize to athletes taking massively supraphysiological doses of AASs illicitly. Two relatively recent applications of AASs in clinical medicine are for treatment of postmenopausal women and for men infected with human immunodeficiency virus (HIV). In menopausal women, androgens in small doses, often administered synergistically with estrogen, have been shown to reduce depression and increase libido (Sands and Studd 1995; Sherwin and Gelfand 1985). In one study of surgically menopausal women, androgen administration was also associated with higher hostility scores than was administration of estrogen or placebo (Sherwin and Gelfand 1985). In a more recent study of surgically menopausal women, testosterone improved sexual function, depressed mood, and sense of well-being (Shifren et al. 2000). In men with HIV infection, hypogonadism is a common finding (Croxson et al. 1989); thus, administration of testosterone or other AASs seems justified as a potential replacement therapy. Evidence from controlled studies in which AASs were administered to HIV-positive men suggests that these men experience improved mood, energy, and libido (Grinspoon et al. 2000; Rabkin et al. 2000). Again, however, it must be recognized that all of these studies investigated the effects of modest doses of AASs in specialized populations. A final clinical application of AASs, though uncommon, is in the treatment of female-to-male transsexuals. An interesting finding to emerge from this area is that androgens may increase performance on visuospatial abilities on neuropsychological testing (Cherrier et al. 2001; Janowsky et al. 1994; Van Goozen et al. 1994). This finding appears consistent with the observation that men tend to perform better than women on visuospatial tasks (see review in Halpern 1992). At present, however, it remains unclear to what degree the differences between the sexes are attributable to perinatal organizing effects of androgens on the developing brain, and to what degree these differences are due to an acute activating effect of androgens in adulthood.

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Laboratory Studies Using Modest Doses of Anabolic-Androgenic Steroids More than 25 published laboratory studies have examined the effects of various AASs on athletic performance; studies conducted before 1984 were reviewed by Haupt and Rovere (1984) and updated by Elashoff and colleagues (1991); others have appeared more recently (Bhasin et al. 1996; Crist et al. 1988; Friedl et al. 1991). Most of these studies were focused almost entirely on the athletic or physiological effects of AASs and did not systematically assess psychiatric effects in their subjects. Also, many studies employed relatively modest doses of AASs—doses far lower than those typically used illicitly by athletes (Pope and Katz 1988). Nevertheless, several studies anecdotally reported psychiatric changes in some of their subjects, such as increased libido, irritability, aggression, and euphoria (Haupt and Rovere 1984). In several studies, AASs were administered to healthy volunteers for physiological or endocrinologic investigations. For example, Friedl and colleagues (1989, 1991; Hannan et al. 1991) compared testosterone decanoate (100 mg or 300 mg/week) and nandrolone decanoate (also at 100 or 300 mg/week) in 30 healthy men for 6 weeks. The men in the highdosage groups exhibited higher scores on the Hostility and Resentment and Aggression subscales of the Minnesota Multiphasic Personality Inventory. One subject receiving 300 mg of nandrolone reported an uncharacteristic episode of anger, and another described an episode of confusion and crying. Similar doses of AASs were also used in a physiological study by Forbes and colleagues (1992), in which the investigators administered testosterone enanthate, at a dosage of approximately 3 mg/ kg per week, to seven healthy men for 12 weeks. No psychiatric effects were reported, but it is not clear whether the authors were specifically assessing such effects. In an endocrinologic investigation, Matsumoto (1990) administered placebo or testosterone enanthate at various dosage levels (25, 50, 100, or 300 mg/week) to 51 men for a 6-month period. The authors noted only “minor behavioral alterations” in 3 of the subjects, of whom 1 was receiving placebo, 1 was receiving 100 mg of testosterone, and 1 was receiving 300 mg of testosterone per week. Bagatell and colleagues (1994) documented no marked psychiatric changes in a group of 19 healthy men treated with testosterone 200 mg/week for 20 weeks. The authors concluded that “concerns of adverse effects of exogenous [testosterone] on male sexual and aggressive behavior have perhaps been overstated.” However, these authors failed to note that the

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dosage used in their study was far lower than that used by most athletes in the field (Pope and Katz 1994).

Naturalistic Studies As can be seen from the above review, most medical and laboratory studies of AASs have used only physiological or modestly supraphysiological doses of AASs, and in addition have only rarely measured psychiatric effects in a systematic way. Therefore, these studies provide little evidence regarding the effects to be expected of athletes who may frequently selfadminister combinations of several AASs simultaneously (a practice known as “stacking”), such that their total weekly dosage of AASs may be 5–10 times greater than that typically administered in laboratory studies (Brower 1991, 2002; Pope and Brower 2000; Pope and Katz 1988, 1994). To assess these effects, one must examine naturalistic studies of actual illicit AAS users in the field. Before 1988, only a few anecdotal reports had appeared describing psychiatric effects of AASs in athletes (Annitto and Layman 1980; Freinhar and Alvarez 1985; Tennant et al. 1988). Since 1988, however, many studies have appeared in which investigators have assessed groups of AAS-using athletes using psychiatric interviews or rating scales. These studies are summarized below. In 1988, Pope and Katz (1987, 1988) interviewed 41 AAS users (39 men and 2 women), recruited from gymnasiums in Boston and Los Angeles, using the Structured Clinical Interview for DSM-III-R (SCID). The authors found that 5 (12.2%) of the subjects reported manic syndromes during AAS use, compared with none of the subjects during periods when they were not taking AASs (P=0.06). Five (12.2%) of the subjects reported psychotic symptoms (paranoid or grandiose delusions, and in one case, auditory hallucinations) during the on-AAS periods, compared with none of the subjects during the off-AAS periods (P=0.06). Also, 5 (12.2%) of the subjects reported an episode of major depression on stopping AASs; however, 2 of these subjects had also experienced a major depressive episode at some other time in their lives. Choi and colleagues (1990) compared 6 men, of whom 3 were AAS users and three nonusers, in a longitudinal design. Subjects rated themselves repeatedly on several scales, including the Buss-Durkee Hostility Inventory (BDHI), the Profile of Mood States (POMS), and the Rosenzweig Picture-Frustration Study. They also received unstructured interviews. On both the BDHI and the POMS, users showed increased

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 337 hostility when taking AASs compared with when they were not taking AASs or compared with nonusers. One AAS user in the study admitted to attempted murder during a previous period of AAS use. Lefavi and colleagues (1990) compared 13 current users of AASs, 18 former users, and 14 nonusers. On the Multidimensional Anger Inventory (MDAI), users scored significantly higher than nonusers on two subscales: Anger-Arousal and Hostile Outlook. The MDAI was not employed in assessing the former users, but this group also reported increases in aggression in association with their past AAS use. Perry and colleagues (1990) compared 20 weightlifters who were currently using AASs with a comparison group of 20 weightlifters who had never used AASs. On the Symptom Checklist–90 (SCL-90), users reported significantly higher scores during the periods when they were taking AASs than did the nonusers on the Depression, Anxiety, and Hostility subscales. Scores on the Depression, Somatization, and Paranoid Ideation subscales were also significantly higher in the users while taking AASs compared with these same users during periods when they were not taking AASs. No significant differences were found on any subscale when comparing the users at times when they were not taking AASs with the nonusers. However, in contrast to these robust differences on the SCL-90, the authors did not find an increased incidence of major psychiatric disorders among the AAS users when interviewing them using the Diagnostic Interview Schedule. Moss and colleagues (1992) sought personality pathology in 50 current or past AAS users compared with 25 nonuser athletes, using the Multidimensional Personality Questionnaire. No significant differences were found on this instrument, except a trend toward slightly higher aggression scores among the users compared with the nonusers. The authors also used the POMS, the BDHI, and the SCL-90 to compare the 25 current AAS users with the 25 nonusers. In general agreement with the studies of Choi et al. (1990) and Perry et al. (1990), described above, Moss and colleagues (1992) found that current AAS users displayed significantly higher ratings of hostility on the POMS and significantly higher scores on the Somatization and Hostility subscales of the SCL-90. On the BDHI, the Verbal Aggression subscale significantly differentiated users from nonusers, and trends approaching significance were also found on the Irritability and Guilt subscales. However, the authors reported that they were unable to confirm the presence of specific psychiatric disorders in association with AAS use. Bahrke and colleagues (1992) reported almost entirely negative findings in a comparison of 12 current AAS users, 14 former users, and 24 nonusers. In this study, both the current users and the former users de-

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scribed subjective increases in enthusiasm, aggression, irritability, and libido in association with AAS use compared with the nonusers. However, when administered the POMS and the BDHI, the current and former AAS users did not exhibit any significant differences from the nonusers on any of the subscales of either instrument. The authors concluded that, despite perceived psychological changes in association with AAS use, these changes, if present, were too subtle to be detected with objective testing. In 1994 Pope and Katz published a new study, using the SCID in the same manner as their 1988 study described above, to interview 88 current or past AAS users and 68 nonusers recruited from gymnasiums in Boston and Los Angeles. In this study they found that 23% of the AAS users displayed a major mood syndrome (mania, hypomania, or major depression) in association with AAS use. This figure was significantly higher than the prevalence of these syndromes in these same users during periods when they were not taking AASs (6%) or the prevalence of major mood syndromes in the comparison group of nonusers (4%). This difference did not appear to be attributable to differences in premorbid psychological characteristics of users compared with nonusers, nor did it appear to be attributable to use of drugs other than AASs, because users rarely abused other drugs simultaneously with AASs. The authors concluded that mood disturbances associated with AAS use represented a potential public health problem. Burnett and Kleiman (1994) compared 24 adolescent athletes who had used AASs, 24 comparison athletes who reported that they had never used AASs, and 24 nonathletic adolescents, using the Millon Adolescent Personality Inventory and the POMS. In a comparison of the 5 AAS-using athletes currently taking AASs versus the 19 AAS-using athletes who were not currently taking AASs, the former group exhibited significantly higher levels of depression, anger, and vigor (P<0.05 for all comparisons) and a trend toward significantly higher total mood disturbances (P<0.10) than the latter group. Parrott and colleagues (1994) examined 21 amateur athletes, attending a Welsh needle-exchange clinic, who were using high doses of anabolic steroids for periods of 6–14 weeks, separated by AAS-free periods. On the BDHI and a feeling state questionnaire, subjects reported markedly and significantly higher levels of aggression, alertness, irritability, anxiety, suspiciousness, and negativism while taking AASs compared with periods when they were not taking AASs. Malone and colleagues (1995), also using the SCID, compared 31 current AAS users, 46 former users, and 87 nonusers. Like Pope and Katz (1994), these authors found that hypomania was associated with AAS

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 339 use and that major depression was associated with discontinuation of AASs. Particularly alarming was the authors’ finding that 5 (6.5%) of the 77 current or past AAS users reported a suicide attempt during a period of discontinuing AAS use. Interestingly, the authors found a higher prevalence of psychiatric diagnoses in the former users than in the current users, suggesting perhaps that selection factors might have influenced which subjects presented for study. Two other naturalistic studies of AAS users have been partially reported in the literature but have not been published in detail. In the first of these, Cooper and Noakes (1994) in South Africa studied 12 AAS-using bodybuilders over a 4-month period. Initially, subjects were hesitant to reveal the full magnitude of AAS effects on their personal lives, according to the authors, but these effects became more obvious as the observation period progressed. One subject repeatedly threatened to shoot his mother while taking AASs; another kicked car doors in a parking lot continuously for 6 minutes. The authors noted no comparable behavioral changes in a control group. They concluded that “the true extent of the psychiatric and behavioral problems associated with AAS use is almost certainly underestimated.” In a second study, Fudala and colleagues (1996) reported longitudinal data on 6 paid volunteers self-administering AASs. Subjects’ reports of four effects (changes in aggression, libido, frequency of sexual activity, and mood swings) indicated that increases in these effects were reported 2–10 times more often than decreases when subjects were taking a “cycle” of AASs. Changes were also noted on rating scales such as the POMS and the BDHI, but these changes were not always clearly related to periods of AAS use. In summary, 12 naturalistic investigations, to our knowledge, have examined psychiatric symptoms and syndromes reported in association with AAS use among athletes in the field. These studies have used either various rating scales (such as the POMS, SCL-90, and BDHI) or various interview instruments (such as the Diagnostic Interview Schedule and the SCID). The findings of these studies initially appear to be somewhat contradictory, with some studies finding virtually no psychiatric changes in AAS users (Bahrke et al. 1992) and others describing robust changes (Pope and Katz 1988). However, a simple explanation of the differences seems to emerge when one examines the dosages of AASs reported by the athletes examined in the 10 published studies. For this analysis, we have defined a low dosage of AASs as the equivalent of 300 mg of testosterone per week or less; a medium dosage as the equivalent of 300– 1,000 mg/week; and a high dosage as the equivalent of 1,000 mg/week or more. When the dosages used by subjects in the various studies are examined, it will be seen that there appears to be an association between

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dosage and degree of psychopathology. For example, the earlier study of Pope and Katz (1988), which reported a very high prevalence of psychiatric syndromes, also included a large number of high-dosage AAS users. Indeed, the 8 men in this study who displayed psychotic symptoms or a manic episode reported an average weekly dosage of 900 mg. Similarly, among the 25 men who reported a weekly dosage of 1,000 mg or more in the more recent study of Pope and Katz (1994), 11 (44%) reported mania, hypomania, or major depression. At the other extreme is the study of Bahrke and colleagues (1992), whose subjects reported a mean weekly AAS dosage of only 318 mg, and in which even the heaviest AAS user used only 620 mg/week. These users displayed virtually no psychiatric changes. Again similarly, when examining the 12 users in the recent Pope and Katz (1994) study who reported using 300 mg or less per week, only 1 subject (8%) reported hypomanic symptoms, and none reported mania or major depression. Studies examining subjects reporting intermediate levels of AAS use found intermediate levels of psychopathology. In short, therefore, the literature appears to be consistent when dosage is taken into account: dosages of 300 mg/week or less rarely produce psychopathology; dosages of 1,000 mg/week or more do so frequently. However, the naturalistic studies described above are subject to several methodological limitations. First, they rely on subjects’ self-reports of use of drugs obtained illicitly. Therefore, the dosage or identity of these drugs often cannot be confirmed. Second, subjects’ retrospective accounts of psychiatric syndromes may be colored by various biases, such as influences from the gymnasium subculture or expectations regarding the effects of AASs. Third, various forms of selection bias may operate; for example, subjects with prominent psychopathology might be more likely or less likely to volunteer to participate in a research study. Fourth, in a retrospective investigation it is difficult to differentiate the psychiatric effects of AASs themselves from the influences of subjects’ premorbid personalities, use of other psychoactive substances, and other factors. Several more recent reviews have commented on these methodological limitations of studies examining illicit AAS users (Bahrke and Yesalis 1994; Riem and Hursey 1995; Rubinow and Schmidt 1996).

Laboratory Studies of High-Dosage Anabolic-Androgenic Steroid Use Four laboratory studies have appeared in which dosages equivalent to at least 500 mg/week of testosterone were administered to normal vol-

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 341 unteers under placebo-controlled, double-blind conditions. In the first, by Su and colleagues (1993), 20 healthy volunteers were administered placebo, followed by methyltestosterone (40 mg/day), followed by methyltestosterone (240 mg/day), with each treatment interval lasting 3 days. Most of the subjects exhibited few psychiatric changes; however, one man exhibited marked depressive symptoms after treatment was discontinued; one exhibited hypomanic symptoms during treatment with methyltestosterone; and one became frankly manic with methyltestosterone—to the point where he requested to be placed in seclusion. In the second study, Bhasin and colleagues (1996; Tricker et al. 1996) administered testosterone enanthate (600 mg/week) for 10 weeks to 21 healthy volunteers. These investigators did not administer psychiatric ratings to their subjects, but they asked each subject and one of the subject’s significant others to rate the subject’s mood and behavior. No significant differences were found in the study between the group administered testosterone and a similar group administered placebo for the same period. In the third study, Yates and colleagues (1999) administered testosterone cypionate (500 mg/week) to 18 healthy volunteers. Seventeen of these subjects exhibited few psychiatric changes, but one developed a marked personality change and was described by the authors as closely approaching the full DSM-IV criteria (American Psychiatric Association 1994) for a manic episode. In the fourth study, Pope and colleagues (2000b) administered testosterone cypionate, in dosages increasing to 600 mg/week over a 6-week period, to 50 healthy men in a placebo-controlled crossover design. Two of the men in this study developed prominent hypomanic episodes, and 6 others developed mild hypomanic symptoms. The subjects in the study by Pope et al. (2000b) were drawn from three groups: 1) men who had previously used illicit AASs but who had not done so within the last 3 months, 2) men who lifted weights regularly but who had never used AASs, and 3) men who neither lifted weights regularly nor used AASs. The authors assessed the level of the subjects’ manic symptoms in response to testosterone, using a regression analysis that included a term for group status. It was found that group status contributed no significant effect to manic symptoms, regardless of whether the three groups were treated as ordered or unordered categories. This observation suggests that a biological effect of testosterone, rather than psychosocial variables related to weightlifting or prior AAS use, accounts for the differences observed. Collectively, a total of 109 men received markedly supraphysiological doses of AASs under double-blind conditions in these four studies; of these, 5 (4.6%) displayed prominent hypomanic or manic reactions. The

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95% confidence interval for this rate is 1.4%–10.4%. However, it must be recognized that this rate may well represent an underestimate of the true prevalence of severe psychiatric reactions in the field, for several reasons. First, illicit AAS users may take much larger dosages of AASs per week than can be ethically administered in the laboratory, with some taking as much as several thousand milligrams per week at the peak of an AAS cycle (Pope and Katz 1988). Second, illicit users may stack multiple AASs together simultaneously—a practice that may augment psychiatric effects in unknown ways. Third, subjects in laboratory studies were generally selected with careful exclusion criteria, including exclusion of subjects with a history of major psychiatric disorder or recent substance dependence. Actual illicit users are of course not subject to such restrictions. For all of these reasons, it seems likely that the approximately 5% rate in these four laboratory studies represents a “lower bound” for the true rate of prominent hypomanic or manic reactions caused by AAS abuse. Probably the outstanding finding of these four laboratory studies, as well as that of the field studies described above, is that psychiatric responses to AASs are nonuniform: a majority of users exhibit little or no psychiatric change, whereas a minority exhibit prominent and sometimes severe psychiatric effects. The mechanism of this response remains unknown; none of the studies described above has provided data indicating why certain subjects are vulnerable to these effects, whereas most are not. One possible hypothesis, on the basis of preliminary data in animals, is that high doses of AASs increase dopaminergic and 5-hydroxytryptaminergic metabolism (Thiblin et al. 1999). A recent human study (Daly et al. 2001) appears to support this hypothesis, in that it found significantly higher levels of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid of men receiving the AAS methyltestosterone as opposed to placebo. In this study, 5-HIAA levels correlated significantly with increased energy, diminished sleep, and sexual arousal.

Specific Syndromes Associated With Anabolic-Androgenic Steroid Use In addition to the hypomanic symptoms associated with AAS use and the depressive symptoms associated with AAS withdrawal in many of the studies described above, several specific syndromes have been described in association with AAS use. These include AAS dependence, “muscle

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 343 dysmorphia,” violence toward others, and progression to opioid abuse or dependence.

Anabolic-Androgenic Steroid Dependence A series of investigations have suggested that AASs may possess dependence-inducing properties. For example, in several studies, Brower and colleagues found that a substantial number of AAS users met DSM-III-R criteria (American Psychiatric Association 1987) for substance dependence (Brower 1992, 1997, 2002; Brower et al. 1989a, 1990). The causes for this dependence syndrome may be both physiological and psychological. First, the withdrawal syndrome from discontinuing AASs may precipitate a period of pronounced depression, which may be associated with suicidal ideation or even completed suicide (Allnut and Chaimowitz 1994; Brower et al. 1989b; Elofson and Elofson 1990; Malone et al. 1995; Pope 1990). Users who experience this withdrawal depression may thus be tempted to quickly resume use of AASs to “self-medicate” these symptoms. A detailed discussion of this hypothesis is presented by Kashkin and Kleber (1989), who postulated that a delayed depressive withdrawal syndrome, preceded by an acute hyperadrenergic withdrawal state, may contribute to a syndrome of “addiction” to AASs. In addition, the desire to look bigger and stronger, or to avoid losing muscle gains previously achieved, may prompt AAS users to continue to take these drugs repeatedly once they have first tried them. Brower and colleagues (1989a, 1990) suggested that individuals who felt that they were not big enough or strong enough, and who took larger doses of AASs for longer periods, were the ones who were most likely to become dependent.

Muscle Dysmorphia The speculations outlined above regarding psychological mechanisms for AAS dependence are supported by the observation that many individuals using AASs display a sort of “reverse anorexia nervosa” in which they perceive themselves to be small and weak even when they are in fact large and muscular. In recent studies from our laboratory, we have called this syndrome muscle dysmorphia and described its characteristics in greater detail (Olivardia et al. 2000; Phillips et al. 1997; Pope et al. 1993, 1997). Other investigators have also found that feeling “not big enough” may represent a risk factor for use of AASs (Bahrke et al. 2000; Brower et al. 1994; Kanayama et al. 2001; Pope et al. 2000a). The role of this syndrome of body image distortion in weightlifters who use AASs clearly deserves further investigation.

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Violence Several reports have noted that occasional users of AASs become uncharacteristically violent when taking these drugs (Choi et al. 1990; Conacher and Workman 1989; Dalby 1992; Pope and Katz 1990; Pope et al. 1996; Stanley and Ward 1994). In two of these reports (Pope and Katz 1990; Stanley and Ward 1994), the individuals displayed psychotic symptoms apparently associated with AAS use. Although it is difficult to confirm in retrospective observations that the violence was specifically attributable to AAS use, many of the individuals described in these reports exhibited no premorbid history of violence, no criminal record, and no apparent history of psychiatric disorder prior to AAS use—observations suggesting that AASs represented the principal etiologic factor in the violent behavior. Our anecdotal experience suggests that AAS-induced violence is frequently directed at women (Pope et al. 2000a). In an examination of this hypothesis, Choi and Pope (1994) studied 23 AAS users and 14 nonusers, recruited in the course of a study described earlier (Pope and Katz 1994), using the Dyadic Adjustment Scale and the Conflict Tactics Scale to assess users’ relationships with wives or girlfriends. Although the former scale did not detect effects of AASs, the Conflict Tactics Scale revealed several significant differences between the AAS users when taking the drug versus not taking the drug and between the users taking the drug versus the nonusers. Several users described striking incidents of violence toward women while taking AASs: for example, one reported that he threw a brick at his girlfriend, and another reportedly fractured several bones in his girlfriend’s hand by squeezing it. Neither of these subjects reported comparable behavior toward women when they were not taking AASs. During the last several years, we have also consulted on approximately 20 legal cases in which individuals were charged with various violent crimes that appeared to have been committed at times when the individuals were taking AASs. Several of these cases involved murder or attempted murder. We described this experience, and presented an example of a particularly striking murder case, in a paper (Pope et al. 1996). Again, it is not possible to conclude with certainty that AASs played an etiologic role in these crimes. It is noteworthy, however, that most of these men reported no history of any DSM-IV psychiatric disorder before their AAS exposure, and most also displayed no prior history of criminal convictions or violent activity. In several of the cases, however, the individual had used alcohol as well as AASs at the time of the crime, which suggests a possible additive effect. In many of these cases, the role of

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 345 AASs was raised as an issue in the legal defense, either under the rubric of “involuntary intoxication” or, less frequently, insanity. We are not aware of any case in which an “AAS defense” has led to a verdict of not guilty by reason of insanity, but there have been several cases in which the evidence of AAS use may have acted as a mitigating factor, apparently leading to a more lenient sentence. Three of these criminal cases are described in a separate publication (Pope and Katz 1990); a more detailed discussion of the forensic issues surrounding AASs and criminal behavior has also appeared (Bidwell and Katz 1989).

Progression to Opioid Abuse or Dependence AAS use may also possibly serve as a “gateway” to abuse of opioid agonist/antagonists such as nalbuphine (McBride et al. 1996; Wines et al. 1999) or to ordinary opioid agonists such as heroin (Arvary and Pope 2000; Kanayama et al., in press; Wines et al. 1999). Specifically, in one series of 227 men with opioid dependence admitted to a New Jersey treatment facility (Arvary and Pope 2000), 21 (9%) reported a history of AAS use. Fourteen (67%) of these 21 men reported that they were first introduced to opioids by fellow AAS users at the gym, and 17 (81%) reported that they first purchased opioids from the same individual who had first sold them AAS. In another study of 223 male substance abusers admitted to an inpatient treatment facility (Kanayama et al., in press), 6 (7%) of the 88 men listing opioids as their drug of choice, plus a seventh man admitted for both cocaine and opioid dependence, stated that they used AAS when younger, then first learned of opioids from AAS users at the gym, and subsequently purchased opioids for the first time from the same person who had previously sold them AAS. Although it is not possible to say with certainty that AAS use was a causal factor in introducing these men to opioid abuse or dependence, their histories are certainly suggestive of this hypothesis. The present authors are personally aware of several cases of men in the last 3 years who were apparently introduced to opioids in this manner and who subsequently died of unintentional overdoses of intravenous opioids. Thus, the gravity of this syndrome should not be minimized.

Anabolic-Androgenic Steroid Use in Women The previous discussion of the psychiatric effects of AASs is focused almost exclusively on data from men using these drugs. However, sub-

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stantial data suggest that some women have experimented with AASs as well. However, the number of women using AAS is almost certainly much lower than the number of men. Admittedly, some anonymous student surveys have suggested that rates of AAS use in girls may be at least 1.5%—or about one-third the rate in boys (Durant et al. 1993; Middleman et al. 1995), and one survey found a rate of 2.8% in girls as opposed to only 2.6% in boys (Faigenbaum et al. 1998). However, since these estimates were based on anonymous survey responses, they must be regarded with some caution, because of the risk of false positive responses by students who had used either corticosteroids or nutritional supplements that they misidentified as “steroids” (Pope et al. 2000a). Studies in which subjects were interviewed personally, such as the National Household Survey (1994), thus probably provide somewhat more reliable estimates—and in that survey the ratio of women to men is much lower. In the 1994 survey (the most recent to collect AAS data), the number of American men estimated to have used AAS in the past 3 years was 413,458, as compared with 31,316 women—a ratio of 13 to 1 (National Household Survey 1994). With subjects who reported that they had ever used a needle to inject AAS (perhaps a better measure of serious AAS use), the survey estimated 205,499 men versus 8,404 women—a ratio of 25 to 1. In the only large interview study that recruited subjects of both sexes, Malone and colleagues (1995) obtained 71 male AAS users and 6 female users—a ratio of 12 to 1. Because of the relative infrequency of female AAS users, few studies have examined the psychiatric effects of AASs in women. One anecdotal report described 10 women athletes who had used AASs (Strauss et al. 1985); these women described various masculinizing effects and, in some cases, increases in aggression. However, given the small sample size and lack of a control group in this study, it is difficult to generalize from these findings. Other more recent studies have documented adverse effects on lipoprotein profiles (Moffat et al. 1990) and neuroendocrine measures (Malarkey et al. 1991) in small groups of women using AASs, but they have not systematically sought psychiatric symptoms. More recently, our group reported a comparison of 25 women athletes who had used AASs with 50 who had not (Gruber and Pope 2000). None of the AAS-using women in this study described a frank episode of mania or major depression in association with AAS use or withdrawal, probably because the doses that they used were lower than those frequently used by male users. However, a majority of these women reported increases in irritability and aggression during AAS use and depressive symptoms after discontinuing AASs.

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Clinical Implications At present, our understanding of the psychiatric effects of AASs remains limited, so recommendations for the clinician must be tentative. However, several general impressions emerge. First, convincing data now exist to suggest that AASs can produce prominent psychiatric effects in some individuals who use these drugs. These effects appear to be dose related: when AASs are administered in physiological or modestly supraphysiological doses, as replacement therapy in hypogonadal men or in treatment of disorders such as muscular dystrophy, the incidence of psychiatric effects appears to be low. Similarly, laboratory studies of subjects receiving 300 mg/week of testosterone or its equivalent have also rarely documented psychiatric effects. In the field, in studies examining athletes who ingested AASs illicitly, dosages of 300 mg/week of testosterone or its equivalent also rarely produced psychiatric effects. However, many athletes take much larger doses of AASs, and it is these individuals who may be most likely to be encountered by the psychiatric clinician. Individuals taking 1,000 mg or more of testosterone equivalent per week may display frank manic episodes, occasionally accompanied by psychotic symptoms. Little has been written about the treatment of such episodes, although individual case reports (Annitto and Layman 1980; Freinhar and Alvarez 1985; Pope and Katz 1987, 1988; Stanley and Ward 1994) suggest that elimination of the offending agent and temporary treatment with neuroleptics may lead to prompt remission of the symptoms. At present, it is unclear whether mood-stabilizing agents such as lithium, valproate, or carbamazepine would be useful in treating AAS-induced hypomanic or manic syndromes. It is difficult to estimate the frequency of AAS-induced manic episodes that come to the attention of clinicians, because the possible etiologic role of AASs is often not assessed. However, the possibility of AAS use should be considered in manic individuals who are unusually muscular. Because AAS users often deny that they have used these drugs, the patient’s history may be unreliable. If the clinician remains suspicious, a formula for calculating normalized fat-free mass index in men has recently been published by our laboratory; this formula provides an approximate method for determining whether an individual exhibits a degree of muscularity beyond that attainable by natural means, thus raising the suspicion of AAS abuse (Kouri et al. 1995). The reader is referred to the original paper for a full presentation of this formula. Urine testing for AASs is available, but it is expensive and is subject to various

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limitations (Aguilera et al. 1996, 1999; Catlin and Cowan 1992; Catlin et al. 1987). A less expensive screening test that may be of some value is to determine the plasma testosterone level. If it is well above the normal range, this finding would suggest that the patient may have been illicitly taking exogenous testosterone. If it is well below the normal range, then the patient may very likely have been using some other exogenous AAS, thus suppressing his own endogenous testosterone production. Episodes of major depression following AAS withdrawal may also require psychiatric intervention. One report described successful treatment of four such episodes with fluoxetine (Malone and Dimeff 1992). Another report described an AAS user whose withdrawal depression did not respond to desipramine or fluoxetine but ultimately responded to electroconvulsive therapy (Allnut and Chaimowitz 1994). Given the risk of suicide in some individuals withdrawing from large doses or long courses of AASs, such intervention may be important. At present, it is not clear why some individuals develop manic or depressive symptoms in association with AAS use while the majority of users do not. There is little evidence in the various retrospective studies reviewed above to suggest that a prior history of psychiatric disorder or a family history of psychiatric disorder increases the risk of these syndromes, although further investigation is clearly required to resolve this question. Similarly, there is little reason to assume that the prior personality of the user, his history of aggressive or violent behavior, or his expectations regarding the effects of AASs are particularly predictive of a AAS-induced mood syndrome. Presumably, individuals who have displayed a mood syndrome in association with a previous course of AAS use will be at increased risk to display a similar syndrome on using AASs in the future, but even this is not certain. In the retrospective study cited earlier (Pope and Katz 1994), we noted anecdotally that individuals displaying adverse responses to AASs on one occasion were likely to do so on another, but this was not invariably the case. Assessment of this question is complicated by the fact that individuals may use different combinations and doses of AASs on different occasions, making comparison difficult. In short, therefore, it seems most likely that AAS-induced mood syndromes represent an idiosyncratic response that is largely unpredictable, although such syndromes probably do become more likely with increasing dosages. Treatment of AAS use and dependence may be difficult in many cases, because athletes exhibiting this syndrome rarely seek treatment (Pope et al. 2000a). However, preliminary recommendations, based on models developed from treatment of other types of substance dependence, have

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 349 been published (Brower 1992, 1994, 2002; Corcoran and Longo 1992; Goldberg et al. 1991, 1996a, 1996b, 2000). Pharmacotherapy for depression during AAS withdrawal and pharmacotherapy or psychotherapy to deal with body image disorders such as muscle dysmorphia (Neziroglu et al. 1997; Phillips 2001; Phillips et al. 1997; Rosen et al. 1995) may be useful elements in such a treatment program. It is not clear whether AAS users will benefit from treatment in mixed groups with other types of substance abusers, because many AAS users scrupulously avoid abuse of other substances and pay close attention to their health while using AASs (Pope and Katz 1994). Thus, in our experience, AAS users do not integrate easily into groups of other substance abusers. Similarly, we are not aware of a 12-step type of program that has been employed successfully with AAS users. Individual therapy, ideally with a therapist who is familiar with AASs and with the gymnasium subculture, may therefore be the treatment of choice. Finally, forensic psychiatrists should be aware of the possibility that AASs may be involved in acts of violence. In cases where an athlete or an unusually muscular individual has committed a violent crime, the possibility of AAS use should always be considered and, if possible, assessed via urine testing. The psychiatrist’s index of suspicion should be particularly high in instances where the individual abruptly becomes very depressed, with prominent vegetative features such as anhedonia and psychomotor retardation, immediately after being incarcerated, but then seems to regain his normal personality several weeks later. This pattern, which we (Pope and Katz 1990) and others (Stanley and Ward 1994) have noted in men who were incarcerated in the midst of a course of AAS use, likely reflects the abrupt syndrome of AAS withdrawal, during which hypothalamic-pituitary-testicular function is grossly attenuated, followed by return of more normal mood as testicular function reverts to baseline. Of course, even in cases where it is established beyond doubt that an individual has committed violence under the influence of AASs, the forensic implications may vary, depending on prevailing laws regarding “voluntary intoxication” or “diminished capacity” caused by a substance that the individual has intentionally ingested. In conclusion, studies regarding the clinical effects of AASs and clinical treatment of AAS users remain limited. Virtually all of the relevant literature has appeared just within the last 10 years. With increased attention now being directed at the psychiatric syndromes associated with AAS use, the understanding of the epidemiology, nature, and treatment of these syndromes will doubtless expand rapidly in the near future.

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Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 353 Friedl KE, Jones RE, Hannan CJ, et al: The administration of pharmacological doses of testosterone or 19-nortestosterone to normal men is not associated with increased insulin secretion or impaired glucose tolerance. J Clin Endocrinol Metab 68:971–975, 1989 Friedl KE, Dettori JR, Hannan CJ, et al: Comparison of the effect of high-dose testosterone and 19-nortestosterone to a replacement dose of testosterone on strength and body composition in normal men. J Steroid Biochem Mol Biol 40:607–612, 1991 Fudala PJ, Calarco JS, Weinrieb R, et al: A pilot evaluation of anabolic steroid users across and between cycles of use, in Problems of Drug Dependence 1995: proceedings of the 57th Annual Scientific Meeting, College on Problems of Drug Dependence, Scottsdale, AZ, June 10–15, 1995 (NIDA Res Monogr 162). Bethesda, MD, National Institutes of Health, 1996, p 48 Glazer G: Atherogenic effects of anabolic steroids on serum lipid levels. Arch Intern Med 151:1925–1933, 1991 Goldberg L, Bents R, Bosworth E, et al: Anabolic steroid education and adolescents: do scare tactics work? Pediatrics 87:283–286, 1991 Goldberg L, Elliot DL, Clarke GN, et al: The Adolescents Training and Learning to Avoid Steroids (ATLAS) prevention program. Background and results of a model intervention. Arch Pediatr Adolesc Med 150:713–721, 1996a Goldberg L, Elliot D, Clarke GN, et al: Effects of a multidimensional anabolic steroid prevention intervention: The Adolescents Training and Learning to Avoid Steroids (ATLAS) Program. JAMA 276:1555–1562, 1996b Goldberg L, MacKinnon DP, Elliot DL, et al: The Adolescents Training and Learning to Avoid Steroids Program: preventing drug use and promoting health behaviors. Arch Pediatr Adolesc Med 154:332–338, 2000 Griggs RC, Pandya S, Florence JM, et al: Randomized controlled trial of testosterone in myotonic dystrophy. Neurology 39:219–222, 1989 Grinspoon S, Corcoran C, Stanley T, et al: Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab 85:60–65, 2000 Gruber AJ, Pope HG Jr: Psychiatric and medical effects of anabolic-androgenic steroid use in women. Psychother Psychosom 69:19–26, 2000 Guirdham A: Treatment of mental disorders with male sex hormone. Br Med J 1:10–12, 1940 Halpern DF: Sex Differences in Cognitive Ability. Hillsdale, NJ, Erlbaum, 1992 Hannan CJ, Friedl KE, Zold A, et al: Psychological and serum homovanillic acid changes in men administered androgenic steroids. Psychoneuroendocrinology 16:335–343, 1991 Haupt HA, Rovere GD: Anabolic steroids: a review of the literature. Am J Sports Med 12:469–484, 1984 Janowsky JS, Oviatt SK, Orwoll ES: Testosterone influences spatial cognition in older men. Behav Neurosci 108:325–332, 1994

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Johnston LD, O'Malley PM, Bachman JG: Monitoring the Future: National Survey Results on Drug Use, 1975–2001, Vol 1: Secondary School Students (NIH Publ No 02-5106). Bethesda, MD, National Institute on Drug Abuse, 2002 Kanayama G, Pope HG Jr, Hudson JI: “Body image” drugs: a growing psychosomatic problem. Psychother Psychosom 70:61–65, 2001a Kanayama G, Pope HG Jr, Gruber AJ, et al: Over-the-counter drug use in gymnasiums: an underrecognized substance abuse problem? Psychother Psychosom 70:137–140, 2001b Kanayama G, Cohane G, Weiss RD, et al: Past anabolic-androgenic steroid use among men admitted for substance abuse treatment: an underrecognized problem? J Clin Psychiatry (in press) Kashkin KB, Kleber HD: Hooked on hormones? an anabolic steroid addiction hypothesis. JAMA 262:3166–3170, 1989 Kouri E, Pope HG, Katz DL, et al: Fat-free mass index in users and non-users of anabolic-androgenic steroids. Clin J Sport Med 5:223–228, 1995 Kouri EM, Pope HG Jr, Oliva PS: Changes in lipoprotein-lipid levels in normal men following administration of increasing doses of testosterone cypionate. Clin J Sport Med 6:152–157, 1996 Kutscher EC, Lund BC, Perry PJ: Anabolic steroids: a review for the clinician. Sports Med 32:285–296, 2002 Lefavi RG, Reeve TG, Newland MC: Relationship between anabolic steroid use and selected psychological parameters in male bodybuilders. Journal of Sport Behavior 13:157–166, 1990 Lenders JWM, Demacher PNM, Vos JA, et al: Deleterious effects of anabolic steroids on serum lipoproteins, blood pressure and liver function in amateur bodybuilders. Int J Sports Med 9:19–23, 1988 Lombardo JA, Sickles RT: Medical and performance-enhancing effects of anabolic steroids. Psychiatric Annals 22:19–23, 1992 Luisi M, Franchi F: Double-blind group comparative study of testosterone undecanoate and mesterolone in hypogonadal male patients. J Endocrinol Invest 3:305–308, 1980 Malarkey WB, Strauss RH, Leizman DJ, et al: Endocrine effects in female weight lifters who self-administer testosterone and anabolic steroids. Am J Obstet Gynecol 165:1385–1390, 1991 Malone DA Jr, Dimeff RJ: The use of fluoxetine in depression associated with anabolic steroid withdrawal: a case series. J Clin Psychiatry 53:130–132, 1992 Malone DA Jr, Dimeff R, Lombardo JA, et al: Psychiatric effects and psychoactive substance use in anabolic-androgenic steroid users. Clin J Sports Med 5: 25–31, 1995 Matsumoto AM: Effects of chronic testosterone administration in normal men: safety and efficacy of high-dosage testosterone and parallel dose-dependent suppression of luteinizing hormone, follicle-stimulating hormone, and sperm production. J Clin Endocrinol Metab 70:282–287, 1990

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 355 McBride AJ, Williamson K, Petersen T: Three cases of nalbuphine hydrochloride dependence associated with anabolic steroid abuse. Br J Sports Med 30:69– 70, 1996 Middleman AB, Faulkner AH, Woods ER, et al: High-risk behaviors among high school students in Massachusetts who use anabolic steroids. Pediatrics 96: 268–272, 1995 Moffat RJ, Wallace M, Sady S: Effects of anabolic steroids on lipoprotein profiles of female weight lifters. The Physician and Sports Medicine 18:106–115, 1990 Moss HB, Panzak GL, Tarter RE: Personality, mood, and psychiatric symptoms among anabolic steroid users. Am J Addict 1:315–324, 1992 National Household Survey on Drug Abuse. Data from this survey available at: http://www.icpsr.umich.edu/cgi-bin/SDA11/hsda3 Neziroglu F, McKay D, Todaro J, et al: Effect of cognitive-behavior therapy on persons with BDD and comorbid Axis II diagnoses. Behavior Therapy 27: 67–77, 1996 O’Carroll R, Bancroft J: Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry 145:146–151, 1984 O’Carroll R, Shapiro C, Bancroft J: Androgens, behavior, and nocturnal erection in hypogonadal men: the effects of varying the replacement dose. Clin Endocrinol (Oxf) 23:527–538, 1985 Olivardia R, Pope HG Jr, Hudson JI: Muscle dysmorphia in male weightlifters: a case-control study. Am J Psychiatry 157:1291–1296, 2000 Parrott AC, Choi PY, Davies M: Anabolic steroid use by amateur athletes: effects upon psychological mood states. J Sports Med Phys Fitness 34:292–298, 1994 Perry PJ, Yates WR, Andersen KH: Psychiatric symptoms associated with anabolic steroids: a controlled, retrospective study. Ann Clin Psychiatry 2:11– 17, 1990 Phillips KA: Pharmacologic treatment of body dysmorphic disorder: a review of empirical data and a proposed treatment algorithm. Psychiatr Clin North Am Annual of Drug Therapy 7:59–82, 2000 Phillips KA, O’Sullivan RL, Pope HG Jr: Muscle dysmorphia (letter). J Clin Psychiatry 58:361, 1997 Pope HG Jr: Anabolic-androgenic steroid use and suicide. Physician Sportsmedicine 18:16, 1990 Pope HG Jr, Brower KJ: Anabolic-androgenic steroid abuse, in Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 7th Edition. Edited by Sadock BJ, Sadock VA. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 1085–1095 Pope HG Jr, Katz DL: Bodybuilders’ psychosis (letter). Lancet 1:863, 1987 Pope HG Jr, Katz DL: Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 145:487–490, 1988 Pope HG Jr, Katz DL: Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry 51:28–31, 1990

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Pope HG Jr, Katz DL: Psychiatric and medical effects of anabolic-androgenic steroid use. Arch Gen Psychiatry 51:375–382, 1994 Pope HG Jr, Katz DL, Champoux R: Anabolic-androgenic steroid use among 1010 college men. The Physician and Sports Medicine 16:75–81, 1988 Pope HG Jr, Katz DL, Hudson JI: Anorexia nervosa and “reverse anorexia” among 108 male bodybuilders. Compr Psychiatry 34:406–409, 1993 Pope HG Jr, Kouri EM, Powell KF, et al: Anabolic-androgenic steroid use among 133 prisoners. Compr Psychiatry 37:322–327, 1996 Pope HG Jr, Gruber AJ, Choi PY, et al: Muscle dysmorphia: an underrecognized form of body dysmorphic disorder. Psychosomatics 38:548–557, 1997 Pope HG Jr, Phillips KA, Olivardia R: The Adonis Complex: The Secret Crisis of Male Body Obsession. New York, Free Press, 2000a Pope HG Jr, Kouri EM, Hudson JI: The effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Arch Gen Psychiatry 57:133–140, 2000b Pope HG Jr, Cohane G, Kanayama G, et al: Testosterone gel supplementation in treatment-refractory depressed men: a randomized placebo-controlled trial. Am J Psychiatry (in press) Rabkin JG, Wagner GJ, Rabkin R: A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry 57:141–147, 2000 Radokovich J, Broderick P, Pickell G: Rates of anabolic-androgenic steroid abuse among students in junior high school. J Am Board Fam Pract 6:341–345, 1993 Riem KE, Hursey KG: Using anabolic-androgenic steroids to enhance physique and performance: effects on moods and behavior. Clin Psychol Rev 15:235– 256, 1995 Rosen JC, Reiter J, Orosan P: Cognitive/behavioral body image therapy for body dysmorphic disorder. J Consult Clin Psychol 63:263–269, 1995 Ross J, Winters F, Hartmann K, et al: 1988–89 Survey of Substance Abuse Among Maryland Adolescents. Baltimore, MD, Maryland Department of Health and Mental Hygiene, Alcohol and Drug Abuse Administration, 1989 Rubinow DR, Schmidt PJ: Androgens, brain, and behavior. Am J Psychiatry 153: 974–984, 1996 Salmimies P, Kockett G, Pirk KM: Effects of testosterone replacement on sexual behavior in hypogonadal men. Arch Sex Behav 11:345–353, 1982 Sands R, Studd J: Exogenous androgens in postmenopausal women. Am J Med 98(suppl):76S–79S, 1995 Scott DM, Wagner JC, Barlow TW: Anabolic steroid use among adolescents in Nebraska schools. Am J Health Syst Pharm 53:2068–2072, 1996 Shahidi NT, Diamond LK: Testosterone-induced remission in aplastic anemia of both acquired and congenital types: further observations in 24 cases. N Engl J Med 264:953–967, 1961 Sherwin BB, Gelfand MM: Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology 10:325–335, 1985

Psychiatric Effects of Exogenous Anabolic-Androgenic Steroids 357 Shifren JL, Braunstein GD, Simon JA, et al: Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 343:682–688, 2000 Skakkebaek NE, Bancroft J, Davidson DW, et al: Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double-blind controlled study. Clin Endocrinol (Oxf) 14:49–61, 1981 Stanley A, Ward M: Anabolic steroids—the drugs that give and take away manhood. A case with an unusual physical sign. Med Sci Law 34:82–83, 1994 Strauss R, Liggett M, Lanese R: Anabolic steroid use and perceived effects in ten weight-trimmed women athletes. JAMA 253:2871–2873, 1985 Su T-P, Pagliaro M, Schmidt PJ, et al: Neuropsychiatric effects of anabolic steroid in male normal volunteers. JAMA 269:2760–2764, 1993 Tennant F, Black DL, Voy RO: Anabolic steroid dependence with opioid-type features (letter). N Engl J Med 319:578, 1988 Thiblin I, Finn A, Ross SB, et al: Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids. Br J Pharmacol 126:1301–1306, 1999 Tierney R, McLain LG: The use of anabolic steroids in high school students. Am J Dis Child 144:99–103, 1990 Tricker R, Casaburi R, Storer TW, et al: The effect of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men. J Clin Endocrinol Metab 81:3754–3758, 1996 U.S. Senate, Committee on the Judiciary: On the Steroid Abuse Problem in America, Focusing on the Use of Steroids in College and Professional Football Today (congressional hearing). Washington, DC, U.S. Government Printing Office, 1990 Van Goozen SH, Cohen-Kettenis PT, Gooren LJ, et al: Activating effects of androgens on cognitive performance: causal evidence in a group of female-tomale transsexuals. Neuropsychologia 32:1153–1157, 1994 Vogel W, Klaiber EL, Braverman DM: A comparison of the antidepressant effect of a synthetic androgen (mesterolone) and amitriptyline in depressed men. J Clin Psychiatry 46:6–8, 1985 Wang C, Alexander G, Berman N, et al: Testosterone replacement therapy improves mood in hypogonadal men: a clinical research center study. J Clin Endocrinol Metab 81:3578–3583, 1996 Wettstein A: Uber die kunstliche Herstellung des Testikelhormons Testosteron. Schweiz Med Wochenschr 16:912, 1935 Wilson IC, Prange AJ Jr, Lara PP: Methyltestosterone with imipramine in men: conversion of depression to paranoid reaction. Am J Psychiatry 131:21–24, 1974 Wines JD Jr, Gruber AJ, Pope HG Jr, et al: Nalbuphine hydrochloride dependence in anabolic steroid users. Am J Addict 8:161–164, 1999 Yates WR, Perry P, MacIndoe J, et al: Psychosexual effects of three doses of testosterone in cycling and normal men. Biol Psychiatry 45:254–260, 1999

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Yesalis CE (ed): Anabolic Steroids in Sport and Exercise, 2nd Edition. Champaign, IL, Human Kinetics, 2000 Yesalis CE, Buckley WA, Wang MO, et al: Athletes’ projections of anabolic steroid use. Clin Sports Med 2:155–171, 1990 Yesalis CE, Kennedy NJ, Kopstein AN, et al: Anabolic-androgenic steroid use in the United States. JAMA 270:1217–1221, 1993 Yesalis CE, Barsukiewicz CK, Kopstein AN, et al: Trends in anabolic-androgenic steroid use among adolescents. Arch Pediatr Adolesc Med 151:1197–1206, 1997 Zeifert M: Massive dose testosterone therapy in male involutional psychosis. Psychiatr Q 16:319–332, 1942

Part V Thyroid Hormones

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Chapter 14 Thyroid Function in Psychiatric Disorders David O’Connor, M.D. Harry Gwirtsman, M.D. Peter T. Loosen, M.D., Ph.D.

Thyroid Physiology The principal hormones of the hypothalamic-pituitary-thyroid (HPT) axis are thyroxine (T4) and triiodothyronine (T3), the latter being the more potent biologically (Larsen and Ingbar 1992). Although both T4 and T3 are released from the thyroid gland, about 90% of circulating T3 is derived from T4 by monodeiodination in (mainly) liver, kidney, and other tissues by the enzyme 5¢-deiodinase type I (5¢D-I). In serum, more than 99.5% of T4 and T3 are bound to thyroxin-binding globulin (TBG), albumin, and thyroxine-binding prealbumin (TBPA), leaving less than 0.5% of T4 and T3 unbound and biologically active (Larsen and Ingbar 1992). Alterations in either deiodination or serum protein concentrations (as in liver disease, starvation, or chronic illness) can therefore profoundly affect thyroid hormone economy (Israel and Orrego 1984; Israel et al. 1979). Biosynthesis and release of T4 and T3 from the thyroid gland are primarily controlled by the anterior pituitary hormone thyrotropin (thyroid-stimulating hormone [TSH]). In turn, biosynthesis and release of TSH from thyrotropes are mediated principally by the tripeptide thyrotropin-releasing hormone (TRH). TRH is released directly into the portal venous system, which connects the hypothalamus and the pituitary gland,

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from hypothalamic neurons that originate in the paraventricular nucleus. TRH also stimulates the release of prolactin from pituitary lactotroph cells. Homeostatic control within the HPT axis is ensured through negative-feedback inhibition by T4 and T3 at the thyrotrope, leading to diminished synthesis and release of TSH. Thyroid hormones have also been shown to selectively reduce TRH biosynthesis in the hypothalamus, which may provide yet another means of regulation (Segerson et al. 1987). Finally, many neurotransmitters and non-HPT-axis hormones affect TRH and TSH release (Morley 1981). A wealth of laboratory studies provide evidence for both a neuroregulatory role of thyroid hormones (Table 14–1) and a homeostatic mechanism by which brain intracellular T3 concentrations are enzymatically maintained within narrow limits ( J. L. Leonard 1990). The enzyme 5¢-deiodinase type II (5¢D-II)—found in the central nervous system, anterior pituitary, brown adipose tissue, and placenta—has been shown to increase threefold to fivefold within 24 hours of thyroidectomy and to decrease by 80%–90% within 2–4 hours after injection of a saturating dose of T3 ( J.L. Leonard 1990). The thyroid hormone–induced changes in 5¢D-II activity in vivo and in cell cultures are due to changes in the half-life of the enzyme (in euthyroid animals the half-life of 5¢D-II is about 30 minutes; it increases to 4–6 hours in hypothyroid animals) and do not depend on transcription or translation. Moreover, T4 and reverse T3 (rT3) are more than 100-fold more effective than T3 ( J.L. Leonard 1990). In contrast, 5¢D-I activity is decreased in thyroidectomized rats, and at least 3–5 days of hypothyroidism are required to observe this decline in activity (J.L. Leonard 1990). Taken together, these findings suggest that a well-balanced thyroid economy is important for the brain to function normally. The evidence supporting thyroid imbalance in those with mental illness is the subject of this chapter.

Assessment of Thyroid Function The intactness of the HPT axis can normally be evaluated by measuring the concentrations of serum thyroid hormones, although the assays for free T3 (FT3) and free T4 (FT4) are not without limitations in that nonthyroidal illness can affect their performance, leading to falsely low results (Tunbridge and Caldwell 1991). If such assessment provides ambiguous results, or if one suspects more subtle changes in HPT axis function (e.g., subclinical hypothyroidism), it is necessary to assess serum TSH concentrations (Larsen and Ingbar 1992; Toft 1991). Additional guidelines for

Thyroid Function in Psychiatric Disorders TABLE 14–1.

363

Evidence for a neuroregulatory role of thyroid hormones

Thyroid hormone receptors are widely distributed throughout the brain (Dratman et al. 1982). Both thyroxine (T4) and triiodothyronine (T3) enter the brain by a high-affinity saturable transport mechanism (Dratman et al. 1976, 1982). Within the brain T4 and T3 are differentially distributed regionally and are highly localized in synaptosomes (Dratman et al. 1976, 1982). The rate of conversion of T4 to T3 is many times greater in brain than in liver (J.L. Leonard 1990). There is evidence that T4 may be converted into T3 within nerve terminals (Dratman and Crutchfield 1978). Despite extremes of T4 availability, brain T4 and T3 concentrations and brain T3 production and turnover rates are kept within narrow limits (Dratman et al. 1983; J.L. Leonard 1990), suggesting that small changes in brain thyroid hormones may produce significant changes in behavior. Hyperthyroidism increases striatal b-adrenoreceptors and striatal dopaminergic activity, whereas hypothyroidism reduces striatal and hypothalamic b-adrenoreceptors (Atterwill et al. 1984). Hyperthyroidism increases, and hypothyroidism decreases, presynaptic a2-adrenoreceptor function (Atterwill et al. 1984). Hypothyroidism causes a significant increase in serotonin and substance P levels in rat brain nuclei (Savard et al. 1983).

the laboratory evaluation of the thyroid axis are provided in Chapter 17 of this volume.

Thyroid Function in a General Psychiatric Population The prevalence of one or more thyroid abnormalities in acutely hospitalized psychiatric patients ranges from 6% to 49% (Table 14–2). Most prominent among these findings are the euthyroid sick syndrome (characterized by abnormal concentrations of circulating iodothyronines in otherwise euthyroid patients [Larsen and Ingbar 1992]) and mild, transient hyperthyroxinemia. Both findings have been observed in schizophrenia and depression alike (Roca et al. 1990; Spratt et al. 1982); they usually normalize on recovery (Chopra et al. 1990; Morley and Shafer 1982; Spratt et al. 1982). It is therefore necessary to interpret blood thyroid function tests with caution in all recently hospitalized patients. The euthyroid sick syndrome, attributable largely to reduced extrathyroidal conversion of T4 to T3 (Chopra et al. 1983), is common in many acute and chronic illnesses (Larsen and Ingbar 1992). Whether

Transient hyperthyroxinemia in acutely hospitalized psychiatric patients

Study

N

Thyroid measure

Weinberg and Katzell 1977 Caplan et al. 1983 Cohen and Swigar 1979

50 100 480

6 6 18

Mental state improved after remission of the thyrotoxicosis.

Spratt et al. 1982

645

T4 increased FT4I increased Estimated FT4I increased or decreased T4 increased

33

No difference between schizophrenic and depressed patients. Thyroid function without therapy in 22 patients serially followed.

Morley and Shafer 1982

386

FT4 increased FT4 or FT3I increased Total T3 increased

18 19 17

One or more thyroid hormones increased T4 increased FT4I increased Total T3 increased FT3I increased TSH increased Thyroid hormones

49

45

Chopra et al. 1990

84

Levy et al. 1981 McLarty et al. 1978

150

1,206 Thyroid hormones

Prevalence (%) Comment

24 16 20 13 17 7 0.5–0.7

In half of the patients, return to normal within several weeks.

Elevations particularly common in patients with paranoid schizophrenia (38%) and in patients with amphetamine abuse (32%). Return to normal levels on retesting 2 or 3 weeks later. Significant positive correlations between psychiatric symptom severity and FT4I among depressed and schizophrenic patients. On repeat testing 7–21 days after admission, serum TSH (and/or T4) normalized in 3 of the 5 patients studied.

Euthyroid sick syndrome in 7% of patients; when blood was sampled serially, 27%. Hypothyroidism (0.5%), hyperthyroidism (0.7%).

Note. FT4 =free thyroxine; FT3I=free triiodothyronine index; FT4I=free thyroxine index; T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone.

PSYCHONEUROENDOCRINOLOGY

Roca et al. 1990

364

TABLE 14–2.

Thyroid Function in Psychiatric Disorders

365

patients with nonthyroidal illnesses with low T4 or T3 concentrations, or both, are hypothyroid is not clear; the clinical significance of the euthyroid sick syndrome therefore remains uncertain (Brent and Hershman 1986; Chopra et al. 1983). Pathophysiologically, transient hyperthyroxinemia may result from centrally mediated hypersecretion of TSH, particularly among depressed patients in whom high TSH concentrations are found in the face of elevated thyroid hormone levels (Roca et al. 1990)—a finding that distinguishes this phenomenon from ordinary hyperthyroidism. Being centrally mediated, transient hyperthyroxinemia may be the result of environmental circumstances (e.g., acute hospitalization) or of being acutely mentally ill.

Thyroid Function in Mood Disorders Peripheral Thyroid Hormones Depression Peripheral thyroid hormone concentrations were assessed in acutely depressed inpatients and outpatients and were compared with concentrations in nondepressed control subjects, euthymic patients, or both; the results are equivocal. Most depressed patients appear to be euthyroid (Briggs et al. 1993; Kirkegaard 1981; Loosen 1986, 1988; Vandoolaeghe et al. 1997). However, some investigators reported serum T4 levels in the upper normal range (Dewhurst et al. 1968; Hatotani et al. 1974; Kirkegaard and Faber 1981; Kjellman et al. 1983; Kjellman et al. 1993; Styra et al. 1991) or found increased serum concentrations of rT3 (Kirkegaard and Faber 1981; Kjellman et al. 1983; Linnoila et al. 1979), the hormonally inactive analog of T3 (Larsen and Ingbar 1992). Other investigators reported lowered thyroid function in depressed patients, including reduced mean levels of free T4 index (FT4I) and FT4 (Custro et al. 1994; Natori et al. 1994; Rinieris et al. 1978a, 1978b; Rybakowski and Sowinski 1973) and of T3 (Custro et al. 1994; Joffe et al. 1985; Linnoila et al. 1979; Natori et al. 1994; Orsulak et al. 1985; Rupprecht et al. 1989; Wahby et al. 1989). Two studies involving a total of 366 depressed outpatients who were screened carefully for evidence of thyroid disease (Briggs et al. 1993; Fava et al. 1995) concluded that because of the low incidence of abnormal findings (e.g., increased serum TSH levels were found in 2% and 2.6% of patients), routine thyroid function tests are not indicated. Are there dynamic changes in thyroid function when the individual patient shifts from depression into remission? If so, are these changes related to the applied treatment or to aspects of remitting symptoms?

366

PSYCHONEUROENDOCRINOLOGY

Although these questions cannot be answered with certainty, studies that have addressed them have revealed remarkably consistent results. Most (Baumgartner et al. 1988; Board et al. 1957; Brady and Anton 1989; Brady et al. 1994; Ferrari 1973; Gibbons et al. 1960; Hoeflich et al. 1992; Joffe and Singer 1987, 1990; Kirkegaard and Faber 1986; Kirkegaard et al. 1975, 1977; Kusalic et al. 1993; Mason et al. 1989; Muller and Boning 1988; Southwick et al. 1989; Unden et al. 1986; Whybrow et al. 1972), but not all (Karlberg et al. 1978; Kolakowska and Swigar 1977; Leichter et al. 1977; Shelton et al. 1993), studies reported significant reductions in serum T4 concentrations after remission was induced by a wide range of somatic treatments, including various antidepressants (e.g., chlorimipramine [Baumgartner et al. 1988]; maprotiline [Baumgartner et al. 1988; Hoeflich et al. 1992]; desipramine [Baumgartner et al. 1988; Brady and Anton 1989; Joffe and Singer 1990]; fluvoxamine [Hoeflich et al. 1992]; sertraline [McCowen et al. 1997]; imipramine [Brady et al. 1994]), lithium, sleep deprivation, or electroconvulsive therapy (ECT). Four studies (Joffe and Singer 1990; Kusalic et al. 1993; Roy-Byrne et al. 1984; Southwick et al. 1989) documented that the T4 reduction was greater in those who responded to treatment than in nonresponders, suggesting that reduction of thyroid function may facilitate treatment response. This concept is further supported by a study by Joffe et al. (1992), in which six depressed patients were treated with the antithyroid drug methimazole (20 mg/day) for 4 weeks. Three patients responded to treatment (defined as greater than a 50% change in score on the Hamilton Rating Scale for Depression to a score below 10), and two patients had a partial response (greater than a 25% change in score). These five patients showed reductions in T4 level and FT4I but not in TSH level during the 4-week trial. Alternatively, increased thyroid function may facilitate treatment response. This was first noted by Whybrow et al. (1972), who showed that heightened thyroid activity before treatment was positively correlated with a prompt clinical response to imipramine.

Bipolar Disorder Serum concentrations of thyroid hormones have been shown to be increased in some acutely ill adult (Mason et al. 1989; Muller and Boning 1988; Southwick et al. 1989; Styra et al. 1991) and adolescent (Sokolov et al. 1994) patients with bipolar disorder. Other investigators found reduced thyroid hormone concentrations in acutely ill bipolar patients (Bartalena et al. 1990a; Chang et al. 1998; Rybakowski and Sowinski 1973), and normal concentrations in euthymic (Kjellman et al. 1985) bipolar patients. In contrast to depression, changes in serum T4 concen-

367

Thyroid Function in Psychiatric Disorders

trations are not common during recovery from mania (Bauer and Whybrow 1988). The relationships between bipolar disorder and various forms of hypothyroidism are discussed under “Thyrotropin, Subclinical Hypothyroidism, and Antithyroid Antibodies” below.

Seasonal Affective Disorder Serum thyroid hormone concentrations appear to be normal in patients with seasonal affective disorder (SAD) (Bauer et al. 1993; Coiro et al. 1994; Lingjaerde et al. 1995).

Thyrotropin, Subclinical Hypothyroidism, and Antithyroid Antibodies Assessment of the TRH-induced TSH response and development of supersensitive TSH assays have allowed both identification of milder forms of hypothyroidism and standardization of varying degrees of hypothyroidism (Evered 1986; Wenzel et al. 1974). Assessment of basal TSH with a supersensitive TSH assay is now seen as providing a reliable index of thyrotrope activity across the entire spectrum of thyroid disease; it has therefore replaced the TRH test in both medicine (Toft 1991) and psychiatry (Maes 1993; Maes et al. 1993). The diagnostic criteria for the different forms of hypothyroidism, including subclinical hypothyroidism, are listed in Table 14–3.

TABLE 14–3.

Grades of hypothyroidism

Grade

Clinical features

Overt

Obvious symptoms and Low signs of hypothyroidism Mild or nonspecific Low or symptoms or signs normal None Normal

Mild Subclinical

Serum T4 Serum T3 Serum TSH Usually low Normal

Very high

Normal

Slightly elevated

Moderately high

Note. T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone. Source. Adapted from Ross 1991.

Like overt hypothyroidism, subclinical hypothyroidism can arise from a variety of causes—for example, iodine and medications containing iodine, ablative treatment of hyperthyroidism, inadequate replacement therapy for overt hypothyroidism, lithium therapy, and (most commonly) autoimmune (Hashimoto’s) thyroiditis (Larsen and Ingbar 1992). Asymptomatic autoimmune thyroiditis (based on the evidence of circulating thyroid anti-

368

PSYCHONEUROENDOCRINOLOGY

bodies with normal thyroid function) is common, particularly in older women (Tunbridge and Caldwell 1991). Overt hypothyroidism develops at the rate of 5% per year in subjects with antibodies and raised TSH level. Whether subclinical hypothyroidism should be treated on the basis of preventing such deterioration continues to be a matter of debate. Treatment may be indicated to prevent progression to overt hypothyroidism, especially in patients with elevated levels of both TSH and microsomal antibody titers (Tunbridge and Caldwell 1991). The major benefits of treatment, based on two randomized trials, appear to be improvements in clinical symptoms and psychometric test results (Ross 1991).

Depression The following TSH and autoimmune dysfunctions are not uncommon in depression: a blunted TSH response to TRH, an abnormal circadian TSH rhythm, elevated basal TSH concentrations, and elevated titers of antithyroid antibodies. The latter two findings are frequently seen together in subclinical hypothyroidism. Abnormal circadian TSH rhythm. Depression is often associated with disturbances in various circadian behavioral rhythms (e.g., changes in emotional well-being during the day, frequently worsening in the early morning) and biological rhythms (e.g., abnormalities in body temperature and cortisol secretion). To these circadian dysfunctions we can add an abnormal diurnal TSH rhythm, most commonly a lack of the nocturnal TSH surge (Table 14–4). In addition to depression and anorexia nervosa (discussed under “Thyroid Function in Eating Disorders” below), this abnormality can be found in central hypothyroidism (Adriaanse et al. 1993), in euthyroid patients with suprasellar extensions of pituitary lesions (Adriaanse et al. 1993), and after naloxone administration (Samuels et al. 1994). The latter, of course, suggests that endogenous opioids have significant stimulatory effects on TSH secretion, predominantly during the nocturnal TSH surge. Subclinical hypothyroidism. Between 1% and 4% of patients with a variety of affective illnesses show evidence of overt hypothyroidism, and between 4% and 40% show evidence of subclinical hypothyroidism (see Table 14–5). Subtle, but not overt, thyroid dysfunctions are therefore rather common in depressed patients, and they are not clinically innocuous. Comorbid subclinical hypothyroidism can lower the threshold for the occurrence of both depression (Haggerty et al. 1993) and panic disorder (Joffe and Levitt 1992) and can be associated with cognitive dysfunction (Haggerty et

TABLE 14–4.

Circadian variation in thyroid function in depression N

Diagnosis

Weeke and Weeke 1978 Weeke and Weeke 1980 Golstein et al. 1980 Kijne et al. 1982 Kjellman et al. 1984

12 ED

Unden et al. 1986

31

Souetre et al. 1988

8

Souetre et al. 1989

16

Bartalena et al. 1990b Coiro et al. 1994

15 7

4 ED

Thyroid measure

Comment

T4, T3, FT4, FT3, TSH 0200h and 2400h

Absence of diurnal TSH variation and free hormones related to symptom severity No difference from control subjects

T3, TSH q1h for 24h

13 ED: 5 BP, 8 UP 9 ED 32 MDD

TSH q60 min/day or q30 min/night for 24h Nocturnal TSH peak absent in UP T4, T3, TSH q4h No difference between depression and recovery TSH q2h for 24h 24-hour TSH secretion reduced during depression, normalization on recovery MDD T4, T3, TSH q4h, but q2h (2400h–0800h) TSH reduced in depression. No change in T3, T4 between depressed patients and control subjects BP TSH q1h for 25h, body temperature Nocturnal body temperature increased and nocturnal TSH surge blunted during depression; both normalized on recovery ED, 15 recovered TSH q1h for 25h, body temperature Amplitude reduction during depression significantly correlated with depression scores; normalization of circadian rhythms on recovery ED TSH q1h (2400h–0200h) Nocturnal TSH surge abolished in 14 patients SAD TSH q1h (2300–0200h and 0700–0900h) No difference between spring/summer and fall/winter tests. At both periods, patients lacked nocturnal TSH surge

369

Note. BP = bipolar depression; ED = endogenous depression; FT 3 = free triiodothyronine; FT 4 = free thyroxine; MDD = major depressive disorder; SAD=seasonal affective disorder; T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone; UP=unipolar depression.

Thyroid Function in Psychiatric Disorders

Study

370

TABLE 14–5.

Hypothyroidism in affectively ill patients

Study

N

Diagnosis

250 Depression and/or anergia

Gold et al. 1982 Targum et al. 1984

100 21

Haggerty et al. 1987 102

Tappy et al. 1987 Joffe et al. 1992

Gewirtz et al. 1988 Maes et al. 1993

Custro et al. 1994

157 104 139

15 62 101 57

1 (grade 1) Of the 20 patients with some degree of hypothyroidism, 6 were 4 (grade 2) later discharged after thyroid replacement alone. 4 (grade 3) Depression and/or anergia 15 (grades 1–3) Of these 15 patients, 60% had detectable antimicrosomal antibodies. Refractory depression 24 (grade 3) Five of 7 patients who responded to combined thyroid hormoneantidepressant treatment had grade 3 hypothyroidism. Affective disorder 10 (grade 3) Dexamethasone nonsuppressors were significantly more likely to have elevated TSH levels than suppressors. 20% of patients had antithyroid antibodies. Psychogeriatric admissiona 4 (grade 1) 15% of 27 patients with neurotic depression had grade 1 Medical-surgical admissions 2 (grade 1) hypothyroidism. Unipolar depression 14 (grade 3) Depression with grade 3 hypothyroidism differed from depression without grade 3 hypothyroidism by the presence of a concurrent panic disorder and a poorer antidepressant response. Refractory depression 40 (grades 2, 3) The 6 women with hypothyroidism all responded behaviorally to thyroid substitution. Minor depression 8.8 (grade 3) Diagnoses made by use of ultrasensitive TSH assay. Of the Major depression melancholic patients, 8.8% showed some degree of subclinical Melancholic hypothyroidism.

75 Mood disturbance (in women)

56 (grade 3)

Five of 9 endogenously depressed women were subclinically hypothyroid, but none of the 66 patients with minor depression. All five women were positive for antithyroid antibodies.

PSYCHONEUROENDOCRINOLOGY

Gold et al. 1981

Prevalence (%) Comment

TABLE 14–5.

Hypothyroidism in affectively ill patients (continued)

Study

N

Ordas and Labbate 1995 Fava et al. 1995

Note.

Prevalence (%) Comment

260 Major and minor depression 3.1 (grade 3)

Eight of 260 patients showed subclinical hypothyroidism.

200 Depression (in outpatients) 2.6 (grade 3)

TSH concentration was slightly elevated in 2.6% of patients; no relationship to response rate was found. 52% (range 29%–100%) of patients showed evidence of subclinical hypothyroidism.

Refractory depression (review of six studies)

52 (grade 3)

grade 1=overt hypothyroidism; grade 2=mild hypothyroidism; grade 3=subclinical hypothyroidism; TSH=thyroid-stimulating hormone.

Thyroid Function in Psychiatric Disorders

Howland 1993

Diagnosis

371

372

PSYCHONEUROENDOCRINOLOGY

al. 1986, 1990b) or a reduced response to standard psychiatric treatments (Haggerty et al. 1990b; Joffe and Levitt 1992). That some depressed patients with subclinical hypothyroidism respond behaviorally to thyroid hormone replacement (Gewirtz et al. 1988; Gold et al. 1981, 1982) suggests that it may be useful to intervene therapeutically and to broaden the list of index symptoms for initiating thyroid hormone replacement to include depression and memory deficits in addition to the somatic symptoms of fatigue, weight gain, and cold intolerance (Haggerty and Prange 1995). Haggerty et al. (1993) demonstrated that the lifetime frequency of major depression was significantly higher in subjects with subclinical hypothyroidism (56%) than in those without it (20%). TSH: sources of variance. Serum TSH concentrations (at baseline or after TRH stimulation) can be associated with treatment response (Fava et al. 1992; Poirier et al. 1995), anxiety (Poirier et al. 1995), insomnia (Poirier et al. 1995), severity of illness (Maes et al. 1994; Poirier et al. 1995), and both global and regional cerebral blood flow and cerebral glucose metabolism (Marangell et al. 1997). Other investigators, however, did not find associations between TSH concentrations and treatment response (Fava et al. 1995), levels of anxiety (Kavoussi et al. 1993), severity of illness (Vandoolaeghe et al. 1997), or length of episode and duration of illness (Vandoolaeghe et al. 1997). Antithyroid antibodies. In a wide spectrum of depressed patients, prevalence of abnormal antithyroid antibody titers can range from 6.9% to 20% (Table 14–6), compared with the prevalence of about 5% found in the general population (Tunbridge and Caldwell 1991). It is not obvious whether abnormal antibody titers are clinically relevant if they are accompanied by normal serum TSH concentrations (Joffe 1987; Nemeroff et al. 1985). Summarizing the experience of the Chapel Hill group, Prange et al. (1990) concluded that in 148 patients with mental disorders, the prevalence of antithyroid antibodies was 7% in schizophrenia, 8% in major depression, 20% in bipolar depression, and 33% in a mixed bipolar episode. Patients with antithyroid antibodies had a poorer average treatment response than those without antibodies.

Bipolar Disorder When examining thyroid function in bipolar illness, it is useful to distinguish between rapid-cycling and non–rapid-cycling bipolar disorder. By definition, rapid cyclers experience four or more affective episodes per year (American Psychiatric Association 1994). Approximately 10%–15% of bipolar patients experience rapid cycling; although they are similar to other bipolar patients nosologically and demographically, they tend to

TABLE 14–6.

Antithyroid antibodies in affectively ill patients

Study

N 100

Nemeroff et al. 1985 Haggerty et al. 1987

Prevalence (%) Comment

45

Depression and/or anergia Affective disorder

9 20

102

Affective disorder

20

9 10

Haggerty et al. 1990a

99 68

Affective disorder Non–affective disorder

Joffe et al. (1987)

58

Unipolar depression

9

218 19 51

Major depression Bipolar depressed Bipolar mixed Bipolar manic Adjustment disorder Medical outpatients

7 16 19 4 3 7

Haggerty et al. (1997)

80 144 Note.

Of 15 patients with some form of thyroid abnormality, 60% had positive antibody titers. Each of the 9 patients with symptomless autoimmune thyroiditis had normal baseline serum TSH, T4, T3 uptake, and FT4I concentrations. TSH levels were normal in 7 of these patients and were elevated in 14. Thyroid antibodies were present in 14% of the dexamethasone nonsuppressors and 19% of the suppressors. Although the overall frequency of positive antibody titers did not differ in affective and nonaffective disorders, patients with bipolar affective disorder–mixed or bipolar affective disorder–depressed had a higher rate of positive antibody titers than other patients. Antimicrosomal and antithyroglobulin antibodies. The presence of detectable antibody titers was not related to abnormal thyroid function tests. Major depression was not associated with excessive rate of thyroid antibodies; thyroid autoimmunity was more common in subtypes of bipolar disorder in which depressive symptoms are prominent.

Thyroid Function in Psychiatric Disorders

Gold et al. 1982

Diagnosis

FT4I=free thyroxine index; T3 =triiodothyronine; T4 =thyroxine; TSH=thyroid-stimulating hormone.

373

374

PSYCHONEUROENDOCRINOLOGY

have a longer duration of illness and a more refractory course (Dunner and Fieve 1974). Furthermore, women are disproportionately represented, making up 80%–95% of rapid-cycling patients compared with about 50% of non–rapid-cycling patients (Bauer and Whybrow 1988). A variety of factors may predispose bipolar illness to a rapid-cycling course, including treatment with tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), lithium, and antipsychotics (Wehr et al. 1988). To these factors we can now add comorbid hypothyroidism. Wehr and Goodwin (1979) first reported that TCA induced rapid cycling in 5 female bipolar patients; 3 had a history of thyroid disorder. Cho et al. (1979) demonstrated that 6% of lithium-treated women developed hypothyroidism; most (71%) were rapid cyclers. Cowdry et al. (1983), in a retrospective chart review, found some variety of hypothyroidism in 92% of 24 rapid-cycling patients and in 32% of 19 non–rapid-cycling patients. Bauer et al. (1990) reported that 23% of 30 patients with rapidcycling bipolar disorder had grade 1 hypothyroidism, whereas 27% had grade 2 and 10% had grade 3 abnormalities. Other investigators confirmed the high prevalence of hypothyroidism of some sort in bipolar illness but found similar rates in rapid-cycling and non–rapid-cycling patients (Bartalena et al. 1990a; Joffe et al. 1988; Post et al. 1997; Wehr et al. 1988). Instead they demonstrated that spontaneous or lithium-induced hypothyroidism was associated with female sex (Joffe et al. 1988) or duration of lithium treatment (Bartalena et al. 1990a; Joffe et al. 1988). Sack et al. (1988) demonstrated that the nocturnal TSH rise was absent in rapidcycling patients. If hypothyroidism during bipolar illness predisposes to a rapid-cycling course, what are the effects of treatment with thyroid hormones? O’Shanick and Ellinwood (1982) first suggested that such treatment may be beneficial. In the most extensive study to date, Bauer and Whybrow (1990) entered 11 rapid-cycling bipolar patients whose symptoms were refractory to their current treatment into an open trial of high-dose T4. T4 was added to the baseline medication regimen, and the dosage was increased until clinical response occurred or until side effects precluded further increase. When the patients received T4, their depressive and manic symptoms decreased significantly. Four patients then underwent single- or double-blind placebo substitution; three relapsed into either depression or rapid cycling. Treatment response did not depend on thyroid status at intake. In 9 of 10 responsive patients, it was necessary to achieve supranormal levels of serum FT4 to induce clinical response; however, side effects were minimal and there were no signs of T4-induced hypermetabolism. Baumgartner et al. (1994a) treated 6 patients with severe forms of non–rapid-cycling bipolar disorder whose symptoms had previously been

Thyroid Function in Psychiatric Disorders

375

refractory to all current antidepressant or prophylactic medications with supraphysiological doses of T4 (250–500 mg/day) as “art adjuvant” to their previous medications for an average of 28 months. The mean number of relapses declined and the mean duration of hospitalizations shortened significantly during follow-up. Three patients had no further relapses at all. The side effects were negligible. However, Cowdry et al. (1983) noted that efforts to treat rapid cycling with thyroid hormones have met with inconsistent results.

Seasonal Affective Disorder Bauer et al. (1993) compared thyroid function in patients in a current major depressive episode during the course of recurrent major mood disorder with seasonal pattern to thyroid function of control subjects 1) before and after 4 weeks of light treatment and b) at baseline and after 4 weeks of arising early without exposure to bright light. No consistent abnormalities in TSH, TSH response to TRH infusion, or thyroid autoantibodies were seen in depressive patients at baseline. Coiro et al. (1994) evaluated the diurnal TSH secretion in 7 SAD patients and in 8 control subjects without SAD. Both groups were tested in the fall/winter (when patients were suffering depressive symptoms) and in spring/summer (when patients were euthymic). In all tests, the mean peak TSH response to TRH was significantly lower in the SAD patients than in control subjects. No significant differences were observed in either group between the spring/summer and fall/winter tests. At both periods, SAD patients showed normal TSH levels in the morning but did not experience a nocturnal TSH surge. These data point to an abnormal diurnal TSH secretion in SAD, regardless of the phase of the illness. Raitiere (1992), studying 49 consecutive SAD patients over a 21-month period, reported that 35% had elevated serum TSH levels, and an additional 16% had an exaggerated TSH response to TRH; both findings are consistent with mild primary hypothyroidism.

Cerebrospinal Fluid Studies Depression The studies evaluating concentrations of various hormones of the HPT axis in the cerebrospinal fluid (CSF) of affectively ill patients are summarized in Table 14–7. As shown in Table 14–7, some depressed patients show increased CSF concentrations of T4, rT3, free rT3, or TRH. The pathophysiological significance of these findings is currently not well understood.

Thyroid hormones in cerebrospinal fluid of psychiatric patients

Study

N

Linnoila et al. 1983

Banki et al. 1988

Thyroid measure

Comment

34 MDD 11 BPD 12 MDD

rT3 increased

rT3 increased in unipolar depression

15 20 14 4

TRH increased

MDD Neurological disease MDD Somatization disorder Neurological disease ED Non-ED Mania Schizophrenia MDD Alcoholism Abstinent alcoholics

Roy et al. 1994 Roy et al. 1990 Adinoff et al. 1991

12 21 13 8 9 17 51 13

Fossey et al. 1993

45 Anxiety disorder

Gjerris et al. 1985

FT4, FrT3 increased Decrease in both hormones with recovery

TRH increased

TRH higher in depressed patients, both before and after recovery, than in neurological disease TRH markedly higher in depressed patients than in the other patient groups

TRH

No significant difference among patient groups

TRH TRH TRH

No significant difference between patients and control subjects No significant difference between patients and control subjects Inverse correlation between TRH-induced TSH response and cerebrospinal fluid TRH concentrations TRH levels in patients with panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder not different from those of control subjects

TRH

Note. BPD=bipolar disorder; ED=endogenous depression; FrT3 =free reverse triiodothyronine; FT4 =free thyroxine; MDD=major depressive disorder; rT3 =reverse triiodothyronine; TSH=thyroid-stimulating hormone.

PSYCHONEUROENDOCRINOLOGY

Kirkegaard and Faber 1991 Kirkegaard et al. 1979

Diagnosis

376

TABLE 14–7.

Thyroid Function in Psychiatric Disorders

377

Effects of Somatic Treatments on Thyroid Function Lithium Lithium has important effects on thyroid function. It potently inhibits the conversion, by monodeiodination, of T4 to T3, and it inhibits iodine uptake, thyroid hormone production, and thyroid hormone secretion by the thyroid gland (Burrow et al. 1971; Carlson et al. 1973). During lithium treatment, affectively ill patients commonly show, in varying degrees and combinations, reduced levels of T3 and T4, increased levels of TSH, an exaggerated TSH response to TRH, and clinical evidence of subclinical hypothyroidism, overt hypothyroidism, and goiter. Sudden onset of thyrotoxicosis has also been noted, though much less frequently (Joffe and Levitt 1993; Loosen 1986; Myers et al. 1985). Therefore, lithium maintenance is likely to suppress thyroid function in a sizable portion (i.e., 6%–30%) of affectively ill patients, particularly female patients. Increases in antithyroid antibody titers are also common during lithium therapy, especially in patients who present with positive antithyroid antibody titers and hypothyroidism before treatment (Calabrese et al. 1985; Lazarus et al. 1986; Myers et al. 1985). These effects appear to be temporary; that is, they may reverse even if lithium is continued. They are almost always fully reversed after discontinuation of lithium. Nevertheless, it appears useful to regularly monitor thyroid function during lithium therapy. Although indications for frequency and type of testing remain controversial, we recommend assessing thyroid function (i.e., basal TSH and FT4) before lithium administration to identify dynamic changes during treatment. If such assessment points to thyroid pathology, further tests—such as assessment of T3, FT3, T3 uptake, and antimicrosomal antibodies—may be necessary. After initiation of lithium, thyroid function tests should be repeated during the first half year every 3 months, and thereafter every 6 or 12 months. Such monitoring will allow early identification of subclinical or clinical hypothyroidism—which, as demonstrated in the section “Bipolar Disorder” above, is likely to predispose patients to a rapid-cycling course, and which may be treated by supplementing with thyroid hormone if discontinuation of lithium is not feasible.

MAOIs To date, only one study has evaluated whether MAOIs can adversely affect thyroid function. Joffe and Singer (1987) treated depressed patients with phenelzine for 4 weeks and reported no change in thyroid function.

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Although the study suggests that MAOIs do not have a noticeable effect on thyroid function, one may caution against the use of MAOIs in the presence of hyperthyroidism. Increased thyroid hormone concentration results in increased myocardial sensitivity to a number of central and peripheral mediators of cardiac activity, including catecholamines and indoleamines. Therefore, cardiac toxicity could result from the use of MAOIs in patients with hyperthyroidism (Larsen and Ingbar 1992).

TCAs Although TCA toxicity is increased in the presence of hyperthyroidism (Loosen and Prange 1984; Prange et al. 1969), there appear to be no morphologic or functional changes in the HPT axis during TCA administration in healthy volunteers (Kirkegaard et al. 1977; Widerlov et al. 1978) or in depressed patients (Coppen et al. 1974; Karlberg et al. 1978). (The change in serum T4 concentrations during antidepressant treatment noted above does not appear to be specific to TCAs, as it is seen during a wide range of antidepressant treatments, including TCAs, selective serotonin reuptake inhibitors, sleep deprivation, and ECT.) Hoeflich et al. (1992) treated 41 depressed patients with either maprotiline or fluvoxamine for 4 weeks. Serum T4 levels and body temperature decreased and serum TSH increased significantly during treatment, but there were no significant differences between treatment groups or between responders and nonresponders. Shelton et al. (1993) treated 39 depressed patients with either desipramine or fluoxetine. Twenty-six percent showed some abnormality in baseline thyroid hormone levels. There were no demonstrable differences for any of the thyroid indices from baseline to the 3- or 6week samples for the total group or for either drug. There was a significant group-by-time interaction for total T4 between the drug treatment groups, which was caused by a small but significant increase in T4 in the desipramine sample. Correlations between the change in hormones over the 6-week period and treatment response were calculated. There was a significant association between a decline in T3 levels and response to fluoxetine but not desipramine. Brady et al. (1994) assessed the comparative efficacy of fluvoxamine and imipramine in patients with major depressive disorder. Although serum thyroid hormone concentrations were normal at baseline, both T4 and T3 levels decreased significantly in the imipramine group but not in the fluvoxamine group. In the imipramine group, decreases in depression scores were also significantly correlated with decreases in T3 concentrations. McCowen and colleagues (1997) found elevated serum TSH concentrations in nine T4-substituted patients with hypothyroidism (with

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duration of the illness ranging from 1 to 23 years) who were treated with sertraline. FT4I values decreased in all patients in whom they were measured. No patient had symptoms of hypothyroidism. The effects of sertraline were not due to changes in T4 absorption or serum concentrations of TBG; sertraline may increase the clearance of T4. Taken together, the data suggest that routine monitoring of thyroid function in patients with major depressive disorder taking TCAs is not necessary. However, TCAs—and, to a lesser degree, selective serotonin reuptake inhibitors—should be used with caution in patients with overt thyroid disease, particularly hyperthyroidism, because they may promote tachycardia and cardiac arrhythmias in this condition. The theoretical basis for these effects is similar to that described above for MAOIs. The effects of sertraline in hypothyroid patients substituted with T4 described above (McCowen et al. 1997) also need to be considered.

Carbamazepine and Valproic Acid Carbamazepine, an anticonvulsant agent increasingly used in the management of bipolar patients, is known to decrease thyroid function in both epileptic (Ericsson et al. 1985; Isojarvi et al. 1995; Larkin et al. 1989; Tanaka et al. 1987) and affectively ill patients. Roy-Byrne et al. (1984) first reported that carbamazepine decreased serum thyroid hormone levels in depressed patients. This decrease was greater in responders than in nonresponders and was not due to changes in mean dosage and blood level of carbamazepine. Herman et al. (1991) observed that during carbamazepine treatment serum thyroid hormone concentrations decreased significantly, whereas the metabolic rate did not. Marangell et al. (1994) documented increased CSF TRH concentrations during carbamazepine treatment. Carbamazepine induction of hepatic microsomal enzymes has been proposed as a mechanism for the enhanced nondeiodinative clearance of thyroid hormones (Ahima et al. 1996). However, Joffe et al. (1984) demonstrated that the TRH-induced TSH response was reduced after carbamazepine treatment, suggesting that carbamazepine may decrease thyroid function primarily by reducing TSH secretion at the pituitary level. Whether the thyroid-suppressing effects of carbamazepine are related to its therapeutic effects is unknown; however, they are of clinical importance because side effects of carbamazepine—such as sedation, lethargy, and fatigue—could be interpreted as signs of early hypothyroidism. It is therefore useful to monitor thyroid function during carbamazepine treatment. Kramlinger and Post (1990) assessed the clinical and laboratory effects of adding lithium to carbamazepine in 23 patients with affective disorders. Lithium produced a ro-

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bust reversal of carbamazepine-induced leukopenia, increasing white blood cell counts, predominantly neutrophils, to levels significantly above placebo baseline values. The combination also produced additive antithyroidal effects, resulting in greater decreases in T4 and FT4 and a modestly higher TSH level than with carbamazepine alone. Valproic acid, another anticonvulsant agent increasingly used in the management of bipolar patients, does not appear to suppress thyroid function in epileptic adults (Ericsson et al. 1985; Larkin et al. 1989) or children (Tanaka et al. 1987). It has been proposed that valproic acid does not affect thyroid function because it has no influence on hepatic microsomal enzyme induction, indicating enzyme induction as the likely mechanism for thyroid suppression in patients receiving anticonvulsants (Larkin et al. 1989).

ECT The effects of ECT on hormones of the HPT axis are remarkably consistent. Most (Aperia et al. 1985; Dykes et al. 1987; Papakostas et al. 1991; Scott et al. 1989) but not all (Deakin et al. 1983) studies reported that serum TSH levels rise acutely during ECT; the TSH rise seems to attenuate after a series of ECT treatments (Aperia et al. 1985; Hofmann et al. 1994). A blunted TSH response to TRH during ECT has also been reported (Decina et al. 1987), although not all studies agree (Hofmann et al. 1994; Papakostas et al. 1981). In rats, ECT can induce synthesis of TRH in multiple subcortical limbic and frontal cortical regions, which are known to be involved in depression (Sattin 1998). Seizure activity (Papakostas et al. 1991; Scott et al. 1989) and seizure duration (Dykes et al. 1987; Scott et al. 1989) are associated with these dynamic changes in HPT axis function during ECT, but not treatment response (Decina et al. 1987; Dykes et al. 1987; Papakostas et al. 1991), treatment modality (i.e., unilateral vs. bilateral ECT) (Decina et al. 1987), or psychopathology (i.e., diagnosis of depression or schizophrenia) (Papakostas et al. 1991). Prange et al. (1990), studying 50 patients with major depressive disorder, first reported that baseline thyroid hormone concentrations were inversely related to ratings of ECT-induced organicity. This finding, suggesting that the course of ECT may be beneficially affected by thyroid hormones, was confirmed when the same investigators demonstrated that patients given a small amount of T3 required fewer ECT treatments than patients receiving placebo, although the percentage decrease was not different among groups (Stern et al. 1991).

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Sleep Deprivation The antidepressant effects of one night of sleep deprivation have been well documented (Kuhs and Toelle 1991; Leibenluft and Wehr 1991). Changes in serum thyroid hormone and TSH concentrations during partial or total sleep deprivation are very common. Although study designs and methodologies differed, all studies reported that serum TSH levels increased significantly during total (Baumgartner et al. 1990a, 1990c; Kaschka et al. 1989; Kasper et al. 1988, 1992; Leibenluft et al. 1993; Parekh et al. 1998) or partial (Baumgartner et al. 1990b, 1993) sleep deprivation; the TSH rise did correlate with clinical response in some (Baumgartner et al. 1990a; Kaschka et al. 1989; Kasper et al. 1992; Parekh et al. 1998) but not other (Baumgartner et al. 1990b, 1990c; Kasper et al. 1988; Leibenluft et al. 1993) studies. Increases in serum thyroid hormone levels during sleep deprivation have also been reported (Baumgartner et al. 1990a, 1990b, 1990c; Kaschka et al. 1989; Kasper et al. 1992; Parekh et al. 1998); the thyroid hormone increase did (Kasper et al. 1992) or did not (Baumgartner et al. 1990b) correspond with clinical response. In patients with rapid-cycling bipolar disorder, the normal nocturnal circadian increase in serum TSH was absent, and sleep deprivation failed to increase TSH concentration (Sack et al. 1988).

Phototherapy There is no evidence that thyroid function plays a role in the response of winter depressive symptoms to light treatment (Bauer et al. 1993; Joffe et al. 1991).

Summary: Thyroid Function in Mood Disorders Depression Most longitudinal studies have revealed intriguing dynamic reductions in serum T4 concentrations in depressed patients during a wide range of somatic treatments, including various antidepressants, lithium, sleep deprivation, and ECT. There is also evidence that the T4 reduction was greater in treatment responders than in nonresponders. However, despite their consistency, the data need to be viewed with caution. Transient hyperthyroxinemia was also seen in acutely ill psychiatric patients with diagnoses other than depression (suggesting that the finding is disease nonspecific), and T4 levels normally quickly declined, even if there was no therapeutic intervention or notable behavioral change. It is therefore

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important to control for acute hospitalization and to perform longitudinal studies, ideally without treatment or at least with delayed treatment. It has been speculated that the increased serum T4 concentrations in depression, together with the blunted TSH response to TRH, reflect glucocorticoid activation of the TRH neuron, leading to increased TRH secretion with resultant downregulation of the TRH receptor on the thyrotrope. Normalization of thyroid function after treatment may therefore result in part from an inhibitory response of the TRH neuron to antidepressant treatment (Jackson 1998). Although overt thyroid disease is rare in major depression, more subtle forms of thyroid dysfunction are common, particularly in female patients. They include a blunted TSH response after administration of TRH, an absent or flat diurnal TSH curve, positive antithyroid antibody titers, and evidence of subclinical hypothyroidism (the latter two are often seen together in the same patient). Are these findings clinically relevant? In the case of positive antibody titers (without the clinical picture of subclinical hypothyroidism), it is not known. However, TSH blunting has shown promising clinical utility in predicting the outcome of standard antidepressant treatment and in assessing the risk for violent suicide attempts, although both need replication in larger samples (Loosen 1986). Pathophysiologically, the low TSH response to TRH in the presence of normal serum thyroid hormone levels and the lack of the nocturnal TSH surge, observed in some patients with depression or SAD, are suggestive of mild central hypothyroidism (Coiro et al. 1994). The possible medical and psychiatric consequences of subclinical hypothyroidism are still a matter of intense debate. Medically, it is not known whether subclinical and overt hypothyroidism share the same risk for cardiovascular disease. Often T4 replacement therapy is now initiated in subclinical hypothyroidism because of the risk that the condition may deteriorate into overt hypothyroidism, and because of the evidence that such replacement may improve clinical and behavioral symptoms. Psychiatrically, comorbid subclinical hypothyroidism appears to negatively affect the clinical course of depression; replacement therapy has therefore been advocated in depressed patients with comorbid subclinical hypothyroidism (Haggerty and Prange 1995). There does not appear to be a need to routinely screen for thyroid abnormalities in depressed patients. Two studies including a total of 366 depressed patients concluded that routine thyroid function tests are not indicated because only a very small percentage of patients showed even such mild thyroid abnormalities as subclinical hypothyroidism (Briggs et al. 1993; Fava et al. 1995).

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Bipolar Disorder Bipolar disorders are often associated with various forms of hypothyroidism. As in depression, such comorbidity is seen more frequently in female patients. As in depression, such comorbidity seems to negatively affect the course of the illness (by predisposing the individual patient to a rapidcycling course). As in depression, substitution with T4 has proved useful in some patients, but often high doses are necessary to induce clinical response (Bauer and Whybrow 1988; Baumgartner et al. 1994a). Conceptually, these findings have led to the hypothesis that a relative central thyroid hormone deficit may predispose to the marked and frequent mood swings that characterize rapid-cycling bipolar disorder. However, there are several confounding issues in studies involving rapid cycling and thyroid function (Bauer et al. 1990). First, because of their more severe course, rapid-cycling patients are more likely to have received thyroid hormone treatment and may then be erroneously classified as hypothyroid in retrospective studies. Second, the female preponderance in rapidcycling bipolar disorder may elevate the rate of hypothyroidism, because both disorders are more common in women. Last, the use of lithium and carbamazepine, known goitrogens, is not examined in some studies. It also remains to be determined whether the alleged central thyroid hormone deficit serves only as a risk factor for the development of rapid cycling in a known bipolar patient, or whether it can predispose most affectively ill patients to any major behavioral change (e.g., the switch from depression into recovery or from depression into mania).

Thyroid Function in Alcoholism Effects of Ethanol Administration on Thyroid Function The short-term effects of ethanol on HPT axis function have been investigated only in nonalcoholic subjects (Leppaeluoto et al. 1975; Van Thiel et al. 1979; Ylikahri et al. 1978). The data indicate that ethanol administration does not acutely affect serum thyroid hormone concentration or TSH response to TRH.

Peripheral Thyroid Hormones and TSH Acute Alcohol Withdrawal Major manifestations of moderate to severe ethanol withdrawal include tachycardia, tremor, diaphoresis, and increased temperature. The origin

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of these symptoms has been attributed, in part, to increased sympathetic tone with both peripheral and central components. The similarity between these withdrawal features and the clinical symptoms of hyperthyroidism is apparent, although overt hyperthyroidism has not been shown to be a consequence of ethanol withdrawal. Nine studies (Baumgartner et al. 1994b; Dackis et al. 1984; de la Fuente et al. 1982; Geurts et al. 1981; Kallner 1981; Loosen et al. 1979; Mueller et al. 1989; Roejdmark et al. 1984; Valimaki et al. 1984) assessed baseline serum thyroid hormone concentrations during ethanol withdrawal. Five studies found notable differences between alcoholic subjects and healthy control subjects: an increase in FT4I and total T4 (Loosen et al. 1979), a decrease in T4 (Geurts et al. 1981), a decrease in T3 (de la Fuente et al. 1982; Kallner 1981), and a decrease in FT4 and FT3 (Baumgartner et al. 1994b). Transient changes in serum T4 concentrations can also occur as the individual patient shifts from intoxication to withdrawal (Geurts et al. 1981), or from withdrawal to postwithdrawal or abstinence (Baumgartner et al. 1994b; Dackis et al. 1984; Loosen et al. 1979). Mostly, these changes are mild; they almost never reach the magnitude observed in overt thyroid disease. Eleven studies (Anderson et al. 1992; Banki et al. 1984; Dackis et al. 1984; de la Fuente et al. 1982; Kallner 1981; Loosen et al. 1979; Mueller et al. 1989; O’Hanlon et al. 1991; Pienaar et al. 1995; Thakore and Dinan 1993; Valimaki et al. 1984) assessed the TRH-induced TSH response in acute alcohol withdrawal. All studies demonstrated a blunted TSH response in some patients; a retrospective analysis reveals that 89 (34%) of a total of 260 patients showed a blunted TSH response.

Abstinence Without Liver Disease The most consistent HPT axis finding in abstinent alcoholic individuals without liver disease is a blunted TSH response to TRH (Casacchia et al. 1985; Dackis et al. 1984; Garbutt et al. 1991, 1992; Knudsen et al. 1990; Loosen et al. 1979, 1983; Marchesi et al. 1989; Mueller et al. 1989; Pienaar et al. 1995; Radouco-Thomas et al. 1984; Sellman and Joyce 1992; Thakore and Dinan 1993; Willenbring et al. 1990); a retrospective analysis of these studies reveals that 75 (27%) of a total of 283 patients showed a blunted TSH response. Reduced serum concentrations of T4 (Dackis et al. 1984), T3 (Agner et al. 1986; Loosen et al. 1983), and FT3 (Baumgartner et al. 1994b) have also been reported. The blunted TSH response in abstinent alcoholic subjects does not appear to be the result of a disturbed feedback inhibition of thyroid hormones on TSH (Garbutt et al. 1992).

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Abstinence With Liver Disease Cirrhosis and less severe forms of liver injury are associated with changes in protein synthesis and with alterations in the metabolism of many substances, including thyroid hormones (Chopra et al. 1974; Nomura et al. 1975). Alcoholic individuals with liver disease therefore exhibit a different profile of HPT axis changes than do alcoholic individuals without liver disease. With regard to serum thyroid hormone concentrations, the data are quite uniform. For the most part, T4 levels are not changed (Agner et al. 1986; Green et al. 1977; Hepner and Chopra 1979; Israel et al. 1979; Monza et al. 1981; Nomura et al. 1975), whereas T3 levels are decreased (Agner et al. 1986; Chopra et al. 1974; Green et al. 1977; Hegedus et al. 1988b; Hepner and Chopra 1979; Israel et al. 1979; Nomura et al. 1975; Rumilly et al. 1983; Van Thiel et al. 1979). Despite decreased T3 levels, overt hypothyroidism is not present. T3 reductions appear to derive from decreased conversion of T4 to T3 (thought to be secondary to liver cell damage and loss of deiodinating capacity [Agner et al. 1986; Hepner and Chopra 1979; Israel et al. 1979; Orrego et al. 1987]), are inversely correlated with an index of liver disease (Israel et al. 1979) or with the general severity of the cirrhotic condition (Rumilly et al. 1983), and can be associated with increased rates of early death (Hepner and Chopra 1979). The data suggest that assessment of serum T3 concentrations may be useful in gauging prognosis and complementing other indices of severity. The data further suggest that manipulations of HPT axis hormones may be useful therapeutically. Orrego et al. (1987) reported that the administration of propylthiouracil, an inhibitor of the conversion of T4 to T3, increased the rate of survival in alcoholic patients with severe liver disease. Although the underlying mechanism for this effect is not clear, it has been suggested that propylthiouracil lowers oxygen demand in hepatocytes by decreasing thyroid hormone levels, which in turn renders the cells less likely to experience hypoxic injury (Israel and Orrego 1984; Israel et al. 1979). Hegedus et al. (1988) reported that individuals with chronic alcoholism and liver cirrhosis exhibit reductions in thyroid gland volume, as assessed by ultrasonic examination, and an increase in thyroid gland fibrosis at autopsy compared with control subjects, raising the question of a direct toxic effect of long-term ethanol ingestion on the thyroid gland. Notably absent in the abstinent alcoholic subjects with liver disease is the blunted TSH response to TRH commonly seen in those without liver disease. However, elevated basal TSH levels are rather common (Chopra et al. 1974; Green et al. 1977; Monza et al. 1981; Nomura et al. 1975; Van Thiel et al. 1979); it is not apparent whether they are of clinical sig-

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nificance. The most likely factor contributing to elevated basal TSH levels and, possibly, absence of a blunted TSH response, is the reduced serum T3 concentration noted above. Other possible factors are a decreased TSH clearance, increased serum estrogen levels (which are not unusual in patients with liver damage and which could potentiate TSH release), or a combination thereof. Estrogens do acutely inhibit the rate of hormone release from the thyroid in adults, but any effect appears to be transient because thyroid function is similar in healthy women and men (Gambert 1991), and both men and women taking long-term estrogen therapy have normal serum FT4, FT3, and TSH levels (Gambert 1991).

Subjects at Risk for Developing Alcoholism The persistence of a blunted TSH response in some abstinent alcoholic individuals raises the question of whether TSH blunting is a precursor of alcoholism or a sequela of heavy alcohol consumption. Six studies (Garbutt et al. 1994, 1995; Loosen et al. 1987b; Monteiro et al. 1990; Moss et al. 1986; Radouco-Thomas et al. 1984) evaluated the TSH response in subjects at risk for developing alcoholism; the results of these studies, which normally compared family history–positive (FHP) and family history–negative (FHN) young men, are not consistent. Monteiro et al. (1990) noted no differences in TSH response between groups. In a study of very young subjects, ages 8–17 years, Moss et al. (1986) demonstrated that FHP boys exhibited a higher basal TSH and a higher peak TSH response after TRH administration compared with FHN boys. Girls, when compared by family history, did not differ in basal or TRHstimulated TSH levels. Three studies (Garbutt et al. 1994; Loosen et al. 1987b; Radouco-Thomas et al. 1984) allow the individual identification of a blunted TSH response; analysis of these studies reveals that 18 (46%) of 39 FHP subjects and 3 (5%) of 61 FHN subjects showed a blunted TSH response. These latter findings are consistent with the hypothesis that the TRH-induced TSH response may be a marker of vulnerability to alcoholism. An association between the marker and the risk for late-onset alcoholism has also been suggested (Garbutt et al. 1995).

CSF Studies in Alcoholism Roy et al. (1990) reported that CSF TRH concentrations were not significantly different among 51 alcoholic patients and 15 nonalcoholic control subjects. However, among the control subjects there was a significant

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correlation between CSF concentrations of 5-hydroxyindoleacetic acid and CSF concentrations of TRH. This correlation was lacking in the alcoholic subjects. Adinoff et al. (1991) administered TRH and measured CSF concentrations of TRH in 13 abstinent alcoholic subjects. They found an inverse correlation between the TSH response to TRH and endogenous CSF TRH concentrations. This finding supports the hypothesis that as the concentration of CSF TRH increases, anterior pituitary TRH receptor density decreases, resulting in a blunted TSH response to TRH stimulation.

Summary: Thyroid Function in Alcoholism Short-term administration of ethanol to nonalcoholic volunteers does not produce changes in peripheral thyroid hormone levels. However, with long-term ethanol abuse, as occurs in alcoholic patients, perturbations in thyroid function are common, although their clinical relevance remains unknown because they typically do not reach the level of overt thyroid disease. There is strong evidence that alcoholic patients with liver disease have low T3 levels and increased levels of basal TSH. The extent of T3 reduction (which usually parallels the extent of liver damage) and the failure to increase T3 levels with recovery are indicative of a poor prognostic outcome. In a related way, pharmacologic inhibition of the conversion of T4 to T3 is associated with increased survival in alcoholic individuals with severe liver disease, presumably by reducing the metabolic demand on the liver—a finding that is likely to add important new components to the management and treatment of patients with severe alcohol-induced liver disease. A blunted TSH response to TRH is common in patients without chronic liver disease. A review of the literature reveals that it is present in 35% of patients during acute withdrawal and in 27% of patients during abstinence. TSH blunting is also common in subjects at high risk for developing alcoholism. These findings suggest that TSH blunting may be a precursor of alcoholism (i.e., a trait marker) rather than a sequela of heavy alcohol consumption (i.e., a state marker). Although a blunted TSH response is unlikely to become useful as a clinical marker due to its low sensitivity and specificity (Loosen et al. 1987a), it nevertheless could further the understanding of the pathophysiology of the illness and the biology of vulnerability; it also could aid in the clarification of subtypes. It will be necessary to perform prospective studies to confirm that the HPT axis alterations observed in the offspring of alcoholic fathers are truly predictive of the increased risk for developing alcoholism.

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Thyroid Function in Anxiety Disorders Peripheral Thyroid Hormones Panic Disorder Orenstein et al. (1988) evaluated 144 consecutive female psychiatric patients and found that those with a lifetime history of either panic disorder or agoraphobia with panic attacks were more likely than other patients to report a personal or family history of hyperthyroidism or goiter. However, as noted elsewhere (Stein and Uhde 1993), the study was retrospective and did not determine whether patients with panic disorder have a higher rate of overt thyroid dysfunction than nonpsychiatric control subjects or individuals with other psychiatric disorders. Other studies have bridged this gap by showing that patients with panic disorder have an abnormally high prevalence of goiter (Chiovato et al. 1998) or thyroid illness (Lesser et al. 1987). Matuzas et al. (1987) reported that 50% of 65 consecutively admitted patients with panic attacks had mitral valve prolapse (according to both cardiac auscultation and echocardiography), and that 26% of 42 women and 8% of 13 men had thyroid abnormalities. Several studies have evaluated peripheral thyroid hormone indices in patients with panic disorder; they found no significant difference between patients and control subjects (Chiovato et al. 1998; Lesser et al. 1987; Munjack and Palmer 1988; Stein and Uhde 1988; Yeragani et al. 1987). Stein et al. (1991) demonstrated that the QKd interval in the electrocardiogram, a presumptive index of end-organ thyroid hormone activity, was normal in 15 patients with panic disorder.

Other Anxiety Disorders Studies that evaluated thyroid function in generalized anxiety disorder or obsessive-compulsive disorder (Joffe and Swinson 1988) did not reveal consistent abnormalities. Munjack and Palmer (1988) did not find any abnormal values of T4 concentration, FT4I, or TSH concentration in 41 patients with generalized anxiety disorder. Lindemann et al. (1984) reported that 9% of 295 phobic patients had some form of thyroid dysfunction, with women showing a higher prevalence rate (11%) than men (3%). The difference in prevalence of thyroid illness between this sample and the general population was significant for both women and men. However, Tancer et al. (1990) found normal concentrations of thyroid hormones or antithyroid antibodies in patients with social phobia. Only one study evaluated thyroid function in patients with posttraumatic stress disorder (PTSD). Mason et al. (1994), studying 96 male combat veterans

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with PTSD and 24 male control subjects, reported that PTSD patients showed moderately elevated T4 levels and normal FT4 levels, marked and sustained elevation in levels of both T3 and FT3, as well as elevated T3:T4 ratios and normal TSH levels.

Thyrotropin and Antithyroid Antibodies Panic Disorder Serum TSH levels, either at baseline or after TRH stimulation, were shown to be normal (Chiovato et al. 1998; Munjack and Palmer 1988; Stein and Uhde 1988, 1991) or reduced (Tukel et al. 1999) in patients with panic disorder. Reductions in TSH response to TRH were especially seen in patients who presented with depressive symptoms (Gillette et al. 1989; Stein and Uhde 1991). Positive thyroid microsomal antibody titers have also been reported in patients with panic disorder (Chiovato et al. 1998; Matuzas et al. 1987), but not all studies agree (Stein and Uhde 1989).

Cerebrospinal Fluid Studies Fossey et al. (1993) reported that CSF concentrations of TRH were not different between nonpsychiatric control subjects and patients with panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder.

Summary: Thyroid Function in Anxiety Disorders In contrast to depression and bipolar disorder, there is little evidence for abnormal thyroid function in anxiety disorders. Most studies found peripheral thyroid hormones to be normal in both panic disorder and generalized anxiety disorder. Although there is preliminary evidence of an abnormally high prevalence rate of goiter and thyroid illness in patients with panic disorder (Chiovato et al. 1998; Lesser et al. 1987), serum TSH concentrations and indices of end-organ thyroid hormone activity such as the QKd interval were found to be normal. Finally, during an experimentally induced panic attack, no changes in serum thyroid hormones or TSH were noted (Vieira et al. 1997).

Thyroid Function in Premenstrual Dysphoric Disorder Peripheral Thyroid Hormones Schmidt et al. (1993) reported that 13 of 124 women (10%) with premenstrual dysphoric disorder had evidence of either grade 1 or 2 hypo-

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thyroidism or hyperthyroidism, and 18 women (30%) had abnormal TSH responses to TRH, either blunted (n=6) or exaggerated (n=12). Girdler et al. (1995) showed that although women with premenstrual dysphoric disorder had normal thyroid hormone concentrations during the follicular or luteal phase of their menstrual cycle, they had significantly greater variability in TSH, T4, and FT4I than did control women. However, other studies (R.F. Casper et al. 1989; Nikolai et al. 1990) reported no evidence of thyroid dysfunction in women with premenstrual dysphoric disorder. In three studies, patients received T4 supplementation in a double-blind design; there was no evidence for T4 being superior to placebo (R.F. Casper et al. 1989; Myers et al. 1985; Nikolai et al. 1990).

Thyrotropin and Antithyroid Antibodies Serum TSH concentrations in women with premenstrual dysphoric disorder are usually normal in both the follicular and the luteal phase of the menstrual cycle (R.F. Casper et al. 1989; Roy-Byrne et al. 1987). Schmidt et al. (1993) reported that 16 of 124 (13%) women with premenstrual dysphoric disorder had elevated thyroid antibody titers.

Thyroid Function in Eating Disorders Peripheral Thyroid Hormones and TSH Anorexia Nervosa It is well known that patients with anorexia nervosa demonstrate clinical signs consistent with hypothyroidism, including cold intolerance, constipation, low resting metabolic rate (RMR), bradycardia, elevated serum levels of carotene, and slowed deep tendon reflexes. In the undernourished state of anorexia nervosa, serum T4 and FT4 levels are in the normal range (though lower than those found in matched control subjects), but serum T3 levels are often in the hypothyroid range, occasionally as low as T3 levels seen in acute myxedema (Moore and Mills 1979), as are FT3 and TBG concentrations. The diminished TBG levels partially account for the decrease in T4 and T3 levels, but not for the reduced FT3 concentrations. It appears that T3 is more sensitive than T4 to nutritional state (Table 14–8). Starvation produces acute decreases in serum T3 concentrations in laboratory animals (where they are made more profound by hyperactivity [Brooks et al. 1990]), in healthy volunteer subjects (Gorozhanin and

TABLE 14–8.

Thyroid function in anorexia nervosa Finding

No. studies References

T4

AN in normal range

5

T4 FT4 FT4 T3 FT3 TBG T4, T3, TBG

AN<matched controls AN<matched controls AN in normal range AN<normal range AN<normal range AN<normal range ANWR=normal

3 2 1 4 1 1 6

rT3 TSH

AN>normal AN=normal

2 5

TSH TRHDTSH

AN<normal Normal TSH response

1 5

TRHDTSH

Delayed TSH response (66%–69% of patients)

11

TRHDTSH

Blunted TSH response (12%–24% of patients)

14

Brown et al. 1977; Burman et al. 1977; Collu 1979; Moore and Mills 1979; Moshang et al. 1975 Kokei et al. 1986; Miyai et al. 1975; Tamai et al. 1986 Kokei et al. 1986; Tamai et al. 1986 Collu 1979 Collu 1979; Croxson and Ibbertson 1977; Moore and Mills 1979; Moshang et al. 1975 Komaki et al. 1992 Tamai et al. 1986 Chopra et al. 1975; Croxson and Ibbertson 1977; Komaki et al. 1992; Miyai et al. 1975; Pirke et al. 1985a; Tamai et al. 1986 Kokei et al. 1986; Leslie et al. 1978 R.C. Casper and Frohman 1982; Leslie et al. 1978; Lundberg et al. 1972; Miyai et al. 1975; Moshang et al. 1975 Hurd et al. 1977 Brown et al. 1977; Gwirtsman et al. 1983; Lundberg et al. 1972; Miyai et al. 1975; Moshang et al. 1975 R.C. Casper and Frohman 1982; Croxson and Ibbertson 1977; Gold et al. 1980; Gwirtsman et al. 1983; Leslie et al. 1978; Lundberg et al. 1972; Miyai et al. 1975; Tamai et al. 1986; Vigersky and Loriaux 1977; Vigersky et al. 1976; Wakeling et al. 1979 Beumont et al. 1976; Brown et al. 1977; R.C. Casper and Frohman 1982; Croxson and Ibbertson 1977; Gold et al. 1980; Gwirtsman et al. 1983; Leslie et al. 1978; Lundberg et al. 1972; Macaron et al. 1978; Miyai et al. 1975; Moshang et al. 1975; Tamai et al. 1986; Travaglini et al. 1976; Vigersky et al. 1976

391

Note. AN=anorexia nervosa (underweight phase); ANWR=anorexia nervosa (recently weight recovered); FT3 =free triiodothyronine; FT4 =free thyroxine; rT3 =reverse triiodothyronine; T3 =triiodothyronine; T4 =thyroxine; TBG=thyroxin-binding globulin; TSH=thyroid-stimulating hormone; TRHDTSH=Thyrotropin response to TRH.

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Thyroid measure

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Lobkov 1990; Jung et al. 1985), and in obese patients (Portnay et al. 1974; Vagenakis et al. 1975). The pattern of low normal T4, diminished T3, and normal TSH concentrations is known as the low T3 syndrome or the euthyroid sick syndrome (Carter et al. 1974; Chopra et al. 1983). There is evidence that the peripheral signs of hypothyroidism (i.e., bradycardia, hypercholesterolemia) are related to the diminished T3 seen in anorexia nervosa (Bannai et al. 1988). Both low thyroid indices and TBG abnormalities demonstrated in anorexia nervosa and in protein-calorie malnutrition are corrected after weight gain (Table 14–8). In anorexic patients, T3 levels may even increase into the hyperthyroid range during the weight gain phase of treatment (Moore and Mills 1979). This increase in T3 secretion may be partially responsible for the diet-induced thermogenesis and increased resting energy expenditure observed in anorexia nervosa patients, which enhances their adaptive resistance to refeeding (Moukaddem et al. 1997). Reverse T3, the metabolically inactive enantiomer of T3, has been found to be increased in experimentally starved control subjects (Komaki et al. 1986; Vagenakis et al. 1975), in patients with anorexia nervosa (Table 14–8), and in obese individuals. It has also been found in proteincalorie malnutrition and other disease states (Chopra et al. 1975; Kokei et al. 1986). It is thought that the tissue conversion of T4 and T3 to rT3 represents a physiological adaptation to malnutrition and decreased caloric intake, with the goal of preserving energy and preventing the (unnecessary and potentially harmful) further burning of calories. There is also evidence that the thyroid gland secretes less T3 in anorexia nervosa and that this mechanism is another contributor of the low T3 reported in this illness (Kiyohara et al. 1989). Baseline levels of TSH in anorexia nervosa are in the normal range in all studies but one, in which decreased TSH levels were found (Table 14–8). In anorexia nervosa TSH secretion may be more predominantly regulated by normal FT4 than by T3 levels (Bannai et al. 1988; Haraguchi et al. 1986), because high TSH levels have been reported in the presence of low FT4 concentrations (Matsubayashi et al. 1988). TSH levels also do not seem to be altered in acutely starved control subjects or overweight patients (Portnay et al. 1974). TSH has a circadian rhythm in healthy individuals (Azukizawa et al. 1976; Vagenakis 1979), with a peak occurring during or after the onset of sleep, and a nadir in the late afternoon. Both indirect (Croxson and Ibbertson 1977) and direct (Gwirtsman et al. 1988) measurements of these circadian rhythms in anorexia nervosa indicate a loss of the nighttime surge, with a general resetting of the curve upward. Although these data are preliminary and require replication, it is noteworthy that in experimental animals both hypothyroidism and

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hypothalamic lesions can abolish TSH periodicity (Vagenakis 1979), implying that such dysregulation in anorexia nervosa may reflect hypothalamic dyscontrol. A number of investigations have examined the TSH response to TRH in small samples of anorexic patients; some show a normal curve, but most (67%) demonstrate a delayed response. In clinical hypothyroidism, the TSH response to TRH is exaggerated, and when this is due to disease in the hypothalamus, the peak response of TSH after TRH is often delayed (Moshang et al. 1975; Vagenakis 1979). Although some studies suggest that acute starvation of volunteers (Fichter et al. 1986; Jung et al. 1985; Vinik et al. 1975) and obese patients (Carlson et al. 1977) diminishes the TSH response to TRH, other studies have failed to find this (Portnay et al. 1974; Vagenakis 1977). In approximately 12%–24% of anorexic patients, the TSH response has been blunted (Table 14–8). Delayed TSH responses to TRH are seen in both restricting-type and bulimic-type anorexia (Kiriike et al. 1987). After weight rehabilitation, most anorexic patients develop a more rapid response to peak TSH after TRH, and fewer blunted responses are reported (Leslie et al. 1978; Moore and Mills 1979) but many continue to be abnormal (Kiyohara et al. 1987). Although comorbid mood disturbances are common in patients with anorexia nervosa, the HPT axis aberrations in depression and anorexia are divergent, in that approximately 30% of depressed patients demonstrate blunted rather than delayed TSH responses to TRH (Loosen and Prange 1982) and reduced rather than elevated CSF TRH levels (Banki et al. 1988; Kirkegaard et al. 1979; Lesem et al. 1994). Thyroid disease in patients with eating disorders is seen at twice the rate of the healthy population (Hall et al. 1995), although classic thyroid illness is rarely described together with anorexia nervosa. When these illnesses co-occur, the hypermetabolic state of Graves’ disease can mask the hypometabolism of anorexia nervosa (Kuboki et al. 1987). Patients with eating disorders will occasionally abuse exogenous thyroid supplements to control their weight (Kornhuber et al. 1996). In one case of severe thyrotoxicosis, the patient refused treatment for years until forced by symptoms of congestive heart failure and thyroid storm (Rolla et al. 1986).

Bulimia Nervosa Several studies have examined thyroid function and RMR in bulimic patients, with equivocal results. Some investigators found RMR (Devlin et al. 1990; Obarzanek et al. 1991) and serum T3 levels (Kiyohara et al. 1988; Obarzanek et al. 1991; Pirke et al. 1985b) to be significantly reduced in bulimic patients with normal weight, especially when patients

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were studied during abstinence from binge eating, whereas other investigators found thyroid indices, including basal TSH, to be normal (Devlin et al. 1990; Gwirtsman et al. 1983; Mitchell and Bantle 1983). Two studies conducted at the National Institutes of Health reported that bulimic patients studied shortly after admission had either normal thyroid indices or slightly diminished T3 levels. However, after 3 weeks of abstinence from binge eating and purging, T4 and T3 levels declined significantly, whereas TSH levels increased modestly (Spalter et al. 1993). After 7 weeks of abstinence, all thyroid indices, including FT4, FT3, rT3, and TBG levels were reduced compared with the acute binge-eating phase and compared with control subjects. The nocturnal TSH surge in the bulimic patients was similar to that of control subjects and was unaffected by changes in thyroid indices (Altemus et al. 1996). The authors concluded that this represented a form of subclinical hypothyroidism during abstinence, with an impaired feedback on the pituitary or the hypothalamus. In one study (Spalter et al. 1993), levels of T3 were directly correlated with caloric intake and were inversely correlated with body weight. RMR has also been reported to decline significantly during abstinence from binge eating and purging (Altemus et al. 1991; T. Leonard et al. 1996), compared with the same patients during active binge eating. The data suggest that binge-purge behavior may transiently increase thyroid indices and RMR, whereas decreases in thyroid indices following abstinence from binge eating and purging behaviors are probably related to either diminished caloric consumption or else may reflect hypothalamic-pituitary dysregulation. Thus, normal-weight bulimic subjects who are abstinent from binge-purge cycles may have a variant of the euthyroid sick syndrome (Spalter et al. 1993).

Binge-Eating Disorder Binge-eating disorder is a newly described eating disorder in which individuals engage in binge eating episodes but do not purge their food, leading inevitably to obesity (American Psychiatric Association 1994). Recent epidemiological surveys indicate that this disorder is highly prevalent among the obese, perhaps exceeding 30% (Spitzer et al. 1992). RMR or baseline thyroid indices do not differ in binge-eating and nonbinging obese patients (Wadden et al. 1993). However, a low RMR can be a predictor of certain forms of obesity (Astrup et al. 1996; Ravussin and Gautier 1999). Furthermore, the physiological role of leptin on energy intake may be through a modulatory effect on the HPT axis—specifically, by regulating pro-TRH gene expression in the paraventricular nucleus (Ahima et al. 1996; Legradi et al. 1997).

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Summary: Thyroid Function in Eating Disorders Thyroid abnormalities are common in anorexia nervosa. Acutely ill patients often demonstrate the low T3 or euthyroid sick syndrome, characterized by normal concentrations of T4 and FT4, but low T3, FT3 and TBG concentrations. Because the euthyroid sick syndrome usually returns to normal after nutritional rehabilitation, it is thought to represent a physiological adaptation to the acute effects of starvation rather than being causally linked to the illness. Delayed TSH responses to TRH are also common in anorexia nervosa. Because delayed TSH responses may continue after weight gain (Kiyohara et al. 1987), it is possible that they are caused by other symptoms of abnormal eating, such as vomiting (Kiyohara et al. 1987), or that they are the result of hypothalamic dysfunction, perhaps involving a central TRH deficiency (Croxson and Ibbertson 1977; Lesem et al. 1994; Lundberg et al. 1972).

Thyroid Function in Schizophrenia Schizophrenia has attracted psychoendocrine investigation for more than 100 years. Kraepelin (1896), Bleuler (1954), and Gjessing (1974) observed certain endocrine disturbances and proposed related therapies. For example, thyroid extract was widely used in schizophrenic patients (Bleuler 1954; Brauchitsch 1961), and T4 is still considered to be of some use in periodic catatonia (Gjessing 1974). It was suggested that an active or even hyperactive HPT axis may beneficially modify the course of the illness (Brauchitsch 1961). Komori et al. (1997) confirmed the early work by Gjessing when they documented that periodic catatonia could be abolished by a combination of thyroid hormone and reserpine.

Peripheral Thyroid Hormones Early studies of thyroid function in schizophrenic patients have been ably reviewed (Bleuler 1954; Michael and Gibbons 1963). The results of more recent studies are equivocal in demonstrating normal thyroid function (Brambilla et al. 1976; Johnstone et al. 1987; Plunkett et al. 1964; Rinieris et al. 1980; Simpson and Cooper 1966), decreases in serum T3 (Prange et al. 1979) or T4 (Rao et al. 1984), or increases in FT4I (Morley and Shafer 1982; Prange et al. 1979; Spratt et al. 1982). Roca et al. (1990)

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found that 22 of 45 (49%) acutely hospitalized psychiatric patients had significant elevations of one or more thyroid hormone levels; these researchers also observed significant positive correlations between psychiatric symptom severity and FT4I in schizophrenic patients. MacSweeney et al. (1978) reported a significantly higher incidence of thyroid disease in mothers of 104 schizophrenic patients than in a carefully matched control group. DeLisi et al. (1991) noted that family histories of thyroid disorders were significantly more common among schizophrenic patients than among community control subjects.

Thyrotropin and Antithyroid Antibodies Dewhurst et al. (1968) found increased baseline TSH levels in 5 of 20 (25%) schizophrenic patients. TSH elevations correlated significantly with ratings of paranoid symptoms. Later studies found basal TSH concentrations to be decreased (Rao et al. 1984) or normal (Prange et al. 1979) in schizophrenic patients. Rao et al. (1995) reported a significantly decreased TSH MESOR (i.e., the daily mean) in schizophrenic patients, pointing to an abnormality in the circadian TSH secretion. In the only study assessing thyroid antibodies in a schizophrenic population, Othman et al. (1994) demonstrated that 51 of 249 patients (20%) with chronic schizophrenia had thyroid antibodies.

Effects of Somatic Treatments on Thyroid Function There is evidence that peripheral thyroid hormone concentrations can decrease during neuroleptic therapy (Baumgartner et al. 1988; Rinieris et al. 1980), although not all studies agree (Baptista et al. 1997; Konig et al. 1998; Naber et al. 1980). Baseline TSH concentrations have been reported to be increased (Grunder et al. 1999), decreased (Grunder et al. 1995), or unchanged (Konig et al. 1998; Naber et al. 1980) during therapy with various neuroleptics; the TRH-induced TSH response is usually unchanged during such treatment (Grunder et al. 1995, 1999; Konig et al. 1998; Markianos et al. 1994; Naber et al. 1980).

Summary: Thyroid Function in Schizophrenia There is little evidence for abnormal thyroid function in schizophrenic patients. However, the finding of an abnormally high prevalence rate of thyroid disorders in the family history of schizophrenic patients (DeLisi et al. 1991) and the intriguing behavioral effects of T4 in periodic catatonia, first described by Gjessing (1974), deserve further study.

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Conclusion The literature provides much support for the notion that there are many associations between thyroid hormones and behavior, although the exact nature of these associations remains unknown. The effects of thyroid hormones (or the lack thereof) during early human development on brain function, their use to supplement the treatment regimen of some patients who respond poorly to standard antidepressants, and their often marked psychological effects in patients with thyroid disorders are beyond the scope of this review and have been discussed elsewhere (Ahmed Smith and Loosen 1998; Bauer and Whybrow 1988; Loosen 1986). The clinical studies of thyroid function in mental illness discussed here have brought forward a plethora of findings; some are clinically relevant. First, abnormal thyroid function is often observed in mood disorders. In a similar way, mood disturbances are among the most prominent psychological sequelae of overt thyroid disease. In both depression and bipolar disorder, comorbid thyroid dysfunctions are not clinically innocuous; they can negatively affect short-term and long-term outcome and can complicate treatment. (Routine thyroid function tests are not indicated in psychiatric patients, because only a very small percentage of patients show even such mild thyroid abnormalities as subclinical hypothyroidism. However, if thyroid dysfunction exists as a comorbid condition in mood disorders, early aggressive treatment is warranted.) Second, the euthyroid sick syndrome and mild, transient hyperthyroxinemia are common among acutely hospitalized psychiatric patients; both are disease nonspecific and usually normalize on recovery. Thyroid function tests obtained at admission therefore need to be interpreted with caution. Third, lithium and carbamazepine (but not valproic acid) decrease thyroid function; careful, repeated thyroid status assessments are therefore necessary during the course of treatment. Fourth, abnormal thyroid function can be associated with a symptom of a disease rather than with the disease itself. The effects of starvation on thyroid function are well known; starvation and symptoms leading to starvation (e.g., loss of appetite, weight loss) therefore need to be considered when interpreting results. In a similar way, disease complications can lead to false-negative results. In alcoholic patients without liver disease a blunted TSH response to TRH is common. However, in those with liver disease TSH responses are normal, possibly due to decreased T3 concentrations (which, in turn, are thought to be the direct result of alcohol-induced liver damage). Fifth, there appears to be no direct causal relationship between thyroid function and various clinical states. Rather, changes in thyroid function can fa-

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cilitate behavioral change in a positive direction (e.g., dynamic reductions in serum T4 concentrations in depression during such diverse treatments as various antidepressants, lithium, sleep deprivation, or ECT) or a negative direction (e.g., comorbid subclinical hypothyroidism facilitates a rapid-cycling course in bipolar disorder and thus affects outcome and complicates treatment). Sixth, acute manipulations of thyroid function (by administering thyroid hormones directly or by interfering with their metabolism) can be clinically useful in a variety of conditions: the addition of T3 has been shown to shorten the course of ECT and to attenuate the cognitive side effects of ECT; a small dose of T3 can enhance the effect of antidepressants in women and can convert treatment nonresponders into responders in both sexes; substitution with T4 has proved useful in some rapid-cycling bipolar patients, although high doses are often necessary to induce clinical response; T4 can beneficially affect the course of periodic catatonia; and pharmacologic inhibition of the conversion of T4 to T3 by propylthiouracil can be associated with increased survival in alcoholic individuals with severe liver disease. The exact mechanism(s) by which such manipulations exert their clinical effect are unknown.

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Scott AI, Milner JB, Shering PA: Diminished TSH release after a course of ECT: altered monoamine function or seizure activity? Psychoneuroendocrinology 14:425–431, 1989 Segerson TP, Kauer J, Wolfe HC, et al: Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus. Science 238: 78–80, 1987 Sellman JD, Joyce PR: The clinical significance of the thyrotropin-releasing hormone test in alcoholic men. Aust N Z J Psychiatry 26:577–585, 1992 Shelton RC, Winn S, Ekhatore N, et al: The effects of antidepressants on the thyroid axis in depression. Biol Psychiatry 33:120–126, 1993 Simpson GM, Cooper TB: Thyroid indices in chronic schizophrenia. J Nerv Ment Dis 142:58–62, 1966 Sokolov ST, Kutcher SP, Joffe RT: Basal thyroid indices in adolescent depression and bipolar disorder. J Am Acad Child Adolesc Psychiatry 33:469–475, 1994 Souetre E, Salvati E, Wehr TA, et al: Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry 145:1133–1137, 1988 Souetre E, Salvati E, Belugou JL, et al: Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Res 28:263–278, 1989 Southwick S, Mason JW, Giller EL, et al: Serum thyroxine change and clinical recovery in psychiatric inpatients. Biol Psychiatry 25:67–74, 1989 Spalter AR, Gwirtsman HE, Demitrack MA, et al: Thyroid function in bulimia nervosa. Biol Psychiatry 33:408–414, 1993 Spitzer RL, Devlin M, Walsh BT: Binge eating disorder: a multisite field trial of the diagnostic criteria. Int J Eat Disord 11(3):191–203, 1992 Spratt DI, Pont A, Miller MB, et al: Hyperthyroxinemia in patients with acute psychiatric disorders. Am J Med 73:41–48, 1982 Stein MB, Uhde TW: Thyroid indices in panic disorder. Am J Psychiatry 145: 745–747, 1988 Stein MB, Uhde TW: Autoimmune thyroiditis and panic disorder. Am J Psychiatry 146:259–260, 1989 Stein MB, Uhde TW: Endocrine, cardiovascular, and behavioral effects of intravenous protirelin in patients with panic disorder. Arch Gen Psychiatry 48:148– 156, 1991 Stein MB, Uhde TW: The thyroid and anxiety disorders, in The Thyroid Axis and Psychiatric Illness. Edited by Joffe RT, Levitt AJ. Washington, DC, American Psychiatric Press, 1993, pp 255–277 Stein MB, Muir-Nash J, Uhde TW: The QKd interval in panic disorder: an assessment of end-organ thyroid hormone responsivity. Biol Psychiatry 29:1209– 1214, 1991 Stern RA, Nevels CT, Shelhorse ME, et al: Antidepressant and memory effects of combined thyroid hormone treatment and electroconvulsive therapy: preliminary findings. Biol Psychiatry 30:623–627, 1991

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Chapter 15 Psychiatric and Behavioral Manifestations of Hyperthyroidism and Hypothyroidism Michael Bauer, M.D., Ph.D. Martin P. Szuba, M.D. Peter C. Whybrow, M.D.

F

or nearly 200 years, physicians have recognized that adequate thyroid function is a prerequisite for normal brain development and mental functioning. However, interest in the role that thyroid metabolism plays in psychiatric disorders has burgeoned in the past 40 years, as scientific and technological progress has illuminated the relationship between thyroid hormones and behavior. With knowledge of the role of neurotransmitters and their metabolism in controlling behavior and an awareness of the complexity of neuronal interactions, the understanding of brain function has expanded rapidly. As technology advanced, the chemical dissection of the thyroid hormone system gained specificity—for example, by locating thyroid hormones, nuclear thyroid hormone receptors, and thyroid-related peptides such as thyrotropin-releasing hormone (TRH) in the brain (reviewed in Bauer et al. 2002). At the clinical level, highly sensitive radioimmunoassays for measuring hormones of the hypothalamic-pituitary-thyroid (HPT) system, the use of thyroid hormones in the treatment of mood disorders (Bauer and Whybrow 2001; Prange et al. 1969), and the finding of abnormal thyroid-stimulating hormone (TSH) responses to TRH in various psychiatric disorders, particularly the mood disorders (Loosen and Prange 1982), have all made their contributions in improving the understanding of the relationships between thyroid, brain, and behavior (Bauer and Whybrow 2002). The association between thyroid function and behavior was first noticed early in the nineteenth century. Hyperfunction of the thyroid gland was described by Parry (1825), who attributed the observed “various nervous af-

419

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fectations” to an earlier frightening incident experienced by the patient. Graves (1835) described the syndrome named after him and suggested a relationship between the thyroid gland and the syndrome globus hystericus, but it was not until the end of the nineteenth century that a thyrotoxic syndrome of endocrine origin was clearly distinguished from the group of neuroses. By the 1880s, behavioral changes in hypothyroid patients had been noted, culminating in a report from the Clinical Society of London (1888) describing a variety of mental disturbances. In the twentieth century, interest in the relationship between thyroid function and mental disorders grew significantly. A causative role of hypothyroidism in psychopathology was demonstrated by Asher (1949) in a case series suggesting that thyroid hormone deficiency may lead to depression and psychosis (“myxedematous madness”) and was reversible with administration of desiccated thyroid. During the last four decades, systematic studies revealed that disorders of the thyroid gland are frequently associated with mental disturbances (Treadway et al. 1967; Whybrow and Bauer 2000a, 2000b; Whybrow et al. 1969). Thyroid disorders are common, occurring in up to 6% of the general population. Rates of abnormal thyroid metabolism in psychiatric populations are higher than in the rest of the population (Whybrow 1995). In part this may be iatrogenic; various psychotropic medications—including lithium, neuroleptics, carbamazepine, and antidepressants—disturb HPT axis function to varying degrees. Furthermore, given that the initial (and sometimes the only) manifestations of hyperthyroid and hypothyroid states are often neurobehavioral, the association of thyroid disease and behavior, including psychiatric sequelae, is of substantial clinical importance to the psychiatrist. Most individuals who report clinical symptoms of thyroid dysfunction complain of a mental disturbance that remits on correction of their thyroid illness. This observation is important, because it indicates the involvement of the HPT system in the modulation of behavior (Whybrow 1995). Therefore, it is useful for the clinical psychiatrist to be familiar with the behavioral syndromes of thyroid dysfunction. In this chapter we review the psychiatric and behavioral manifestations of thyroid disorders in patients with hyperthyroidism (thyrotoxicosis) and hypothyroidism.

Hyperthyroidism and Thyrotoxicosis Hyperthyroidism is a condition that results from sustained increases in thyroid hormone biosynthesis and secretion by the thyroid gland. Distinct from hyperthyroidism is thyrotoxicosis, the clinical syndrome of

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hypermetabolism that results from sustained increased serum concentrations of free thyroxine (FT4), free triiodothyronine (FT3), or both (Braverman and Utiger 2000b). Subsequently, the secretion of TSH is suppressed, resulting in decreased serum TSH concentrations. The distinction between hyperthyroidism and thyrotoxicosis is important, because although most patients with thyrotoxicosis have hyperthyroidism, this is not uniformly the case (e.g., those in whom thyrotoxicosis is caused by exogenous thyroid hormone administration).

Epidemiology and Etiology Thyrotoxicosis is a common thyroid disorder with multiple causes. Graves’ disease, which is associated with a diffuse toxic goiter and exophthalmos, is the most frequent cause. It accounts for approximately 60%–90% of all cases of thyrotoxicosis. Less frequent causes of thyrotoxicosis are toxic multinodular goiter (multiple nodules that are benign but can produce substantial amounts of thyroid hormones), autonomously functioning thyroid adenomas (toxic adenomas), exogenous thyrotoxicosis (including thyrotoxicosis factitia), excessive replenishment in hypothyroidism, and TSH-secreting pituitary adenomas (Larsen et al. 1998). Graves’ disease is an autoimmune thyroid disease that occurs most frequently in women ages 20–40 years (Davies 2000). Patients with autoimmune thyroid disease show immune reactivity (both antibodies and cell-mediated immunity) directed predominantly at three thyroid autoantigens: thyroglobulin, thyroid peroxidase, and the TSH receptor (Marcocci and Chiovato 2000). Autoimmune thyroid disease clusters in families, and the concordance rate for Graves’ disease is higher for monozygotic (22%) than for dizygotic twins (0%) (Brix et al. 1998). Besides genetic factors, several factors may play a role in the pathogenesis of Graves’ disease, including stress, cigarette smoking, and possibly infectious organisms (Chiovato and Pinchera 1996; McLachlan and Rapoport 2000; Whybrow and Bauer 2000b). There has been much debate surrounding the role of psychosocial stress and trauma in the precipitation of Graves’ disease. Anecdotal reports and a considerable body of clinical opinion seem to support an association, but objective evidence remains elusive. One of the major challenges is determining a precise date of onset for thyrotoxicosis. The rapidity of onset is variable, and the disorder is probably subclinical for weeks or months, so the thyrotoxicosis may have already begun by the time of the putative precipitating event. Furthermore, the presence of a disturbance in psychophysiology may affect the individual’s reaction to an event. Unfortunately, information distinguishing these relationships is difficult to

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obtain retrospectively (Whybrow and Bauer 2000b). Although prospective studies would be more effective in obtaining this information, they are difficult to conduct. However, in one such study, 239 women from the general population who had “thyroid hot spots”— areas of the thyroid gland found on screening to concentrate radioactive iodine activity—were studied closely over time, with each subject’s thyroid and psychological status being evaluated independent of one another. Through the 12-year follow-up period, the hot spots appeared to wax and wane in direct relationship with life stress, with some women developing clinical thyrotoxicosis during conditions of severe or prolonged life strain (Voth et al. 1970; Wallerstein et al. 1965). Two retrospective controlled studies have been conducted that explore the onset of Graves’ disease. In a case-controlled study, patients developing Graves’ thyrotoxicosis reported more negative life events—such as divorce, bereavement, and educational and occupational failure—than did control subjects (Winsa et al. 1991). In another study, reports from a sample of 70 age- and sex-matched patients attending an endocrine clinic yielded similar results (Sonino et al. 1993). In this study the patients had greater life change in the year preceding the diagnosis of Graves’ thyrotoxicosis (both positive and negative) compared with control subjects. Blinded raters judged rates of negative life events to be significantly greater among study patients versus control subjects. Environmental stress may also play a role in the course of thyrotoxicosis. Support for this notion has been found in a longitudinal study of patients receiving antithyroid drug therapy. In this study, the course of thyrotoxicosis appeared to be related to the person’s ability to cope psychologically with life stress, particularly when confronted with bereavement or loss (such as financial difficulty) (Ferguson-Rayport 1956). If coping was successful, the illness subsided; if not, the exacerbation progressed. Individual case reports provide additional support for this finding (Cushman 1967). One patient with Graves’ disease experienced a rapid increase in thyroid secretion after a surgical biopsy for a benign breast tumor. Another patient, who had been successfully treated for Graves’ thyrotoxicosis, had a recurrence of illness within 2 months after the death of two young family members. In conclusion, psychological stress may be associated with the onset of thyrotoxicosis symptoms and may also influence its clinical course.

Clinical Manifestations The clinical manifestations of an excessive availability of thyroid hormones are numerous and are found in all systems of the body, including the brain. Usually the manifestations of the illness are insidious, and fam-

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ily members or friends may notice changes in the individual’s appearance or behavior even before they are apparent to the patient. Physical symptoms include increased perspiration, weight loss, palpitations, heat intolerance, fatigue, weakness, and menstrual disturbances. In Graves’ disease, the eyes may protrude (exophthalmos) and a palpable goiter is found. The most common physical signs are tachycardia or atrial arrhythmia, warm and moist skin, tremor, hyperreflexia, and muscle weakness (Braverman and Utiger 2000b; Larsen et al. 1998). In severe cases, myopathies, peripheral neuropathies, and retinopathy may appear. Although they are etiologically distinct, many of the effects of hyperthyroidism on physical appearance, physical function, behavior, mood, and cognitive function are similar regardless of the origin of the illness.

Neuropsychiatric Symptoms and Signs Various neuropsychiatric symptoms may occur in thyrotoxicosis. However, the behavioral state in hyperthyroidism is best characterized as one of intense dysphoria, usually with pronounced anxiety. In the early stages, anxiety and tremor may occur alone with few physical manifestations. Other common complaints include nervousness, emotional lability, restlessness, and impaired concentration. Patients feel irritable and jittery; they also have insomnia with fatigue and often feel too weak and tired to carry through with their plans. Speech can also be rapid and disjointed. An uncommon presentation of behavioral change with thyrotoxicosis mimics a depressive disorder and usually occurs in elderly patients. These patients feel apathy, lethargy, pseudodementia, and depressed mood and often lack the standard physical findings associated with hyperthyroidism in young people (Peake 1981; Taylor 1975). Studies estimating the prevalence of emotional and cognitive dysfunction in hyperthyroidism are subject to many limitations. Most reports are based on collections of unselected patients with hyperthyroidism, but from the studies summarized in Table 15–1, certain trends emerge. Investigation of the neuropsychiatric status of thyrotoxic patients has corroborated the clinical impressions of anxiety, mood, and cognitive disturbances. Studies using modern diagnostic criteria have shown that in patients with thyrotoxicosis, the prevalence of anxiety disorders was approximately 60%, and the prevalence of depressive disorders was between 31% and 69% (Kathol and Delahunt 1986; Trzepacz et al. 1988b). Other studies using objective neuropsychiatric measurements have confirmed these clinical impressions. Studies have shown increased anxiety (Greer et al. 1973) on a standardized questionnaire, increased depression on the Minnesota Multiphasic Personality Inventory (MMPI)

424 TABLE 15–1.

PSYCHONEUROENDOCRINOLOGY Prevalence of psychiatric dysfunction in hyperthyroid patients

Study

N

Prevalence (%)

Findings

Mandelbrote and Wittkomer 1955 Kleinschmidt and Waxenberg 1956 Bursten 1961 Wilson et al. 1962

25

65

Neurosis

17

12

Psychosis

54 26

Hermann and Quarton 1965 Whybrow et al. 1969

24 10

MacCrimmon et al. 1979 Wallace et al. 1980

19 19

Rockey and Griep 1980

14

19 54 58 8 4 100 20 40 10 95 >50 71 79 64

Kathol et al. 1985 32 Trzepacz et al. 1988a, 1988b 13

7 34 69 62 20 23

Psychosis Cognitive impairment Depression Elation Psychosis Fatigue and/or irritability Depression Subjective confusion Paranoia Fatigue Nervousness, irritability Fatigue Nervousness Social withdrawal or irritability Major depression Organic mood disorder Major depression Generalized anxiety disorder Panic disorder Hypomania

scale (Artunkal and Togrol 1964), and increased depression and anxiety on the MMPI (MacCrimmon et al. 1979). In addition, a study using the Clyde Mood Scale also found an increased jittery score and reduced score for clear thinking among thyrotoxic patients (Robbins and Vinson 1960). Cognitive dysfunction, including decreased concentration and impaired memory, are also correlated with the thyrotoxic state. Patients with thyrotoxicosis were found to resemble those with an organic brain syndrome when assessed for neurotic and cognitive traits using standardized measures (Robbins and Vinson 1960). Performance on tasks requiring concentration and memory was also shown to decline in direct proportion to the degree of increase in serum thyroxine (T4) (MacCrimmon et al.

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1979). In addition, patients with thyrotoxicosis were shown to perform poorly on the Porteus maze and the Trail Making Tests, another indication of cognitive impairment (Whybrow et al. 1969). Psychosis, mania, and delirium have been reported and may accompany a thyrotoxic storm (a relatively rare but life-threatening syndrome characterized by exaggerated manifestations of thyrotoxicosis) (Greer and Parsons 1968; Wartofsky 2000). Patients who typically develop a true manic episode while thyrotoxic have either an underlying mood disorder or a family history (Checkley 1978; Hasan and Mooney 1981; Reus et al. 1979). In the patients who do develop a psychotic illness, evidence of delirium is often present (Beierwaltes and Ruff 1958; Whybrow et al. 1969).

Laboratory Diagnosis A biochemical diagnosis of (overt) thyrotoxicosis is easily obtained by measurement of levels of FT4, FT3, or both (increased) and of serum TSH levels (decreased). Subclinical thyrotoxicosis is defined as a low serum TSH concentration and normal serum FT4 and FT3 concentrations associated with few or no symptoms or signs of thyrotoxicosis (Ross 2000). Mild overt thyrotoxicosis is diagnosed when asymptomatic patients show low TSH concentrations but have slightly high serum free thyroid hormone concentrations. Ultrasensitive TSH assays now permit detection of subnormal TSH values. In the absence of pituitary disease, if serum TSH values are less than 0.2 mU/L, hyperthyroidism is the likely diagnosis. In cases of ambiguity, a TRH challenge test can be of substantial value in quantifying the hyperthyroid state. In the standard TRH test, 500 mg of TRH is given intravenously and TSH values are drawn at baseline and at 15, 30, 45, and 60 minutes. Peak values in normal women are usually more than 6 mU/L above baseline values. In normal men, TSH levels usually rise more than 6 mU/L before age 30 and by more than 2 mU/L after age 40. Suppressed responses in the absence of pituitary disease are virtually diagnostic of thyrotoxicosis, but if subjects show normal responses to TRH infusion, thyrotoxicosis can be ruled out.

Treatment of Neuropsychiatric Symptoms After successful treatment of thyrotoxicosis the psychiatric symptoms usually remit. Administration of an adrenergic antagonist agent such as propranolol may be useful in controlling the anxiety associated with thyrotoxicosis. Among acutely psychotic patients, dopamine blockade may be required to reduce excitement. Haloperidol or one of the newer atyp-

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ical antipsychotic medications (e.g., risperidone or olanzapine) may be used. There is a report of haloperidol precipitating thyrotoxic storm (Hoffman et al. 1978). A combination of the b-adrenergic blocker propranolol and propylthiouracil, an antithyroid drug, has also been described to be effective in controlling manic behavior secondary to thyrotoxicosis (Lee et al. 1991). Most studies conducted between 1956 and 2000 found substantial improvement in neuropsychiatric symptoms that paralleled the resolution of the thyrotoxicosis (Table 15–2). After return to normal thyroid status, patients had improvement in cognitive function (MacCrimmon et al. 1979; Robbins and Vinson 1960), and in a study by Artunkal and Togrol (1964) all 20 patients had improved MMPI profiles. Whybrow et al. (1969) also found improvement in nervousness, anxiety, and motor tension. In some studies, however, patients showed incomplete neuropsychiatric recovery after reaching normal thyroid status. One study found 8 of 17 persons (47%) with various nonpsychotic and psychotic symptoms to be improved on reestablishment of euthyroid status (Kleinschmidt and Waxenberg 1956). In another study, of 45 patients who were hyperthyroid 10 years previously, only 25% were found to have markedly impaired neuropsychological functioning (Bommer et al. 1990). Trzepacz et al. (1988b) reported that patients’ mood and anxiety symptoms had improved, but some attention deficit remained. A recent study investigating the epidemiology of somatic and somatopsychic complaints in patients with remitted hyperthyroidism confirmed the impression of residual symptoms. In this study, one-third of patients had long-term mental sequelae and residual complaints such as lack of energy (Fahrenfort et al. 2000). The incomplete remission of neuropsychiatric symptoms experienced by some euthyroid patients is indicative of irreversible central nervous system (CNS) damage. Although the underlying pathophysiological mechanisms are unknown, it may be speculated that the autoimmune processes associated with thyrotoxicosis play a role. In one study, a higher number of previous hyperthyroid episodes was associated with more residual neuropsychiatric symptoms, indicating a relationship between disease severity and treatment outcome (Bommer et al. 1990). In conclusion, most research has found that scores on various mood, anxiety, and cognitive measures return to normal after a return to euthyroid status. The fact that most psychiatric symptoms are reversible after treatment suggests that they are secondary to the hormonal abnormality. Unfortunately, in some patients neuropsychiatric sequelae may persist despite a return to normal thyroid status.

TABLE 15–2.

Recovery of psychiatric function after treatment of hyperthyroidism N

Outcome

Kleinschmidt and Waxenberg 1956 Robbins and Vinson 1960 Artunkal and Togrol 1964 Whybrow et al. 1969 MacCrimmon et al. 1979, Wallace et al. 1980 Rockey and Griep 1980 Trzepacz et al. 1988a

17

47% showed decreased mood and psychotic symptoms

10 20 10 19

Cognitive and neurosis scores improved Minimal change Cognitive and psychopathological scores normalized Cognitive and psychopathological scores normalized

14 10

Emanuele et al. 1989 Bommer et al. 1990

4 45

Freedman et al. 1993 Fahrenfort et al. 2000

15 303

Global measures improved in all, except 1 depressed subject All mood and anxiety symptoms improved after 2 weeks of propranolol treatment; cognitive symptoms improved only after 6 months of antithyroid treatment Agoraphobia markedly better after treatment of hyperthyroidism in all subjects 10 years after treatment, patients had persistent feelings of hostility and impaired cognitive performance More relaxed, improved concentration and abstracting abilities after treatment One-third showed residual neuropsychiatric symptoms years after treatment

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Study

427

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Interactions Between the Hyperthyroid State and Psychotropic Drugs Particularly important is an awareness that if the patient’s thyrotoxicosis was misdiagnosed and treated as psychosis or an affective state of other origin, some psychotropic medications may be harmful. Both experimental (Coville and Telford 1970) and clinical (Prange et al. 1970) evidence indicates that increasing levels of thyroid hormones potentiate catecholaminergic effects, perhaps by increasing b-adrenergic sensitivity. Augmented thyroid function may therefore increase the toxicity of medications that affect catecholamines. When the thyrotoxicosis is apathetic, mimicking depression, administration of a tricyclic antidepressant drug can be hazardous (Folks and Petrie 1982). The sensitivity to both the anticholinergic and adrenergic effects of these drugs is increased in patients with thyrotoxicosis, and serious cardiotoxic effects may occur, especially in elderly patients. Although little has been written on the effects of monoamine oxidase inhibitors in hyperthyroidism, it has been demonstrated that hyperthyroxinemia in animals increases the acute toxicity of these drugs (Carrier and Buday 1961). Treatment with lithium may interfere with thyroid physiology in the periphery and in the brain (Lazarus 1998). The most prominent clinical effects of lithium treatment are goiter (occurring in about 15%–20% of patients) and hypothyroidism (in about 5% of patients). Although it rarely occurs, lithium treatment can also confound thyrotoxicosis (Reus et al. 1979). In a thyrotoxic patient who has psychiatric symptoms simulating mania, administration of lithium may result in masking of the thyrotoxic state (Wharton 1980). Lithium has antithyroid actions (Lazarus 1998; Rogers and Whybrow 1971), and its administration can result in transient symptomatic improvement of thyrotoxicosis (Lazarus et al. 1974) but with exacerbation of thyrotoxicosis and also ophthalmopathy when the lithium is discontinued (Reus et al. 1979; Rosser 1976; Segal et al. 1973). Thompson and Baylis (1986) described a case of a 47-yearold woman treated with lithium for bipolar disorder who developed exophthalmos and goiter; without biochemical evidence of thyroid disease, she received no treatment. However, she returned to the endocrine clinic 6 months later with flagrant thyrotoxicosis. Notably, she had stopped taking lithium 7 weeks before this appointment, suggesting that her lithium treatment had prevented the full-blown manifestations of Graves’ disease by suppressing thyroid function; when the lithium was stopped, the hyperthyroidism manifested itself. A series of case reports also suggest that hyperthyroid humans may be at increased risk of toxicity from neuroleptics. Hyperthyroidism may

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increase the risk for severe dystonic reactions (Witschy and Redmond 1981). There is also a case report of thyroid storm coinciding with haloperidol administration in a 13-year-old girl (Weiner 1979). Hyperthyroid rats are more sensitive than euthyroid rats to side effects of neuroleptics and are more likely to develop psychomotor activation from phenothiazines. Furthermore, administration of triiodothyronine (T3) to humans increases sensitivity to chlorpromazine (Prange 1985). Taken together, these clinical and animal findings suggest that the anticholinergic effects of neuroleptics theoretically may worsen the tachycardia and cardiac dysrhythmias in hyperthyroid persons, demanding careful monitoring of heart rate and electrocardiography in such cases.

Hypothyroidism Hypothyroidism is defined as deficient thyroidal production of thyroid hormone. The diminution in serum concentrations of thyroid hormone causes an increased secretion of TSH, resulting in elevated serum TSH levels (>4.7 mU/L). Hypothyroidism is a progressive and graded disorder, ranging from mild cases in which the only indication of disorder is an abnormal laboratory value to severe cases with widespread symptoms that can progress into life-threatening myxedema coma (Braverman and Utiger 2000a; Larsen et al. 1998). Grade I is defined by a low serum free thyroxine index (FTI) (serum T4 ´T3 resin uptake), an elevated TSH concentration, and multiple clinical findings, including physical and behavioral signs. In grade II hypothyroidism there is a normal FTI but elevated serum TSH levels and a few clinical signs of hypothyroidism, notably behavioral slowing and mild disturbances of mood and cognition. In grade III hypothyroidism there are no changes in peripheral thyroid indices and no clinical symptoms, but a slight increase in basal TSH levels and an exaggerated TSH response to TRH infusion are found. Grade IV hypothyroidism (symptomless thyroiditis) is characterized by the presence of antithyroid antibodies in the serum but with normal circulating thyroid hormone levels, basal TSH, and a normal TRH stimulation test (Table 15–3) (Wenzel et al. 1974).

Epidemiology and Etiology Hypothyroidism is the most common clinical disorder of thyroid function (Braverman and Utiger 2000a). Inadequate thyroid hormone production from the thyroid gland accounts for 95% of all cases of hypothyroidism

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TABLE 15–3.

Grades of hypothyroidism

Grade Hypothyroidism FTI I II III

Overt Mild Subclinical

IV

Symptomless thyroiditis

Basal TSH

Decreased Increased Normal Increased Normal Slightly increased Normal Normal

Serum TSH response to Signs and TRH symptoms Increased Increased Increased

Multiple One or more None

Normal

Serum antithyroid antibodies

Note. FTI=free thyroxine index (serum thyroxine´triiodothyronine resin uptake); TRH= thyrotropin-releasing hormone; TSH=thyroid-stimulating hormone.

and is referred to as primary hypothyroidism. Primary hypothyroidism is a prevalent disease worldwide. It is endemic in iodine-deficient regions, but it is also a common disease in iodine-replete areas, as demonstrated by a number of population-based studies. The most extensive data has been obtained from the Whickham Survey, a study of 2,779 adults randomly selected from the general population who were evaluated between 1972 and 1974 and again 20 years later (Tunbridge et al. 1977; Vanderpump et al. 1995). In these studies, most striking is the high prevalence of thyroid microsomal antibodies (10.3% in women, 2.7% in men), overt hypothyroidism (1.8% in women, 1% in men), and subclinical hypothyroidism (7.5% in women, 2.8% in men). These data from the Whickham Survey also demonstrate the marked female preponderance. Hypothyroidism is usually brought about through either iodine deficiency or iatrogenic, idiopathic, or autoimmune processes. Iodine deficiency persists in many parts of the world and is the most common cause of primary hypothyroidism worldwide (Braverman and Utiger 2000a). In the industrialized countries, where iodine supplementation is commonplace, thyroid hormone deficiency is most frequently caused by inadequate production and secretion of thyroid hormones due to destruction of the thyroid gland as a consequence of disease or therapies to control thyrotoxicosis (Larsen et al. 1998). In the United States, the most frequent cause of hypothyroidism is iatrogenic, resulting from surgical or radiation ablation of the thyroid gland to treat Graves’ disease. In adults, idiopathic hypothyroidism usually occurs between ages 40 to 60. Up to 80% of these patients have antithyroid antibodies, and many have additional autoimmune illnesses (Weetman 2000). The elevated TSH levels found in Hashimoto’s thyroiditis (thought to be immunologically mediated) can result in enlargement of the thyroid.

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Decreased thyroidal secretion of thyroid hormone can also be caused by insufficient stimulation of the thyroid gland by TSH, due to factors directly interfering with pituitary TSH release (secondary hypothyroidism) or indirectly diminishing hypothalamic TRH release (tertiary hypothyroidism). In clinical practice it is not always possible to discriminate between secondary and tertiary hypothyroidism, which are consequently often referred to as “central” hypothyroidism. Diminished TSH release due to pituitary failure is a rare cause of hypothyroidism. In this manifestation, the thyroid gland is normal, but because of inadequate stimulation from the pituitary, secretion of thyroid hormone is low. The most common causes of pituitary hypothyroidism are postpartum necrosis and pituitary tumors damaging pituitary thyrotrophs. Laboratory tests reveal diminished TSH levels and diminished TSH released in response to a TRH challenge. In very rare cases, symptoms and signs of thyroid hormone deficiency are caused by mutations in the nuclear thyroid hormone receptor TRb with the consequence that tissues do not respond normally to the presence of thyroid hormone. This condition, known as resistance to thyroid hormone, is typically associated with deficits in attention. It is characterized by an increased thyroidal secretion of thyroid hormones and increased thyroid hormone concentrations in serum, secondary to the compensatory effects of the body to overcome the resistance to thyroid hormone (Hauser et al. 1993).

Clinical Manifestations In adults, the onset of hypothyroidism is usually insidious. Symptoms may be present for a period of years before dramatic events occur. Physical symptoms include enlarged thyroid, constipation, cold intolerance, weight increase with decreased appetite, fatigue, dry and rough skin, hair loss, puffiness of the face, lethargy, and slowed motor activity (Braverman and Utiger 2000a). The behavioral presentation of thyroid hormone deficiency varies considerably depending on the cause, duration, and severity of the hypothyroid state. Characteristically there is a slowing of mental and physical activity and a slowing of many organ functions.

Neuropsychiatric Symptoms and Signs Cognitive dysfunction and depression are the most common psychiatric syndromes associated with hypothyroidism. In severe forms of hypothyroidism, psychotic and delusional symptoms may occur (“myxedema madness”), and the syndrome may mimic melancholic depression and dementia (Treadway et al. 1967). The reversible nature of most psychiatric

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symptoms after treatment with thyroxine indicates that they are secondary to the hormonal abnormality. A wide variety of neuropsychiatric symptoms are associated with hypothyroidism, including impaired cognition, mood changes, anxiety, irritability, and psychotic symptoms. Vague symptoms of inattentiveness, slowing of thought, weakness, fatigue, and poor memory are prevalent in mild hypothyroidism. Depressive mood is the most common mood change, but it may be accompanied by anxiety and insomnia. Progressively, the patients’ ability to carry out daily activities or to interact with others deteriorates. In addition, impaired perception with paranoia and visual hallucinations may develop (Whybrow and Bauer 2000a; Whybrow et al. 1969). The few studies examining behavioral changes have confirmed these clinical impressions (Table 15–4). In one study, 5 of 7 consecutive patients with hypothyroidism were depressed and one was anxious (Whybrow et al. 1969). Of 30 consecutive patients with hypothyroidism, 22 had some psychopathology; however, the severity of the hypothyroidism and the psychiatric symptoms were unrelated (Jain 1972). In this study, 33% had anxiety and 43% had depression. In a study by Haggerty et al. (1993), of 31 persons at risk for hypothyroidism with no manifestations of the disease, 16 were found to have subclinical hypothyroidism; these patients were considerably more likely to have a lifetime history of depression than a matched control group of 15 euthyroid subjects.

TABLE 15–4.

Prevalence of psychiatric dysfunction in hypothyroid patients

Study Clinical Society of London 1888

N

Prevalence (%) Findings

109

50 65 98

7

86 100 14

Jain 1972

30

43 33 27 7

Drinka and Voeks 1987

16

0

Haggerty et al. 1993

16

56

Whybrow et al. 1969

Psychosis Impaired memory Psychomotor slowing Subjective disorientation Mood symptoms Psychosis Depressed mood Anxiety Confusion Psychosis No higher incidence of nonvegetative, depressive symptoms vs. control subjects Lifetime episode of major depression

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Significant cognitive impairment can be caused by hypothyroidism, including short-term memory loss; disorientation; and impaired perception, attention, and problem solving (Dugbartey 1998). The Clinical Society of London (1888) conducted a classic study of untreated myxedema and found intellectual slowness in almost all cases. In a study in which the intellectual function of 15 patients with hypothyroidism was compared with age- and sex-matched control subjects diagnosed with brain damage or neurosis, “a generalized suppression of intellectual functions which would become statistically significant if the groups were larger” was found (Reitan 1953). In another study, disorientation was found in 6 of 7 consecutive patients with hypothyroidism (Whybrow et al. 1969).

Overt Psychiatric Manifestations Approximately 5% of all patients with hypothyroidism have psychosis. Gross mental changes may include disorientation, distractibility, hallucinations, and paranoia. Visual and auditory distortions may result in bizarre behavior and paranoid ideas (Whybrow and Bauer 2000a). The study of untreated myxedema conducted by the Clinical Society of London in 1888 found delusions and hallucinations in almost half of the 109 patients studied. Today, however, as a result of early diagnosis and effective treatment, psychotic features have become rare manifestations of hypothyroidism. In recent years, investigators have become increasingly aware of an association between grade II and III hypothyroidism and mood disorders. Grade II or III hypothyroidism was found in 20 of 250 consecutive persons with major depression admitted to an inpatient unit (Gold et al. 1981). Among women with postpartum depression, about 5% also have postpartum thyroiditis. An investigation of 145 women with high serum thyroid antibody concentrations 6 weeks postpartum (thyroglobulin and microsomal antibodies) found that 47% had significant symptoms of depression compared with 32% of women with normal serum antibody concentrations (Harris et al. 1992).

Laboratory Diagnosis In most cases of florid hypothyroidism, T4 level and FTI are below normal and TSH level is elevated (>4.7 mU/L). Frequently, patients with primary hypothyroidism may also manifest hypercholesterolemia. However, as noted earlier, subtle cases of hypothyroidism that may not produce physical abnormalities but are associated with psychiatric disturbance oc-

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cur when T4 and T3 serum levels are in the normal range. The TSH level may be solely elevated or the pituitary thyrotrophs may be abnormally sensitive to TRH stimulation in individuals with these psychiatric manifestations. This suggests that the CNS may be more sensitive to the alteration of the thyroid economy than are other organs. Therefore, in psychiatric practice, it is important to measure TSH levels, after TRH challenge if necessary.

Treatment of Neuropsychiatric Symptoms In the majority of cases, the behavioral changes associated with hypothyroidism remit after treatment with thyroid hormone and the return to euthyroid status (Table 15–5). Of the available thyroid hormone replacement preparations, T4 is currently recommended as the drug of choice in view of its long half-life, ready quantitation in the blood, ease of absorption, and availability of multiple tablet strengths (Brent and Larsen 2000). Replenishment of thyroid hormone must be undertaken gradually, however. Rapid increases of thyroid hormones can compromise cardiac function, especially in elderly patients or patients with cardiac disease, and can initially worsen the behavioral disturbance. Residual symptoms may sometimes persist, particularly after severe and prolonged hypothyroidism (Whybrow et al. 1969).

TABLE 15–5.

Recovery of psychiatric function after treatment of hypothyroidism

Study

N

Outcome

Asher 1949

14

9 recovered, 2 died, 3 were unchanged after 12 weeks of treatment; all patients were initially severely psychotic

Schon et al. 1961

24

Cognitively improved at 5 months

Tonks 1964

18

Only 8 of the severely psychiatrically ill patients improved

Whybrow et al. 1969

4

Mood scales improved in 3; psychosis resolved in 1; no cognitive improvement in any

Nyström et al. 1988

20

20% of patients with subclinical hypothyroidism showed memory improvement after 6 months of thyroid replacement

Russ and 11 Ackerman (1989)

Major depression did not respond to standard antidepressants until thyroid supplementation was used

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435

After T4 treatment is initiated, exacerbation of psychosis may occur, particularly if supplementation is conducted too rapidly (Browning et al. 1954); therefore, severely disturbed patients should ideally be hospitalized. Therapy with a major tranquilizing drug may be necessary in some patients, but the drug should be given with caution and in conjunction with T4 therapy to avoid precipitating myxedema coma. Haloperidol and the phenothiazines are the drugs most often used. When the hypothyroidism is mild and complicating a predominantly depressive syndrome, the therapeutic goal is to provide sufficient T4 to reduce the serum TSH concentration to normal; however, the amount may not be sufficient to reverse the melancholia (Treadway et al. 1967). In such cases, antidepressant drugs or even electroconvulsive therapy may be necessary. If the patient has a family history of affective disorder, particularly bipolar, initiation of treatment to correct hypothyroidism may lead to mania. In such cases, addition of a mood-stabilizing drug may be required. A review article revealed 18 hypothyroid cases of significant psychiatric sequelae, predominantly mania, during replacement therapy for hypothyroidism (Josephson and Mackenzie 1980). All but one of these patients had psychiatric symptoms before the initiation of treatment. These results suggest the need to proceed cautiously when correcting hypothyroid status in patients who have experienced significant behavioral changes. Although subclinical hypothyroidism is associated with lesser mood syndromes, it has not yet been established if correcting the thyroid deficit will reverse such symptoms (Haggerty et al. 1990). Recently, Bunevicius and colleagues (1999) compared the effects of T4 alone (at the usual replacement dosage) with those of T4 (50 mg/day less than the usual dosage) plus T3 (12.5 mg/day) in 33 patients with hypothyroidism in a randomized, double-blind, 2´5 week crossover study. Partial substitution of T3 for T4 improved neuropsychological function significantly in 6 of 17 tests and mood in 10 of 15 visual self-rating scales. Therefore, a combination of T4 plus T3 may be beneficial in patients who do not respond sufficiently to an adequate trial of monotherapy with T4. In summary, the majority of patients who undergo mood, cognitive, and psychotic changes due to hypothyroidism will return to normal with treatment. Nonetheless, response is not uniform, and differences may be due to other psychiatric illnesses or the duration or severity of the hypothyroidism (Whybrow and Bauer 2000a). There is some indication that a combination of T4 plus T3 is superior to T4 alone.

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Interactions Between the Hypothyroid State and Psychotropic Drugs Adjuvant psychotropic medication may be necessary in some hypothyroid persons either because the symptoms do not fully remit with normalization of thyroid status or because the exigencies of the clinical situation so dictate. Systematic studies to determine the proper therapeutic regimen of psychotropic agents for patients with hypothyroid-induced psychiatric disorders are needed. However, certain caveats worthy of note have accumulated in the literature regarding such treatment of hypothyroid individuals with psychotropic medications. As noted above under “Interactions Between the Hyperthyroid State and Psychotropic Drugs,” treatment with lithium can cause hypothyroidism. This must be considered when using this medication in those with a history of thyroid dysfunction. Although it is associated with a slight lowering of serum levels of T4 and T3, carbamazepine has not been found to cause hypothyroidism (Strandjord et al. 1980). The antipsychotic agents have been the subject of a few case reports of untoward effects in hypothyroidism, for example, hypothermia and coma. Gomez and Scott (1980) further suggested that hypothyroidism can predispose to neurolepticinduced cardiac dysrhythmias. However, in the case they reported, a diminutive woman received some 270 mg of haloperidol, 400 mg of thioridazine, and 40 mg of trifluoperazine in the 4 days before her cardiac arrest. The use of sedative-hypnotics of the benzodiazepine and barbiturate classes has not been associated with untoward effects, although there is some evidence that hypothyroidism may slow drug metabolism by liver microsomal enzyme (Kato et al. 1969). Antidepressant therapy may not be efficacious until thyroid status is corrected, as may be expected on theoretical grounds (Whybrow and Prange 1981). Rapid-cycling mood illness in clinical or subclinical hypothyroidism may be induced by tricyclic (Extein et al. 1982) or occasionally by monoamine oxidase inhibitor (Mattson and Seltzer 1981) antidepressants, although there are few data suggestive of increased toxicity otherwise in using these drugs in hypothyroid persons.

Brain Imaging to Study the Thyroid System and Brain Activity In Vivo Despite the evidence of a close relationship between thyroid status and behavioral disturbances, the actions of thyroid hormones in CNS func-

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tion in the mature mammalian brain have rarely been investigated in vivo. This lack of interest seems to have originated in the 1950s and 1960s, when early physiological studies suggested that oxygen consumption in the mature human brain did not change with changing thyroid status (Sokoloff et al. 1953; reviewed in Bauer and Whybrow 2002). Currently, no methods for direct in vivo measurements of brain thyroid metabolism exist. However, studies using brain imaging techniques to evaluate the relationships between the brain, thyroid hormones, and behavior have recently been initiated and may provide such assessment. Studies using magnetic resonance spectroscopy and positron emission tomography have indicated that the adult human brain, particularly the frontal lobe, is responsive to thyroid hormone (Bauer et al. 2002b; Silverman et al. 2002; Smith and Ain 1995). These studies provide a neuroanatomical basis for the prevalent neurological and psychiatric signs found in hypothyroidism (Dugbartey 1998). The study by Smith and Ain (1995) indicated that hypothyroid patients exhibit decreased cerebral metabolism in the frontal lobes (as measured by 31P magnetic resonance spectroscopy) that returned to normal after T4 replacement therapy. Animal studies in adult hypothyroid rats found a significant decline in 14C-2-deoxyglucose uptake throughout the brain, except for the brainstem and pons, indicating a general decline in metabolic and functional activity during thyroid hormone deficiency (Calza et al. 1997). Therefore, by further elucidating the relationship among thyroid status, brain, and mood disorders, functional brain imaging techniques may provide new insights into the pathophysiology and treatment of these disorders.

Summary and Conclusion Disorders of the thyroid gland are frequently associated with mental disturbances. Hyperthyroidism and hypothyroidism can induce disturbances of mood and intellectual function, and in severe states there may be a profound disturbance of behavior that can mimic melancholic depression and dementia. The mental changes accompanying thyroid gland dysfunction are usually reversed with return to euthyroid status. The cellular and molecular mechanisms that can uniformly explain the many psychiatric symptoms associated with thyroid illness are not yet understood. The manifestations of both hypothyroidism and hyperthyroidism are manifold, from very mild cognitive deficits and dysphoria to psychosis and delirium. Thyroid hormones are widely distributed in the brain and have a multitude of effects on the CNS, and many of the limbic

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system structures where thyroid hormones are prevalent have been implicated in the pathogenesis of mental disorders. The specific neurochemical basis and functional pathways for the therapeutic effects of thyroid hormones on mental functions are also unknown. The influence of the thyroid system on neurotransmitters that putatively play a major role in the regulation of mood and behavior, particularly serotonin and norepinephrine, may contribute to the mechanisms of action (Bauer et al. 2002a; Whybrow and Prange 1981). However, it is not clear whether these are the seminal disturbances accounting for behavioral change. Furthermore, within the CNS, the regulatory cascade through which the thyroid hormones, particularly T3, exert their effects is not well understood: deiodinase activity, nuclear binding to genetic loci, and ultimately protein synthesis may all be involved. What is clear, however, is that without optimal thyroid function, psychiatric and mood symptoms often emerge. Therefore, despite the lack of understanding of fundamental mechanisms, the evaluation of thyroid status is of vital concern to the physician and especially to the psychiatrist. In addition to what has been learned about the association of thyroid dysfunction with behavior and mood, the adjunctive treatment of mood disorders with thyroid hormones has become a valuable strategy (Bauer and Whybrow 2001). These issues are addressed in detail in other chapters of this volume.

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Kathol RG, Delahunt JW: The relationship of anxiety and depression to symptoms of hyperthyroidism using operational criteria. Gen Hosp Psychiatry 8: 23–28, 1986 Kathol RG, Delahunt JXV, Cooke R: Urinary free cortisol levels and dexamethasone suppression testing in organic affective disorder associated with hyperthyroidism. Am J Psychiatry 142:1193–1195, 1985 Kato R, Takanaka A, Takahashi A, et al: Species differences in the alterations of drug metabolizing activity of liver microsomes by thyroxine therapy. Jpn J Pharmacol 9:5–18, 1969 Kleinschmidt H, Waxenberg S: Psychophysiology and psychiatric management of thyrotoxicosis: a two year follow up study. Mt Sinai J Med 23:131–153, 1956 Larsen PR, Davies TF, Hay ID: The thyroid gland, in Williams Textbook of Endocrinology, 9th Edition. Edited by Wilson JD, Foster DW, Kronenberg HM, et al. Philadelphia, PA, WB Saunders, 1998, pp 389–515 Lazarus JH: The effects of lithium therapy on thyroid and thyrotropin-releasing hormone. Thyroid 8:909–913, 1998 Lazarus JH, Richard AR, Addison GM: Treatment of thyrotoxicosis with lithium carbonate. Lancet 2:1160–1163, 1974 Lee S, Chow CC, Wing YK, et al: Mania secondary to thyrotoxicosis. Br J Psychiatry 159:712–713, 1991 Loosen P, Prange A: Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients. Am J Psychiatry 139:405–416, 1982 MacCrimmon DJ, Wallace JE, Goldberg WM, et al: Emotional disturbance and cognitive deficits in hyperthyroidism. Psychosom Med 41:331–340, 1979 Mandelbrote BM, Wittkomer E: Emotional factors in Graves’ disease. Psychosom Med 17:109–113, 1955 Marcocci C, Chiovato L: Thyroid-directed antibodies, in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 414–431 Mattson A, Seltzer R: MAOI-induced rapid cycling affective disorder in an adolescent. Am J Psychiatry 13:677–679, 1981 McLachlan SM, Rapoport B: Genetic factors in thyroid disease, in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 474–487 Nyström E, Caidahl K, Fager G, et al: A double-blind cross-over 12 month study of L-thyroxine treatment of women with “subclinical” hypothyroidism. Clin Endocrinol (Oxf) 29:63–76, 1988 Parry CH: Collections From the Unpublished Writings of the Late C. H. Parry, Vol 2. London, Underwoods, 1825 Peake RL: Recurrent apathetic hyperthyroidism. Arch Intern Med 141:258–260, 1981 Prange AJ Jr: Psychotropic drugs and the thyroid axis: a review of interactions. Adv Biochem Psychopharmacol 40:103–110, 1985

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Prange AJ Jr, Wilson IC, Rabon AM, et al: Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry 126:457–469, 1969 Prange AJ Jr, Meek JL, Lipton MA: Catecholamines: diminished rate of norepinephrine biosynthesis in rat brain and heart after thyroxine pretreatment. Life Sci 9:401–406, 1970 Reitan RM: Intellectual functions in myxoedema. Arch Neurol Psychiatry 69: 436–449, 1953 Reus VI, Gold P, Post R: Lithium-induced thyrotoxicosis. Am J Psychiatry 136: 724–725, 1979 Robbins LR, Vinson DB: Objective psychological assessment of the thyrotoxic patient and the response to treatment. J Clin Endocrinol 20:120–129, 1960 Rockey P, Griep R: Behavioral dysfunction in hyperthyroidism: improvement with treatment. Arch Intern Med 140:1194–1197, 1980 Rogers M, Whybrow PC: Clinical hyperthyroidism occurring during lithium treatment: two case histories and a review of thyroid function in 19 patients. Am J Psychiatry 128:158–163, 1971 Ross DS: Subclinical thyrotoxicosis, in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 1007–1012 Rosser R: Thyrotoxicosis and lithium. Br J Psychiatry 128:61–66, 1976 Russ MJ, Ackerman SH: Antidepressant treatment response in hypothyroid patients. Hosp Community Psychiatry 40:954–956, 1989 Schon M, Sutherland A, Rawson R: Hormones and neuroses—the psychological effects of thyroid deficiency. Proceedings of the Third World Congress of Psychiatry, Montreal, Vol 2. Toronto, Ontario, McGill University Press, 1961, pp 835–839 Segal RL, Rosenblatt S, Eliasoph I: Endocrine exophthalmos during lithium therapy of manic-depressive disease. N Engl J Med 289:136–138, 1973 Silverman DHS, Geist CL, Van Herle K, et al: Abnormal regional brain metaboLism in patients with hypothyroidism secondary to Hashimoto’s disease (abstract). Society of Nuclear Medicine 49th Annual Meeting, Los Angeles, CA, June 15–19, 2002. J Nucl Med 43 (5, suppl):254P, 2002 Smith CD, Ain KB: Brain metabolism in hypothyroidism studied with 31P magnetic-resonance spectroscopy. Lancet 345:619–620, 1995 Sokoloff L, Wechsler RL, Mangold R, et al: Cerebral blood flow and oxygen consumption in hyperthyroidism before and after treatment. J Clin Invest 32: 202–208, 1953 Sonino N, Girelli ME, Boscaro M, et al: Life events in the pathogenesis of Graves’ disease. A controlled study. Acta Endocrinol 128:293–296, 1993 Strandjord RE, Aanderud, S, Myking O: Serum levels of thyroid hormones in patients treated with carbamazepine, in Advances in Epileptology. Twelfth Epilepsy International Symposium. Edited by Conger R, Angeleri F, Perry J. New York: Raven, 1980, pp 439–443 Taylor JW: Depression in thyrotoxicosis. Am J Psychiatry 132:552–553, 1975

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Thompson CJ, Baylis PH: Asymptomatic Graves’ disease during lithium therapy. Postgrad Med J 62:295–296, 1986 Tonks CM: Mental illness in hypothyroid patients. Int J Psychiatry 110:706–710, 1964 Treadway CR, Prange AJ Jr, Doehne EF, et al: Myxedema psychosis: clinical and biochemical changes during recovery. J Psychiatr Res 5:289–296, 1967 Trzepacz PT, McCue M, Klein I, et al: Psychiatric and neuropsychological response to propranolol in Graves’ disease. Biol Psychiatry 23:678–688, 1988a Trzepacz PT, McCue M, Klein I, et al: A psychiatric and neuropsychological study of patients with untreated Graves’ disease. Gen Hosp Psychiatry 10:49–55, 1988b Tunbridge WMG, Evered DC, Hall R, et al: The spectrum of thyroid disease in the community: the Whickham Survey. Clin Endocrinol (Oxf) 7:481–493, 1977 Vanderpump MP, Tunbridge WM, French JM, et al: The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 43:55–68, 1995 Voth HM, Holzman PS, Katz JB, et al: Thyroid hot spots: their relationship to life stress. Psychosom Med 32:561–568, 1970 Wallace I, MacCrimmon D, Goldberg W: Acute hyperthyroidism: cognitive and emotional correlates. J Abnorm Psychol 89:519–527, 1980 Wallerstein RS, Holzman PS, Voth HM, et al: Thyroid hot spots: a psychophysiological study. Psychosom Med 27:508–523, 1965 Wartofsky L: Thyrotoxic storm, in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 679–684 Weetman AP: Chronic autoimmune thyroiditis, in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 721–732 Weiner M: Haloperidol, hyperthyroidism, and sudden death. Am J Psychiatry 136:717–718, 1979 Wenzel KW, Meinhold H, Raffenberg M, et al: Classification of hypothyroidism in evaluating patients after radioiodine therapy by serum cholesterol, T3-uptake, total T4, fT4-index, total T3, basal TSH and TRH test. Eur J Clin Invest 4:141–148, 1974 Wharton RN: Accidental lithium carbonate treatment of thyrotoxicosis as mania. Am J Psychiatry 137:747–748, 1980 Whybrow PC: Sex differences in thyroid axis function: relevance to affective disorder and its treatment. Depression 3:33–42, 1995 Whybrow PC, Bauer M: Behavioral and psychiatric aspects of hypothyroidism, in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger RD. Philadelphia, Lippincott Williams & Wilkins, 2000a, pp 837–842

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Whybrow PC, Bauer M: Behavioral and psychiatric aspects of thyrotoxicosis, in Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 8th Edition. Edited by Braverman LE, Utiger RD. Philadelphia, PA, Lippincott Williams & Wilkins, 2000b, pp 673–678 Whybrow PC, Prange AJ Jr: A hypothesis of thyroid-catecholamine-receptor interaction. Arch Gen Psychiatry 38:106–113, 1981 Whybrow PC, Prange AJ Jr, Treadway CR: Mental changes accompanying thyroid gland dysfunction. Arch Gen Psychiatry 20:48–63, 1969 Wilson W, Johnson J, Smith R: Affective changes in thyrotoxicosis and experimental hypermetabolism. Recent Advances in Biological Psychiatry 4:234– 242, 1962 Winsa B, Adami H-O, Bergstrom R, et al: Stressful life events and Graves’ disease. Lancet 338:1475–1479, 1991 Witschy J, Redmond F: Extrapyramidal reaction to fluphenazine potentiated by thyrotoxicosis. Am J Psychiatry 138:246–247, 1981

Chapter 16 Thyroid Hormone Treatment of Psychiatric Disorders Stephen Sokolov, M.D., F.R.C.P.C. Russell Joffe, M.D.

T

here has been a long-standing interest in thyroid hormones as treatments for psychiatric disorders, largely arising from observed associations between psychiatric symptomatology and thyroid disease states. Clinical case studies, in particular, have documented the occurrence of psychiatric symptoms in both hyperthyroid and hypothyroid illness. Several general observations have emerged. In hyperthyroidism, anxiety and emotional lability are most commonly observed (Bauer and Whybrow 1988; MacCrimmon et al. 1979), with symptoms of mania, psychosis, and marked cognitive impairment in more severe forms, including thyrotoxicosis (Fava et al. 1987). Hypothyroidism, on the other hand, is most commonly associated with symptoms of depression (Bauer and Whybrow 1988; Hall 1983; Jain 1972; Whybrow et al. 1969). When psychiatric and cognitive symptoms are present in thyroid illness, successful treatment of the thyroid illness is usually associated with resolution of these symptoms (Hall 1983; MacCrimmon et al. 1979; Whybrow et al. 1969), especially in patients with hypothyroidism (Hall 1983; Whybrow et al. 1969). The rationales for the proposed use of thyroid hormones as treatments for psychiatric illnesses are derived from several observations. First, it has been noted that psychiatric symptoms are present in thyroid disease and that these symptoms improve with treatment of the underlying thyroid illness (Hall 1983; Jain 1972; MacCrimmon et al. 1979; Prange et al. 1978). Second, there have been observations in animal experiments that thyroid hormones enhance antidepressant toxicity, and it

445

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has been speculated that similar use in humans may enhance the therapeutic effect of antidepressants (Breese et al. 1974). Finally, data from animal studies suggest that thyroid hormones may interact with biogenic amines, in some instances potentiating the effects of the amines (Breese et al. 1974). Approaches undertaken in the use of thyroid hormones in psychiatric illnesses include their use as monotherapy and in combination with other psychotropic agents. Thyrotropin-releasing hormone (TRH), thyroidstimulating hormone (TSH), and the peripheral thyroid hormones thyroxine (T4) and triiodothyronine (T3) have been used and investigated in various psychiatric illnesses, including major depression, bipolar disorder, and anxiety disorders.

Major Depression Thyroid hormone medications have been employed using several approaches. These include monotherapy as antidepressant medication, combination therapy to accelerate the effect of antidepressants, and combination therapy to augment (potentiate) the effects of antidepressant medication in patients who do not respond to antidepressants. In addition, there is some evidence to suggest that thyroid hormones may be useful in ameliorating cognitive side effects associated with administration of electroconvulsive therapy (ECT).

Thyrotropin-Releasing Hormone TRH is a tripeptide released from the hypothalamus whose principal endocrine role is to regulate synthesis and secretion of TSH, which in turn regulates thyroid hormone synthesis and release. TRH may also affect brain function in a manner separate from its role within the thyroid axis by acting as a neurotransmitter (Griffiths 1985). Effects of the administration of exogenous TRH include reversal of drug-induced sedation or anesthesia; stimulation of motor activity; and other effects on cardiac, respiratory, gastrointestinal, and neurological function (Griffiths 1985; Prange et al. 1978). Use of TRH in antidepressant therapy was suggested by its apparently widespread role in the central nervous system and by its potential for stimulating the thyroid axis. The use of this hormone in combination with ECT has been suggested on the basis of its beneficial effect on neurological and cognitive function.

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Monotherapy Thirteen double-blind studies have evaluated the effect of TRH on symptoms of major depression by intravenous, oral, or intrathecal administration (Coppen et al. 1974; Ehrensing et al. 1974; Furlong et al. 1976; Hollister et al. 1974; Karlberg et al. 1978; Kastin et al. 1972; Kiely et al. 1976; Marangell et al. 1997; Mountjoy et al. 1974; Prange et al. 1972; Van Den Burg et al. 1975, 1976; Vogle et al. 1977). The equivocal results of the oral and intravenous TRH studies may be explained by the relatively short half-life of TRH in serum (5.3±0.5 minutes after intravenous administration) and by the impermeability of the blood-brain barrier to peripherally administered TRH (Marangell et al. 1997). To overcome these limitations, Marangell and co-workers (1997) used a double-blind, placebo-controlled crossover design and administered TRH intrathecally in a group of patients with highly refractory depression. Although robust improvement was seen in the majority of subjects, the improvement was short-lived. Therefore, the fact that the majority of studies of TRH do not demonstrate a significant antidepressant effect is likely accounted for by the peripheral route of administration. When effects were demonstrated, they were mostly either minimal or transient (Furlong et al. 1976; Kastin et al. 1972; Prange et al. 1972; Van Den Burg et al. 1975, 1976). Although robust effects were demonstrated in the one study using a central route of administration, response was short-lived, and in clinical practice administration of TRH intrathecally is impractical (Marangell et al. 1997). On the basis of investigations to date, it cannot be concluded that TRH monotherapy has a significant role in the treatment of depression.

Combination With ECT Khan et al. (1994) administered 500 mg of TRH in a randomized, double-blind, placebo-controlled crossover design to eight depressed patients undergoing ECT. Infusion of TRH (but not placebo) before ECT treatments resulted in greater levels of arousal and better cognitive functioning after treatment, as assessed by a neuropsychiatric battery. TRH infusion did not result in alteration of ECT variables such as energy required to induce the seizure or seizure duration. The study design did not allow distinction between whether TRH administration reversed anesthetic effects or ECT-specific effects on cognition. More recently, Zervas et al. (1998), in a placebo-controlled crossover design, administered 400 mg of TRH intravenously before two treatments of ECT. Administration of ECT was associated with improvement in 24-hour recall but not in immediate cognitive measures. In summary, there is lim-

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ited evidence that TRH has some efficacy in preventing cognitive side effects of ECT. Further replication using larger numbers of subjects is required.

Thyroid-Stimulating Hormone On the basis of the known physiological role of TSH in stimulation of thyroid hormone synthesis and release, it was postulated that TSH administration might have antidepressant effects. In the only study to examine antidepressant effects of TSH, Prange et al. (1969) administered 10 IU of TSH intravenously to 20 depressed women 24 hours before initiating imipramine therapy. The researchers observed that TSH-treated women experienced a more rapid response than did patients who received a saline injection. The precise mechanism of this effect is not clear, and although these results are intriguing, replication of these data is required before it can be concluded that TSH administration has substantial clinical utility.

Thyroxine The original studies evaluating thyroid hormone treatment of depression used T3, on the basis of the observation that T3 is several times more biologically active than T4. However, it was assumed that in the treatment of psychiatric illness, T4 would function similarly to T3 and that because it had a considerably longer half-life than T3, its psychotropic effects would be more enduring. A number of studies, however, have attempted to evaluate T4 augmentation (Bauer et al. 1998; Rudas et al. 1999; Targum et al. 1984). In the earliest study, Targum et al. (1984) administered T4 as an augmentation agent in 21 patients who had not responded to treatment with a tricyclic antidepressant. Although 7 patients responded, 5 of these had evidence of subclinical hypothyroidism, as determined by a maximum TSH response to TRH greater than 25 mIU/mL at baseline before thyroid hormone augmentation. Therefore, in this study, it appeared that T4 may have played a role as replacement therapy for subclinical hypothyroidism—a role presumably distinct from the use of T3 in augmentation therapy of euthyroid depressed patients (see “Augmentation” under “Triiodothyronine” below). Bauer et al. (1998) openly added supraphysiological doses of T4 (mean, 482±72 mg/day) to antidepressant medication in 12 bipolar and 5 unipolar patients with highly refractory depression. High-dosage T4 was generally well tolerated, with 10 patients responding robustly and 7 of the 10 maintaining excellent response over the follow-

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up period. Rudas et al. (1999), also in an open trial, added 150–300 mg of T4 to the treatment regimens of 9 patients with chronic or recurrent depression that was refractory to the current antidepressant treatment. Five patients responded fully over the course of the 8-week trial, and 1 patient had a partial response. Two patients had to withdraw from the study due to restlessness and tremor at 100 mg/day. Conclusions that can be made on the basis of these studies are limited in that all were open trials and one trial (Bauer et al. 1998) studied a heterogeneous group of illnesses. In addition, the use of high-dosage T4 is potentially hazardous, as it can be associated with increased risk of osteoporosis (Greenspan and Greenspan 1999). In the only study to directly compare T3 and T4, Joffe and Singer (1990) (using a double-blind, randomized, controlled design) found T3 to be superior to T4. However, the findings are limited by the failure to include a placebo control group; the findings also require replication before it can be definitively concluded that T4 is less effective than T3 in the treatment of depression. At present there is little evidence for the efficacy of T4 administration at nearly physiological doses in treatment-resistant depression, and beneficial effects may be limited to patients with depression associated with subclinical hypothyroidism. Although the more recent studies using supraphysiological doses are intriguing, replication using controlled methodology is required, and the treatment may be associated with certain medical risks. Finally, although there is preliminary evidence to suggest that T4 is an inferior augmentation agent to T3 when the two agents are directly compared, further replication is required.

Triiodothyronine T3 has been used in the treatment of depression in four distinct ways: as monotherapy; in combination with ECT; in conjunction with antidepressants to produce a more rapid response (acceleration); and in conjunction with antidepressants to potentiate response in patients who have not responded to adequate antidepressant treatment (augmentation).

Monotherapy Two early anecdotal reports suggested that T3 might be effective in increasing spontaneous motor activity and improvement in depression symptoms in a mixed cohort of psychiatric patients (Feldmesser-Reiss 1958; Flach et al. 1958). Unfortunately, these data have not been replicated using current methodological and diagnostic paradigms. Monother-

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apy with T3 for depression is therefore not considered to be clinically useful at this time.

Combination With ECT Prange et al. (1990) reported retrospective data on thyroid hormone measures in psychiatric inpatients before ECT. Patients with higher pre-ECT free T4 index values had less post-ECT cognitive disturbance. In a doubleblind study, Stern et al. (1991) randomly assigned 20 male patients with major depression, schizoaffective disorder depressed type, or bipolar disorder depressed phase to receive either 50 mg of T3 or placebo before each ECT treatment. The T3-treated group required fewer treatments and showed less cognitive impairment after ECT. However, the study design did not allow differentiation between whether T3 improved anestheticrelated or ECT-related cognitive effects. To address this, Stern et al. (1995) attempted to investigate the effects of T3 on electroconvulsive shock (ECS)–related memory effects using ECS and ECS-sham treatments in rats. T3 was found to decrease ECS-related retrograde and anterograde amnesia but not ECS-sham–related cognitive effects, suggesting that T3 may specifically improve the ECS-related cognitive effects. There is preliminary evidence to suggest significant benefits may be associated with use of T3 in combination with ECT. In particular, T3-ECT combination may be associated with improved antidepressant effect and in diminishing cognitive side effects (Prange et al. 1990; Stern et al. 1991). Although the cognitive improvement appears similar to that noted in the use of TRH with ECT (see “Combination with ECT” under “Thyrotropin-Releasing Hormone” above), the effects may not be mediated through the same mechanism, because the evidence is that TRH (and not T3) acts as a neurotransmitter (Griffiths 1985). Further replication of these data is needed.

Acceleration There is some evidence to suggest that when used in combination with antidepressant medication T3 is effective in accelerating the onset of antidepressant response. Several studies undertaken more than 30 years ago (Prange et al. 1969; Wheatley 1972; Wilson et al. 1970) examined the use of 25–50 mg/day of T3 started simultaneously with tricyclic antidepressant treatment. In these studies, patients receiving T3 responded more quickly to antidepressants than patients who did not receive T3. For reasons that are not clear, this effect appeared to be more prominent in women. Other reports (Feighner et al. 1972) suggest that the acceleration effect of T3 may not be consistently observed.

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Although these results are of potential importance both theoretically and clinically, further replication would be required using current diagnostic criteria and careful assessment of early response to treatment before T3 can be regarded as a therapeutic tool to reduce the lag in onset of antidepressant response.

Augmentation In addition to reports of the T3 acceleration effect, 11 studies (Banki 1975, 1977; Earle 1970; Gitlin et al. 1987; Goodwin et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b; Ogura et al. 1974; Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979) examined the addition of small amounts of T3 to augment response in patients who did not respond to a trial of tricyclic antidepressants. These studies are reviewed in Table 16–1. The six open studies (Banki 1975; Earle 1970; Ogura et al. 1974; Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979) demonstrated that of subjects who did not respond to tricyclic antidepressants, approximately 25%–91% (weighted mean, 63.1%) had a response within 2–4 weeks after the addition of 5–50 mg of T3 to their antidepressant. The one negative open trial (Thase et al. 1989) consisted of a study sample of severely ill patients with highly recurrent major depressive illness, possibly explaining the lack of response to T3. The five controlled studies (Banki 1977; Gitlin et al. 1987; Goodwin et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b) are generally supportive of the results from the open studies, with rates of response approximating 50%. The one negative study (Gitlin et al. 1987) is difficult to evaluate owing to several methodological issues (for example, it used a 2-week crossover design, which may not be the most appropriate protocol for evaluating the efficacy of antidepressant treatment with a delayed onset and cessation of action of unknown duration). Across the six studies, response to antidepressant augmentation with T 3 was not affected by sex, bipolar/unipolar diagnosis, type of heterocyclic antidepressant used, or baseline thyroid status of the patients. A recent metaanalysis of 292 patients treated in six studies suggests that T3 augmentation is twice as likely to produce a response as control treatments (Aronson et al. 1996). Two of the controlled T3 augmentation studies warrant special note. First, Joffe and Singer (1990) conducted the only study to directly compare T3 augmentation to T4 augmentation. Using a double-blind design, the researchers found that 9 of 17 patients responded significantly better to T3 (P=0.026, Fisher exact test) than to T4 (4 of 21 patients). All

Augmentation of tricyclic antidepressants with triiodothyronine (T3) N

Dosage (mg/day)

Tricyclic

Design

Response (%)

Earle 1970 Ogura et al. 1974 Banki 1975 Banki 1977 Tsutsui et al. 1979 Goodwin et al. 1982 Schwarcz et al. 1984 Gitlin et al. 1987 Thase et al. 1989 Joffe and Singer 1990 Joffe et al. 1993b

25 44 52 33 11 12 8 16 20 38 51

25 20–30 20–40 20 5–25 25–50 25–50 25 25 37.5 37.5

AMI, IMI Various Various AMI Various Various DMI IMI IMI DMI, IMI DMI, IMI

Open Open Open Partially controlled Open Double-blind Open Double-blind, placebo Open Double-blind vs. T4 Double-blind, placebo and lithium

14 (56.0) 29 (65.9) 39 (75.0) 23 (69.7) 10 (90.9) 8 (66.7) 4 (50.0) T3 =placebo 5 (25.0) 9 of 17 (52.9) for T3, superior to T4 10 of 17 (58.8) for T3, T3 >placebo, T3 =lithium

Note.

AMI=amitriptyline; DMI=desipramine; IMI=imipramine; T4 =thyroxine.

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Study

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TABLE 16–1.

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patients were euthyroid. Potential shortcomings of this study are the lack of a placebo group and the possibility that there was a delayed (undetected) onset of effect of T4 owing to the short duration of the trial period and the considerably longer half-life of T4 compared with T3. Second, in a randomized, double-blind, placebo-controlled design, Joffe et al. (1993b) directly compared T3 and lithium augmentation in 51 patients who did not respond to adequate treatment with desipramine or imipramine. Subjects received 2 weeks’ treatment with either 37.5 mg/day of T3, 900–1,200 mg/day of lithium, or placebo in addition to their antidepressant. Lithium doses were adjusted by a nonblind overseer at the end of the first week of treatment to standardize serum levels to 0.58 mmol/ L or above. Ten of 17 patients (58.8%) responded to T3, 9 of 17 (52.9%) responded to lithium, and 3 of 16 (18.8%) responded to placebo. Both T3 and lithium were significantly better than placebo (T3 versus placebo, P=0.018; lithium versus placebo, P=0.038, Fisher exact test) and did not differ from each other. These findings are interesting in light of clinical lore suggesting that lithium is the “gold standard” for antidepressant augmentation, and as such, the efficacy of T3 augmentation has been met with skepticism (reviewed in Joffe et al. 1993b; Nemeroff 1991). The open and controlled studies of T3 augmentation (Banki 1975, 1977; Earle 1970; Gitlin et al. 1987; Goodwin et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b; Ogura et al. 1974; Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979) suggest that the use of T3 augmentation is effective in patients who do not respond to tricyclic antidepressants. In general, rates of response in these studies are comparable to those reported with lithium augmentation (reviewed in Joffe et al. 1993b). Furthermore, when lithium augmentation and T3 augmentation are directly compared (Joffe et al. 1993b), T3 may be at least comparable in efficacy. However, although T3 and lithium augmentation may have comparable response rates, they may not necessarily be effective in the same individuals; several case series suggest that nonresponse to one does not predict nonresponse to the other (Garbutt et al. 1986; Joffe 1988a). Side effects and tolerability. T3 administration is generally considered a well-tolerated treatment with few side effects. The likely low incidence of side effects associated with T3 augmentation probably relates to the small doses being used (25–50 mg), which are below what would be considered physiological replacement doses. However, the studies to date have commented only generally on side effects and have not systematically logged adverse reactions (Banki 1975, 1977; Earle 1970; Gitlin et al. 1987; Goodwin et al. 1982; Joffe and Singer 1990; Joffe et al. 1993b; Ogura et al. 1974; Schwarcz et al. 1984; Thase et al. 1989; Tsutsui et al. 1979).

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Several case reports of more severe adverse effects have appeared. Gitlin (1986) reported a case of a 59-year-old man with a history of angina who responded to 25 mg/day of T3 augmentation but experienced an exacerbation of his angina. Cole et al. (1993) reported on a case of a 68-year-old woman augmented with 50 mg of T3 who developed paroxysmal atrial fibrillation 2–3 days after an orthopedic procedure. She returned to sinus rhythm after discontinuation of the T3. Although the exact incidence of significant T3-related adverse effects is unknown, these case reports suggest caution in the use of T3 augmentation in elderly patients or patients with preexisting cardiac conditions. The adverse effects possibly associated with long-term T3 treatment are unknown. This is relevant because T3 augmentation treatment is reserved for patients with refractory illness. Patients with refractory illness are at greater risk of relapse and recurrence and are therefore more likely to be candidates for long-term maintenance therapy with the agents to which they acutely respond. Are patients receiving long-term maintenance therapy with T3 then at increased risk of osteoporosis (mediated through effects of thyroid hormone on accelerated bone turnover and shortening of the bone remodeling cycle)? Although there are no longterm studies on the use of T3, some inferences can be drawn from the literature on T4 replacement. A recent meta-analysis of the data (Greenspan and Greenspan 1999) suggested that an increased risk of osteoporosis was most associated with dosages of T4 resulting in full suppression of TSH (i.e., to less than 0.1 mU/mL) as measured by ultrasensitive assay. Dosages of T4 resulting in partial suppression of TSH (to between 0.2 and 0.5 mU/mL) were equivocal in effect. The authors recommended that premenopausal and postmenopausal women who are taking fully suppressive doses of T4 and are not receiving hormone replacement therapy should have cortical bone mineral density assessed every 1–2 years (Greenspan and Greenspan 1999). It is possible that this should also apply to women with depression who are not receiving hormone replacement therapy and are taking maintenance doses of T3 resulting in full suppression of TSH. Antidepressant class. All clinical trials of T3 augmentation used T3 in combination with tricyclic antidepressants. Therefore, the evidence for efficacy of T3 augmentation of other antidepressant classes is limited to several case reports that suggest efficacy of T3 augmentation with monoamine oxidase inhibitors (Hullett and Bidder 1983; Joffe 1988b) and selective serotonin reuptake inhibitors (Joffe 1992). On the basis of these case reports and our own clinical experience, it appears that T3 can be helpful when combined with nontricyclic antidepressants, although the

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precise rate of response is not clear. To confirm this impression, controlled trials of T3 augmentation in alternate classes of antidepressants are required. Mechanism of action. There is evidence to suggest that the effects of T3 augmentation are not mediated through the enhancement of plasma levels of tricyclic antidepressants (Goodwin et al. 1982). Furthermore, it is unlikely that T3 acts as hormone replacement therapy, because the majority of depressed patients are euthyroid and baseline thyroid function does not appear to predict response to T3 (Joffe et al. 1993a). There are several competing hypotheses regarding the mechanism of action of T3 augmentation. First, Whybrow and Prange (1981) suggested that the therapeutic effects of T3 may occur through potentiation of catecholamine effects at central adrenergic receptor sites mediated through an increase in b-adrenergic receptor activity. This is an attractive and potentially unifying hypothesis, because catecholamine deficiency is postulated to be of etiologic importance in depression. However, further systematic investigation is warranted. Second, Bauer and Whybrow (1988) suggested that depression may be associated with a state of relative thyroid hypofunction and that increases in thyroid hormone levels are required to promote antidepressant response. Third, Joffe et al. (1984) speculated that T3 may possibly act by lowering brain thyroid hormone levels through negative feedback mechanisms within the thyroid axis. That is, exogenously administered T3 increases serum levels of circulating T3. This is detected by the hypothalamus and pituitary, which downregulate endogenous production and release of T4 and T3. Levels of brain T3 and T4 would be reduced because brain T3 and T4 derive almost exclusively from T4 circulating in the blood. This potentially explains the lack of efficacy for T4 augmentation because exogenous T4 would presumably result in an increase in both brain T3 and T4, whereas T3 circulating in the blood does not cross the blood-brain barrier appreciably (Joffe et al. 1992). To attempt to clarify whether it was “prothyroid” or “antithyroid” mechanisms that were associated with response to T3 augmentation, Joffe et al. (1992) openly treated seven euthyroid patients with highly treatment-refractory illness for 4 weeks with 20 mg/day of methimazole—an antithyroid compound used in the treatment of clinical hyperthyroidism. Of the six patients who tolerated methimazole, three were considered responders, as defined by a decrease in scores on the Hamilton Rating Scale for Depression by 50% to a final score less than 10. Although these data are interesting, they are nonetheless preliminary. Conclusion. T3 augmentation therapy in patients who do not respond to treatment with antidepressants remains to date the best-evaluated use

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of thyroid hormones in psychiatric illness. There is evidence that T3 augmentation results in rates of response comparable to lithium augmentation. On the basis of the controlled studies, T3 can be recommended as a viable treatment strategy in refractory depression. Unresolved issues, however, include the following: What is the most appropriate dose? What is an adequate duration of a T3 trial? What is the appropriate length of time that T3 should be continued? What are the risks of long-term treatment with T3, and what monitoring should be performed? (Joffe 1998). Clinical recommendations regarding the use of T3 augmentation are summarized in Table 16–2.

TABLE 16–2.

Triiodothyronine (T3) augmentation: clinical recommendations

Indication Evidence

Refractory depression Double-blind, placebo-controlled data only with tricyclic antidepressants Case reports of effectiveness with SSRIs and MAOIs Usual dosage 25–50 mg/day Usual duration of trial 2–4 weeks? Duration of treatment Unknown Adverse effects Gastrointestinal discomfort, headaches, and anxiety— usually short-lived. Possible angina or arrhythmia in vulnerable patients Theoretically may increase risk of osteoporosis in women if T3 results in full suppression of TSH (<0.1 mU/mL) Monitoring ? Cortical bone densitometry every 1–2 years in women with full suppression of TSH Note. MAOI=monoamine oxidase inhibitor; SSRI=selective serotonin reuptake inhibitor; TSH=thyroid-stimulating hormone.

Bipolar Disorder A number of studies have investigated whether a higher prevalence of clinical and subclinical thyroid illness exists in patients with rapid-cycling bipolar illness (Bartalena et al. 1990; Bauer et al. 1990; Cho et al. 1979; Cowdry et al. 1983; Joffe et al. 1988; Wehr et al. 1988). The three positive studies (Cho et al. 1979; Cowdry et al. 1983; Bauer et al. 1990) suggest a higher prevalence of subclinical and clinical hypothyroidism associated with rapid cycling. Cho et al. (1979) reported that 31.7% of rapid-cycling versus 2.1% of non–rapid-cycling women had evidence of grade I clinical

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hypothyroidism. Cowdry et al. (1983) reported 92% of rapid-cycling versus 32% of non–rapid-cycling patients had evidence of either grade I or II hypothyroidism. Bauer et al. (1990) found higher prevalence of a variety of grades of hypothyroidism in their sample of rapid cyclers compared to published prevalence in non–rapid-cycling bipolar illness (grade I, 23%; grade II, 27%; grade III, 10%). As a result of these findings the use of thyroid hormone has been suggested in rapid-cycling bipolar patients. On the other hand, Wehr et al. (1988) observed a high prevalence of hypothyroidism in both rapid-cycling and non–rapid-cycling patients (47% vs. 39%). Joffe et al. (1988) evaluated 43 bipolar outpatients who had received at least 3 months of treatment with lithium carbonate. Thyroid function tests were obtained on all patients, and detailed life charting was obtained on 39 patients. Seventeen patients were classified as rapid cyclers and 25 as non–rapid cyclers. None of the thyroid indices correlated with course-of-illness variables, but patients who developed clinical hypothyroidism had a significantly longer mean duration of lithium treatment. Bartalena et al. (1990) compared 11 rapid-cycling and 11 non– rapid-cycling women matched for age and mode of treatment. A high prevalence of subclinical hypothyroidism was found in both groups. Therefore, the three negative studies (Bartalena et al. 1990; Joffe et al. 1988; Wehr et al. 1988) found a higher-than-expected prevalence of hypothyroidism in both rapid-cycling and non–rapid-cycling groups compared with rates in the healthy population. However, no significant difference was found between the rapid-cycling and non–rapid-cycling groups. Furthermore, in one study (Joffe et al. 1988), it was suggested that hypothyroidism in bipolar illness may be more closely correlated with duration of lithium treatment than with rapid-cycling status. More recently, Zarate et al. (1997) retrospectively evaluated a sample of 72 medication-free subjects presenting in first-episode mania or mixed state. Elevations in TSH concentration but not in other thyroid measures differentiated between mixed-episode and manic patients. This is interesting, because bipolar patients who experience mixed episodes may be more prone to rapid cycling (Keller et al. 1986). Finally, Frye et al. (1999) reported that in a cohort of 52 patients, lower measures of T4 were associated with greater mood instability and severity in patients receiving lithium or carbamazepine.

Non–Rapid Cycling Baumgartner et al. (1994) reported on the use of high-dosage T4 in non– rapid-cycling patients with treatment-refractory bipolar disorder. Six

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patients were treated with 250–500 mg/day of T4. Four of the six patients obtained a significant response as measured by mean number of relapses and mean length of hospitalizations during the follow-up period (12–46 months). However, four of the patients in the study had evidence of subclinical hypothyroidism. Therefore, it is unclear whether the beneficial effect of T4 was due to its being employed as thyroid replacement therapy.

Rapid Cycling Although the specificity of hypothyroidism in rapid-cycling bipolar disorder is not known, T4 has been used by several investigators in an attempt to treat rapid-cycling bipolar illness. Reports to date have used dosages of T4 up to 500 mg/day in combination with mood stabilizers— high enough to induce a hypermetabolic state (Bauer and Whybrow 1990; Leibow 1983; Stancer and Persad 1982). First, Stancer and Persad (1982) openly treated 10 rapid-cycling patients whose illness had been refractory to conventional treatments (lithium, ECT, neuroleptics) with supraphysiological thyroid hormone. Five of 7 women treated with 300–500 mg/day of T4 obtained complete remission of their illness (follow-up period, 1.5–9 years), 2 women treated with 240–400 mg/day of T3 had temporary or slight responses, and 2 men treated with T4 also responded minimally. Subsequently, Leibow (1983) reported a single case of rapid cycling that responded to 400 mg/day of T4. More recently, Bauer and Whybrow (1990) openly treated 11 rapid-cycling patients with 150–400 mg/day of T4. Depressive symptoms improved in 10 of 11 patients, and manic symptoms improved in 5 of the 7 patients who exhibited these symptoms at baseline. Three of 4 patients who were randomized in either a single- or double-blind manner to discontinuation of T4 subsequently relapsed. In the reports to date, supraphysiological T4 has been reported to be generally well tolerated because the treatment algorithms have called for slow dose titration, with the upper limit of dosing usually determined by the appearance of side effects. There is nevertheless a risk of iatrogenically induced hyperthyroidism, and as such this treatment technique needs to be used with caution. With respect to other risks of treatment, there is a theoretical risk of osteoporosis owing to the observation of a higher prevalence of this condition in untreated hyperthyroidism (Greenspan and Greenspan 1999). To address this concern, Gyulai et al. (1997) followed up on 10 of the 11 patients previously treated by Bauer and Whybrow (1990). Serial bone densitometry was performed, and no difference was observed in bone density in patients treated with high-dosage

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T4 compared with age- and sex-matched control subjects. With respect to thyroid hormone therapy in bipolar illness, there is limited controlled evidence for the efficacy of supraphysiological T4 in the treatment of rapid cyclers. Unfortunately, the available data arise from a total of 22 cases reported in the literature, and all the studies to date have used uncontrolled designs. Furthermore, the hypothesis underlying the use of high dosages of T4—the greater prevalence of hypothyroidism in rapid-cycling bipolar illness—is brought into question by several surveys (Bartalena et al. 1990; Joffe et al. 1988; Wehr et al. 1988) and by the observation that response to T4 is not related to baseline thyroid function tests (Bauer and Whybrow 1990). Nevertheless, the dramatic nature of the responses obtained in the open trials (Bauer and Whybrow 1990; Leibow 1983; Stancer and Persad 1982) suggests that supraphysiological T4 may be an important treatment for the highly refractory illness of this patient group. However, further replication using larger numbers of patients and more rigorous study designs are required.

Anxiety Disorders Anxiety is a well-recognized symptom associated with thyroid disease, especially hyperthyroidism (Kathol and Delahunt 1986). Kathol et al. (1986) observed depression and anxiety disorders to occur frequently in patients with hyperthyroidism in an endocrinology clinic. Twenty-three of 29 patients met the criteria for either generalized anxiety disorder or panic disorder. In most patients, the symptoms resolved with antithyroid therapy. Stein and Uhde (1990) administered 20–30 mg/day of T3 in a singleblind manner to 8 euthyroid panic disorder patients who had not responded to treatment with tricyclic antidepressants alone. The duration of the trial was from 2 to 5 weeks. The results were that 3 patients experienced no change in their anxiety, 4 experienced an exacerbation in their symptoms, and only 1 responded. Although the literature of the thyroid and anxiety disorders is limited, the available data suggest that patients with anxiety disorder may differ biologically from depressed patients with respect to the thyroid axis. This appears to be preliminarily confirmed by the single available clinical trial of T3 augmentation in panic disorder, suggesting that although a history of depression may predict response to T3 augmentation, pure panic disorder is not associated with a positive response to this treatment.

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Conclusion Thyroid hormone treatments have been used in a variety of psychiatric illnesses suggested by observations of a variety of psychiatric symptoms in frank thyroid disease. With respect to anxiety disorders, the limited evidence currently available suggests that T3 augmentation is not useful in pure panic disorder and in fact may worsen symptoms. In bipolar illness, there are several studies, albeit uncontrolled ones, suggesting that hypermetabolic doses of T4 (and possibly T3) may result in dramatic improvement in rapid-cycling patients who are unresponsive to conventional mood-stabilizing therapy. Recently reported follow-up data on some of the original patients treated with supraphysiological T4 suggest that these patients may not be at risk of decreased bone density. With regard to both panic disorder and bipolar illness, replication of the available data using controlled designs is needed before definitive conclusions regarding the utility of thyroid treatments in these conditions can be drawn. Furthermore, as a consequence of the potential risks, the unavailability of controlled data, and the availability of safer alternatives (atypical antipsychotics, novel anticonvulsants) we cannot recommend the use of highdosage T4 as a treatment for rapid-cycling bipolar disorder, but its use may be better justified once further data are available. Several types of thyroid hormone treatment have been investigated in major depression. The use of T3 to augment antidepressants in patients who do not respond to treatment is the best-evaluated treatment. Although T3 acceleration may be more prominently effective in women, there does not appear to be any sex difference with respect to response in T3 augmentation. Recent evidence suggests that in augmentation, the type of thyroid hormone used may be important and that T3 may be a superior agent to T4. Further evidence obtained through the largest clinical trial to date with reasonable clinical power suggests that T3 augmentation is comparable to lithium augmentation. A notable caveat is that all studies to date have evaluated T3 augmentation in patients did not respond to tricyclic antidepressants. However, there are reports in the literature of positive response to T3 augmentation of other classes of antidepressants. Nevertheless, there has been a significant shift in treatment practices to the first-line use of selective serotonin reuptake inhibitors. To confirm a comparable degree of response as is seen with tricyclics, randomized trials of T3 augmentation of this class of antidepressants are required. In conclusion, we can recommend that T3 augmentation be considered as a primary augmentation strategy (comparable to lithium) in the augmentation of tricyclic antidepressants. In the case of selective

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serotonin reuptake inhibitors, lithium augmentation should precede consideration of T3 augmentation, given the presence of controlled data that lithium is an effective augmenter of response to selective serotonin reuptake inhibitors.

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Part VI Laboratory Testing

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Chapter 17 Laboratory Evaluation of Neuroendocrine Systems David Michelson, M.D. Philip W. Gold, M.D.

O

ver the past two decades there has been a rapid increase in the understanding of neuroendocrine physiology and how it relates to normal and pathological brain activities. Neuroendocrine function—the actions of hormones produced and active in the nervous system—has come to be understood as being critical to the workings of the brain, and particularly to the integrative processes that characterize much of human behavior. This information has come from several sources, including extrapolations from animal models, clinical research in human subjects, and observations of abnormalities in people with psychiatric and neurological illnesses. An important part of this work has been the development of a variety of tests to characterize human neuroendocrine systems. In this chapter we focus on some of the tests of human neuroendocrine function that are important in psychiatric illness, on the proper uses and interpretation of these tests, and on their relevance to clinical practice. This survey is by no means complete, and it excludes from consideration a number of neuroendocrine hormones. In particular we focus on the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis, with briefer overviews of the hypothalamic-pituitary-gonadal (HPG) axis and of growth hormone. The guidelines presented in this chapter can stand alone but can also usefully complement the guidelines presented in other chapters of this book dedicated to the individual endocrine axes.

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Basic Principles in the Evaluation of Neuroendocrine Systems In humans, neuroendocrine function is generally tested under two different conditions. The first is the basal or nonstimulated state. Typically such studies examine a particular hormone and its metabolites and, if it is an effector outside the brain, its products. Because the system is not being manipulated, substances measured presumably reflect basal activity. An example of such a test is quantitation of 24-hour excretion of urinary free cortisol (UFC), an end product of HPA axis activation. In most studies, about half of the people with depression have elevated 24-hour UFC compared with control populations (Gold et al. 1988) (see Chapter 6 in this volume). Integrated 24-hour UFC reflects adrenal production of cortisol, which in turn is related to levels of hypothalamic and pituitary activity. Its elevation suggests increased activity at some level of the HPA axis—hence the observation that HPA axis activity in about half of depressed patients is increased. Basal studies can provide several kinds of information. When they are integrative (i.e., they reflect the sum of activity over a given period), such as 24-hour UFC, they provide a quantifiable picture of the general level of activity of a system, but not the character of that activity. To obtain a picture of the pattern of activity of the HPA axis in depression, one might turn to repeated blood sampling at specific time points. Such a strategy can provide information about whether release follows normal patterns, whether there are disturbances in circadian rhythms, and whether elevations in overall activity result from brief bursts of increased activity in a setting of otherwise normal tone, or from more modest but sustained hyperactivity. This points to an important consideration in designing and using tests of basal neuroendocrine function: the need to consider what kind of information is being sought and whether the proposed methodology can provide it. The second condition under which neuroendocrine systems are commonly studied is using provocative stimuli. In these paradigms, an exogenous agent that is known to affect one or another component of a system of interest is administered or an environmental condition is altered, thus “provoking” a change in the system’s activity. The widely used dexamethasone suppression test is an example of this kind of intervention. Under normal conditions, increasing the level of glucocorticoid negative feedback has powerful suppressive effects on the activity of the HPA axis (i.e., this provocation decreases activity). The failure to suppress HPA axis activity after administration of dexamethasone in some depressed patients suggests an alteration in normal function, further evidence of a

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change in its regulation. Provocative tests can also be used to activate a system, allowing comparison of different populations under nonbasal conditions. The rationale for such tests rests on the observation that certain body systems that appear to function adequately under unstressed conditions become pathological in the setting of increased demand. Thus, for example, a person with coronary disease who is asymptomatic at rest or while walking slowly may show signs of cardiac compromise while exercising vigorously on a treadmill. In addition to providing an opportunity to change the conditions under which a system is studied, provocative tests can be aimed at specific elements of a system. Most neuroendocrine systems have multiple components as well as feedback loops that can compensate for changes at different levels of the system. A subtle defect at one level with potential pathophysiological implications may be relatively compensated elsewhere and may not be detectable except by targeted manipulations. In a situation in which basal testing can show an alteration in overall axis function but not its locus, provocative tests can often tease out the function of the parts of the axis and provide clues to pathophysiological mechanisms. As with basal tests, different provocative tests provide different kinds of information. Using different doses of an agent may yield very different results. There may be insensitivity at low doses that can be overridden at high doses, or preservation of basal function but loss of reserves needed for stimulation. The response to a bolus may be different than to a constant infusion. The internal milieu may affect response (e.g., circadian rhythms). Using physiological and pharmacologic doses may provide different information. Thus again the information sought and the conditions under which it is obtained are critical in planning studies and interpreting results.

Appropriate Use of Neuroendocrine Tests Neuroendocrine testing is broadly useful in two kinds of situations: determining abnormalities in individuals that are of clinical relevance, and characterizing differences among populations of subjects with and without a particular condition. In the enthusiasm for developing biological grounding for psychiatry, one problem that sometimes arises is confusion between these aims. A number of medical conditions can present with psychiatric symptoms, or indeed may appear to be primary psychiatric illnesses. For such illnesses (e.g., thyroid disease or Cushing’s syndrome), neuroendocrine tests can clarify the differential diagnosis and help determine the appropriate treatment. The important issue in using tests in this setting is ensuring that the test chosen will provide the information required and

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then using it in a manner consistent with good clinical decision making. The second situation—characterizing neuroendocrine abnormalities present in a particular psychiatric syndrome—is primarily appropriate for research settings, for several reasons. First, the demonstration of a neuroendocrine abnormality in the setting of an illness is, initially at least, an association that may or may not have treatment implications. Second, the response to many neuroendocrine tests is often widely variable among individuals, and demonstrating an abnormality is typically a statement that, as a group, people with a particular illness have a different neuroendocrine profile than people without the illness. Within groups, however, there may be wide variation and thus much overlap between healthy and ill populations (this is the case in, for example, HPA axis activation in depression). Data from these sorts of tests about a particular individual are not useful unless they have some diagnostic or treatment implications, and they should not be routinely obtained outside the context of a research study. Keeping these basic principles in mind, let us now consider some of the neuroendocrine tests used in psychiatry.

Hypothalamic-Pituitary-Adrenal Axis The HPA axis regulates glucocorticoid production and release. In addition to the hypothalamus and the pituitary and adrenal glands, its activity involves a complex set of interrelated feedback loops, including elements of the immune system, the limbic areas of the brain, and the locus coeruleus. Stress responses are mediated through the HPA axis initially by the release of corticotropin-releasing hormone (CRH), a 41–amino acid peptide, synthesized in the parvocellular cells of the paraventricular nucleus of the hypothalamus. It is released into the hypophyseal portal blood of the median eminence and is transported to the anterior lobe of the pituitary. Although relatively little is known about the determinants of extrahypothalamic CRH secretion, the regulation of CRH secretion by the hypothalamus is becoming increasingly well understood. Preclinical studies in rats have shown that the neurotransmitters norepinephrine, acetylcholine, and serotonin stimulate the release of CRH (Calogero et al. 1988a, 1988b, 1989), as do the cytokines interleukin-1 and interleukin-6 (Naitoh et al. 1988; Sapolsky et al. 1987). CRH is not the only neuropeptide that stimulates pituitary adrenal activation. The hypothalamus also produces and secretes a second important stimulant of glucocorticoid secretion, the 9–amino acid peptide arginine vasopressin (AVP). Most hypothalamic AVP is produced in the

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magnocellular region and is transported to the posterior pituitary to be released as an element active in maintaining fluid and volume balance by conserving free water. However, AVP is also produced in smaller amounts in the parvocellular region of the hypothalamus, and, like CRH, it acts at the anterior pituitary to induce the release of adrenocorticotropic hormone (ACTH) (Salata et al. 1988). Compared with CRH, AVP is a relatively weak secretagogue of ACTH; however in the presence of CRH AVP has a powerful synergistic effect that causes greater ACTH release than either AVP or CRH alone can induce (DeBold et al. 1984). AVPinduced ACTH secretion may not be glucocorticoid suppressible (Bilezikjian et al. 1987), and this may permit AVP to play an important role in the maintenance of chronic stress responses. Exposure to CRH, AVP, or the two together leads to pituitary activation, and this in turn results in the release of ACTH, a 39–amino acid peptide that acts at the adrenal cortex to release cortisol, the primary peripheral stress hormone. ACTH interacts with adrenal cell membrane receptors, ultimately causing activation of adenylate cyclase, increase in cyclic adenosine monophosphate concentrations, and protein phosphorylation. (The biochemistry and relevance to psychoneuroendocrinology of CRH, AVP, and ACTH are further discussed in Chapter 3 of this volume.) The major effect of ACTH on steroidogenesis is to stimulate the ratelimiting step (conversion of cholesterol to pregnenolone). Cortisol is derived from cholesterol, which is both synthesized in the adrenal gland and also taken up by the gland in low-density lipoprotein or high-density lipoprotein particles synthesized in the liver. In the adrenal cortex, cholesterol is converted first to pregnenolone, then to 17a-OH-pregnenolone, 17a-OH-progesterone, 11-deoxycortisol, and finally cortisol. ACTH is the primary circulating cortisol releasing factor, and it stimulates both the release of cortisol and cortisol synthesis. Cortisol has an exceptionally wide range of actions. Although a complete review of these would exceed the scope of this chapter (for a detailed discussion see Chapter 19 in this volume), two very general categories are critical. These are 1) counterregulatory effects, particularly with respect to the immune system, on which cortisol acts to decrease activity and prevent unrestrained and potentially self-injurious activity in response to an immune trigger, and 2) the mobilization and optimization of energy use in the setting of acute stress (providing a metabolic substrate for the fight-orflight response) (Chrousos and Gold 1992; Munck et al. 1984). To test HPA axis function, it is necessary to be familiar not only with the elements of the axis, but also with the ways in which they are typically secreted and metabolized. The major secretory products of the HPA

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axis are released into the circulation with a circadian rhythm, with diurnal peaks and nadirs. Cortisol and ACTH secretion are highest in the morning and lowest in the evening. All three of these hormones are secreted in a pulsatile fashion, with pulses of CRH leading to ACTH release, which then leads to cortisol release. CRH has a very short half-life (several minutes) in the peripheral circulation; ACTH has a slightly longer half-life (10–20 minutes), and the half-life of cortisol is approximately 45–60 minutes. The characteristics described above suggest some of the issues that arise in testing the HPA axis. First is the problem of hierarchy—the most accessible and stable product of the axis, cortisol, is also the farthest removed from the brain. Direct measurement of CRH is extremely difficult because of its short half-life and the relative inaccessibility of the brain to direct measurement. Basal sampling measures must be taken with care, because secretory pulses that occur between measurements spaced too far apart may be undetected. The phenomenon of negative feedback coupled with circadian variation means that time of day will usually affect the result of a test.

Basal HPA Axis Activity To examine the nonstimulated activity of the HPA axis, two measures are commonly used. These are plasma measurements of ACTH and cortisol, and quantitation of 24-hour UFC (see Table 17–1 for normal values). Hyperactivity of the HPA axis can often be detected by measurement of plasma ACTH and cortisol. Concentrations of the hormones over brief intervals (minutes to hours) are quite variable, both because of diurnal variation in the activity of the axis and because of the pulsatile nature of the activity and relatively short-half-lives of these substances. In individuals or in small groups, therefore, single samples of cortisol and especially of ACTH rarely provide meaningful information. Plasma sampling should usually be serial, and sampling time points should be at or within the plasma half-life of cortisol (30–60 minutes) or ACTH (10–20 minutes) to allow detection of pulses. We have shown that sampling at 15-minute intervals over 2 hours between 6:00 P.M. and 8:00 P.M. demonstrates modest hypercortisolism in both depressed patients and patients with multiple sclerosis (Gold et al. 1986; Michelson et al. 1994). Other studies have shown that sampling at 20-minute intervals between 1:00 P.M. and 4:00 P.M. discriminates cortisol hypersecretors (Halbreich et al. 1982). Consideration should be given to whether morning (i.e., peak) or evening (nadir) concentrations are of interest; typically subtle hyperactivity will be more visible during periods of relative quiescence.

Laboratory Evaluation of Neuroendocrine Systems TABLE 17–1.

Hormone

Normal values of pituitary-adrenal hormones at the National Institutes of Health Clinical Pathology Laboratory Normal values

Adrenocorticotropin <60 pg/mL

Cortisol Urinary free cortisol

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7–25 mg/dL (A.M.) 2–14 mg/dL (P.M.) 20–90 mg/24 hours

Comments Diurnal rhythm, lowest in the evening; large variations and short half-life Diurnal rhythm, lowest in evening Increased with stress or exercise

Absent overt pituitary or adrenal failure, hypoactivity is difficult to detect using this technique, but conditions such as depression and multiple sclerosis have been shown to be associated with elevations in evening plasma cortisol levels using serial sampling (Gold et al. 1988; Michelson et al. 1994). Care should be taken to avoid artifactual increases or decreases in ACTH and cortisol levels; common reasons for false elevation of ACTH and cortisol level include sampling in the context of a stressful situation (e.g., a patient in pain), sampling in the context of stress (e.g., vigorous exercise, novelty, illness), and obtaining an insufficient number of samples so that a single pulse of activity skews the results. Experience in our laboratory has also shown that the needle stick required to insert an intravenous catheter can be associated with a rise in ACTH and cortisol (M. A. Altemus, unpublished data), either because of the pain or because of apprehension, and we therefore wait an hour after catheter insertion before any sampling is done. Artifactually low ACTH values can be the result of failure to chill samples immediately after they are drawn, allowing protease degradation of ACTH, and failure to spin and freeze samples within 2 hours of collection (after which point significant degradation of ACTH occurs even in chilled samples). To obtain an integrated measure of cortisol production through the day, quantitation of 24-hour urinary excretion of free cortisol is the most commonly used measure. Among patients with depression, most studies have shown significant elevations of 24-hour UFC excretion in up to half of subjects (Gold et al. 1988). Patients with multiple sclerosis have been found to have similar elevations. Studies of 24-hour UFC excretion in depressed patients that follow daily UFC excretion over a period of weeks show a pattern of alternation between elevated and normal values, suggesting that even at the higher levels of activity typical of many depressed patients, HPA axis negative feedback mechanisms are not entirely abol-

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ished (M.A. Kling, unpublished data). From a practical perspective, this also means that measuring 24-hour UFC excretion only once or twice may underestimate the number of patients with HPA axis activation, because some collections are likely to occur during periods of relative quiescence. Cortisol in the urine is highly stable and so collection is technically easy, with many assay techniques not requiring refrigeration or preservatives. However, careful instructions to patients on how to collect the sample are important, because the rate of cortisol excretion varies and incomplete collections may yield inaccurate results. We generally ask patients to begin the collection at a specified hour of the morning by having them empty their bladder and discarding that void. All subsequent voids are collected, and at the same time the following day the patient is instructed to void one last time and include it in the collection (a detailed sample set of instructions for patients can be found in the Orth et al. 1992 reference). Averaging results from collections from multiple days provides more accurate measures than single-day collections, because levels of activity and stress can cause variation in cortisol production, and also because patients will often have difficulty collecting all the urine produced during a 24-hour period. Production can be artifactually increased by exposure to any significant stress during the collection period, and subjects must be instructed not to perform unusual activities or to exercise strenuously during periods of collection. In addition to cortisol, it is useful to quantitate 24-hour urine creatinine excretion to assess the adequacy of the collection. People of average weight and build normally excrete creatinine at the rate of about 1.0 g/24 hours, and values significantly below this level suggest an incomplete collection. Free cortisol is secreted into saliva and can be quantitated using assays described below. Levels have been shown to accurately reflect serum levels of free cortisol (Evans et al. 1984; Orth et al. 1992), and reference ranges have been published (Aardal and Holm 1995). This procedure is particularly useful in situations in which plasma and urine collections are impractical or problematic, such as screening children for Cushing’s syndrome or other conditions (Gispen-de Wied et al. 1998; Martinelli et al. 1999), in ambulatory outpatient settings, and in settings in which information about ACTH is not required. Clinically, basal measurements of HPA axis function are most important in several situations. Hypercortisolism is a defining feature of Cushing’s syndrome, which is part of the differential diagnosis of major depression. Particularly in early Cushing’s syndrome it can be difficult to distinguish the two clinically; the absence of elevations of 24-hour UFC would point one away from Cushing’s syndrome, whereas elevations might lead to further workup (described below) (see Chapter 8 in this volume).

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A second situation in which it may be useful to have a picture of unstimulated HPA axis activity is in refractory depression, because an emerging literature suggests that steroid inhibition may have some therapeutic benefit in such patients. We note, however, that these data are highly preliminary, and the role of antiglucocorticoids in the treatment of depression has yet to be demonstrated in adequately designed and controlled trials. (This topic is discussed further in Chapter 6 of this volume.)

Provocative Tests of HPA Axis Function Because the HPA axis contains three distinct components, tests that examine its stimulated activity can be aimed at different levels and provide different information. Most research to date has examined pituitary and adrenal function and has inferred information about hypothalamic function for the simple reason that satisfactory stimulatory agents of the hypothalamic CRH neuron are quite limited. There is, however, an evolving body of work describing central stimulation of hypothalamic CRH release, which is reviewed here. Administration of naloxone moderately stimulates both ACTH and cortisol release; the mechanism of action is thought to be blockade of tonic opiate inhibitory effects on the hypothalamic CRH neuron. In our laboratory, however, the variability in response among healthy subjects has been high, and we have been unable to show significant differences in either ACTH or cortisol response to naloxone between healthy volunteers and patients with depression (Michelson et al. 1996a). Insulin-induced hypoglycemia has also been used as a central stimulus of hypothalamic CRH release, and it does induce a significant response in most subjects (Fish et al. 1986). It has the disadvantages, however, of being a rather severe and nonspecific stress as well as being both cumbersome and risky to administer, because the actual provocative effect, hypoglycemia, can be life threatening. More recently, we and others have shown that graded treadmill exercise is a potent, safe, and reliable stressor that leads to hypothalamic CRH release and consequent pituitary-adrenal activation (Deuster et al. 2000; Luger et al. 1987; Singh et al. 1999). Exercise has the advantage of being dose dependent (i.e., the degree of activation of the HPA axis is a function of the amount of lactate produced by the body, and this can be controlled by the percentage of maximal aerobic capacity to which subjects exercise). Because the HPA axis response correlates with the percentage of maximal aerobic capacity achieved rather than with the degree of aerobic conditioning of individual subjects, subjects with different levels of physical fitness can still be meaningfully compared in terms of HPA axis response to exercise. Exercise-induced HPA axis activation, therefore,

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holds out the promise of providing more direct assessment of hypothalamic CRH neuron function than has generally been possible. Importantly it may also provide a means to investigate putative states of centrally induced HPA axis hypoactivity, which, because of dynamic compensatory mechanisms, are notoriously difficult to document by conventional stimuli of pituitary and adrenal activity. In addition to the paradigms described above, several other potential stimuli of hypothalamic CRH release have been proposed and are in varying stages of development.

CRH Stimulation Test At the level of the anterior pituitary, there now exists a large body of work using CRH-induced stimulation of corticotroph ACTH release. CRH stimulation has been performed in a variety of pathological states and has been shown to have characteristic patterns of abnormal response in major depression. Clinically it has been used to diagnose Cushing’s syndrome and to distinguish it from depression. Because these studies are reviewed elsewhere in this volume, the emphasis in this chapter is on the methodology and utility of the test. The CRH test is generally performed using natural or synthetic ovine CRH (oCRH). Compared with human CRH, oCRH has the advantage of a relatively long half-life (approximately 30–60 minutes) and of inducing a more potent ACTH response. Although some researchers administer it in a single 100-mg or 250-mg dose, more commonly it is administered on a weight-adjusted basis of 1 mg/kg body weight. CRH can be given as a bolus through a peripheral intravenous catheter, and it elicits a peak ACTH response in 15–30 minutes and a peak cortisol response in 45–90 minutes. The expected responses are a cortisol rise of at least 10 mg/dL above baseline; ACTH responses are more variable (Nieman and Loriaux 1989). Most researchers report that the ACTH and cortisol responses correlate inversely with basal plasma cortisol levels (i.e., that the response is subject to glucocorticoid negative feedback), and probably for this reason the response to oCRH administration is greatest in the evening when plasma cortisol levels are at a nadir. Response to oCRH is generally measured as the peak response over baseline of ACTH and cortisol or as the net integrated area under the response curve after subtracting the baseline. Because oCRH is a peptide, it is not thought to cross the blood-brain barrier. Administration of oCRH has few significant side effects other than a transient metallic taste and flushing in 15%–20% of subjects. As a research tool, the response to oCRH is most helpful when the patterns of ACTH and cortisol response can be used to determine the locus of hyperactivity of the HPA axis. Although some suggestive data are

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now beginning to emerge, attempts to document putative subtle (i.e., nonaddisonian) states of hypoactivity of the CRH neuron in the setting of an intact pituitary (e.g., chronic fatigue syndrome) have generally been less successful than characterization of HPA axis hyperactivity (e.g., melancholic depression, Cushing’s syndrome). Clinically, the CRH test is most useful in the diagnosis of Cushing’s syndrome. In the early stages of Cushing’s syndrome, before the stigmata of florid, sustained hypercortisolism set in, depressed mood may be the only sign of the illness, and 50% of patients may show no evidence of increased plasma ACTH (Tyrrel et al. 1978). Under these conditions, it can be extremely difficult to distinguish Cushing’s syndrome from pseudo-Cushing’s states such as primary depressive illness. The CRH test has been used to differentiate these. In depression, the intact pituitary is hyporesponsive because of persistent hyperstimulation from the CRH neuron, and it has an extremely attenuated response to exogenous CRH administration. Among patients with Cushing’s disease, a pituitary adenoma secreting ACTH exhibits a robust response to oCRH so that the blunted response expected in the setting of hypercortisolism (due to glucocorticoid negative feedback) is not seen. Unfortunately, however, there is considerable variation in individual response, and so the CRH test alone is not sufficiently sensitive or specific to be used generally, and diagnostic workups using modifications of the CRH test have been proposed. One suggested algorithm for differentiating Cushing’s syndrome and pseudo-Cushing’s syndrome involves the initial collection of two or three 24-hour urine samples for determination of UFC excretion. If the UFC is increased, a dexamethasone suppression test is performed. A negative result in either of these tests rules out Cushing’s syndrome but not depression. If both are positive, a CRH test is performed shortly after dexamethasone administration (0.5 mg every 6 hours for 8 doses); depressed patients are more responsive to negative feedback, and their characteristic ACTH blunting is exaggerated, providing better differentiation of the two groups (Orth 1995; Yanovski et al. 1993). The following are guidelines for the CRH stimulation test, which tests the ability of the pituitary to release ACTH:

Dose: 1 mg/kg ovine CRH as an intravenous injection Timing: Insert intravenous catheter at 6:00 P.M. Starting at 7:00 P.M., sample for ACTH and cortisol at 15-minute intervals Inject ovine CRH at 8:00 P.M. Test ends at 10:00 P.M.

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ACTH release is often blunted in depression, but cortisol release is often normal or increased; in Cushing’s disease ACTH release is normal or exaggerated and cortisol release is normal or increased.

AVP Infusion As noted above, AVP is also a stimulus to pituitary ACTH release. Compared with CRH, relatively fewer studies have examined its role in states of HPA axis dysfunction, perhaps because it is a less potent stimulus than CRH. However, when it is presented to the pituitary in the presence of CRH, a synergism between the two peptides leads to greater ACTH release than either one alone can achieve. In addition, there is evidence in animal models that AVP-induced HPA axis activation is not glucocorticoid suppressible. These two facts have led some researchers to suggest that AVP serves as an important modulator of stress responses, and AVP may also play an important role in chronic HPA axis activation. Studies of AVP effects on the human HPA axis are much more limited than studies of CRH, and no single means of administration has become the standard. Nonetheless, AVP infusion may be helpful in determining the pathophysiological mechanisms that maintain hypercortisolism in different states. We have developed a paradigm in which we administer AVP in a 60-minute infusion of 1 mIU/kg per minute for 60 minutes. We are currently attempting to determine whether this test can be used to demonstrate hyposecretion of CRH in various fatigue states (the response to AVP in the absence or relative paucity of CRH should be blunted). We have also used AVP infusion together with oCRH stimulation to provide evidence that HPA axis hyperactivity in states of immune activation may be physiologically distinct from that of depression (Michelson et al. 1994). Studies with AVP are generally well tolerated by subjects. The most important side effects in our experience, occurring in 5%–10% of subjects, are abdominal or bladder cramping, and women who undergo the test at the end of the menstrual cycle may experience painful, exaggerated uterine cramping. These effects typically resolve within minutes of discontinuing the infusion.

ACTH Stimulation Test The best direct test of adrenal function is ACTH stimulation. Clinically this is most important in cases of suspected adrenal failure (Addison’s disease). Failure of the adrenal gland to significantly increase cortisol secretion (to at least 20 mg/dL) in response to a bolus of ACTH indicates inadequate adrenal responsivity. As a research tool, ACTH stimulation has been used in a variety of ways. The adrenal gland is quite sensitive to changes in the stimulatory environment, and it hypertrophies both ana-

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tomically and functionally in the setting of persistent increased ACTH secretion (Dallman 1984–1985; Payet et al. 1980). Thus, ACTH stimulation is used to test not only for primary changes in adrenal function, but also for changes in its activity that reflect alterations in HPA axis tone. The ACTH dose-response curve of adrenal cortisol secretion has been well characterized, and by using different doses, it has been possible to demonstrate changes in the regulatory environment of the adrenal gland in different diseases. At supramaximal doses (e.g., 250 mg), the integrity of the adrenal gland is tested (i.e., Addison’s disease can be ruled out), but subtle changes in function may not be detectable. In subjects with depression, the response to supramaximal stimulation has been shown to be increased (Amsterdam et al. 1993), whereas submaximal and maximal doses (0.05 mg/kg and 0.2 mg/kg respectively) may differentiate depressed subgroups (Amsterdam et al. 1989). Using the lowest effective stimulatory dose (0.003 mg/kg), Demitrack and colleagues (1991) have been able to demonstrate alterations in adrenal function consistent with hypoactivity of the HPA axis in a state of putative HPA axis hypofunction (chronic fatigue syndrome). The following are guidelines for the ACTH stimulation test, which tests the ability of the adrenal gland to release cortisol: Dose: 250 mg ACTH as an intravenous injection Timing: Insert intravenous catheter at 5:00 P.M. Starting at 6:00 P.M., sample for cortisol at 15-minute intervals for 1 hour. Inject ACTH at 6:00 P.M. Test ends at 7:00 P.M.

In settings of primary adrenal failure, cortisol release is impaired.

Dexamethasone Suppression Test One of the earliest neuroendocrine tests to become widely used in psychiatry was the dexamethasone suppression test. In this procedure, the synthetic steroid dexamethasone is administered to subjects, and over the ensuing 24 hours plasma cortisol is measured. The expected effect is inhibition of pituitary-adrenal activity due to negative feedback induced by dexamethasone occupancy of type II glucocorticoid receptors. Increased activity of the HPA axis is associated with dexamethasone nonsuppression. Several different methodologies for dexamethasone administration and sampling of cortisol and ACTH have been proposed. However, the usual procedure is 1 mg of dexamethasone administered at 11:00 P.M., with blood sampled at 8:00 A.M., 4:00 P.M., and 11:00 P.M. the following

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day (in outpatients the test may be performed with a single sample taken at 4:00 P.M., though some sensitivity may be lost). Although the dexamethasone suppression test has been widely studied and provides an interesting research tool, it is of little clinical value because it is neither highly sensitive (i.e., it produces many false negatives) nor specific (it produces many false positives). Most studies suggest that its sensitivity is about 50% and its specificity is 90% or less (Arana and Baldessarini 1987), although in some subpopulations such as the psychotically depressed it may be more meaningful (Nelson and Davis 1997). Although there is evidence that dexamethasone nonsuppression following successful treatment of depression is a predictor of poorer outcome (i.e., earlier relapse) (Ribeiro et al. 1993; Zobel et al. 1999), these findings are, in our judgment, neither sensitive nor specific enough to usefully guide clinical practice. The following are guidelines for the dexamethasone suppression test, which tests the negative feedback response of the HPA axis to glucocorticoids: Dose: 1 mg dexamethasone orally Timing: Administer at 11:00 P.M. Draw blood for cortisol determination at 8:00 A.M., 4:00 P.M., and 11:00 P.M. (in outpatients may draw blood at 4:00 P.M. only).

Approximately half of patients with depression do not appropriately suppress cortisol secretion. Factors reported to cause nonsuppression in the absence of depression: • • • • • • • • •

Cushing’s disease Severe stress Increased metabolism of dexamethasone Recent hospitalization Pregnancy or increased estrogen Recent weight loss Medications (e.g., carbamazepine, phenytoin, barbiturates) Alcohol withdrawal Serious medical illness Factors reported to cause suppression despite the presence of depression:

• Addison’s disease • Exogenous glucocorticoid administration • Medication

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Methods and Problems in Measurements The study of the HPA axis requires plasma and urine measurements of relevant substances, particularly cortisol and ACTH, and obtaining useful test results requires proper handling and assaying of specimens. Normal values for ACTH and cortisol vary through the day, with higher levels occurring in the morning and lower levels at night. Furthermore, because of its short half-life, variations in ACTH concentrations are large, even over brief periods of time. In our laboratory, normal reference values for plasma ACTH are less than 60 pg/mL, whereas normal reference values for cortisol are 7– 25 mg/dL in the morning and 2–14 mg/dL in the evening. Normal reference values for 24-hour excretion of UFC are 20–90 mg/24 hours. The majority of circulating cortisol (90% or more) at any time is bound to proteins, primarily cortisol-binding globulin (CBG). Plasma cortisol is thus in two pools—bound and free. In most circumstances this is of little concern, because as long as there are free binding sites, the relationship between bound and free cortisol remains relatively constant and measurements of total cortisol correlate well with free cortisol and hence biological availability. In the setting of high total cortisol concentrations, however, carrier proteins become saturated, leading to more rapid, nonlinear increases in the free cortisol pool. Under conditions in which the concentration of CBG changes, the equilibrium between bound and free cortisol also changes. Estrogen, for example, increases CBG, so that conditions of increased estrogen are associated with higher levels of CBG (e.g., pregnancy, use of oral contraceptives). When protein synthesis decreases (e.g., during chronic illness or in liver disease), CBG concentrations also tend to decrease (Rosner 1991). Under these conditions assay of free cortisol is needed to obtain an accurate picture of cortisol bioavailability. The assay of cortisol can be performed by several different methods, but radioimmunoassay (RIA) is most commonly used because it is rapid, reliable, and inexpensive. Assay of ACTH is methodologically more problematic. Because ACTH is a peptide and is cleaved in the plasma by peptidases, there are a number of different cleavage products in the circulation, some biologically active and some not. ACTH is most commonly measured by RIA and by immunoradiometric assay. Different RIAs measure different fragments, and therefore results of different assays cannot always be reliably compared, and they may also yield information that is biologically different. From a practical perspective, the clinician or clinical researcher measuring ACTH needs to be aware of several potential pitfalls when measuring ACTH. First, as noted above, values can be spuriously elevated by samples drawn after a painful stimulus. Conversely, improperly handled specimens (i.e., delayed handling, failure to chill

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specimens) will be spuriously low. Specimens to be compared should ideally be assayed together to reduce problems of interassay variability; if this is not possible there is at least an absolute requirement to use a single assay methodology to make reliable comparisons. Finally, because secretion is pulsatile and the half-life short, single time-point ACTH values are rarely meaningful.

Hypothalamic-Pituitary-Thyroid Axis Although disorders of the HPT axis are among the most common problems seen by internists, they are highly relevant for the practicing psychiatrist as well. Thyroid dysfunction can manifest itself in psychiatric symptoms, and psychiatric illness has been associated with abnormalities of the HPT axis (Jackson 1998; Rosner 1991). A complete description of the physiology and pathophysiology of the HPT axis is beyond the scope of this chapter; however, we briefly review the organization and function of the axis to provide a background against which its laboratory examination can be considered. Like glucocorticoid secretion, thyroid hormone secretion involves hypothalamic, pituitary, and end-organ elements. Thyrotropin-releasing hormone (TRH), a three–amino acid peptide, is secreted from the paraventricular nucleus of the hypothalamus and is carried in the portal circulation to the anterior pituitary. There it stimulates the release of thyroidstimulating hormone (TSH), a glycoprotein, from thyrotroph cells. TSH is carried in the peripheral blood to the thyroid gland, where it in turn stimulates secretion of the thyroid hormones tetraiodothyronine (T4) (thyroxine) and triiodothyronine (T3). T4 and some T3 are produced by the thyroid, but the predominant circulating hormone is T4, and most T3 is produced from peripheral conversion of T4 at the tissues by deiodination of the T4 outer ring. T4 can also be metabolized by deiodination of its inner ring, which results in the production of metabolically inactive reverse T3 (rT3). Regulation of the axis is dynamic, with circulating T4 levels feeding back at the pituitary to control TSH secretion (increased T4 levels inhibit TSH secretion, whereas decreased levels stimulate TSH secretion). Also like the HPA axis, the activity of the HPT axis is pulsatile and has a circadian rhythm. TSH secretion decreases in the afternoon and early evening and increases late at night and in the early hours of the morning. Thyroid function can become disordered at either extreme of function (hypoactivity and hyperactivity), and as with the HPA axis, pathology can occur at the level of the end-target gland (the thyroid) or the pituitary. Central (i.e., hypothalamic) hypothyroidism, though it does occur, is rare.

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Basal Measurement The appropriate evaluation of thyroid function in patients depends on their clinical presentation. With the advent of the sensitive assay for TSH (see “Assays” below), the following algorithm has been recommended (Klee and Hay 1987; Surks et al. 1990; Utiger 1995). In apparently euthyroid people in whom thyroid screening is indicated, the first step and the single best screening test of thyroid function is measurement of TSH. If TSH levels are within the normal range, no further testing need be done. If TSH levels are abnormally high (associated with hypothyroidism) or low (associated with hyperthyroidism), a further test to evaluate free T4 (FT4) concentration is indicated. Because T4 is largely bound to proteins in the plasma, the total plasma T4 concentration is not always an accurate reflection of the FT4 that is biologically active at the cellular level. Biologically meaningful measurement of T4 therefore requires either direct measurement of the FT4 concentration or measurement of total T4 and some measure of protein binding of T4 to allow calculation of the free thyroxine index (FTI). Therefore, in patients with illnesses in which thyroid dysfunction should be ruled out (including many psychiatric patients), a sensitive TSH test and either direct or estimated determination of FT4 is appropriate. In patients who present with clinical pictures suggestive of either hypothyroidism or hyperthyroidism, both TSH and either direct or estimated FT4 should be evaluated initially. T3 is not a good general measure of thyroid function because levels fluctuate rapidly and may reflect nonthyroidal factors. In particular, nonthyroidal illness is often associated with decreases in concentrations of T3 that result from decreased conversion of T4. Nonthyroidal illness is associated with a number of other abnormalities of thyroid hormones as well, which can include increased rT3, decreases in both T3 and T4 (the euthyroid sick syndrome), and, paradoxically, increases in T4 (Gow et al. 1986; Wartofsky and Burman 1982). These changes are thought to result from several different factors, which include alterations in protein binding due to changes in protein production as well as metabolic changes associated with the state of illness. Distinguishing true hypothyroidism from the euthyroid sick syndrome can be difficult; the most useful tools are probably determinations of TSH and FT4, but in severely ill patients even these may not provide definitive answers (Surks et al. 1990). Normal values for thyroid hormones are listed in Table 17–2.

Thyroid Antibodies The most common cause of hypothyroidism (outside of areas of endemic iodine deficiency) is autoimmune thyroiditis (Utiger 1995). Although a

486 TABLE 17–2.

Hormone

PSYCHONEUROENDOCRINOLOGY Normal values of pituitary-thyroid hormones at the National Institutes of Health Clinical Pathology Laboratory Normal values

Comments

Thyroxine 5–10 mg/dL Includes protein-bound hormone Free thyroxine 0.9–1.9 ng/dL Thyroid-stimulating hormone 0.4–4.6 mU/mL Diurnal rhythm, lowest in evening Triiodothyronine 88–162 ng/dL Includes protein-bound hormone Free triiodothyronine 250–550 pg/dL

variety of antibodies have been described, only two are commonly assayed in patients suspected of having autoimmune thyroiditis: antimicrosomal antibodies (also called antithyroid peroxidase antibodies) and antithyroglobulin antibodies. It is important to be aware that although these tests can provide confirmation of a presumptive diagnosis of autoimmune thyroiditis, they are not highly specific, and many healthy people, patients with nonthyroidal illnesses, and those with subclinical thyroid disease will also test positively for these antibodies.

Provocative Tests of Thyroid Function In contrast to the HPA axis, provocative tests of the HPT axis are not widely used. The TRH stimulation test, in which exogenous TRH is administered to subjects and response is measured by determining the increase in TSH secretion, has limited clinical value owing to the wide variability of response among individuals (Utiger 1995). It has been used as a psychiatric research tool, and it has been reported that 25%–30% of depressed patients have blunted responses to TRH (Joffe and Levitt 1993). However, these findings have also been reported in other psychiatric illnesses, and there are no generally accepted clinical psychiatric applications for the TRH stimulation test at this time.

Assays TSH Radioimmunoassays of TSH have been available for some years and have become the most widely available method for determining serum TSH levels. Early assays were not sensitive enough to distinguish between low normal TSH levels and those typical of hyperthyroidism. Second-generation assays extended the lower limits of detection to 0.1–0.2 mU/L, permit-

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ting identification of patients with mildly low TSH, whereas third-generation assays can reliably detect TSH levels as low as 0.01–0.02 mU/L and thus can be used to screen for both hyperthyroidism and hypothyroidism (Gow et al. 1986). TSH is quite stable, so special handling of samples is not required. When interpreting a low normal or borderline low value, it is therefore important to be aware of the assay being used. Clinicians should be aware that TSH is secreted with a circadian rhythm, reaching a nadir in the early evening and a peak in the early hours of the morning. Some commonly prescribed drugs can affect its concentration in the plasma, including levodopa and glucocorticoids, which inhibit its production, and perhaps most importantly thyroid hormone replacement, which inhibits TSH release by means of negative feedback.

T4 As noted above, T4 can be measured as total T4 or as FT4. When total T4 is measured, it is important to assess what portion is not bound to protein and hence is biologically available. A number of methodologies for measuring total T4 exist, including competitive protein binding assays, immunoassays, and enzyme assays. The most commonly used methodology, however, is probably RIA. Although RIAs vary in sensitivity, typical assays have lower limits of detection around 0.4 mg/dL (however, more sensitive assays are available) (Whitley et al. 1994b). As noted above, serum T4 levels should be measured together with an estimate of how much hormone is bound by proteins to estimate the percentage of FT4. This is commonly done using the T3 resin uptake test. In this procedure, radiolabeled T3 is added to serum, and then a resin that binds T3 is also added to the serum. Finally, the resin is separated out and the amount of T3 that has been bound to it is measured (T3 is used because it does not displace T4 already bound to protein and thus measures only open binding sites). This result is expressed as a percentage of the total T3 added. The difference between the total added T3 and the amount bound to the resin represents T3 bound to available protein binding sites in the serum. Often this result is expressed as a ratio of the percentage uptake in patient serum to the percentage uptake in a reference serum and is called the thyroid hormone binding ratio (THBR). The normal value for this ratio is an interval around 1.0; the width of the interval varies somewhat from one laboratory to another. The FTI, an estimate of FT4, is calculated from the T4 and THBR. As an example, consider the situation of an elevated T3 resin uptake (and hence an elevated THBR). This implies decreased available protein binding sites for thyroid hormone (more T3 than expected is binding to the resin because fewer protein sites are available to bind it). It can occur when

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protein production (primarily thyroxine-binding globulin) is low (fewer binding sites available), when thyroid hormone concentrations are increased (normal number of binding sites but fewer available because of increased T4 occupying them), or when another substance (e.g., a drug) competes for binding sites (normal number of binding sites but fewer available). In these situations, however, the serum T4 values will differ—in hyperthyroidism there is more T4 produced and circulating, and hence both THBR and serum T4 levels are higher and the FTI is high, whereas in the other two situations T4 is lower (production is adjusted to maintain homeostasis) while THBR is elevated and the FTI is normal. Some common conditions and the expected associated T4 values are shown in Table 17–3.

TABLE 17–3.

Common conditions that alter observed thyroxine (T4) and free thyroxine (FT4) concentrations

Condition Pregnancy, liver disease, drugs (estrogens, oral contraceptives, opiates) Genetic TBG deficiency, chronic illness,a drugs (salicylates, phenytoin, steroids) Exogenous T4 administration Exogenous T3 administration

Observed effect

Cause

T4 increased, FT4 normal

Increased thyroxine-binding globulin (TBG) production

T4 decreased, FT4 normal

Decreased TBG concentration or binding

T4 normal, FT4 Endogenous T4 replaced normal T4 decreased, Endogenous T4 suppressed FT4 decreased

a

Chronic illness may also lead to other changes in thyroid function.

Direct measurement of FT4 can be done by equilibrium dialysis (serum and a buffer are separated by a membrane that allows passage of FT4 but not protein, and after an incubation period equilibrium is reached and T4 in the protein-free dialysate is measured) or by RIA. For most purposes, the choice of measuring FT4 or T4 and a calculated FTI will depend on cost and convenience. T4 is stable, and no special handling of specimens is required. Many factors can influence measurement of thyroid hormones, including psychiatric illnesses. Physiologically, pregnancy is associated with increases in T4 levels due primarily to increased serum thyroxine-binding globulin (Glinoer et al. 1990). Illness, as noted earlier, can alter hormone metabolism, catabolic demands, and protein production, leading to both

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apparent and real abnormalities. Drugs that compete for protein binding sites (e.g., salicylates, phenytoin) or alter protein production (e.g., steroids, including glucocorticoids and estrogens) alter measured T4 levels (note, however, that changes in binding proteins do not affect the actual “metabolic state”). Exogenous administration of T4 or T3 suppresses thyroid production and release of hormone.

Gonadotropins and Sex Steroids Hypogonadotropic hypogonadism can accompany a number of conditions commonly encountered by psychiatrists, including drug abuse, liver disease associated with alcoholism, and obesity. It can also occur in illnesses such as anorexia nervosa and depression, perhaps related to HPA axis activation and CRH-induced suppression of gonadotropin release. In some women, phases of the menstrual cycle are associated with mood changes, and these changes appear to be linked to alterations in HPG regulation (Schmidt et al. 1998). Similarly, the menopause, with its attendant alterations in gonadal steroids, is associated with mood changes (Schmidt et al. 1997). A comprehensive evaluation of gonadotropins and sex steroids is outside the scope of usual psychiatric practice; however, questions related to gonadotropins and sex steroids arise commonly, and many patients receive psychiatric care in the setting of medical workup or treatment of problems involving the HPG axis (e.g., fertility or sexual problems, replacement estrogens). We restrict our focus to several basic elements and measurements likely to be encountered in the course of psychiatric practice, and again we note that it is important to keep in mind the distinction between research applications and those intended to guide clinical practice, which are more limited. Normal values for gonadotropins and sex steroids are listed in Table 17–4. The HPG axis consists of the hypothalamus, the pituitary, and the ovaries (in women) or the testes (in men). The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile fashion. This single releasing factor acts at the anterior pituitary to induce the release of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In women, the relative amounts of FSH and LH secreted in response to GnRH are modulated by feedback from circulating estrogen and progesterone and follow a cyclic pattern, whereas in men modulation also appears to be negative-feedback dependent but without a cyclic pattern. In men, FSH stimulates spermatogenesis and LH controls Leydig cell production of testosterone; in women FSH stimulates ovarian follicular

490 TABLE 17–4.

PSYCHONEUROENDOCRINOLOGY Normal values of pituitary-gonadal hormones at the National Institutes of Health Clinical Pathology Laboratory

Hormone Luteinizing hormone Male Female

Follicle-stimulating hormone Male Female

Estradiol Male Female

Progesterone Male Female

Normal values 6–17 mIU/mL Follicular: 3–20 mIU/mL Ovulatory: >35 mIU/mL Luteal: 3–22 mIU/mL Postmenopausal: >25 mIU/mL 7–20 mIU/mL Follicular: 6–23 mIU/mL Ovulatory: 18–46 mIU/mL Luteal: 2–19 mIU/mL Postmenopausal: >25 mIU/mL <50 pg/mL Follicular: 10–200 pg/mL Midcycle: 100–400 pg/mL Luteal: 15–260 pg/mL Postmenopausal: <50 pg/mL <0.4 ng/mL Follicular: 0.1–1.5 ng/mL Luteal: 2.5–28 ng/mL Postmenopausal: <0.2 ng/mL

Testosterone (total) Male Female

300–1,200 ng/dL 20–80 ng/dL

Testosterone (free) Male Female

9–30 ng/dL 0.3–1.9 ng/dL

growth and LH stimulates ovulation, luteinization of the ovarian follicle, and (together with FSH) sex steroid production.

Follicle-Stimulating Hormone and Luteinizing Hormone In men, LH and FSH levels are not associated with the cyclic variation characteristic of the menstrual cycle in women. Nonetheless, because the hormones are secreted in a pulsatile fashion, levels can vary significantly

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from one measurement to another. In women, both LH and FSH are secreted at various levels throughout the menstrual cycle. LH has a marked rise just before ovulation in midcycle, whereas FSH is highest at the beginning of the follicular phase, declines as the follicular phase progresses, and has another peak just before ovulation. During the onset of menopause, there is much variation as ovarian function becomes irregular and the pituitary is exposed to varying levels of negative feedback from ovarian sex steroids. In postmenopausal women (and in men and women with primary gonadal failure) levels of both LH and FSH are persistently elevated due to the lack of negative feedback from gonadal production of sex steroids. By contrast, in pituitary or hypothalamic hypogonadism, LH and FSH are hyposecreted. Thus, under different circumstances, similar LH and FSH levels in different patients may reflect healthy normal physiology or a pathophysiological process; interpretation requires knowledge of the clinical context. LH and FSH are stable in serum, and no special handling is required.

Testosterone Testosterone, the most important male sex steroid, is secreted with a diurnal rhythm, peaking early in the morning and declining in the evening. Like other steroids, the majority of testosterone is bound to proteins in the plasma. These include a specific binding protein called sex hormone– binding globulin (SHBG) (sometimes referred to as testosterone/estradiol–binding globulin), and albumin, which binds testosterone more weakly. Bound testosterone equilibrates with a smaller pool of free testosterone. As with other protein-bound hormones, the total plasma pool of testosterone is altered by conditions that affect protein levels and by substances that compete for protein binding sites. The best measure of bioavailable testosterone is probably the pool of free testosterone and albumin-bound testosterone, because the latter is relatively weakly bound (Whitley et al. 1994a). Total testosterone, free testosterone, and bioavailable testosterone (i.e., free and albumin-bound testosterone) can all be measured.

Estrogen and Progesterone Although there are a number of circulating estrogens, the most important are estradiol, estriol, and estrone. The major portion of circulating estrogens in women is made up of estradiol, which is secreted by the ovary. Other estrogens present in significant quantities include estrone, which is a metabolite of estradiol, and estriol. In pregnant women, the placenta

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secretes estriol; in nonpregnant women circulating estriol is derived from metabolism of estradiol. For most purposes in nonpregnant women assessment of estrogens can be accomplished by measurement of estradiol. Although estradiol is bound to SHBG and albumin, its affinity for SHBG is lower than that of testosterone, and for clinical purposes it is not generally necessary to measure plasma free estradiol (Winters 1994). Estradiol varies with menstrual cycle, rising through the follicular phase to a peak just before ovulation, and falling sharply toward the end of the luteal phase. Estrogen is stable but has a tendency to adsorb to plastic tubes and so should be collected in glass (Wartofsky and Burman 1982). Unlike estrogen, progesterone is present in significant amounts in nonpregnant women only during the luteal phase. Circulating progesterone is bound by proteins, primarily CBG (Whitley et al. 1994a), but free progesterone is not routinely assayed. Progesterone is stable and does not require special collection procedures.

Growth Hormone Growth hormone is an anterior pituitary hormone that promotes linear growth as well as other metabolic functions, some immediate and some delayed (e.g., decrease in blood glucose levels acutely, reduction in body fat, increase in nitrogen balance). Its secretion is controlled by two hypothalamic factors: growth hormone–releasing hormone, which induces pituitary growth hormone release, and somatostatin, which inhibits pituitary growth hormone release. Many of its actions are mediated through a second hormone, insulin-like growth factor I (IGF-I). Although psychiatrists will not generally be the primary physicians treating or investigating disorders of growth hormone, some children with severe psychosocial stressors experience suppression of growth hormone secretion and delayed growth and may initially come to psychiatric attention or require psychiatric care as part of overall treatment. Growth hormone may also be of importance in depressive disorders, because emerging data suggest that bone mineral density, the normal regulation of which is linked to growth hormone, is decreased in depressed patients (Michelson et al. 1996b). Evaluation of growth hormone usually requires both basal and stimulated measurement. Single samples of growth hormone do not provide an accurate picture of pituitary growth hormone secretory activity, because secretion is pulsatile and values can vary widely. Basal function is therefore best assessed by frequent, multiple samples, overnight if possible. Plasma IGF-I has not been shown to be well correlated with tissue activity, and therefore is not a widely used measure (however, in patients with growth hormone receptor abnormalities resulting in Laron dwarf-

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ism, plasma growth hormone levels are high and IGF-I levels are low, and in patients with acromegaly IGF-I values are high). Typically patients with suspected growth hormone abnormalities undergo provocative testing to assess pituitary growth hormone release. Many agents—including arginine, clonidine, levodopa, and insulin—induce growth hormone release and are used to assess the functional capacity of the pituitary somatotroph. Normal responses are generally defined as pituitary secretion increasing plasma growth hormone concentrations to some minimum threshold whose specific value depends on the particular provocative agent and the growth hormone assay used.

Prolactin Prolactin is a 199–amino acid peptide hormone secreted by the anterior pituitary. Its best-characterized physiological action is the stimulation and maintenance of lactation at the breast. Prolactin secretion is tonically inhibited by dopamine from tuberoinfundibular neurons; consequently, conditions that interfere with dopamine secretion can lead to increases in prolactin secretion and potentially galactorrhea. This can be particularly important in psychiatric patients who take drugs that interfere with dopamine secretion. Although many drugs have been associated with galactorrhea, antipsychotic agents, many of which have specific effects blocking dopamine receptors, are particularly relevant to psychiatric practice (for some newer agents, particularly clozapine and olanzapine, changes in prolactin have been demonstrated to be minimal [Breier et al. 1999; Tollefson and Kuntz 1999]). One case report showed a strong correlation between plasma prolactin levels and severity of galactorrhea (Gioia and Asnis 1988), and the authors suggested obtaining weekly plasma prolactin levels as a way of adjusting medication dosage. However, serum prolactin levels vary widely in patients with galactorrhea (Frantz and Wilson 1992), and the usefulness of plasma prolactin levels in neuroleptic-induced galactorrhea remains uncertain. Although they were at one time proposed for diagnostic use, prolactin stimulation and suppression tests are not generally favored by endocrinologists in current practice because the results are too variable to be generally useful (Frantz and Wilson 1992).

Summary Over the past several decades, rapid growth in the knowledge of neuroendocrinology and the involvement of neuroendocrine factors in normal brain functioning as well as psychiatric illness has opened many

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exciting new lines of inquiry. One of these has been the effort to develop laboratory measures that can inform diagnosis and guide clinical decision making. As discussed in this chapter, much progress has been made, and for some illnesses such as depression it seems likely that it will soon be possible to match different neuroendocrine patterns with specific pathophysiologies. As yet, however, the primary role of neuroendocrine testing in the clinical practice of psychiatry remains largely in distinguishing primary psychiatric illness from other conditions that can cause psychiatric symptoms. The challenge that lies ahead is to further expand and refine the knowledge of the neurobiology of psychiatric illnesses and the therapeutic armamentarium. In so doing it will be possible to develop tests that can reliably differentiate the underlying pathology of similar phenotypes and that can inform clinical interventions.

References Aardal E, Holm AC: Cortisol in saliva—reference ranges and relation to cortisol in serum. Eur J Clin Chem Clin Biochem 33(12):927–932, 1995 Amsterdam JD, Maislin G, Berwish N, et al: Enhanced adrenocortical sensitivity to submaximal doses of cosyntropin (alpha 1-24-corticotropin). Arch Gen Psychiatry 46:550–554, 1989 Amsterdam JD, Winokur A, Abelman E, et al: Cosyntropin (ACTH alpha 1-24) stimulation test in depressed patients and healthy subjects. Am J Psychiatry 140:907–909, 1993 Arana GW, Baldessarini RJ: Development and clinical application of the dexamethasone suppression test in psychiatry, in Hormones and Depression. Edited by Halbreich U. New York, Raven Press, 1987, pp 113–133 Bilezikjian VM, Blount AL, Vale WW: The cellular actions of vasopressin in corticotrophs of the anterior pituitary: resistance to glucocorticoid actions. Mol Endocrinol 1:451–458, 1987 Breier AF, Malhotra AK, Su TP, et al: Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 156:294–298, 1999 Calogero AE, Gallucci WT, Bernardini R, et al: Effect of cholinergic agonists and antagonists on rat hypothalamic corticotropin-releasing hormone secretion in vitro. Neuroendocrinology 47:303–308, 1988a Calogero AE, Gallucci WT, Chrousos GP, et al: Catecholamine effects upon rat hypothalamic corticotropin-releasing hormone secretion in vitro. J Clin Invest 82:839–846, 1988b Calogero AE, Bernardini R., Margioris AN, et al: Effects of serotonergic agonists and antagonists on corticotropin-releasing hormone secretion by explanted rat hypothalami. Peptides l0:189–200, 1989

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Chrousos GP, Gold PW: The concepts of stress and stress system disorders. JAMA 267:1244–1252, 1992 Dallman MF: Control of adrenocortical growth in vivo. Endocr Res 10:213–242, 1984–1985 DeBold CR, Sheldon WR, DeCherney GS, et al: Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest 73:533–538, 1984 Demitrack MA, Dale JK, Gold PW, et al: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 73:1224–1230, 1991 Deuster PA, Petrides JS, Singh A, et al: Endocrine response to high-intensity exercise: dose-dependent effects of dexamethasone. J Clin Endocrinol Metab 85:1066–1073, 2000 Evans P, Peters J, Dyas J, et al: Salivary cortisol levels in true and apparent hypercortisolism. Clin Endocrinol (Oxf) 20:709–715, 1984 Fish HR, Chernow B, O’Brian JT: Endocrine and neurophysiologic responses of the pituitary to insulin-induced hypoglycemia. Metabolism 35:763–780, 1986 Frantz A, Wilson G: Endocrine disorders of the breast, in Williams Textbook of Endocrinology, 8th Edition. Edited by Wilson J, Foster D. Philadelphia, PA, WB Saunders, 1992, pp 953–976 Gispen-de Wied CC, Jansen LM, Wynne HJ, et al: Differential effects of hydrocortisone and dexamethasone on cortisol suppression in a child psychiatric population. Psychoneuroendocrinology 23:295–306, 1998 Glinoer D, De Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 71:276–287, 1990 Gioia P, Asnis G: Serial plasma levels in neuroleptic-induced galactorrhea: a case report. J Clin Psychiatry 49:29–31, 1988 Gold PW, Loriaux DL, Roy A, et al: Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N Engl J Med 314:1329–1335, 1986 Gold PW, Goodwin FK, Chrousos GP: Clinical and biochemical manifestations of depression, I: relation to the neurobiology of stress. N Engl J Med 319: 348–353, 1988 Gow SM, Elder A, Caldwell G, et al: An improved approach to thyroid function testing in patients with non-thyroidal illness. Clin Chim Acta 158:49–58, 1986 Halbreich U, Zumoff B, Kream J, et al: The mean 1300–1600 h plasma cortisol concentration as a diagnostic test for hypercortisolism. J Clin Endocrinol Metab 54:1262–1264, 1982 Jackson IM: The thyroid axis and depression. Thyroid 8:951–956, 1998 Joffe RT, Levitt AJ: The thyroid and depression, in The Thyroid Axis and Psychiatric Illness. Edited by Joffe RT, Levitt AJ. Washington, DC, American Psychiatric Press, 1993, pp 195–253

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Klee GG, Hay ID: Assessment of sensitive thyrotropin assays for an expanded role in thyroid function testing: proposed criteria for analytic performance and clinical utility. J Clin Endocrinol Metab 64:461–471, 1987 Luger A, Deuster P, Kyle SB, et al: Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. Physiologic adaptations to physical training. N Engl J Med 316:1309–1315, 1987 Martinelli CE, Sader SL, Oliveira EB, et al: Salivary cortisol for screening of Cushing’s syndrome in children. Clin Endocrinol (Oxf) 51:67–71, 1999 Michelson D, Stone L, Galliven E, et al: Multiple sclerosis is associated with alterations in hypothalamic pituitary adrenal axis function. J Clin Endocrinol Metab 79:848–853, 1994 Michelson D, Altemus M, Galliven E, et al: Naloxone-induced pituitary-adrenal activation does not differ in patients with depression, obsessive compulsive disorder and healthy controls. Neuropsychopharmacology 15:207–212, 1996a Michelson D, Stratakis C, Hill L, et al: Bone mineral density in women with depression. N Engl J Med 335:1176–1181, 1996b Munck A, Guyre PM, Holbrook NJ: Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5:25–44, 1984 Naitoh Y, Fukata J, Toiminaga T, et al: Interleukin-6 stimulates the secretion of adrenocorticotrophic hormone in conscious, free-moving rats. Biochem Biophys Res Commun 155:1459–1463, 1988 Nelson JC, Davis JM: DST studies in psychotic depression: a meta-analysis. Am J Psychiatry 154:1497–1503, 1997 Nieman LK, Loriaux DL: Corticotropin-releasing hormone: clinical applications. Annu Rev Med 40:331–339, 1989 Orth DJ: Medical progress: Cushing’s syndrome. N Engl J Med 332:791–803, 1995 Orth D, Kovacs W, DeBold C: The adrenal cortex, in Williams Textbook of Endocrinology, 8th Edition. Edited by Wilson J, Foster D. Philadelphia, PA, WB Saunders, 1992, pp 489–620 Payet N, Leboux JG, Isler H: Effect of ACTH on the proliferative and secretory activities of the adrenal glomerulosa. Acta Endocrinol (Copenh) 93:365– 374, 1980 Ribeiro SC, Tandon R, Grunhaus L, et al: The DST as predictor of outcome in depression: a meta-analysis. Am J Psychiatry 150:1618–1629, 1993 Rosner W: Plasma steroid-binding proteins. Endocrinol Metab Clin North Am 20: 697–720, 1991 Salata RA, Jarrett DB, Verbalis JG, et al: Vasopressin stimulation of adrenocorticotropin hormone (ACTH) in humans. J Clin Invest 81:766–774, 1988 Sapolsky R, Rivier C, Yamamoto G, et al: Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238:522–524, 1987 Schmidt PJ, Roca CA, Bloch M, et al: The perimenopause and affective disorders. Semin Reprod Endocrinol 15:91–100, 1997

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Schmidt PJ, Nieman LK, Danaceau MA, et al: Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 338:209–216, 1998 Singh A, Petrides JS, Gold PW, et al: Differential hypothalamic-pituitary-adrenal axis reactivity to psychological and physical stress. J Clin Endocrinol Metab 84:1944–1948, 1999 Surks MI, Chopra IJ, Mariash CN: American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA 263:1529–1532, 1990 Tollefson GD, Kuntz AJ: Review of recent clinical studies with olanzapine. Br J Psychiatry Suppl 37:30–35, 1999 Tyrrel J, Brooks R, Fitzgerald P, et al: Cushing’s disease: selective transsphenoidal resection of pituitary microadenomas. N Engl J Med 298:753–757, 1978 Utiger RD: The thyroid: physiology, thyrotoxicosis, hypothyroidism and the painful thyroid, in Endocrinology and Metabolism, 3rd Edition. Edited by Felig F, Baxter JD, Frohman LA. New York, McGraw-Hill, 1995, pp 435– 520 Wartofsky L, Burman K: Alterations in thyroid function in patients with systemic illness: the “euthyroid sick syndrome.” Endocr Rev 3:164–217, 1982 Whitley RJ, Meikle AW, Watts NB: Endocrinology: gonadal steroids, in Tietz Textbook of Clinical Chemistry, 2nd Edition. Edited by Burtis CA, Ashwood ER. Philadelphia, PA, WB Saunders, 1994a, pp 1843–1886 Whitley RJ, Meikle AW, Watts NB: Endocrinology: the thyroid, in Tietz Textbook of Clinical Chemistry, 2nd Edition. Edited by Burtis CA, Ashwood ER. Philadelphia, PA, WB Saunders, 1994b, pp 1698–1739 Winters SJ: Endocrine evaluation of testicular function. Endocrinol Metab Clin North Am 23:709–723, 1994 Yanovski JA, Cutler GB Jr, Chrousos GP, et al: Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration: a new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA 269: 2232–2238, 1993 Zobel AW, Yassouridis A, Frieboes RM, et al: Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression. Am J Psychiatry 156:949–951, 1999

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Chapter 18 Endocrine Imaging in Depression Kishore M. Gadde, M.D. K. Ranga R. Krishnan, M.D.

O

ver the years, researchers have made use of various approaches—such as genetic linking studies; measurement of concentrations of various neurochemicals such as neurotransmitters, neuropeptides, and their metabolites; neuroendocrine challenge paradigms; and correlates of responses to pharmacotherapy—in pursuit of furthering their knowledge of the neurobiological basis of psychiatric disorders. Advances in imaging techniques in the past decade have provided additional tools that facilitated better and dependable visualization of anatomical structures suspected to be involved in the etiopathology of various mental disorders. In this chapter, we focus on anatomical correlates of affective disorders and attempt to tie these findings to the available data from psychoneuroendocrinologic investigations.

Hypothalamic-Pituitary-Adrenal Axis One of the most well-studied biological systems in major depression is the hypothalamic-pituitary-adrenal (HPA) axis (Gold et al. 1984). Hyperactivity of the HPA axis has been recognized in depressed patients through findings of increased cortisol levels in plasma (Sachar et al. 1970) and cerebrospinal fluid and in 24-hour urine samples (Carroll et al. 1976); resistance to suppression of cortisol, adrenocorticotropic hormone (ACTH), and b-endorphin by dexamethasone (Carroll et al. 1981; Krishnan et al. 1990b; Reus et al. 1982; Sherman et al. 1984); increased

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concentrations of corticotropin-releasing hormone (CRH) in cerebrospinal fluid (Nemeroff and Evans 1984); and blunted ACTH response to ovine CRH (Gold et al. 1984). Exogenous administration of corticosteroids has been demonstrated to induce profound mood changes in healthy persons without psychiatric histories (Su et al. 1993; Wolkowitz 1994). Conversely, drugs that lower cortisol levels, such as ketoconazole and metyrapone, have been found to produce varying degrees of moodenhancing effects in patients with Cushing’s syndrome and in individuals with major depression (reviewed by Wolkowitz and Reus 1999). ACTH, released by the anterior pituitary, stimulates cortisol secretion from the adrenal cortex, and ACTH itself is regulated by the hypothalamic peptide CRH. In addition, it is known that the hippocampus, which has an abundance of glucocorticoid receptors (De Kloet and Reul 1987), exerts a significant feedback inhibition of the HPA axis (Jacobson and Sapolsky 1991). Therefore, if one were to investigate anatomical correlates of endocrine dysregulation, the organs and areas of interest would be the adrenal, pituitary, hypothalamus, and hippocampus. To our knowledge, there are no specific imaging studies of the hypothalamus that examined differences between depressed and nondepressed human subjects.

Adrenal Pathology in Depression Each adrenal gland lies bilaterally in the perirenal space. The weight of the normal adrenal, from autopsy reports, varies considerably (Quinian and Berger 1933). On the computed tomographic scan, the adrenal glands show an inverted Y configuration. Computed tomography is an excellent technique—and is probably the single best and most cost-effective technique—for imaging the adrenals (Dunnick 1988). Routine radiographic examinations use 1-cm sections through the whole gland, and slices of 5 mm thickness provide even better detail of pathology when smaller-size pathology is suspected to be present. Neuroendocrine challenge studies have noted that a high dose of ACTH results in a greater-than-normal cortisol response in depressed patients (Kalin et al. 1987); however, this was not the case when a low dose of ACTH was administered (Krishnan et al. 1990b), suggesting that sensitivity of the adrenal cortex to the pituitary hormone is not altered in depression. In animals, hypertrophy of all layers of the adrenal cortex, but not the adrenal medulla, occurs after long-term stimulation with ACTH (Malendowicz 1986). These observations, when taken together with the

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finding of increased weight of adrenals in suicide victims compared with those of subjects that died of causes such as automobile accidents and cardiovascular events (Zis and Zis 1987), raised the possibility of finding hyperplasia or hypertrophy of adrenal glands in depressed individuals. Amsterdam and colleagues (1987), in a pilot study, found a significant enlargement of the adrenal gland, as measured by computed tomography, in 8 of 16 patients with depression. In this study, no relationship was found between 9:00 A.M. serum cortisol levels and adrenal volume. Our group took this a step further and conducted a computed tomographic imaging study of adrenals, using a high-resolution GE 9800 scanner (Nemeroff et al. 1992). The sample size in this study was 38 depressed patients and 11 nondepressed control subjects. Contiguous sections of 5 mm thickness were obtained through the adrenal glands without using contrast material. Assessments consisted of 1) global ratings by two experienced radiologists who were blind to the diagnosis and 2) calculation of adrenal volume. The radiologists globally rated the adrenal glands as normal or enlarged. Calculation of the adrenal volume was done by means of a systematic sampling method (Gundersen and Jensen 1987), which had been previously applied to the measurement of various brain structures (Krishnan et al. 1990a). The radiologists judged the adrenals of 12 of the 38 depressed patients as being enlarged, whereas none of the control subjects were considered to have adrenal enlargement (P<0.046, Fisher exact test). The adrenal volumes of depressed patients (14±5.9 mL) were significantly larger than those of the control subjects (8.9±2.5 mL; t test, P<0.0076; Wilcoxon mean rank test, P<0.034). The adrenal enlargement in this study was thought to be most likely due to hypertrophy or hyperplasia of the adrenal cortex rather than enlargement of the medulla; because the medulla constitutes a very small portion of the gland, it would have to increase enormously in size to account for the overall enlargement of the gland, seen in this study. Also, adrenocortical cells are known to be capable of enlargement as well as proliferation, whereas the adrenal medullary cells are not known to increase in size or multiply except when there is a neoplastic change. Adrenal gland size in this study was not correlated with dexamethasone suppression test (DST) results or depression severity. Hypercortisolemia is one of the most consistent findings in depression. In recent years, investigators have grappled with the question of whether hypercortisolemia has a role in the etiology of mood disturbance or whether it is a secondary response such as a compensatory mechanism—and if it is a compensatory mechanism, whether it is state dependent or a trait phenomenon. It has been observed (Nemeroff and Evans 1984) that persistent DST nonsuppression after a patient’s clinical recov-

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ery from an acute depressive episode is associated with increased risk of relapse. Taken together with the finding of persistent elevation of 24-hour urinary free cortisol in depressed patients after clinical recovery (Kathol and Gehris 1985), it appeared that patients with major depression might not have normalization of some of their neurohormonal regulatory mechanisms even after clinical improvement. Rubin and associates (1995) measured adrenal volumes using magnetic resonance imaging (MRI) in 11 depressed patients and 11 control subjects; both groups included 2 adolescents each. Images were obtained in the axial plane with 5 mm thickness. The depressed patients’ adrenals were scanned during their illness and during full remission. The patients had a mean Hamilton Rating Scale for Depression score of 25.4±4.6 at the time of first imaging, and 2.5±2.5 when the second set of images was obtained. When clinically depressed, the patients had significantly larger adrenal volumes (median, 5.7 mL) compared with the control group (median, 3.4 mL; P<0.02). The log-transformed data of adrenal volumes were presented as median and first and third quartiles. The patient group was found to have a significantly larger adrenal volume when depressed (median, 5.7 mL) than while in remission (median, 2.9 mL; P<0.008). There was no difference between the adrenal volumes of the patients in remission and the control subjects. There were no differences in the basal plasma cortisol levels among the three groups. There were no meaningful relationships between adrenal gland volume and basal cortisol and ACTH levels; neither was there a close correlation between adrenal volume, and cortisol and ACTH responses to ovine CRH. Although it may be rather puzzling that no relationship could be established between functional hyperactivity of the adrenal gland in depression and the gland’s enlargement in such a state, in the studies discussed here, some investigators have argued that the adrenal size reflects the adrenal capacity rather than plasma cortisol concentration at that particular time (Nemeroff et al. 1993). Although there may not be compelling reasons for routine adrenal imaging in psychiatric clinical practice, a clinician should not quickly conclude that an incidental finding of adrenal enlargement in a depressed patient is representative of Cushing’s syndrome in the absence of classic clinical symptoms and signs of this endocrine disorder; enlargement of the adrenals is seen in primary depression as well. Clinicians should also be aware that major depression is extremely common in patients with Cushing’s syndrome (Loosen et al. 1992), and as many as 80% of Cushing’s syndrome patients acknowledge suicidal ideation. Although hypercortisolemia is a common finding in Cushing’s syndrome as well as in primary depression, serum cortisol levels are not generally as high in pri-

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mary depression as in Cushing’s syndrome (Gadde and Krishnan 1994). In addition, adrenal enlargement appears to be of a greater magnitude in patients with Cushing’s syndrome compared with those presenting with primary depression. However, there have been no direct comparisons, and some depressed patients have been found to have adrenal enlargement of similar magnitude to that observed in patients with Cushing’s syndrome.

Pituitary Pathology in Depression The pituitary is a small gland that lies in the sella turcica at the base of the brain, connected to the hypothalamus by the pituitary stalk. The gland is about 1 cm in diameter and weighs 0.5–1 g. The volume of the pituitary gland in a living individual can be estimated with MRI technology using sagittal and coronal sections through the gland. Numerous neuroendocrine investigators have reported that ACTH secretion is increased in depressed patients, and this appears to be in response to hypersecretion of CRH (Gold et al. 1984). Metyrapone, a drug that inhibits 11b-hydroxylase and leads to decreased serum cortisol level, has been given orally or intravenously in clinical neuroendocrine experiments to assess the ability of the pituitary to enhance its secretion of ACTH when cortisol synthesis is inhibited. In depressed patients, after metyrapone administration, ACTH response to CRH was found to be greater than in nondepressed control subjects (Lisansky et al. 1989). Similarly, exaggerated ACTH response to CRH was observed in depressed patients after administration of dexamethasone (Holsboer et al. 1987). In animal experiments, it has been demonstrated that with short-term administration of CRH (Westlund et al. 1985), there is enlargement of pituitary corticotrophs, whereas long-term administration of this peptide results in an increase in numbers of these adenohypophyseal cells that secrete ACTH (Gertz et al. 1987). When taken together, the findings described above raised a strong suspicion that an enlargement of the pituitary might be found in depressed patients. This prompted Krishnan et al. (1991) to conduct an imaging study of pituitary size in depression. This study included 19 patients and 19 control subjects. Sixteen patients had unipolar depression and 3 had bipolar depression, and 14 of the 19 patients had recurrent depression. In this MRI study, the midsagittal T1 image centered around the pituitary stalk was used to measure the central height, maximum length, and crosssectional area of the pituitary, a method previously applied by Lemort et

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al. (1988). The coronal T1 image through the pituitary stalk was used to measure the maximum width of the gland. Estimates of the volume of the pituitary were made by applying the same method used by Gonzalvez et al. (1988). Depressed patients had significantly greater pituitary cross-sectional area (43±10 mm2) than did control subjects (32±9 mm2; P<0.0009). Depressed patients also had a significantly larger pituitary volume (577.5±167 mm3) compared with nondepressed control subjects (408.4±172 mm3; P<0.0007) in this study (Krishnan et al. 1991). The increased volume most likely reflected increase in the size of the anterior pituitary, because the posterior pituitary is a neural tissue composed mainly of glial-like cells called pituicytes, and the only conditions that are expected to enlarge the size of this tissue would be extremely rare neuroendocrine tumors. A difference in pituitary length was also observed, with depressed patients having a greater length of the pituitary (P<0.04). The next step was to study whether there was a relationship between the observed pituitary anatomical changes and DST findings. Hence, another experiment was conducted in our laboratory in which 24 patients (17 females and 7 males) with depression underwent the standard DST; their pituitary volumes were estimated using 3-mm sagittal slices (Axelson et al. 1992). In this study, pituitary volume was measured directly from high-quality hard copies of magnetic resonance images instead of estimating it using linear parameters. After determination of point counts for each sagittal image of the pituitary, the volume was calculated using Cavalieri’s (1966) systematic sampling theorem, with the following formula: Volume=(scan plane thickness)´(number of points)´(area of square on lattice grid)´(magnification factor)2

This study showed a significant positive correlation, after adjusting for age and sex, between pituitary size and 11:00 P.M. postdexamethasone plasma cortisol concentration. A consistent observation in the magnetic resonance studies of the pituitary is that the gland’s volume tends to get smaller with age (Axelson et al. 1992; Lurie et al. 1990), and therefore it is important that an adjustment be made in this regard when comparing pituitary volumes between any diagnostic groups.

Pituitary Pathology in Eating Disorders In addition to affective disorders, the other group of psychiatric conditions in which hypothalamic-pituitary dysfunction has been frequently

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observed is eating disorders (Newman and Halmi 1988). In a preliminary MRI study in our laboratory, Doraiswamy and associates (1990) reported smaller cross-sectional area and height of the pituitary in patients with eating disorders (8 with anorexia and 10 with bulimia). These findings were confirmed in a subsequent study (Doraiswamy et al. 1991) with a larger sample size of 26 patients (all but one were female) with eating disorders (12 with bulimia and 14 with anorexia) and 14 control subjects. Patients with eating disorders were noted to have smaller pituitary crosssectional area (those with anorexia, 36.6±8 mm2; those with bulimia, 37.6±6 mm2; control subjects, 48±11 mm2; P<0.0015) and smaller pituitary height (those with anorexia, 5.1 ± 1 mm; those with bulimia, 5.3±1 mm; control subjects, 6.5±1 mm). There was an inverse relationship between the duration of eating disorder and pituitary size, suggesting that with a prolonged course of anorexia or bulimia, structural changes in the pituitary are likely. However, more studies are needed to confirm these data and to address further questions, such as whether such changes are reversible.

Hippocampal Changes in Depression Glucocorticoid receptors are densely distributed in the hippocampus (Jacobson and Sapolsky 1991; Stumpf and Sar 1975), and the type II glucocorticoid receptor has been implicated in the mediation of responses to stress (De Kloet and Reul 1987). Sapolsky and McEwen (1988) showed that there is a gradual deterioration of hippocampal feedback inhibition of the HPA axis due to downregulation of glucocorticoid receptors from repeated stress. Landfield and Eldridge (1991) suggested that the normal downregulatory process of glucocorticoid receptors in the hippocampus is impaired with aging, due to a hypercortisol state. This failure of adaptation may explain the increased vulnerability of elderly persons to depression. In Cushing’s syndrome, which is manifested by a very high incidence of depression, it was noted that hippocampal volume correlated negatively with plasma cortisol levels (Starkman et al. 1992). To determine if there are anatomical changes in the hippocampus, Axelson and associates (1993) in our laboratory compared hippocampal volumes in 19 depressed patients and 30 nondepressed control subjects using MRI. Contiguous 5-mm-thick, T1-weighted coronal images were obtained and the volume of the amygdala-hippocampal complex (AHC) was measured, applying a systematic sampling method, which was previously used. No attempt was made to separate the hippocampus from the

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amygdala. The uncus, cornu ammonis, dentate gyrus, fimbria, and subiculum were included in the measurement. The two investigators who rated AHC volumes were blind to the diagnoses and to endocrine data. No differences were found in hippocampal volume between depressed patients and nondepressed control subjects. In this study, the patients were also given the standard DST. There was no difference between DST suppressors and DST nonsuppressors in their left or right hippocampal volumes. Also, there were no relationships between the peak postdexamethasone cortisol level at 3:00 P.M. or 11:00 P.M. and either left or right hippocampal volume. Age was negatively correlated with both left and right AHC volumes. A relationship was observed between left hippocampal volume and postdexamethasone cortisol concentration at 11:00 P.M., after covarying for age and sex. In general, the results of this study provided limited support for the hypothesis of Sapolsky and McEwen (1988) regarding a key role for the hippocampus in the hypersecretory state of glucocorticoids in major depression. The finding of reduced hippocampal volumes was noted even after resolution of a depressive episode. Sheline et al. (1999) studied 24 women with a history of depression and found a significant inverse correlation between hippocampal volume and total lifetime duration of depression. There was no significant correlation between age and hippocampal volume in either the patients or the matched control subjects in this study. Interestingly, decreased hippocampal volume and increased pituitary volume have been noted in patients with alcohol dependence also (Beresford et al. 1999). In light of the knowledge that elevated cortisol levels are associated with depressive symptoms as well as cognitive impairments (Sapolsky and McEwen 1988), O’Brien et al. (1996) examined this issue further and found an inverse relationship between hippocampal volume and postdexamethasone cortisol levels in patients with Alzheimer’s disease and suggested that hippocampal damage might explain high rates of abnormal DST results in Alzheimer’s disease.

Summary Adrenal enlargement as a finding in major depression has been replicated, and the changes appear to be state dependent. Pituitary enlargement has been observed in patients with major depression. The pituitary enlargement may be secondary to altered secretion or responsiveness of one or more of the following: corticotropin (ACTH),

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thyrotropin (thyroid-stimulating hormone), and growth hormone. Further studies on pituitary size and psychoneuroendocrine correlates are needed to help understand these aspects more precisely. It is not known whether pituitary size returns to normal after resolution of the acute psychiatric illness. It might be interesting to examine whether endocrine anatomical abnormalities exist in family members of patients with depression. Unlike the increased adrenal volume, which seems to resolve after remission from depression, hippocampal volume loss seems to persist. Explanation for the observed hippocampal volume loss with prolonged history of depression may include repeated stress-induced hypercortisolemia, reduction in neurogenesis, and increased vulnerability to glutamate neurotoxicity (Sheline 2000). The pineal gland and the thyroid are two other structures that have been implicated in depression, and it would be worthwhile to investigate if these structures undergo anatomical changes in depression.

References Amsterdam JD, Marinelli DL, Arger P, et al: Assessment of adrenal gland volume by computed tomography in depressed patients and healthy volunteers: a pilot study. Psychiatry Res 21:384–387, 1987 Axelson DA, Doraiswamy PM, Boyko OB, et al: In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: relationship to dexamethasone suppression test results in patients. Psychiatry Res 46:63–70, 1992 Axelson DA, Doraiswamy PM, McDonald WM, et al: Hypercortisolemia and hippocampal changes in depression. Psychiatry Res 47:163–173, 1993 Beresford T, Arciniegas D, Rojas D, et al: Hippocampal to pituitary volume ratio: a specific measure of reciprocal neuroendocrine alterations in alcohol dependence. J Stud Alcohol 60:586–588, 1999 Carroll BJ, Curtis GC, Mendels J: Neuroendocrine regulation in depression, II: discrimination of depressed from nondepressed patients. Arch Gen Psychiatry 33:1051–1058, 1976 Carroll BJ, Feinberg M, Greden JF, et al: A specific laboratory test for the diagnosis of melancholia: standardization, validation, and clinical utility. Arch Gen Psychiatry 38:15–22, 1981 Cavalieri B: Deometra delqi Indivisibili. Turin, Italy, Unione tipografo Editrice, 1966 De Kloet ER, Reul JMHM: Feedback action and tonic influence of corticosteroids on brain function: a concept arising from the heterogeneity of brain receptor systems. Psychoneuroendocrinology 12:83–105, 1987

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Doraiswamy PM, Krishnan KRR, Hussain MM, et al: A brain magnetic resonance imaging study of pituitary gland morphology in anorexia nervosa and bulimia. Biol Psychiatry 28:110–116, 1990 Doraiswamy PM, Krishnan KRR, Boyko OB, et al: Pituitary abnormalities in eating disorders: further evidence from MRI studies. Prog Neuropsychopharmacol Biol Psychiatry 15:351–356, 1991 Dunnick NR: The adrenal gland, in Radiology: Diagnosis-Imaging-Intervention. Edited by Taveras JM, Ferrucci JT. Philadelphia, PA, JB Lippincott, 1988, pp 16–22 Gadde KM, Krishnan KRR: Endocrine factors in depression. Psychiatr Ann 24: 521–524, 1994 Gertz BJ, Contreras LN, McComb DJ, et al: Chronic administration of CRF increases pituitary corticotroph numbers. Endocrinology 120:381–388, 1987 Gold PW, Chrousos G, Kellner C, et al: Psychiatric implication of basic and clinical studies of corticotrophic releasing factor. Am J Psychiatry 141:619–624, 1984 Gonzalvez JG, Elizando G, Salvidor D: Pituitary gland growth during normal pregnancy: an in vivo study using magnetic resonance imaging. Am J Med 85:217–220, 1988 Gundersen HJ, Jensen EB: The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263, 1987 Holsboer F, Van Bardeleben U, Widemann, et al: Serial assessment of corticotrophin-releasing hormone response after dexamethasone in depression. Biol Psychiatry 22:228–234, 1987 Jacobson L, Sapolsky RM: The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenal axis. Endocr Rev 12:118–134, 1991 Kalin NH, Dawson G, Tariot P, et al: Function of the adrenal cortex in patients with major depression. Arch Gen Psychiatry 44:233–240, 1987 Kathol RG, Gehris T: Persistent elevation of urinary free cortisol and loss of circannual periodicity in recovered depressed patients: a trait finding. J Affect Disord 8:137–145, 1985 Krishnan KRR, Hussain MM, McDonald WM, et al: In vivo stereological assessment of caudate volume in men: effect of normal aging. Life Sci 47:1325– 1329, 1990a Krishnan KRR, Ritchie JC, Saunders WB, et al: Adrenocortical sensitivity to low dose ACTH administration in depressed patients. Biol Psychiatry 27:930– 933, 1990b Krishnan KRR, Doraiswamy PM, Lurie SN, et al: Pituitary size in depression. J Clin Endocrinol Metab 72:256–259, 1991 Landfield PW, Eldridge JC: The glucocorticoid hypothesis of brain aging and neurodegeneration: recent modifications. Acta Endocrinol (Copenh) 125:54– 64, 1991 Lemort M, Haesendonck P, Louryan S, et al: MRI of the sellar region and suprasellar cisterns: normal morphology on sagittal sections, in Brain Anatomy and Magnetic Resonance Imaging. Edited by Gouaze A, Salamon G. New York, Springer-Verlag, 1988, pp 158–163

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Lisansky J, Peake GT, Strassman J, et al: Augmented pituitary corticotropin response to threshold dosage of human CRF in depressives pretreated with metyrapone. Arch Gen Psychiatry 46:641–643, 1989 Loosen PT, Chambliss B, DeBold CR, et al: Psychiatric phenomenology in Cushing’s disease. Pharmacopsychiatry 25:192–198, 1992 Lurie SN, Doraiswamy PM, Figiel GS, et al: In vivo assessment of pituitary gland volume with MRI: effect of age. J Clin Encrinol Metab 71:505–508, 1990 Malendowicz K: A correlated stereological and functional study on the long-term effects of ACTH on rat adrenal cortex. Folia Histochem Cytobiol 24:203– 211, 1986 Nemeroff CB, Evans DL: Correlation between the dexamethasone suppression test in depressed patients and clinical response. Am J Psychiatry 141:247– 249, 1984 Nemeroff CB, Krishnan KRR, Reed D, et al: Adrenal gland enlargement in major depression: a computed tomographic study. Arch Gen Psychiatry 49:384– 387, 1992 Nemeroff CB, Krishnan KRR, Dunnick NR: The adrenal gland and depression: reply to a letter. Arch Gen Psychiatry 50:834–835, 1993 Newman MM, Halmi KA: The endocrinology of anorexia nervosa and bulimia. Endocrinol Metab Clin North Am 17:195–212, 1988 O’Brien JT, Ames D, Schweitzer I, et al: Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer’s disease. Br J Psychiatry 168:679–687, 1996 Quinian C, Berger AA: Observations on human adrenals with especial reference to the relative weight of the normal medulla. Ann Intern Med 6:1180–1192, 1933 Reus VI, Joseph MS, Dallman MF: ACTH levels after the dexamethasone suppression test in depression. N Engl J Med 306:228–239, 1982 Rubin RT, Phillips JJ, Sadow TF, et al: Adrenal gland volume in major depression: increase during the depressive episode and decrease with successful treatment. Arch Gen Psychiatry 52:213–218, 1995 Sachar EJ, Hellman L, Fukushima DK, et al: Cortisol production in depressive illness. Arch Gen Psychiatry 23:289–298, 1970 Sapolsky RM, McEwen BS: Why dexamethasone resistance? two possible neuroendocrine mechanisms, in The Hypothalamic-Pituitary-Adrenal Axis: Physiology, Pathophysiology, and Psychiatric Implications. Edited by Schatzberg AF, Nemeroff CB. New York, Raven Press, 1988, pp 155–169 Sheline YI: 3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity. Biol Psychiatry 48:791–800, 2000 Sheline YI, Sanghavi M, Mintun M, et al: Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19:5034–5043, 1999 Sherman B, Pfohl B, Winokur G: Circadian analysis of plasma cortisol before and after dexamethasone administration in depressed patients. Arch Gen Psychiatry 41:271–275, 1984

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Starkman MN, Gebarski SS, Berent S, et al: Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765, 1992 Stumpf WE, Sar M: Anatomical distribution of corticosterone-concentrating neurons in rat brain, in Anatomical Neuroendocrinology. Edited by Stumpf WE, Grant LE. Basel, Switzerland, Karger, 1975, pp 254–261 Su TP, Pagliaro M, Schmidt PJ, et al: Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA 269:2760–2764, 1993 Westlund KN, Aguilera G, Childs GV: Quantification of morphological changes in pituitary corticotropes produced by in vivo corticotrophin-releasing factor stimulation and adrenalectomy. Endocrinology 116:439–445, 1985 Wolkowitz OM: Prospective controlled studies of the behavioral and biological effects of exogenous corticosteroids. Psychoneuroendocrinology 19:233– 255, 1994 Wolkowitz OM, Reus VI: Treatment of depression with antiglucocorticoid drugs. Psychosom Med 61:698–711, 1999 Zis KD, Zis AP: Increased adrenal weight in victims of violent suicide. Am J Psychiatry 144:1214–1215, 1987

Part VII Stress

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Chapter 19 Stress and Neuroendocrine Function Individual Differences and Mechanisms Leading to Disease Bruce S. McEwen, Ph.D.

Stress is frequently seen as a significant contributor to disease,

including psychiatric illness. Clinical and experimental evidence is accumulating for specific effects of stress on the immune and cardiovascular systems as well as on the central nervous system. However, aspects of stress that precipitate disease have been obscure. Because it fails to account for dynamic aspects of adaptation, the concept of homeostasis has not been able to help us understand the hidden toll of chronic stress on the body or to appreciate the significance of individual differences in the response to stress. Rather than maintaining constancy, systems within the body fluctuate to meet anticipated demands from external forces, a state termed allostasis (Sterling and Eyer 1988). An important component of allostasis is anticipation of real or imagined events, and anxiety is a highly potent stressor that varies among individuals (Schulkin et al. 1994; Sterling and Eyer 1988). Chronic stress, including chronic anxiety and psychosocial stressors, generates a condition called allostatic load, in which there is a hidden toll on the body through the persistent activation of the same physiological systems that normally cope with stressors (McEwen 1998; McEwen and Stellar 1993).

Research in my laboratory related to this article is supported by NIH Grant MH 41256. I also wish to acknowledge intellectual and collegial support from members of the MacArthur Foundation Health and Behavior Network and from scientific colleagues who have participated in activities supported by the MacArthur Foundation.

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The secretion of glucocorticoid stress hormones is a universally acknowledged physiological response to stressful events, and Mason (1959) emphasized the association of the release of these hormones with negative responses to an event. In this chapter I consider the role of glucocorticoids as mediators of allostatic load, after first considering their important role in containment of the body’s primary response to stressful events. A primary focus is on the brain, because this organ interprets and directs the physiological response to stress and is itself a target of stress hormones. Finally, I discuss the differences between the protective and damaging effects of adrenal steroids; this discussion also requires considering the role of other mediators in the response to stress.

Connections Between Stress and Disease Stress is a highly individualized experience, and what is stressful for one person may not be stressful for another. Moreover, genetic factors, influences in early development, and prior experiences play a powerful role in determining whether something is truly stressful to any one person. In Figure 19–1 the factors that contribute to an experience being interpreted as stressful by some individuals and not by others are diagrammed. The figure also illustrates that biological mediators are activated by stressful events and that they alter the brain as well as the immune system, cardiovascular system, metabolic control systems, and adipose tissue. It is difficult to assess whether stress actually causes a disease. Discussed below are examples in which stressful life experiences appear to exacerbate the progression of disease. Of course, ascertaining when disease actually begins is very much dependent on methods of detection. Because of the steady evolution of sensitive methods to pick up early warning signs of disease, the concept of allostatic load offers the possibility that markers of heightened physiological reactivity, such as blood pressure and production of catecholamines and adrenal steroids, may actually predict the onset of outright disease. Among the most consistent and pervasive risk factors for predicting later pathology related to stressful life events are the adrenal steroids.

Paradoxical Role of Glucocorticoids The work of Selye (1956) revealed the delicate balance between the protective effects of adrenal steroids secreted in response to stressful experi-

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ences and the negative consequences that these same hormones may have for many processes. Indeed, the body depends on adequate levels of adrenal steroids to prevent extremes of responses to challenge, and yet too much adrenal steroid is also deleterious. On the positive side, acute elevations of adrenal steroids promote adaptive processes, such as increased appetite (McEwen et al. 1993), memory for emotionally charged events (deQuervain et al. 1998; Roozendaal et al. 1996), and enhanced immunological function (Dhabhar and McEwen 1999) On the negative side, chronic elevations of adrenal steroid levels promote abdominal obesity and insulin resistance (Bjorntorp 1990; Brindley and Rolland 1989; Jayo et al. 1993), suppress immune function (Dhabhar and McEwen 1997; McEwen et al. 1997), and impair memory (see “Importance of the Brain as Controller of and Target for Stress” below as well as Newcomer et al. 1999; Wolkowitz et al. 1990). However, whereas chronic exposure to adrenal steroids suppresses immune defense mechanisms and causes negative consequences such as neural damage, muscular atrophy, and calcium loss from bone (Sapolsky 1992; Sapolsky et al. 1986), an insufficiency of adrenal steroids makes the organism much more vulnerable to inflammatory disturbances and autoimmune responses, fever, and damage from catecholamine metabolites and alcohol (Leonard et al. 1991; Morrow et al. 1993; Ramey and Goldstein 1957; Spencer and McEwen 1990; Sternberg et al. 1989), and it also increases fear response and anxiety (Weiss et al. 1970). Therefore, the adrenocortical system is vital for survival, and there is a generalized inverted U–shaped dose-time response curve to describe its actions that range from protection in the low to intermediate range to exacerbation of pathology at the extreme end of dose and duration of exposure.

Importance of the Brain as Controller of and Target for Stress Fear and anxiety are neural events, and the brain governs the endocrine and autonomic nervous systems and their numerous effects on the immune system and metabolic processes. Moreover, circulating stress hormones feed back on the brain and regulate its structure and function. Therefore, it is imperative to consider the impact of stress on the nervous system. The brain is involved directly in the response to stressors and to diurnal changes in the secretion of adrenal steroids; this was shown after it

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became possible to detect intracellular steroid hormone receptors. In 1968, we reported that in the rat the adrenal glucocorticoid corticosterone was taken up and retained in high levels by the hippocampal formation after rats had been adrenalectomized to remove endogenous hormone from receptor sites (McEwen et al. 1968). The hippocampal localization of corticosterone was a surprise, particularly because the hippocampus was not known to be directly associated with neuroendocrine function, whereas the hypothalamus and preoptic area were known as the hypophysiotropic area and were the sites of uptake and

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(Opposite page) Conceptual model of biology and behavior in which responses that are stressful result from the interpretation of, and behavioral and physiological responses to, environmental challenges that may be stressful to some individuals and less stressful or not stressful to others.

FIGURE 19–1.

A. (1) Physical and psychological challenges operate within a social context that includes individual social status. (2) The processing of this information by the nervous systems is biased by factors such as genetic predisposition that are operated on by developmental history, learning, and socioeconomic status; developmental age and gender are also important factors. (3) Interpretation of a stimulus as threatening results in behavioral responses that vary in degree and cost to the individual and that are therefore stressful to varying degrees. Nonthreatening situations and low-cost responses are not considered stressful because they do not elevate physiological responses; stress refers to responses that are costly in terms of arousal of physiological systems and elicitation of behaviors that are harmful. Thwarted responses may lead to aggression or result in helplessness, which is similar to a response being unavailable. High-cost responses, which may include aggression, are ones that consume energy and that further increase risk to additional challenge. All of these responses, including vigilance and helplessness, have biological counterparts (see below), and they feed back to influence further stimulation and processing of that stimulation. B. Behavioral responses are accompanied by neural, immune, and neuroendocrine responses that act on effectors, such as the brain and cardiovascular systems and adipose tissue and muscle. Chronic or repeated stimulation of these effectors may be due to thwarted or high-cost responses or to anxiety associated with vigilance or helplessness and may lead to allostatic load which, over time, increases risk for pathology and disease. Acute stress more readily precipitates acute disease when chronic stress has laid a pathophysiological foundation. Source. Reprinted from McEwen BS, Stellar E: “Stress and the Individual: Mechanisms Leading to Disease.” Archives of Internal Medicine 153:2093–2101, 1993. Copyright 1993, American Medical Association. Used with permission.

retention of sex steroid hormones. The hippocampus plays a major role in spatial and episodic learning and memory and is also involved in the matching of expectations to actual events in situations where there may be punishment or reward (Eichenbaum and Otto 1992; Gray 1982). Both noradrenergic and serotonergic input play a major role in modulating hippocampal responsiveness. Noradrenergic innervation, acting via a and b receptors, increases excitability of neurons and produces disinhibition, a process that also results in facilitation of neural activity, in the hippocampus (Doze et al. 1991; Dunwiddie et al. 1992). Serotonergic neurotransmission in the hippocampus, acting through postsynaptic 5-hydroxytryptamine type 1A (5-HT1A) receptors, has suppressive effects on long-term potentiation (Sakai and Tanaka 1993) and facilitates extinction or inhibits learning of aversive associations (Deakin and Graeff 1991; Graeff 1993). Thus, disruption of hippocampal neuronal circuitry or alterations in noradrenergic or serotonergic activity of the hippocampus are likely to have profound effects on the role that the hippocampus plays in learning and memory and in the response to novel aversive events (Gray 1982).

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The circuitry, electrophysiology, and neurochemistry of the hippocampus is uniquely sensitive to circulating adrenal steroids. These hormones have an important role in maintaining hippocampal function during the diurnal cycle, and one mechanism for this is the ability of adrenal steroids to biphasically modulate excitability in the form of longterm potentiation in the hippocampus (Diamond et al. 1992; Pavlides et al. 1993, 1994, 1995a, 1995b). In this capacity, adrenal steroids appear to have a role in the phenomenon of jet lag (McEwen et al. 1992, 1993). Adrenal steroids also stabilize the neuronal population of the dentate gyrus, whereas reductions in adrenal steroid levels enhance neuronal turnover by increasing both neuronal death and neurogenesis; in this capacity, it is speculated that the adrenal secretions may participate in seasonal adjustments to hippocampal function (Gould and McEwen 1993). Finally, adrenal steroids play a vital role in containing the response of the body and brain to stressful events, and as long as adrenal secretion is itself contained, adaptation occurs (McEwen et al. 1992, 1993). However, when adrenocortical secretion is no longer self-regulated and becomes persistently augmented, there are several negative consequences: for example, normal hippocampal neuronal circuitry is disrupted and serotonin receptor levels are altered. Both of these consequences may reduce effective cognitive processing of and coping with threatening events.

Adaptation and Maladaptation in the Face of Stressful Events Homeostasis and Allostasis What is stressful? To begin to understand the differences between adaptive and maladaptive responses to stressors, it is necessary to first define what is stressful. Stress is often defined as a perceived threat to homeostasis and as an event or stimulus that causes an often abrupt but always large change in autonomic activity and hormone secretion—particularly hormones such as cortisol and prolactin (see Figure 19–1). The term perceived stress emphasizes the extremely important point that each individual may react differently to an event or situation depending on physical status and prior experiences. Thus, trained athletes and sedentary individuals will react differently to physical exertion, and prior experiences will cause some individuals to be more or less anxious in the face of psychological challenges, such as examinations or events in the workplace.

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Stress represents a physiological response to a large deviation from what is expected, and such a response perturbs the homeostatic balance. The term homeostasis captures the idea of a body set point that is reestablished after stress, but homeostasis fails to consider the dynamic aspect of anticipation of expected events (McEwen 1998; McEwen and Stellar 1993; Sterling and Eyer 1988). Normally, anticipation is a shortlived process, but in psychopathology, expectancies or fears can become self-sustaining and detached from reality in individuals with anxiety disorders and depression. An adjunct to homeostasis is allostasis, and the term was introduced (Sterling and Eyer 1988) because the body is a dynamic system that responds and adapts to new situations. Allostasis refers to the systems of the body (neural, endocrine) that are activated by a stressful challenge and that participate in adaptation—in other words, allostasis, or achieving stability through change, helps to maintain or restore homeostasis (Sterling and Eyer 1988).

Containment by Glucocorticoids Glucocorticoid secretion is one of the most frequent responses to stressful events. Adrenal steroid secretion as a result of stress has multiple actions on the brain and body that have been characterized as containing or counterregulating other responses to stress and trauma such as inflammations, fever, edema, and immune responses (Munck et al. 1984). The term containment implies that glucocorticoids prevent responses from being excessive (Figure 19–2). In the brain, glucocorticoids contain the synthesis of corticotropin-releasing hormone (CRH) and vasopressin, two neuropeptide-releasing hormones that stimulate production of adrenocorticotropic hormone (ACTH); in doing this they prevent hypothalamic CRH—which has anxiogenic, arousing, immunosuppressive, and anorexigenic effects—from becoming hyperactive (McEwen et al. 1992). Other examples of containment are discussed below in conjunction with the noradrenergic and serotonergic systems.

Stress and Noradrenaline Stressors of many kinds activate the release and turnover of noradrenaline, along with the release of catecholamines from the autonomic nervous system. Uncontrollable stressors tend to have more prolonged effects on noradrenaline turnover (Tsuda and Tanaka 1985; Weiss et al. 1981). One of the consequences of repeated stress is the induction of tyrosine hydroxylase, the rate-limiting enzyme for noradrenaline and epinephrine

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FIGURE 19–2.

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Counterregulation of stress effects by adrenal steroids.

A. CRH system and hypothalamic-pituitary-adrenal axis. B. Containment of noradrenergic activity by glucocorticoids. C. Positive and negative effects of adrenal steroids on serotonergic activity and receptor sensitivity. cAMP=cyclic adenosine monophosphate; CRH=corticotropin-releasing hormone; 5-HT= 5-hydroxytryptamine; NA=noradrenaline.

formation, in both the locus coeruleus and the adrenal medulla (see Nisenbaum et al. 1991). Stress-induced activation of catecholamine biosynthesis also increases the catalytic efficiency of tyrosine hydroxylase and leads to increased catecholamine formation (see Nisenbaum et al. 1991). Thus, in the face of increased amount and activity of tyrosine hydroxylase, there is a need for various forms of containment (see Figure 19–2). Glucocorticoids fill this role in several ways, reducing the formation of cyclic adenosine monophosphate in the cerebral cortex in response to noradrenaline (see McEwen et al. 1992), and decreasing catecholamine biosynthesis and release (Pacak et al. 1992, 1993). In view of the importance of noradrenaline in promoting excitability and disinhibition of hippocampal neurons (Doze et al. 1991; Dunwiddie

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et al. 1992), it is interesting that after repeated stress, noradrenergic terminals in the hippocampus retain the potential to release larger amounts of noradrenaline in response to a novel stressor (Nisenbaum et al. 1991). Yet this release is contained to a large extent by presynaptic a-adrenergic mechanisms (Nisenbaum and Abercrombie 1993) that may also be aided by circulating glucocorticoids (Pacak et al. 1992, 1993). A similar situation exists with respect to ACTH and glucocorticoid secretion in response to novel stressors in animals that have been repeatedly stressed, as discussed below under “Neurobiology of Stress and Glucocorticoid Effects on Dendritic Branching.”

Stress and Serotonin Stressors also activate serotonin turnover and thereby activate a system that has both anxiogenic and anxiolytic pathways within the forebrain (Deakin and Graeff 1991; Graeff 1993). Serotonin has a powerful role in the learning and retention of fear (Archer 1982). A primary distinction in the qualitative nature of the actions of serotonin is between the dorsal raphe and median raphe nuclei: dorsal raphe innervation of the amygdala and hippocampus is believed to have anxiogenic effects, very likely via 5-HT2 receptors; conversely, median raphe innervation of the hippocampus reaches 5-HT1A receptors, stimulation of which facilitates the disconnection of previously learned associations with aversive events or suppresses formation of new associations, thus providing a resilience to aversive events (Deakin and Graeff 1991; Graeff 1993). Glucocorticoids have a complex role in regulating the 5-HT system (see Figure 19–2). Circulating glucocorticoids acutely facilitate 5-HT turnover provoked by a wide variety of stressors (Azmitia and McEwen 1974; Neckers and Sze 1975; Singh et al. 1990), and repeated treatment with ACTH or glucocorticoids (or chronic stress) increases 5-HT2 receptors in the cerebral cortex (Kuroda et al. 1992, 1993; McKittrick et al. 1995) while reducing 5-HT1A receptors in the hippocampus (Burnet et al. 1992; Chalmers et al. 1993; Martire et al. 1989; McKittrick et al. 1995; Mendelson and McEwen 1991, 1992). Therefore, although in the short term glucocorticoids facilitate the activity of the whole 5-HT system during stress, in the long term glucocorticoids tip the balance in favor of 5-HT2-mediated actions of 5-HT (at least in the cerebral cortex) and suppress 5-HT1A-mediated responses in the hippocampus. These changes have implications for the pathophysiology of depression (Deakin and Graeff 1991; Graeff 1993). Moreover, the inadequate operation of the serotonergic system has been linked to the pathophysiology of anger and hostility, and suicide and myocardial infarcts are among

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the consequences of the hypoactivity of reduced serotonergic activity (Williams and Chesney 1993; Williams and Williams 1993). There is also a reported link between low fat and cholesterol levels and violent death, and there are indications that reduced serotonergic function may be involved (Muldoon et al. 1990, 1992).

Containment of the Hypothalamic-Pituitary-Adrenal Axis A key to successful adaptation as opposed to maladaptive effects of stress is the self-containment of the hypothalamic-pituitary-adrenal (HPA) axis; that is, the ability of the HPA axis to shut itself down as well as to contain other neurochemical responses to stress such as release of CRH and noradrenaline (see “Stress and Noradrenaline” above). The paraventricular nuclei, which produce the CRH and vasopressin that stimulate ACTH release, are innervated by catecholaminergic and serotonergic inputs. Catecholaminergic input acts via a-adrenergic receptors to facilitate HPA activity and via b-adrenergic receptors to inhibit it (Al-Damluji and White 1992; Saphier 1992). In contrast, serotonergic input to the paraventricular nuclei via 5-HT1A receptors is reported to inhibit HPA activity (Welch et al. 1993). In response to repeated stressors, HPA axis activity tends to become habituated if the stressor is the same, but it tends to become hypersensitive to novel stressors (Akana and Dallman 1992; McEwen 1992). Partial inhibition of glucocorticoid secretion in response to stress unmasks a strong facilitation, indicating that containment by glucocorticoids plays an important role (Akana and Dallman 1992) (see Figure 19–2). As noted, glucocorticoids contain the stress-induced release of catecholamines in the paraventricular nuclei (Pacak et al. 1993). Moreover, the role of glucocorticoids in enhancing 5-HT release in stress (see “Stress and Serotonin” above) may have a role in maintaining inhibition via 5-HT1A receptors (Welch et al. 1993). It therefore appears likely that the relative strengths of catecholaminergic and serotonergic input as a result of the same or different stressors may determine whether or not the HPA axis will become habituated or be enhanced by repeated application of the same stressor. Moreover, the relative densities of the various adrenergic and serotonergic receptor types will play an important role in the net HPA response—that is, to what degree it remains contained. Finally, the efficacy of glucocorticoid feedback on the containment mechanisms will be an important factor in the containment response. In this connection, it is interesting that depressed patients show a larger elevation of ACTH level in response to administration of mifepristone (RU 486) compared with control subjects (Bailey 1991). RU 486 is an antagonist of the type 2 adre-

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nal steroid receptors, and its effect in depressed subjects indicates that there is an increased drive to release ACTH that is held partially in check by glucocorticoid feedback acting via type II receptors (Bailey 1991).

Stress and Progression of Disease: Examples of Allostatic Load Definitions of Allostasis and Allostatic Load When referring to repeated or chronic stress, the body is thought of as maintaining function despite an external load. As noted above, allostasis is a term that means stability through change, and allostatic load refers to the hidden price that is paid when an individual is under continuing stress and is affected by the repeated activation of allostatic systems and by their failure to shut off properly after the stressful event has passed (see Figure 19–3). Although it has been shown that glucocorticoids are beneficial in the body’s and the brain’s response to stressful situations, it has also been noted that it is imperative that the HPA axis shut down again after the end of stress; if it does not, or if the stress persists without respite, then a vicious cycle may ensue in which elevated glucocorticoid levels cause a variety of consequences that can be seen as the exacerbation of a disease or a pathophysiological process that leads to disease.

Heightened Sympathetic Reactivity, Glucocorticoid Increase, Insulin Hypersecretion, and Insulin Resistance Heightened sympathetic activity is one form of allostatic load, and increased heart rate and peripheral resistance in the circulatory system are two outcomes of this activity that result in increased blood pressure and eventually lead to formation of atherosclerotic plaque (J.R. Kaplan et al. 1991a). The combination of elevated insulin and glucocorticoid levels, which can also result in increased sympathetic activity (Troisi et al. 1991), is well known to promote obesity and to be a risk factor for formation of atherosclerotic plaque (Brindley and Rolland 1989). Allostatic load in the form of sympathetic hyperactivity and heightened HPA axis activity are likely contributors to increased formation of atherosclerotic plaque in dominant male cynomolgus monkeys on a normal diet in an unstable social situation (J.R. Kaplan et al. 1991b). Female cynomolgus monkeys that are subordinate show increased atherogenesis that may be due, at least in part, to suppression of ovarian function and its protective effect on the cardiovascular system (Shively and Clarkson 1994). Thus, gender

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FIGURE 19–3.

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Introducing the concept of allostatic load.

The term allostatic load reflects the dynamic nature of physiological response to environmental challenges more completely than the term homeostasis, and it emphasizes the concept that continued responses to external or internal challenges can cause wear and tear on the body, either by the repeated fluctuations of physiological responses or through the increased activity of systems over long periods of time that may have deleterious consequences, for example, obesity and atherosclerosis; atrophy and loss of hippocampal neurons.

differences in the effects of social interactions on allostatic load and the mechanisms leading to pathophysiological changes are very important to keep in mind.

Stress and Immune Function The immune system is sensitive to behavioral influences and to stressful experiences. There are both positive and negative effects. Acute stress enhances immune function (Dhabhar and McEwen 1999), as measured by the trafficking of immune cells to targets where they are needed and by the enhancement of delayed-type hypersensitivity (Dhabhar and McEwen 1999; Dhabhar et al. 1996). Also on the positive side is the effect of sup-

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portive group therapy to double the survival time for breast cancer patients after the end of intervention (Spiegel et al. 1989). On the negative side are reports that psychological stress increases the susceptibility to the common cold (Cohen et al. 1991) and increases the incidence of mononucleosis in medical students with examination stress (Kiecolt-Glaser and Glaser 1991). More prolonged effects of stress on diseases related to the immune system are not so easy to document. Nevertheless, a recent study of type 1 diabetes in children found that stressful life events stemming from actual or threatened losses within the family and occurring during ages 5–9 years increased the relative risk for the disease, even after normalization for confounding factors such as age, gender, and family socioeconomic status (Hagglof et al. 1991). An increased frequency of negative life events is also associated with newly diagnosed Graves’ disease in adults, which suggests a possible interaction between hereditary factors and stress (Winsa et al. 1991). Moreover, psychosocial influences on another autoimmune disease, rheumatoid arthritis, are strongly suggestive but are confounded by the heterogeneity of the disease (Weiner 1992), as is also the case for asthma (Mrazek and Klinnert 1991). Personality features, such as the ability to express anger and irritation, as well as stressful life events, were implicated as risk factors in women with rheumatoid arthritis in whom there was not a family history of this disease (Yehuda et al. 1991). Adrenal steroids have multiple effects on the immune system, acting along with autonomic nervous system innervation (and virtually every hormone in the body) to biphasically modulate immune function (Madden and Felten 1995; McEwen and Sapolsky 1995). These modulatory actions can best be appreciated in states of disease. Although many of the actions of adrenal steroids on the immune system are adaptive and promote the body’s ability to fight an infection, tumor, or inflammatory or autoimmune disorder, continuing high levels of HPA activity and sympathetic neural activity (allostatic load) are deleterious to immune function.

Stress and Depression Insulin resistance and elevated cortisol level are features of endogenous depressive illness (Winokur et al. 1988), and depressed individuals have an increased risk for cardiovascular disease as well as shorter life spans (Anda et al. 1993). Whether or not metabolic disturbances are frequent features of depressive illness, stressful life events are often implicated as precipitating factors in depressive illness (Anisman and Merali 1997), and the model of learned helplessness provides a plausible model for human depression, involving a loss of self-confidence in the ability to cope

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with life events (Seligman 1975). It has been reported that adrenal steroid insufficiency exacerbates learned helplessness in an animal model (Edwards et al. 1990). As noted above (see “Stress and Serotonin”), adrenal steroids potentiate serotonergic activity, and the risk for anger and hostility is linked in some cases to suicidal depression in individuals with low levels of serotonergic activity (Williams and Chesney 1993; Williams and Williams 1993). Recurrent depression is a model of brain and systemic allostatic load. Not only is there an increased incidence of cardiovascular disease in depressive illness (Musselman et al. 1998), there is also exaggerated platelet reactivity and hence increased risk for stroke and myocardial infarction (Musselman et al. 1996), as well as increased abdominal fat deposition (Thakore et al. 1997) and decreased heart rate variability (Krittayaphong et al. 1997). Recurrent depression is also associated with decreased bone mineral density in association with elevated glucocorticoid levels (Michelson et al. 1996). In the brain, recurrent depression has been linked to atrophy of the hippocampus and amygdala (Sheline et al. 1996, 1999) as well as the prefrontal cortex (Drevets et al. 1997). The cellular basis for these changes is not known; reduced glial cell volume is a possibility, along with reduced branching of dendrites, reduced numbers of dentate gyrus granule neurons, and outright loss of pyramidal neurons. This is discussed further under “Neurobiology of Stress and Glucocorticoid Effects on Dendritic Branching” below. It is noteworthy that hippocampal atrophy is also reported in posttraumatic stress disorder, which occurs along with depressive illness in many subjects (Bremner et al. 1995, 1997; Gurvits et al. 1996). It is not clear when the reduced hippocampal volume develops in relation to the traumatic event, although existing evidence suggests that it may be a gradual and delayed event over years, as also appears to be the case for depressive illness.

Stress and Individual Differences in Aging and Risk for Dementia The first clue to an effect of adrenal steroids in the hippocampus was the finding that treatment of guinea pigs with ACTH or cortisone causes necrosis of pyramidal neurons of the hippocampus (aus der Muhlen and Ockenfels 1969). Landfield and co-workers (see Landfield 1987) later found that aging in the rat results in some loss of pyramidal neurons in the hippocampus, which can be retarded by adrenalectomy in midlife. Sapolsky and his colleagues (1985) subsequently demonstrated that injecting corticosterone into young adult rats daily for 12 weeks produced

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a mimicking of the pyramidal neuron loss seen in aging. Sapolsky went on to demonstrate that excitatory amino acids play an important role in the cell loss by showing, first, that corticosterone exacerbates kainic acid– induced damage to the hippocampus as well as ischemic damage, and second, that glucocorticoids potentiate excitatory amino acid killing of hippocampal neurons in culture (Sapolsky 1992) (Figure 19–4). However, the story has turned out to be more complicated and interesting. In addition to permanent damage caused by stress, glucocorticoids, and excitatory amino acids, there are a number of types of structural plasticity exhibited by nerve cells in the hippocampus. They are regulated by stress and by stress hormones, acting in concert with neurotransmitters in the hippocampal formation.

Neurobiology of Stress and Glucocorticoid Effects on Dendritic Branching To examine the response of hippocampal neurons to high levels of glucocorticoids, researchers in my laboratory used the Golgi technique to examine neuronal morphology after both corticosterone exposure and repeated stress. We found that after 21 days of daily corticosterone exposure, apical dendrites of CA3 pyramidal neurons had atrophied (Woolley et al. 1990); moreover, this atrophy is prevented by administering phenytoin, a blocker of excitatory amino acid release and action, before corticosterone each day (Watanabe et al. 1992a) (Figure 19–5). The effect of corticosterone on dendritic length and branching is not found on basal dendrites of CA3 pyramidal neurons, nor is it found on CA1 pyramidal neurons or dentate gyrus granule neurons (Watanabe et al. 1992a; Woolley et al. 1990). The sensitivity of the CA3 pyramidal neurons is reminiscent of the specific damage to CA3 neurons as a result of kainic acid infusion or as a consequence of seizure-inducing stimulation of the perforant pathway into the hippocampus; both of these effects are attributable to the mossy fiber input to CA3 from the dentate gyrus (see Watanabe et al. 1992a). To investigate whether the corticosteroid effect occurs physiologically, we subjected rats to repeated daily restraint stress, which is known to induce glucocorticoid secretion. Restraint stress for 21 days produced atrophy of apical dendrites of CA3 pyramidal neurons without affecting basal dendritic length or branching (Watanabe et al. 1992c); the pattern and specificity of changes were identical to those produced by corticosterone treatment (Woolley et al. 1990). Like corticosterone-induced atrophy, stress-induced atrophy was blocked by phenytoin, which prevents the release and actions of excitatory amino acids (Watanabe et al.

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FIGURE 19–4.

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Schematic diagram of neuronal endangerment.

The synaptic accumulation of glutamate that typically accompanies a necrotic insult, such as ischemia or seizure, is worsened by glucocorticoids (GCs). (a) This is likely to arise from GCs’ inhibiting the removal of glutamate from the synaptic cleft. Such inhibition has been demonstrated to occur at glia and is speculated to occur at neurons as well. (b) However, GCs do not appear to enhance the initial release of glutamate. (c) As a result of these actions of GCs, there is enhanced mobilization of free cytosolic calcium in the postsynaptic neuron. (d) In addition, this accumulation of calcium is augmented by GCs’ inhibiting the efflux of calcium, via both the Ca2+ ATPase and the Ca2+/Na+ exchanger. (e) At present, however, there is no evidence that GCs directly enhance the influx of calcium, either by opening voltage-gated calcium channels or by acting at N-methyl-D-aspartate (NMDA) receptor–gated channels. As a result of the excessive cytosolic calcium, GCs exacerbate calcium-dependent degenerative events. To date, these have been shown to include worsening of the proteolysis of the cytoskeletal protein spectrin, the accumulation of the abnormally phosphorylated tau protein, and the production of oxygen radicals during necrotic insults. Source. Reprinted from McEwen BS, Sapolsky RM: “Stress and Cognitive Function.” Current Opinion in Neurobiology 5:205–216, 1995. Copyright 1995, Current Biology Ltd. Used with permission.

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Schematic summary of actions of adrenal steroids that affect hippocampal function and alter cognitive performance.

FIGURE 19–5.

(a) Adrenal steroids biphasically modulate long-term potentiation (LTP), facilitating it via type I receptors and inhibiting it via type II receptors; type I and type II receptors coexist in hippocampal neurons. (b) The biphasic modulation of excitability is also seen for primed-burst potentiation (PBP) as a function of increasing levels of circulating corticosterone, and this may be relevant to diurnal changes in hippocampal function, to the phenomenon of jet lag, and to the effects of acute stress- or disease-induced elevation of glucocorticoid levels that impair PBP and episodic or verbal memory. (c) Hippocampal circuitry is diagrammed, showing some of the main connections between entorhinal cortex (ENT), Ammon’s horn (H), and the dentate gyrus (DG). f=fornix; pp=perforant pathway. (d), Moderate-duration stress, acting through both glucocorticoids and excitatory amino acids (especially glutamate), causes reversible atrophy of apical dendrites of CA3 pyramidal neurons; severe and prolonged stress causes pyramidal cell loss that is especially apparent in CA3 but spreads to CA1 as well. The mechanistic relationship between reversible atrophy and permanent neuron loss is not currently known, although both glucocorticoids and excitatory amino acids are involved. Source. Reprinted from McEwen BS, Sapolsky RM: “Stress and Cognitive Function.” Current Opinion in Neurobiology 5:205–216, 1995. Copyright 1995, Current Biology Ltd. Used with permission.

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1992a). Moreover, a blocker of N-methyl-D-aspartate (NMDA) receptors also prevents stress-induced dendritic atrophy (Magarinos and McEwen 1995). At the same time, a role for inhibitory neurotransmission was shown by the fact that a benzodiazepine, adinazolam, blocks stress-induced dendritic atrophy (Magarinos et al. 1999). In addition, stress-induced atrophy of apical dendrites of CA3 pyramidal neurons was prevented by administration of cyanoketone, a drug that virtually eliminates the stress-induced surge of corticosterone (Magarinos and McEwen 1995). Thus, stress-induced release of corticosterone synergizes with excitatory amino acid release to produce the atrophy, and there is evidence (see Magarinos and McEwen 1995) that corticosterone actually facilitates the release of glutamate from nerve terminals in the hippocampus. Serotonin also plays a role in the stress- and corticosterone-induced atrophy of dendrites of CA3 pyramidal neurons. This was shown by the finding that tianeptine, a tricyclic antidepressant that facilitates serotonin reuptake, attenuates the atrophy of apical CA3 dendrites caused by repeated restraint stress (Watanabe et al. 1992b). The fact that tianeptine also blocks the atrophy caused by corticosterone treatment rules out the possibility of any type of inhibition by tianeptine of corticosterone secretion having a direct effect on dendritic atrophy. Rather, it appears that serotonin released during stress (or as a result of injecting corticosterone) may synergize with excitatory amino acid release in causing the atrophy. In fact, some evidence for a serotonin-glutamate interaction has been found, and 5-HT2 receptor antagonists are known to attenuate ischemic damage to the hippocampus, a process that also involves glutamate release and that is exacerbated by glucocorticoids (see Watanabe et al. 1992b). It is very important to note that severe and prolonged stress (e.g., repeated cold swim stress or social stress [i.e., dominance-subordinance hierarchies]) has been reported to produce actual loss of hippocampal neurons (Fuchs et al. 1995; Mizouguchi et al. 1992; Uno et al. 1989). We have found that social stress in rats and tree shrews causes the same type of atrophy of apical dendrites of hippocampal CA3 pyramidal neurons as that caused by corticosterone and by repeated restraint stress (Magarinos et al. 1996). Although dendritic atrophy precedes cell loss after corticosterone treatment and repeated restraint stress, the causal relationship of the dendritic atrophy to neuronal loss is not yet known: that is, although it is attractive to suppose that atrophy may represent the first stage of cell damage, the fact that this atrophy occurs on apical but not on basal dendrites argues that it may be an adaptive process by viable neurons. We have determined that the atrophy caused by repeated restraint stress for 21 days is reversible (Conrad et al. 1999); therefore, it may represent a

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mechanism whereby synaptic connectivity is reduced temporarily, perhaps to spare the CA3 pyramidal neurons from excessive bombardment by excitatory input. Reversible and adaptive as it may be, the stress effect on hippocampal CA3 pyramidal neurons is accompanied by transient impairment of learning of a radial maze task (Luine et al. 1994); this impairment can be blocked by the same agents—phenytoin and tianeptine—that prevent the stress-induced atrophy of CA3 apical dendrites (Luine et al. 1994).

Neurogenesis in the Adult Dentate Gyrus Another part of the hippocampus that shows structural plasticity is the dentate gyrus, which develops later than Ammon’s horn and continues to replace neurons during adult life. This finding, first in rodents and then in primates, has recently been extended to the human brain, as described below. Neurogenesis in the dentate gyrus of adult rodents has been reported (M.S. Kaplan and Bell 1984; M.S. Kaplan and Hinds 1977) but never fully appreciated until recently, and the reactivation of interest in this topic occurred in an unusual manner. First, bilateral adrenalectomy of an adult rat was shown to increase granule neuron death by apoptosis (Gould et al. 1990; Sloviter et al. 1989). Subsequently, neurogenesis was also found to increase after adrenalectomy in adult rats (Cameron and Gould 1994) as well as in the developing dentate gyrus (Cameron and Gould 1996a). In adult rats, very low levels of adrenal steroids, sufficient to occupy type I adrenal steroid receptors, completely block dentate gyrus neuronal loss (Woolley et al. 1991); however, in newborn rats, type II receptor agonists protect against neuronal apoptosis (Gould et al. 1997c). This is consistent with the fact that dentate gyrus neuronal loss in the developing rat occurs at much higher circulating steroid levels than in the adult, and it represents another example of the different ways that the two adrenal steroid receptor types are involved in hippocampal function (Lupien and McEwen 1997). In adult rats, newly born neurons arise in the hilus, very close to the granule cell layer, and then migrate into the granule cell layer, presumably along a vimentin-staining radial glial network that is also enhanced by adrenalectomy (Cameron et al. 1993). Most neuroblasts labeled with [3H]thymidine lack both type I and type II adrenal steroid receptors (Cameron et al. 1993), indicating that steroidal regulation occurs via messengers from an unidentified steroid-sensitive cell. Recent data suggest an important signaling role for transforming growth factor a and the epidermal growth factor receptor system (Tanapat and Gould 1997).

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The question of whether dentate gyrus neurogenesis is a widespread phenomenon among mammals was addressed by studies showing that neurogenesis occurs in the marmoset (Gould et al. 1998), a New World primate, as well as in an Old World primate species, the rhesus monkey (Gould et al. 1999a), and in the adult human dentate gyrus (Eriksson et al. 1998). Thus changes in size of the human hippocampus, described under “Changes in Hippocampal Volume and Cognitive Function in Human Subjects” below, may include changes in neuron number in the dentate gyrus. Granule neuron birth is accelerated by seizure-like activity (Parent et al. 1997), and the stimulus for this neurogenesis is likely to be apoptotic cell death, because seizures kill granule neurons (Bengzon et al. 1997), and local increases in apoptosis simulate local neurogenesis (Cameron and Gould 1996b). Granule neuron birth is also accelerated by blocking NMDA receptors or lesioning the excitatory perforant pathway input from the entorhinal cortex (Cameron et al. 1995). Unlike adrenalectomy, these treatments do not increase granule neuron apoptosis, and a single dose of an NMDA blocking drug results in a 20% increase in neuron number in the dentate gyrus several weeks later (Cameron et al. 1995). Therefore, although increased apoptosis leads to increased neurogenesis (Gould and Tanapat 1997), the two processes occur in different regions of the granule cell layer and can be uncoupled from each other. Nevertheless, the adrenal steroid suppression of neurogenesis is through an NMDA receptor mechanism (Gould et al. 1997b; Noguchi et al. 1990). It was recently reported that serotonin may be a positive signal for neurogenesis in the adult dentate gyrus. Treatment with the serotoninreleasing drug d-fenfluramine increased neurogenesis (Jacobs et al. 1998). Likewise, the 5-HT1A agonist 8-hydroxydipropylaminotetralin stimulated neurogenesis, whereas blockade of 5-HT1A receptors had the opposite effect and prevented the effect of d-fenfluramine treatment (Jacobs et al. 1998), as well as preventing increased neurogenesis caused by pilocarpine-induced seizures (Radley et al. 1998). It has been reported that neurogenesis declines in the aging dentate gyrus in rodents (Kempermann et al. 1998) and rhesus monkeys (Gould et al. 1999a). Recent studies of aging rats showed that adrenalectomy could reverse the decline in dentate gyrus neurogenesis (Cameron and McKay 1999), suggesting that it is the result of age-related increases in HPA activity and glucocorticoid levels that have been reported (Landfield and Eldridge 1994; McEwen 1992; Sapolsky 1992; Sapolsky et al. 1986). One reason for turnover of dentate gyrus granule neurons in adult life is to adjust needs for hippocampal function in spatial learning and memory to environmental demands (Sherry et al. 1992). Birds that use space

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around them to hide and locate food, and voles and deer mice that traverse large distances to find mates, have larger hippocampal volumes than closely related species that do not have these behaviors; moreover, there are indications that hippocampal volume may change during the breeding season (Galea et al. 1994; Sherry et al. 1992). Indeed, the rate of neurogenesis in the male and female prairie vole varies according to the breeding season (Galea and McEwen 1999). In contrast, an enriched environment has been found to increase dentate gyrus volume in mice by increasing neuronal survival without altering the rate of neurogenesis (Kempermann et al. 1997). Thus there are several ways to maintain the balance between neuronal apoptosis and neurogenesis. Learning that involves the hippocampus also appears to affect the survival of newly formed dentate granule neurons. When rats were trained in a task involving the hippocampus, the survival of previously labeled granule neurons was prolonged (Gould et al. 1999b). Another important effect is that of acute and chronic stress. Acute stress involving the odor of a natural predator, the fox, inhibits neurogenesis in the adult rat (Galea et al. 1996). Acute psychosocial stress in the adult tree shrew, involving largely visual cues, inhibits neurogenesis (Gould et al. 1997a). Inhibition of neurogenesis is also seen in the dentate gyrus of the marmoset after acute psychosocial stress (Gould et al. 1997a). Chronic psychosocial stress in the tree shrew results in a more substantial inhibition of neurogenesis than after a single acute stressful encounter (Gould et al. 1997a). This finding suggests that there may be other changes such as atrophy of dendritic branching to account for the decrease in dentate gyrus volume. Changes in dentate gyrus volume appear to have consequences for cognitive functions subserved by the hippocampus. In enriched-environment studies (Kempermann et al. 1997), increased dentate gyrus volume was accompanied by better performance on spatial learning tasks. In contrast, decreased dentate gyrus volume in chronically stressed tree shrews is paralleled by impaired spatial learning and memory (Czeh et al. 2001), although this might be as much due to atrophy of dendrites of CA3 pyramidal neurons and dentate granule neurons (see “Neurobiology of Stress and Glucocorticoid Effects on Dendritic Branching” above) as to reduced dentate gyrus neurogenesis.

Changes in Hippocampal Volume and Cognitive Function in Human Subjects A key question is whether there are any parallels to the findings in the rat hippocampus from studies on human disorders. Besides the studies on

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recurrent depressive illness noted above (see “Stress and Depression”), a report on patients with Cushing’s disease indicates that some who show impairment of verbal memory also have decreased hippocampal volume, as determined by magnetic resonance imaging (Starkman et al. 1992). A similar study reported individual differences in hippocampal volume in aging human subjects that correlate negatively with cortisol levels and positively with measures of memory impairment (Convit et al. 1995; Golomb et al. 1994). Another series of longitudinal studies of human brain aging revealed individual differences in HPA activity that parallel declines in hippocampus-specific forms of memory (Lupien et al. 1994, 1998). In the more recent of these studies, deficits in spatial and verbal memory were associated with a 14% smaller hippocampal volume, as well as with elevated cortisol levels (Lupien et al. 1998). What is interesting about hippocampal atrophy in the aging human brain in mild cognitive impairment is that it predicts later onset of Alzheimer’s disease (de Leon et al. 1993). However, the mechanisms by which this progression occurs are not clear, and more remains to be learned about the reversibility and structural basis of the changes in hippocampal volume, not only in mild cognitive impairment with aging but also in recurrent depressive illness, Cushing’s disease, and posttraumatic stress disorder. Any of the mechanisms described above may be involved—ranging from reduced glial cell number to atrophy of dendrites to reduced number of dentate gyrus granule neurons to permanent loss of pyramidal neurons. Some of these events may be reversible, whereas others will be permanent. However, structural changes in the hippocampus, whether reversible or permanent, are not the only way to bring about impairment of memory in aging, depressive illness, and Cushing’s disease. Memory associated with the hippocampus and temporal lobe is acutely inhibited by glucocorticoids through a reversible mechanism involving neuronal excitability (see DeKloet et al. 1998; McEwen and Sapolsky 1995 for reviews; see also Kirschbaum et al. 1996; Lupien et al. 1997; Newcomer et al. 1999; Wolkowitz et al. 1990).

Conclusion I argue in this chapter that containment of a variety of physiological responses to stress is a key feature of successful adaptation. This includes the HPA axis, because when glucocorticoid secretion is augmented for prolonged periods, then (besides the containment effects) other actions of glucocorticoids that are not beneficial begin to accumulate. It has been

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suggested that repeated stress may impair successful behavioral adaptation and may do so via glucocorticoid secretion. Evidence in support of this hypothesis has come from use of the adrenal steroid synthesis inhibitor metyrapone to increase behavioral adaptation to restraint stress (Kennet et al. 1985). One of the adverse events promoted by glucocorticoids is altering the balance between 5-HT2 and 5-HT1A transmission in the forebrain; another deleterious result of repeated, unremitting stress is the atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. These events are associated with some cognitive impairment on a radial maze task. Whereas elevated 5-HT2 transmission in cerebral cortex would enhance the anxiogenic side of stress, the reduced 5-HT1A transmission due to glucocorticoid actions in the hippocampus would impair adaptation to stress by reducing the ability of the hippocampus to suppress negative associations (Deakin and Graeff 1991; Graeff 1993) and by impairing hippocampal function in interpreting the context in which to make appropriate responses (Phillips and LeDoux 1992). At the same time, synaptic connections through CA3 pyramidal neurons that are presumably disrupted by glucocorticoid-induced atrophy of dendrites would reduce the efficacy of the hippocampus in its role in determining the context for appropriate responses and in matching expected outcomes with reality (Gray 1982; Phillips and LeDoux 1992). Such impairment might further increase the likelihood that fears and anxieties would become self-sustaining and less subject to matching with real events. This is a situation in which the concept of allostatic load, with its emphasis on anticipation, is of particular relevance to psychiatric disorders. How might this sequence of events start in the first place? The control of ACTH secretion through the paraventricular nuclei involves both facilitative and inhibitory influences via catecholamines and serotonin. It may be that the balance between these opposing influences breaks down in some individuals under stress, giving rise to persistently elevated cortisol levels. Depressed individuals show a high degree of stress and considerable containment of the ACTH response, as shown by challenge with RU 486 (Krishnan et al. 1992). Nevertheless, if containment breaks down sufficiently that the elevation in cortisol concentration above baseline begins to alter neurochemical features of the brain by increasing 5-HT2 receptors in the cortex and suppressing 5-HT1A receptors in the hippocampus, as well as causing atrophy of dendrites in the hippocampus, then some of the negative features of glucocorticoid action on behavioral adaptation may occur. Stressful life events are acknowledged as an important risk factor for major depressive illness (Anisman and Merali 1997) and posttraumatic

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stress disorder (Green et al. 1992), and possibly also for schizophrenia (Norman and Malla 1993). It is interesting to note that both posttraumatic stress disorder and schizophrenia appear to involve neuroanatomical disturbances in hippocampal volume and structure (Arnold et al. 1991; Barbeau et al. 1995; Bogerts et al. 1993; Bremner et al. 1995; Luchins 1990; Shenton et al. 1992), whereas there are some suggestions that major depressive illness may be linked through glucocorticoid excess to reduced hippocampal volume and cognitive impairment (Axelson et al. 1993; McEwen and Sapolsky 1995; Sheline et al. 1996, 1999). However, we are at a very early stage of understanding the etiology of these disorders and the role of neurological disturbances, and much remains to be learned about the pathways from perceived stress to the neurochemical and neuroanatomical features of these disorders. Therefore, the discussion of the roles of the hippocampus, glucocorticoids, CRH, the HPA axis, serotonin, and noradrenaline will have to be broadened to include other brain structures and neurochemical mediators. Nevertheless, the principles outlined in this chapter concerning anticipation and anxiety leading to allostatic load and the normal role of adrenal steroids in containing various aspects of the primary stress response should be useful in understanding the roles of other mediators and brain regions in coping with potentially stressful events.

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Index Page numbers in boldface type refer to tables or figures.

treatment of, 169–170 dehydroepiandrosterone, 218 Adenylate cyclase, 473 Adiposogenital syndrome, 18–19 Adrenal glands computed tomographic scanning of, 500, 501 enlargement of, 501–503 in Cushing’s syndrome, 502–503 in depression, 35, 501–503, 506 in suicide victims, 501 magnetic resonance imaging of, 502 normal weight of, 500 Adrenal hyperfunction, 170, 171. See also Cushing’s disease and Cushing’s syndrome Adrenal insufficiency, 167. See also Addison’s disease differentiation from steroid withdrawal syndrome, 194 Adrenal tumors, 170–171, 178, 180 Adrenalectomy, 13, 16 Adrenaline, 15, 17 Adrenocorticotropic hormone (ACTH), 31, 32, 473 in Addison’s disease, 169 behavioral effects of, 139, 182 circadian fluctuations in plasma level of, 167, 474

AASs. See Anabolic-androgenic steroids Abel, John Jacob, 15 Acetylcholine, 17, 29, 30 corticosteroid effects on, 197 prolactin regulation by, 108 stimulation of corticotropinreleasing hormone release by, 472 Acromegaly, 111–112, 493 ACTH. See Adrenocorticotropic hormone ADAS (Alzheimer’s Disease Assessment Scale), 221 Addison, Thomas, 12–13 Addisonian crisis, 168 Addison’s disease, 5, 13, 15, 29, 126, 166–170 clinical course of, 168 diagnosis of, 169, 480–481 differential diagnosis of, 168–169 etiology of, 167 gender distribution of, 167 neuropsychiatric symptoms of, 168–169 psychotropic medications for patients with, 170 somatic effects of insufficient adrenal hormones in, 167–168 stress and, 168, 170

547

548

PSYCHONEUROENDOCRINOLOGY

Adrenocorticotropic hormone (ACTH) (continued) in Cushing’s disease, 170–171, 173 relationship between hormone levels and depression, 179 in depression, 179, 502, 503 ectopic tumor production of, 170 functions of, 473 half-life of, 474 measuring plasma level of, 474–475, 475 causes of falsely elevated or decreased levels, 475 timing and frequency of, 474–475 neuropsychiatric effects in multiple sclerosis patients with family history of depression, 192 response to corticotropin-releasing hormone stimulation test, 34, 478–480 secretion of, 166, 473 excessive, 170 Adrenocorticotropic hormone (ACTH) stimulation test, 169, 480–481 Aggression/violence dehydroepiandrosterone effects in animals, 209 induced by anabolic-androgenic steroids, 335, 337–339, 344–345, 349 insulin responses and, 121–122 Aging, 3. See also Elderly persons decline in dehydroepiandrosterone with, 208 decline in pituitary volume with, 504 effect on dexamethasone suppression test, 143–144 hippocampal changes with, 505, 526–527, 533–534 stress and individual differences in, 526–527

Agitation, in hypercalcemia, 123 AHC (amygdala-hippocampal complex), in depression, 505–506 Alcmaeon of Croton, 10–11 Alcoholism arginine vasopressin in, 44 hypothalamic-pituitary-adrenal axis activity in, 37, 38 decreased hippocampal volume and increased pituitary volume, 506 thyroid function in, 376, 383–387 in abstinent patients with liver disease, 385–386 in abstinent patients without liver disease, 384 during acute alcohol withdrawal, 383–384 cerebrospinal fluid studies of, 386–387 effects of ethanol administration on, 383 in subjects at risk for developing alcoholism, 386 Aldosterone deficiency, 167–168 Allopregnanolone, 288, 319 premenstrual syndrome and, 252 Allostasis, 513, 516, 518–518, 523, 524 Allostatic load, 513, 514, 516, 523 Alzheimer’s disease arginine vasopressin in, 45–46 effects of dehydroepiandrosterone and dehydroepiandrosterone sulfate on cognitive performance in, 215, 220–221 estrogen in, 307–308 growth hormone in, 115 hippocampal volume and dexamethasone suppression test in, 506 hypothalamic-pituitary-adrenal axis activity in, 37, 38–39 neurotensin in, 54 somatostatin in, 50, 59

Index Alzheimer’s Disease Assessment Scale (ADAS), 221 g-Aminobutyric acid (GABA) corticosteroid effects on, 197 estrogen-induced increased activity of, 305 g-Aminobutyric acid (GABA) type A receptors allopregnanolone binding to, 288, 319 3¢-5¢-a-tetrahydrodeoxycorticosterone modulation of, 289 Aminoglutethimide for depression, 152 for obsessive-compulsive disorder, 153 Amitriptyline effect on cerebrospinal fluid corticotropin-releasing hormone concentration, 33 triiodothyronine augmentation of, 452 Amygdala-hippocampal complex (AHC), in depression, 505–506 Anabolic-androgenic steroids (AASs), 6, 331–349. See also Testosterone for anemia, 333 antidepressant effects of, 333 classification as schedule III substances, 332 definition of, 331 detecting use of, 347–348 for female-to-male transsexuals, 334 for human immunodeficiency virus–infected men, 334 for hypogonadal men, 334 for muscular dystrophy, 333 physiological effects of, 331–332 for postmenopausal women, 334 prevalence of use of, 332 psychiatric effects of, 332–342 clinical implications of, 347–349 clinical studies of, 332–334

549

dosage and, 339–340, 347 high-dose laboratory studies of, 340–342 mania or hypomania, 336, 338, 341, 347 modest-dose laboratory studies of, 335–336 naturalistic studies of, 336–340 withdrawal depression, 336, 339, 343, 348 syndromes associated with use of, 342–345 dependence, 343 muscle dysmorphia, 343 progression to opioid abuse or dependence, 345 violence, 344–345 treatment for users of, 348–349 use by athletes, 332, 335–338 adolescents, 338 “stacking,” 336 use by women, 345–346 Anabolic Steroids Control Act of 1990 (P.L. 101-647), 332 Ancient concepts of psychoneuroendocrinology, 10–11 Androgens, 6, 12. See also Anabolicandrogenic steroids; Testosterone decrease with aging, 247 deficiency of, 167 effect on visuospatial tasks, 334 in pregnancy and puerperium, 288 postpartum depression and, 291 premenstrual syndrome and, 252 Androstenedione, 308 Anemia, anabolic-androgenic steroids for, 333 Anger/hostility hyperprolactinemia and, 286 induced by anabolic-androgenic steroids, 335–337 serotonergic hypoactivity and, 521, 526

550

PSYCHONEUROENDOCRINOLOGY

Anisomysin, 209 Anorexia nervosa, 31 arginine vasopressin in, 45 dehydroepiandrosterone and dehydroepiandrosterone sulfate in, 213 effects of treatment with, 219 hypothalamic-pituitary-adrenal axis activity in, 37, 39 pituitary pathology, 504–505 neuropeptide Y in, 55 thyroid function in, 390–393, 391 abnormal circadian thyrotropin rhythm, 368 Antiandrogens, for male-to-female transsexuals, 321 Antidepressants. See also specific drugs and classes anabolic-androgenic steroids as, 333 dehydroepiandrosterone effects in animals, 209 dexamethasone suppression test and response of dysthymic patients to, 147 effect on cerebrospinal fluid corticotropin-releasing hormone concentration, 33 effects on thyroid function, 366, 378–379 in hyperthyroidism, 378–379, 428 in hypothyroidism, 435, 436 estrogen augmentation of, 306 glucocorticoids as, 190 impact on glucose regulation, 118–119 neuroendocrine pathophysiology and actions of, 30–31 for perimenopause-related depression, 272 for postpartum depression, 293 for premenstrual syndrome, 315 for steroid-induced psychopathology, 195, 198

triiodothyronine augmentation of, 451–456, 452, 460–461 to accelerate antidepressant response, 450–451 antidepressant class and, 454–455, 460–461 mechanism of action of, 455 precautions for use in elderly cardiac patients, 454 recommendations for, 456, 456 side effects and tolerability of, 453–454 use in Addison’s disease, 170 use in Cushing’s syndrome, 179 use in pregnancy, 293 Antidepressants, tricyclic (TCAs) effects on glucose regulation, 118 effects on thyroid function, 378–379 rapid-cycling bipolar disorder and hypothyroidism, 374 estrogen augmentation of, 306 neuroendocrine pathophysiology and actions of, 31 for steroid-induced psychopathology, 195, 198 triiodothyronine augmentation of, 451–456, 452, 456, 460 use in hyperthyroidism, 378–379, 428 Antidiuretic hormone. See Arginine vasopressin Antiestrogens, 317–318 Antiglucocorticoid medications, 152–153 in bipolar depression, 153 in depression, 152–153 in obsessive-compulsive disorder, 153 in schizophrenia and schizoaffective disorder, 153 Antipsychotics effect on dexamethasone suppression test, 148 effect on neurotensin level, 53 effect on thyroid function, 396

Index galactorrhea induced by, 493 neuroendocrine pathophysiology and actions of, 30 for postpartum psychosis, 295 for steroid-induced psychopathology, 195 use in Addison’s disease, 170 use in hyperthyroidism, 426, 428–429 use in hypothyroidism, 435, 436 Antisocial personality disorder, insulin responses in, 122 Antithyroid antibodies, 367–368, 485–486 in anxiety disorders, 389 in bipolar disorder, 372, 373 in depression, 372, 373 postpartum, 433 in hypothyroidism, 429, 430 lithium-induced increase in, 377 prevalence in general population, 372 in schizophrenia, 372, 396 Anxiety disorders. See also specific anxiety disorders cholecystokinin and, 51–52 Cushing’s syndrome and, 176 diazepam-binding inhibitor and, 57 growth hormone and, 114 hyperprolactinemia and, 111, 286 hypothalamic-pituitary-adrenal axis activity and, 37, 38 thyroid function and, 376, 388–389 cerebrospinal fluid studies of, 389 in hyperthyroidism, 423–424, 424 in hypothyroidism, 432, 432, 445 in panic disorder, 388, 389 peripheral thyroid hormones, 388–389 thyrotropin and antithyroid antibodies, 389

551

Anxiolytics cholecystokinin receptor antagonists as, 52 dehydroepiandrosterone effects in animals, 209 neuroendocrine pathophysiology and actions of, 30 progesterone metabolites as, 319 thyroid hormones as, 446, 459, 460 Appetite. See also Eating disorders in Cushing’s syndrome, 176 dehydroepiandrosterone and dehydroepiandrosterone sulfate levels and, 213 glucocorticoid effects on, 515 neuropeptide Y in, 55 postpartum, 282 during premenstrual phase, 262 Arginine vasopressin (AVP), 43–47, 472–473 disorders associated with alterations of, 44–45 Alzheimer’s disease, 45–46 anorexia nervosa, 45 bipolar disorder, 45 depression, 44–45 neurodegenerative disorders, 45 schizophrenia, 46–47 functions of, 44, 473 corticotropin-releasing hormone and, 44, 45, 473 plasma osmolality, 44 infusion of, 480 modulation of stress response by, 480 synthesis and secretion of, 43–44, 473 Aristotle, 12 Arthritis, rheumatoid, 525 Asthmatic children, cognitive effects of prednisone in, 193 Autism, opioid antagonists for selfinjurious behavior in, 42

552

PSYCHONEUROENDOCRINOLOGY

Autoimmune thyroid disease Graves’ disease, 421–423 Hashimoto’s thyroiditis, 367–368, 430, 485–486 AVP. See Arginine vasopressin Bailey, Percival, 18 Barbiturates, use in hypothyroidism, 436 Battery, Robert, 16 Bayliss, William, 15 BDHI (Buss-Durkee Hostility Inventory), 336–339 Beck Depression Inventory, 333 Benzodiazepines, use in hypothyroidism, 436 Bernard, Claude, 12, 17, 19 Berthold, Arnold Adolph, 12 Binge-eating disorder, thyroid function in, 394 Bipolar disorder arginine vasopressin in, 45 cholecystokinin in, 51 dexamethasone suppression test in manic phase of, 145–146 diabetes and, 117 growth hormone in, 114 ketoconazole for depression in, 153 postpartum psychosis and, 283–284, 295 prevalence of, 117 prolactin in, 111 rapid cycling, 372–375, 383, 456–459 gender distribution of, 374 predisposing factors for, 374 prevalence of, 372 thyroid function in, 366–367, 372–375, 383 antithyroid antibodies, 372, 373 cerebrospinal fluid studies of, 376 rapid cycling and, 374–375, 383, 456–459

thyroid hormone treatment for, 374–375, 446, 456–460 in non–rapid-cycling disease, 457–458 in rapid-cycling disease, 458–459 Blues, postpartum, 282, 290–291 consequences of, 291 endocrine factors in etiology of, 290 natural history of, 282 nonendocrine factors in etiology of, 290 prevalence of, 282 symptoms of, 282 treatment of, 290–291 Bone mineral density hormone replacement therapy effects on, 305 after menopause, 305 recurrent depression and, 526 tamoxifen effects on, 317 Borderline personality disorder dexamethasone suppression test in, 146–147 opioid antagonists for self-injurious behavior in, 43 BPRS (Brief Psychiatric Rating Scale), 149 Brain. See also specific brain structures cholecystokinin in, 50–51 as controller of and target for stress, 515–518 gonadal hormones, behavior and, 304–305 imaging of, 7 in depression hippocampal changes, 505–507 pituitary pathology, 503–504, 506–507 thyroid system, 436–437 lithium blockage of corticosteroneinduced increases in dopamine activity in, 196

Index neurotensin in, 52–53 progesterone receptors in, 319 somatostatin in, 47 substance P in, 56 thyroid function, behavior and, 419–438, 484 early studies of, 419–420 hyperthyroidism and thyrotoxicosis, 420–429 hypothyroidism, 429–436 in vivo brain imaging of, 436–437 thyrotropin-releasing hormone, 419 triiodothyronine, 362 “windows into,” 3, 5 Brain-derived neurotrophic factor, corticosteroid effects on, 197 Breast cancer, tamoxifen for, 317–318 Breastfeeding pharmacotherapy during, 294 lithium, 294 prolactin levels during, 286 Bremer, Frédéric, 18 Brief Psychiatric Rating Scale (BPRS), 149 Bright light exposure, for circadian rhythm disorders, 84 Bromocriptine, for hyperprolactinemia, 109 Brown-Séquard, Charles-Edouard, 13–14 Bulimia nervosa insulin responses in, 121 pituitary pathology in, 504–505 during premenstrual phase, 262 thyroid function in, 393–394 Buserelin, to suppress ovulation, 313 Buss-Durkee Hostility Inventory (BDHI), 336–339 Cannon, Walter Bradford, 19–20 Carbamazepine, effects on thyroid function, 379

553

Cardiovascular disease depression and, 525, 526 precautions for triiodothyronine augmentation of antidepressants in elderly patients with, 454 serotonergic hypoactivity and myocardial infarction, 521 Catechol O-methyltransferase, estrogen inhibition of, 305 Cavalieri’s systematic sampling theorem, 504 CCK. See Cholecystokinin Cerebrospinal fluid concentration of arginine vasopressin, 44 in Alzheimer’s disease, 45–46 in anorexia nervosa, 45 in bipolar disorder, 45 in depression, 44–45 in schizophrenia, 46–47 of cholecystokinin in bipolar disorder, 51 in panic disorder, 52 in schizophrenia, 51 of corticotropin-releasing hormone in Cushing’s syndrome, 182 in depression, 32–33 dexamethasone nonsuppression and, 36 treatment effects on, 33 in other psychiatric disorders, 37, 37–39 anorexia nervosa, 39 anxiety disorders, 38 neurodegenerative disorders, 38–39 schizophrenia, 38 Tourette’s syndrome, 39 of dehydroepiandrosterone and dehydroepiandrosterone sulfate, age effects on, 208 of delta sleep–inducing peptide in depression, 57 lithium effects on, 58 in schizophrenia, 58

554

PSYCHONEUROENDOCRINOLOGY

Cerebrospinal fluid concentration (continued) of diazepam-binding inhibitor in depression, 57 of endogenous opioid peptides, 41 in self-injurious autistic children, 43 of 5-hydroxyindoleacetic acid, methyltestosterone effects on, 342 of neuropeptide Y in anorexia nervosa, 55 in depression, 55 of neurotensin, in schizophrenia, 53–54 antipsychotic effects on, 53 of neurotransmitters and neuropeptides, corticosteroid effects on, 197 of somatostatin, 49–50 in Alzheimer’s disease, 50 in depression, 49 of substance P, 56 of thyroid hormones in alcoholism, 386–387 in anorexia nervosa, 393 in anxiety disorders, 389 in mood disorders, 375, 376 Cerulein, 51 Ceruletide, 51 CFS (chronic fatigue syndrome), dehydroepiandrosterone and dehydroepiandrosterone sulfate levels in, 214 Chlorimipramine, effects on thyroid function, 366 m-Chlorophenylpiperazine (mCPP), 111 Chlorpromazine effect on neurotensin level, 53 use in hyperthyroidism, 429 Cholecystokinin (CCK), 30, 50–52 brain distribution of, 50–51 dopamine and, 51 gastrointestinal, 50

in panic disorder, 51–52 receptors for, 51 in schizophrenia, 51 Cholecystokinin (CCK) receptor antagonists, 52 Cholesterol hypothyroidism and hypercholesterolemia, 433 violent death and low levels of, 522 Chronic fatigue syndrome (CFS), dehydroepiandrosterone and dehydroepiandrosterone sulfate levels in, 214 Chronobiotic disorders, 5, 83–84, 84 Chronobiotics, 83, 100 for circadian rhythm disorders, 83–84 compared with hypnotics, 83–84 CI-988, 52 CIBIC-Plus (Clinician’s InterviewBased Impression of Change with Caregiver Input), 221 Circadian rhythm disorders, 83–84, 84 bright light exposure for, 84 chronobiotics for, 83–84 melatonin for, 98–100, 99 Circadian rhythms, 85–87 entrainment and, 86 light-dark cycle and, 85, 86 suprachiasmatic nucleus and, 85–87, 86 Cirrhosis, thyroid function in patients with, 385–386 Clinical Global Inventory, 333 Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus), 221 Clomiphene, 318 Clonidine, growth hormone responses to, 47 in depression, 114 Clozapine, effect on neurotensin level, 53

Index Clyde Mood Scale, 424 Cognitive-behavioral therapy, for postpartum depression, 293 Cognitive disturbances in Addison’s disease, 168 calcium imbalance and, 123 corticosteroid-induced, 193–194 in Cushing’s syndrome, 174, 176–177 posttreatment improvement in, 178–179 dehydroepiandrosterone and dehydroepiandrosterone sulfate levels and, 208, 215 treatment effects of, 220– 222 in diabetes, 119 electroconvulsive therapy–induced, effect of thyrotropin-releasing hormone on, 447–448 glucocorticoid excess, hippocampal atrophy and, 533–534, 536 in hyperthyroidism, 423–425, 424 effect of treatment on, 426 in hypoparathyroidism, 124 in hypothyroidism, 431–433, 432 progesterone metabolite–induced, 319 Cognitive effects of estrogen, 307–308 Computed tomography of adrenal glands, 500, 501 in depression, 35, 501–503, 506 Conduct disorder, dehydroepiandrosterone sulfate and, 212 Conflict Tactics Scale, 344 Contraceptive hormones, 6, 303–304, 315–317 modes of administration for, 315 mood and behavioral effects of, 315–317 pyridoxine deficiency and, 311 for women with history of depression, 311

555

Corticosteroids, 5. See also specific corticosteroids abuse potential for, 192–193 for Addison’s disease, 169–170 effects on immune system, 515, 525 hippocampal effects of, 152, 197 dendritic branching, 527–531, 529 neuropsychiatric effects of, 139, 173–174, 189–198 cognitive disturbances, 193–194, 515 dosage and, 191–192 duration of, 192 frequency and character of, 189–194 gender and, 191 informing patient of risk of, 198 potential etiologic mechanisms for, 196–198 predictors of risk for, 191–192 related to steroid compound, 196 steroid withdrawal syndrome, 194–195 differentiation from adrenal insufficiency, 194 duration of, 194–195 etiology of, 194 management of, 195 symptoms of, 194 timing of onset of, 192 treatment of, 195–196, 198 paradoxical role of glucocorticoids, 514–515 in pregnancy and puerperium, 289 roles in central nervous system function, 196–197 steroid psychosis, 5 in stress response, 514, 519 (See also Stress) containment, 519, 520, 522–523

556

PSYCHONEUROENDOCRINOLOGY

Corticotropin-releasing hormone (CRH), 19, 31–40, 32, 166, 472 arginine vasopressin and, 44 behavioral effects of, 182 biosynthesis and secretion of, 166, 472 circadian fluctuations in plasma level of, 474 in Cushing’s syndrome, 182 in depression, 32–36 functions of, 31–32 half-life of, 474 neuropeptide Y and, 55 in other psychiatric disorders, 37, 37–39 anorexia nervosa, 39 anxiety disorders, 38 neurodegenerative disorders, 38–39 schizophrenia, 38 Tourette’s syndrome, 39 Corticotropin-releasing hormone (CRH) receptor antagonists, 39–40, 60 Corticotropin-releasing hormone (CRH) receptors, CRH1 and CRH2 subtypes of, 40 Corticotropin-releasing hormone (CRH) stimulation test, 34, 478–480 in Cushing’s syndrome, 173, 184, 478–480 in depression, 34, 479, 480, 502, 503 methodology for, 478–479 Cortisol, 20, 32, 165–184, 473 behavioral effects of, 181–182 circadian fluctuations in plasma level of, 167, 474 lithium blunting of, 196 deficiency of, 167, 169 (See also Addison’s disease) in depression, 35, 144–145, 500–502 in dysthymic disorder, 146–147

excess of, 165–166, 170, 171, 173 (See also Cushing’s disease and Cushing’s syndrome) antiglucocorticoid strategies for, 152–153 differential diagnosis of, 183, 502–503 outcome and, 150–152 specific symptoms associated with, 150 functions of, 473 half-life of, 474 in mania, 145–146 measuring plasma level of, 142, 474–475, 475 causes of falsely elevated or decreased levels, 475 commentary on, 143 timing and frequency of, 474–475 in posttraumatic stress disorder, 147–148 in pregnancy and puerperium, 289 postpartum blues and, 290 postpartum depression and, 291 psychiatric effects of abnormalities of, 139 ratio of dehydroepiandrosterone to, 208, 210–212 response to corticotropin-releasing hormone stimulation test, 34, 478 response to dexamethasone suppression test, 33–34, 139–144 salivary, 141–143, 476 in schizophrenia, 148–150 synthesis and secretion of, 166, 473 urinary free, 142, 143, 151, 470, 475, 475–476 Cortisol synthesis inhibitors, 152 Cortisone, behavioral effects of, 139, 189 Crawford, Albert, 15

Index Cretinism, 13 CRH. See Corticotropin-releasing hormone Criminality, anabolic-androgenic steroids and, 344–345, 349 Cushing, Harvey, 19, 139, 165 Cushing’s disease and Cushing’s syndrome, 5, 29, 139, 165–166 adrenal gland enlargement in, 502–503 adrenocorticotropic hormone– dependent, 170 adrenocorticotropic hormone– independent, 170–171 clinical features of, 165 dexamethasone suppression test in, 173 diagnosis of, 172–173 differential diagnosis of, 182–184 basal hypothalamic-pituitaryadrenal axis testing for, 476–477 corticotropin-releasing hormone stimulation test for, 173, 184, 478, 479 b-endorphin in, 182 etiology of, 171 gender distribution of, 167 hippocampus in, 177, 505 b-lipotropin in, 182 neuropsychiatric symptoms of, 173–182 behavioral effects of adrenocorticotropic hormone and cortisol, 181–182 biological drives, 176 cognition, 174, 176–177 mood and affect, 165–166, 174–176, 502 pathogenesis of, 177 posttreatment improvement of, 178–179 relationship between hormone levels and depression, 179–181

557

somatic effects of excess glucocorticoids in, 172 stress and, 171 testosterone in, 182 treatment of, 178 Cyclic adenosine monophosphate, 520 Cyproheptadine, 47 Cyproterone acetate, for male-tofemale transsexuals, 321 5¢D-I (5¢-deiodinase type I), 361, 362 5¢D-II (5¢-deiodinase type II), 362 Dale, Henry, 17, 18 Danazol, to suppress ovulation, 313 Danocrine. See Danazol DBI (diazepam-binding inhibitor), 57, 59 de Bordeu, Théophile, 11–12 De Medicis Sajous, Charles E., 17 Dehydroepiandrosterone (DHEA), 4–6, 205–227 in Addison’s disease, 169 behavioral effects in animals, 209–210 anti-anxiety effects, 209 anti-aggressive effects, 209 antidepressant effects, 209 eating behavior, 210 memory enhancement, 209 biosynthetic pathway of, 206 concerns about unregulated use of, 207, 224–225, 227 contraindications to, 225 cotreatment with prednisone, 196 decreasing levels with aging, stress, and illness, 208, 212, 247 discontinuation of, 226 dosage of, 226 effects on mood, memory, and functional abilities in humans, 211–215 chronic fatigue syndrome, 214 cognitive performance, 214–215 depression, 211–213

558

PSYCHONEUROENDOCRINOLOGY

Dehydroepiandrosterone (DHEA) (continued) effects on mood, memory, and functional abilities in humans (continued) eating behavior and anorexia nervosa, 213 elderly persons, 214 perimenopause-related depression, 272 pregnancy and postpartum period, 212 schizophrenia, 213–214 guidelines for clinical use of, 225–227 mass marketing of, 207 as a neurosteroid, 207–208 neurotrophic potential of, 210 patient monitoring during treatment with, 225–226 possible mechanisms of neuropsychiatric effects of, 222–224, 223 in pregnancy and puerperium, 288 ratio to cortisol, 208, 210–212 side effects of, 224–225 treatment effects on well-being, mood, and memory in humans, 216–222 Addison’s disease, 218 anorexia nervosa, 219 cognition-enhancing effects, 220–222 depression, 218–219 dysthymia, 219 elderly persons, 217–218 Dehydroepiandrosterone sulfate (DHEA-S) behavioral effects in animals, 209–210 anti-anxiety effects, 209 antidepressant effects, 209 eating behavior, 209–210 memory enhancement, 209 biosynthetic pathway of, 206

cognitive effects of treatment with, 221 decreasing levels with aging, stress, and illness, 208, 212 effects on mood, memory, and functional abilities in humans, 211–215 chronic fatigue syndrome, 214 cognitive performance, 214–215 depression, 211, 213 eating behavior and anorexia nervosa, 213 elderly persons, 214 panic disorder, 213 postmenopausal women, 212–213 schizophrenia, 213 as a neurosteroid, 207–208 neurotrophic potential of, 210 obtaining baseline serum level of, 226 in pregnancy and puerperium, 286, 288 5¢-Deiodinase type I (5¢D-I), 361, 362 5¢-Deiodinase type II (5¢D-II), 362 Delirium, in thyrotoxicosis, 425 Delta sleep–inducing peptide (DSIP), 57–58 in depression, 57–58 lithium effects on level of, 58 in schizophrenia, 58 in sleep disorders, 57 Delusions in hypothyroidism, 431, 433 induced by anabolic-androgenic steroids, 333, 336 postpartum, 283 Dementia. See also Alzheimer’s disease; Cognitive disturbances corticosteroid-induced, 194 effects of dehydroepiandrosterone and dehydroepiandrosterone sulfate on cognitive performance in, 215, 220–221

Index Dementia praecox, 17 Dendritic branching of hippocampal neurons, glucocorticoid effects on, 527–531, 529 Dentate gyrus neurogenesis, 531–533 11-Deoxycortisol, 473 Depo-Provera. See Medroxyprogesterone acetate, depot Depression. See also Antidepressants arginine vasopressin in, 44–45 cardiovascular disease and, 525, 526 corticosteroid-induced, 190, 191 treatment of, 195 corticosteroid-withdrawal, 193, 194 Cushing’s syndrome and, 165–166, 174–175, 502 differential diagnosis of, 183–184, 476, 479 posttreatment improvement in, 178, 179 relationship with hormone levels, 179–181 dehydroepiandrosterone and dehydroepiandrosterone sulfate in, 211–213 effects of treatment with, 218–219 delta sleep–inducing peptide in, 57–58 diabetes and, 117–118 diazepam-binding inhibitor in, 57, 59 due to anabolic-androgenic steroid withdrawal, 336, 339, 343, 348 b-endorphin in, 41–42 growth hormone in, 48, 49, 50, 112–114, 492 hyperparathyroidism and, 123 hyperprolactinemia and, 109, 110, 286 hypoparathyroidism and, 125 hypopituitarism and, 126

559 hypothalamic-pituitary-adrenal axis activity in, 20–21, 31–36, 33, 144–145, 499–500 adrenocorticotropic hormone, 503 antiglucocorticoid medications, 152–153 basal tests of, 476–477 corticotropin-releasing hormone, 32–34, 479, 480, 502 cortisol hypersecretion, 35, 144–145, 500–502 dexamethasone suppression test, 35–36, 140, 141, 144–145, 150, 184 dexamethasone–corticotropinreleasing hormone test, 36 effects of antiglucocorticoid strategies, 152–153 imaging of, 499–507 adrenal pathology, 35, 500–503, 506 hippocampal changes, 505–507, 526 pituitary pathology, 35, 503–504, 506–507 pituitary gland enlargement, 34 principles for evaluation of, 470 relationship between hypercortisolemia and outcome, 150–151 urinary free cortisol, 470, 475 insulin responses in, 121, 525 MK-869 for, 56, 60 neuropeptide Y in, 55 obsessive-compulsive disorder and, 114 perimenopause-related, 265–269 causal relationship for, 269–271 symptoms of, 267, 268 treatment of, 271–272 postmenopausal, 305, 306 postpartum, 267, 282–283, 291–294

560

PSYCHONEUROENDOCRINOLOGY

Depression (continued) postpartum (continued) consequences of, 294 duration of, 283 endocrine factors in etiology of, 291–292 premenstrual syndrome and, 262 prevalence of, 282 psychotic vs. nonpsychotic, 282 recurrence of, 294 risk factors for, 282–283, 283, 292 severity of, 282 symptoms of, 282 thyroiditis and, 433 treatment of, 292–294 poststroke, 110 during pregnancy, 282–283 premenstrual, 250, 251, 259 prolactin in, 109, 110 psychotic, 21, 33 antiglucocorticoid strategies for, 152–153 dexamethasone suppression test in, 141, 144–145 postpartum, 282, 283 recurrent, physiological effects of, 526 schizophrenia and, 148–149 serotonergic hypoactivity and, 521 somatostatin in, 49, 50 substance P in, 56 thyroid function and, 363, 364, 365–366, 368–372, 381–382 abnormal circadian thyrotropin rhythm, 368, 369 antithyroid antibodies, 372, 373 hyperthyroidism, 423–424, 424 hypothyroidism, 431–433, 432, 445 subclinical, 368–372, 370–371 treatment of, 435

peripheral thyroid hormones, 365–366 thyrotropin sources of variance, 372 thyroid hormone treatment for, 372, 446–456, 460–461 approaches to, 446 thyroid-stimulating hormone, 448 thyrotropin-releasing hormone, 446–448 combined with electroconvulsive therapy, 447–448 monotherapy, 447 thyroxine, 448–449 triiodothyronine, 449–456 to accelerate antidepressant response, 450–451 for antidepressant augmentation, 451–456, 452, 456, 460–461 combined with electroconvulsive therapy, 450 monotherapy, 449–450 side effects and tolerability of, 453–454 winter, 83 (See also Seasonal affective disorder) Desipramine effect on cerebrospinal fluid corticotropin-releasing hormone concentration, 33 effect on thyroid function, 366, 378 triiodothyronine augmentation of, 452 Dexamethasone “amphetamine-like” reaction to, 192 cognitive disturbances induced by, 193 effects on dopamine and homovanillic acid levels, 197

Index Dexamethasone suppression test (DST), 5, 21, 139–144, 153–154, 470–471, 481–482 in Alzheimer’s disease, hippocampal volume and, 506 clinical use of, 141–144, 154, 482 age effects, 143–144 salivary cortisol, 141–143 urinary free cortisol, 142, 143 in Cushing’s syndrome, 173 definition of nonsuppression on, 140 in depression, 35–36, 140, 144–145, 184 correlation with pituitary volume, 504 psychotic depression, 141, 144–145 vs. schizophrenia, 141, 145 in dysthymic disorder, 146–147 hypercortisolemia and specific symptoms, 150 in mania, 145–146 plasma dexamethasone concentrations and, 140–141 in posttraumatic stress disorder, 38, 148 protocol for, 33–34, 140, 481–482 relationship of hypercortisolemia to outcome, 150–152 sampling times for, 140 in schizophrenia, 141, 145, 148–150 Dexamethasone–corticotropinreleasing hormone test, 36, 143 DHEA. See Dehydroepiandrosterone 5a-DHT (5a-dihydroprogesterone), 320 Diabetes mellitus, 5 adaptation to, 116 cognitive symptoms in, 119 comorbidity with psychiatric illness, 116 Cushing’s syndrome and, 172 fatigue and, 116

561

impact of antidepressants on glucose regulation in, 118–119 influence of psychosocial factors in, 116–117 prevalence of, 115–116 psychiatric effects of, 115–119 bipolar disorder, 117 depression, 117–118 related to early age at onset, 116 sexual dysfunction and, 116 stress and, 116, 525 vascular complications of, 118, 119 Diagnostic Interview Schedule, 339 Diazepam-binding inhibitor (DBI), 57, 59 Dietary Supplement Health and Education Act of 1994 (P.L. 103417), 207 5a-Dihydroprogesterone (5a-DHT), 320 Dihydrotestosterone, 331 Disinhibition, 517 Distractibility, corticosteroidinduced, 191 Dizocilpine, 210 Dopamine, 30 cholecystokinin and, 51 corticosteroid effects on, 197 estrogen effects on, 287, 305 lithium blockage of corticosteroneinduced increases in brain activity of, 196 prolactin regulation by, 108, 286, 493 Dreams, in Cushing’s syndrome, 176 DSIP. See Delta sleep–inducing peptide DST. See Dexamethasone suppression test Dyadic Adjustment Scale, 344 Dynorphins, 40–41 Dyslipidemia, induced by anabolicandrogenic steroids, 332

562

PSYCHONEUROENDOCRINOLOGY

Dysthymic disorder dexamethasone suppression test in, 146–147 effects of dehydroepiandrosterone treatment in, 219 Eating behaviors. See also Appetite dehydroepiandrosterone and dehydroepiandrosterone sulfate effects on, 213 in animals, 209–210 neuropeptide Y and, 55 Eating disorders diabetes and, 117 insulin responses in, 121 pituitary pathology in, 504–505 ECT. See Electroconvulsive therapy Elderly persons dexamethasone suppression test in, 143–144 effects of dehydroepiandrosterone on mood, memory, and functional abilities in, 214, 217–218 hippocampal glucocorticoid receptors in, 505 hyperthyroidism mimicking depression in, 423 pituitary volume in, 504 precautions for use of triiodothyronine for antidepressant augmentation in cardiac patients, 454 Electroconvulsive therapy (ECT) dehydroepiandrosterone sulfate levels and response to, 213 effect on cerebrospinal fluid corticotropin-releasing hormone concentration, 33 for postpartum psychosis, 295 for steroid-induced psychopathology, 195 for steroid withdrawal syndrome, 195

thyroid function and, 366, 380, 398 thyroid hormone therapy combined with, 446 thyrotropin-releasing hormone, 447–448 triiodothyronine, 450 use in hypothyroidism, 435 Electroencephalography, in Cushing’s syndrome, 177 Elliott, Thomas Renton, 17 Emotional lability, corticosteroidinduced, 191 Endocrine therapy, history of, 13 b-Endorphin(s), 31, 34, 40–41 corticosteroid effects on cerebrospinal fluid levels of, 197 in Cushing’s syndrome, 182 in depression, 41–42 luteal-phase decreases in premenstrual syndrome, 253 in pregnancy and puerperium, 286 postpartum blues and, 290 secretion of, 167 Enkephalins, 40–41 Entrainment, 86 melatonin and, 88 in blind persons, 89, 90 Epinephrine, 15, 17 ERPs (event-related potentials), during dehydroepiandrosterone treatment, 220 Estraderm. See Estradiol, transdermal patch Estradiol, 247, 491–492 crystalline subcutaneous implants, for premenstrual syndrome, 314 effect on serotonergic receptors, 287 effects of dehydroepiandrosterone treatment on, 225, 226 levels during perimenopause, 271 measurement of, 492

Index after menopause, 246, 305 metabolism of testosterone to, 331 in normal menstrual cycle, 246, 492 normal values of, 490 placental production of, 286 in pregnancy and puerperium, 286–287 postpartum blues and, 290 postpartum depression and, 291 in premenopausal women, 308 premenstrual syndrome and, 252, 254, 256 protein binding of, 492 secretion of, 491 transdermal patch for postmenopausal women, 309 for premenstrual syndrome, 314 Estriol, 491–492 Estrogen(s), 491–492 effect on neurotransmitters, 287 effect on thyroid function, 386 for hormone replacement therapy, 305–312 (See also Hormone replacement therapy) adverse effects of, 311–312, 312 Alzheimer’s disease and, 307–308 antidepressant properties of, 305–306 cognitive effects of, 307–308 contraindications to, 311, 312 preparations and dosages of, 308–310 pros and cons of regimens of, 310–311 for male-to-female transsexuals, 321 measurement of, 492 in normal menstrual cycle, 246

563

in oral contraceptives, 315 for postmenopausal depression, 305, 306 in pregnancy and puerperium, 286–288 postpartum blues and, 290 postpartum depression and, 291, 293 for premenstrual syndrome, 314 prolactin regulation by, 108 role in mood, behavior, and anxiety disorders, 287–288, 303 Estrone, 491 in hormone replacement therapy, 308–309 in postmenopausal women, 308 in pregnancy and puerperium, 286–287 17a-Ethinyl testosterone, 313 Euthyroid sick syndrome, 363–365, 364, 485 anorexia nervosa and, 392, 395 Event-related potentials (ERPs), during dehydroepiandrosterone treatment, 220 Exercise-induced hypothalamicpituitary-adrenal axis activation, 477–478 Fatigue in Cushing’s syndrome, 176 dehydroepiandrosterone and dehydroepiandrosterone sulfate levels in chronic fatigue syndrome, 214 in diabetes mellitus, 116 postpartum, 282 Female-to-male transsexuals, anabolicandrogenic steroids for, 334 Fight-or-flight response, 19 Fluoxetine effect on cerebrospinal fluid corticotropin-releasing hormone concentration, 33 effect on thyroid function, 366

564

PSYCHONEUROENDOCRINOLOGY

Fluoxetine (continued) for postpartum depression, 293 use in diabetic patients, 118 Fluvoxamine, effect on thyroid function, 366, 378 Follicle-stimulating hormone (FSH), 246, 247, 247, 489–491 measurement of, 490–491 in men vs. women, 489–490 after menopause, 305, 491 normal values of, 490 during perimenopause and menopause, 271 in pregnancy and puerperium, 285–286 premenstrual syndrome and, 252, 255 secretion of, 304, 489–491 Four bodily humors, 10–11 Freud, Sigmund, 17 Frölich, Alfred, 18 FSH. See Follicle-stimulating hormone GABA (g-aminobutyric acid) corticosteroid effects on, 197 estrogen-induced increased activity of, 305 GABA (g-aminobutyric acid) type A receptors allopregnanolone binding to, 288, 319 3a-5a-tetrahydrodeoxycorticosterone modulation of, 289 Galactorrhea, 493 Galen, 11, 12 “General adaptation syndrome,” 20 Generalized anxiety disorder cholecystokinin in, 52 hypothalamic-pituitary-adrenal axis activity in, 38 thyroid function in, 388, 389 thyroid hormone treatment for, 459 Gerard, Ralph, 22

GHRH (growth hormone–releasing hormone), 47, 48, 492 Gigantism, 111–112 Globus hystericus, 420 Glucagon, 122 insufficiency of, 119, 122 metabolic effects of, 122 Glucagonoma, 122 Glucocorticoids. See also Antiglucocorticoid medications; Corticosteroids; specific hormones antidepressant action of, 190 effects on dendritic branching, 527–531, 529 effects on immune system, 515, 525 excess of, 172 (See also Cushing’s disease and Cushing’s syndrome) hippocampal receptors for, 505 paradoxical role of, 514–515 in stress response, 514, 519 containment, 519, 520, 522–523 Glycogen storage diseases, 119 GnRH (gonadotropin-releasing hormone), 246, 489 in pregnancy and puerperium, 285 secretion of, 304, 489 Goiter, 13 in Graves’ disease, 421 lithium-induced, 428 toxic multinodular, 421 Gonadal hormones, 6. See also specific hormones clinical psychotropic effects of gonadal hormone medications in women, 303–322 effects of female hormones on male-to-female transsexuals, 320–321 gonadotropin-releasing hormone analogs and estrogen for premenstrual syndrome, 312–315

Index hormone replacement therapy, 305–312 oral contraceptives, 315–317 progesterone and progestins, 318–320 tamoxifen and other estrogen antagonists, 317–318 evaluation of, 489–492, 490 (See also Neuroendocrine testing) interaction between brain, behavior and, 304–305 in menstrual cycle–related and perimenopause-related affective disorders, 245–272 in postpartum psychiatric disorders, 281–296 psychiatric effects of exogenous anabolic-androgenic steroids, 331–349 regulation of secretion of, 304 role in mood and anxiety disorders, 287–288 Gonadotropin-releasing hormone (GnRH), 246, 489 in pregnancy and puerperium, 285 secretion of, 304, 489 Gonadotropin-releasing hormone (GnRH) analogs, 313–315 for premenstrual syndrome, 313–315 Graves’ disease, 420. See also Thyrotoxicosis clinical features of, 423 epidemiology of, 421 onset of, 421, 422 pathogenesis of, 421 psychological coping and course of, 422 stress and, 421, 422, 525 thyrotoxicosis due to, 421 in twins, 421 Growth hormone, 47–48, 111–115, 492–493 in Alzheimer’s disease, 115 in anxiety disorders, 114

565

in depression, 48, 49, 50, 112–114, 492 measurement of, 492–493 psychiatric effects of deficiency of, 112–113, 119 psychiatric effects of overproduction of, 111–112 regulation of plasma levels of, 111 releasing and inhibiting factors for, 47, 48, 492 response to exogenous growth hormone–releasing hormone, 48 in schizophrenia, 114–115 secretion of, 47, 111, 492 treatment with, 112, 113 Growth hormone–releasing hormone (GHRH), 47, 48, 492 Gynecomastia, induced by anabolicandrogenic steroids, 331, 332 Hallucinations in hypothyroidism, 432, 433 induced by anabolic-androgenic steroids, 336 postpartum, 283 Haloperidol effect on neurotensin level, 53 for psychiatric symptoms of hypothyroidism, 435, 436 for psychiatric symptoms of thyrotoxicosis, 426 thyroid storm induced by, 426, 429 Hamilton Rating Scale for Depression (Ham-D), 149, 179, 180, 219, 333, 366, 502 Harris, Geoffrey, W., 19 Hashimoto’s (autoimmune) thyroiditis, 367–368, 430, 485–486 hCG (human chorionic gonadotropin), 253 in pregnancy and puerperium, 285 5-HIAA (5-hydroxyindoleacetic acid), 342

566

PSYCHONEUROENDOCRINOLOGY

Hippocampus in alcoholism, 506 in Alzheimer’s disease, 506 cognitive function of human subjects and changes in volume of, 533–534 corticosteroid effects on, 152, 197 serotonin receptor modulation, 197 in Cushing’s syndrome, 177, 505 in depression, 505–507, 526 effects of adrenal steroids on, 518, 526 effects of aging on, 505, 526–527, 533–534 glucocorticoid effects on dendritic branching in, 527–531, 529 glucocorticoid receptors in, 505 neurogenesis in adult dentate gyrus of, 531–533 neuroprotective effects of dehydroepiandrosterone on, 210 in posttraumatic stress disorder, 526 role in learning and memory, 517 serotonergic and noradrenergic modulation of responsiveness of, 517 Hippocrates of Cos, 11 Historical roots of neuroendocrinology, 4, 9–22, 10 ancient concepts, 10–11 birth of modern endocrinology, 14–15 development of neuroendocrinology, 18–19 early modern endocrinology, 11–13 era of organotherapy, 13–14 growth of appreciation for psychiatric aspects of endocrinologic disorders, 15–17 growth of modern neurochemistry, 17–18

homeostasis and stress, 19–20 HPA axis activity and depression, 20–21 present and future, 21–22 Histrionic personality disorder, insulin responses in, 122 HIV (human immunodeficiency virus) infection, anabolicandrogenic steroids for men with, 334 Homeostasis, allostasis, and stress, 19–20, 513, 518–519, 523, 524 Homovanillic acid, dexamethasone effect on plasma level of, 197 Hormone replacement therapy (HRT), 6, 271–272, 303–312 adverse effects of, 311–312, 312 cognitive effects of, 307–308 contraindications to, 311, 312 estrogen preparations and dosages for, 308–310 oral conjugated estrogens, 308–309 oral esterified estrogen and methyltestosterone, 309–310 transdermal patch, 309 indications for, 305 antidepressant augmentation, 306 osteoporosis prevention, 305 postmenopausal depression, 305, 306 mood and behavioral effects of, 306–307 prevalence of use of, 305 progesterone for, 303–304, 310–311 pros and cons of regimens for, 310–311 Hormones. See also specific hormones early definition of, 15 laboratory evaluation of, 469–494 (See also Neuroendocrine testing)

Index in pregnancy and puerperium, 284–289 Hostility/anger hyperprolactinemia and, 286 induced by anabolic-androgenic steroids, 335–337 serotonergic hypoactivity and, 521, 526 Hot flushes, 268, 271 HPA axis. See Hypothalamicpituitary-adrenal axis HPG (hypothalamic-pituitarygonadal) axis, 304, 489–490 assessment of, 489–492 (See also Neuroendocrine testing) hPL (human placental lactogen), 285 HPT (hypothalamic-pituitarythyroid) axis, 361–362 assessment of, 362–363, 419, 484–489 (See also Neuroendocrine testing) homeostatic control within, 362, 484 HRT. See Hormone replacement therapy 5-HT (5-hydroxytryptamine). See Serotonin 5-HTP (5-hydroxytryptophan), 47 Human chorionic gonadotropin (hCG), 253 in pregnancy and puerperium, 285 Human immunodeficiency virus (HIV) infection, anabolicandrogenic steroids for men with, 334 Human placental lactogen (hPL), 285 Hunter, John, 12 Huntington’s disease hypothalamic-pituitary-adrenal axis activity in, 37, 38 neurotensin in, 54 Hydrocortisone, cognitive effects of, 193 17-Hydroxycorticosteroid, 21 in pregnancy and puerperium, 289

567

3a-Hydroxy-5a-dihydroxyprogesterone, 288 5-Hydroxyindoleacetic acid (5-HIAA), 342 3a-Hydroxy-5a-pregnan-20-one, 319, 320 3a-Hydroxy-5a-pregnan-20-one, 319 17-Hydroxyprogesterone, 318 5-Hydroxytryptamine (5-HT). See Serotonin 5-Hydroxytryptophan (5-HTP), 47 Hypercalcemia, 123–124 in Addison’s disease, 169 Hypercholesterolemia, hypothyroidism and, 433 Hypercortisolemia. See also Cortisol antiglucocorticoid strategies for, 152–153 in Cushing’s syndrome, 165–166, 170, 171, 173 differential diagnosis of, 183 outcome and, 150–151 plasma sampling for diagnosis of, 474–475 specific symptoms associated with, 150 Hyperglucagonemia, 122 Hyperglycemia. See also Diabetes mellitus antidepressant-induced, 118 comorbidity with psychiatric illness, 115 glucagonoma and, 122 psychiatric effects of, 115–119 Hyperkalemia, in Addison’s disease, 168, 169 Hyperparathyroidism, 123–124 causes of, 123 hypercalcemia and, 123–124 psychiatric effects of, 123–124 prevalence of, 123 symptoms of, 123, 124 Hyperprolactinemia, 108–109. See also Prolactin anxiety and, 111, 286

568

PSYCHONEUROENDOCRINOLOGY

Hyperprolactinemia (continued) depression and, 109, 110, 286 “functional,” 108 gender-related effects of, 109 hostility and, 286 in pregnancy and lactation, 286 psychotic disorders and, 109 schizophrenia, 110–111 Hyperthyroidism, 420–429. See also Graves’ disease; Thyrotoxicosis cause of, 420 clinical features of, 423 differentiation from thyrotoxicosis, 421 early studies of behavioral changes in, 419–420 interactions between psychotropic drugs and, 428–429 antidepressants, 378–379, 428 antipsychotics, 428–429 lithium, 428 laboratory diagnosis of, 425 neuropsychiatric symptoms and signs of, 423–425, 445 in elderly persons, 423 prevalence of, 423, 424 panic disorder and, 388 Hyperthyroxinemia, transient, 363–365 Hypocalcemia, 124 Hypoglycemia, 119–120 antidepressant-induced, 118 causes of, 119 cognitive symptoms and, 119 comorbidity with psychiatric illness, 115 fasting, in Addison’s disease, 168 idiopathic postprandial, 119–120 insulin-induced, to stimulate hypothalamic corticotropinreleasing hormone release, 477 psychiatric effects of, 119–120 relationship between panic disorder and, 120 symptoms of, 120

Hypogonadotropic hypogonadism, 489 Hypokalemia, in Cushing’s syndrome, 172 Hypomania corticosteroid-induced, 191 in multiple sclerosis patients with family history of depression, 192 induced by anabolic-androgenic steroids, 338, 341 Hyponatremia, in Addison’s disease, 168, 169 Hypoparathyroidism, 124–125 causes of, 124 clinical symptoms of, 124 hypocalcemia and, 124 psychiatric effects of, 124–125 Hypopituitarism, 125–126 causes of, 125–126 clinical features of, 126 diagnosis of, 126 psychiatric effects of, 126 Hypothalamic-pituitary-adrenal (HPA) axis, 4, 5, 9, 31, 32, 139–154, 472–474 in Addison’s disease, 166–170 assessment of, 33–34, 139–144, 472–484 (See also Neuroendocrine testing) in Cushing’s syndrome/Cushing’s disease, 165–166, 170–184 dehydroepiandrosterone and dehydroepiandrosterone sulfate effects on, 222–223 in depression, 20–21, 31, 33, 144–145, 150, 499–500 adrenal gland enlargement, 35 corticotropin-releasing hormone, 32–34 cortisol hypersecretion, 35 dexamethasone suppression test nonsuppression, 35–36 dexamethasone–corticotropinreleasing hormone test, 36

Index imaging of, 499–507 adrenal pathology, 500–503 hippocampal changes, 505–506 pituitary pathology, 503–504 pituitary gland enlargement, 34 psychotic depression, 144–145 urinary free cortisol, 470 hypercortisolemia and specific symptoms, 150 major secretory products of, 472–474 circadian fluctuations in plasma levels of, 167, 474 mediation of stress responses by, 32, 32, 472, 514 containment of, 519, 520, 522–523 habituation vs. enhancement of, 522 in other psychiatric disorders, 37, 37–39, 147–150 anorexia nervosa, 39 anxiety disorders, 38 neurodegenerative disorders, 38–39 posttraumatic stress disorder, 38, 147–148 schizophrenia, 38, 148–150 Tourette’s syndrome, 39 physiology of, 166–167, 472–473 regulatory mechanisms of, 166, 472 relationship of hypercortisolemia to outcome, 150–152 Hypothalamic-pituitary-gonadal (HPG) axis, 304, 489–490 assessment of, 489–492 (See also Neuroendocrine testing) Hypothalamic-pituitary-thyroid (HPT) axis, 361–362. See also Thyroid function assessment of, 362–363, 419, 484–489 (See also Neuroendocrine testing)

569

homeostatic control within, 362, 484 Hypothalamic releasing factors, 4, 29, 30 clinical implications of alterations of, 58–60, 59 corticotropin-releasing hormone, 19, 31–40, 32 Hypothalamo-hypophyseal portal system, 43, 44 Hypothalamus, 18–19 corticotropin-releasing hormone– containing neurons in, 31 production of arginine vasopressin in, 473 regulation of corticotropinreleasing hormone secretion by, 472 Hypothyroidism, 429–436 abnormal circadian thyrotropin rhythm in, 368 anorexia nervosa and, 390, 392 bipolar disorder and, 374–375, 383, 456–459 thyroid hormone treatment for, 457–459 causes of, 429–431 central, 431, 484 clinical features of, 431 definition of, 429 depression and, 368–372, 370–371, 382 due to iodine deficiency, 430 due to resistance to thyroid hormone, 431 early studies of behavioral changes in, 420 epidemiology of, 429–430 grades of, 367, 367, 429, 430 hypercholesterolemia and, 433 iatrogenic, 430 idiopathic, 430 interaction between psychotropic drugs and, 436 lithium, 377, 428, 436

570

PSYCHONEUROENDOCRINOLOGY

Hypothyroidism (continued) laboratory diagnosis of, 433–434 neuropsychiatric symptoms and signs of, 431–433, 445 overt psychiatric manifestations, 433 prevalence of, 432, 432 treatment of, 434–435 primary, 429–430 recovery of psychiatric function after treatment of, 434, 434–435 seasonal affective disorder and, 375 secondary, 431 subclinical, 367, 367–368, 429, 430, 430, 435 causes of, 367 indications for treatment of, 368 progression to overt hypothyroidism, 368 tertiary, 431 IGF-I (insulin-like growth factor I), 111, 223, 492–493 Imaging studies, 7. See also specific imaging modalities of hypothalamic-pituitary-adrenal axis activity in depression, 499–507 adrenal pathology, 500–503, 506 hippocampal changes, 505–507 pituitary pathology, 503–504, 506–507 in vivo brain imaging to study thyroid system and brain activity, 436–437 Imipramine effect on thyroid function, 366, 378 triiodothyronine augmentation of, 452 Immune function glucocorticoid effects on, 515, 525 stress and, 524–525

Insomnia. See also Sleep disturbances in Cushing’s syndrome, 174, 176 delta sleep–inducing peptide in, 57 Insulin, 115–122 antidepressant effects on, 118 in Cushing’s disease, 172 in depression, 121, 525 in eating disorders, 121 glucocorticoid elevation and resistance to, 515, 523–524 in personality disorders and aggression, 121–122 psychiatric effects of hyperglycemia and diabetes, 115–119 psychiatric effects of hypoglycemia or overproduction of, 119–120 Insulin-induced hypoglycemia, to stimulate hypothalamic corticotropin-releasing hormone release, 477 Insulin-like growth factor I (IGF-I), 111, 223, 492–493 Insulin tolerance test (ITT), 107–108, 120 Insulinoma, 119, 120 Interleukin-1, 223 Interleukin-6, 223 Interpersonal therapy, for postpartum depression, 293 Involutional melancholia, 267, 269 Iodine deficiency, 430 Irritability in Cushing’s syndrome, 174, 183 in hyperthyroidism, 423 induced by anabolic-androgenic steroids, 335, 338 postpartum, 282 Isocarboxazid, effect on glucose regulation, 118 ITT (insulin tolerance test), 107–108, 120 Jet lag, 83, 84, 518 melatonin for, 98–99, 99

Index Ketoconazole antidepressant effects of, 152–153 in bipolar illness, 153 in schizophrenia and schizoaffective disorder, 153 for Cushing’s syndrome, 178 Kraepelin, Emil, 17 L-365,260, 52 Laboratory evaluation of neuroendocrine systems, 7, 469–494. See also Neuroendocrine testing Lamotrigine, to prevent steroid psychosis, 196 Laron dwarfism, 492–493 Learned helplessness, 525–526 Leptin, 394 Leucine-enkephalin (leu-enkephalin), 40, 41 Leuprolide acetate, for premenstrual syndrome, 256, 260–261, 314 Levonorgestrel, 316–317 LH. See Luteinizing hormone Light-dark cycles circadian rhythms and, 85, 86 melatonin secretion and, 87 b-Lipoprotein, corticosteroid effects on cerebrospinal fluid levels of, 197 b-Lipotropin, 41 in Cushing’s syndrome, 182 Lithium for augmentation of selective serotonin reuptake inhibitors, 460–461 contraindicated during breastfeeding, 294 effect on delta sleep–inducing peptide, 58 effects on thyroid function, 366, 377 lithium-induced hypothyroidism, 377, 428, 436

571

monitoring recommendations, 377 rapid-cycling bipolar disorder, 374 use in hyperthyroidism, 428 when combined with carbamazepine, 380 hyperparathyroidism induced by, 123 for steroid-induced psychopathology, 195–196, 198 Liver disease, thyroid function in alcoholic patients with, 385–386 Loewi, Otto, 18 Lupron. See Leuprolide acetate Luteal phase of menstrual cycle, 246. See also Premenstrual syndrome mood disorders in, 248–259 Luteinizing hormone (LH), 246, 247, 489–491 measurement of, 490–491 in men vs. women, 489–490 after menopause, 305, 491 normal values of, 490 in pregnancy and puerperium, 285–286 premenstrual syndrome and, 252, 255 secretion of, 304, 489–491 Magnetic resonance imaging in Cushing’s syndrome, 177 in depression adrenal gland enlargement, 35, 502 hippocampal changes, 505 pituitary gland enlargement, 35, 503–504 in eating disorders, 505 Magnetic resonance spectroscopy, studies of thyroid system and brain activity, 437 Male-to-female transsexuals, effects of female hormones in, 304, 320–321

572

PSYCHONEUROENDOCRINOLOGY

Mania. See also Bipolar disorder corticosteroid-induced, 190 dosage and, 192 in multiple sclerosis patients with family history of depression, 192 Cushing’s syndrome and, 176 dexamethasone suppression test in, 145–146 in hypercalcemia, 123 induced by anabolic-androgenic steroids, 336, 338, 341, 347 postpartum psychosis and, 284 during premenstrual phase, 262 in thyrotoxicosis, 425 treatment of, 426 MAOIs. See Monoamine oxidase inhibitors Maprotiline, effect on thyroid function, 366, 378 Maternity blues, 282, 290–291 consequences of, 291 endocrine factors in etiology of, 290 natural history of, 282 nonendocrine factors in etiology of, 290 prevalence of, 282 symptoms of, 282 treatment of, 290–291 mCPP (m-chlorophenylpiperazine), 111 MDAI (Multidimensional Anger Inventory), 337 Medroxyprogesterone acetate depot, for contraception, 316–317 for hormone replacement therapy, 310, 311 for male-to-female transsexuals, 321 Melancholia, involutional, 267, 269 Melanocyte-stimulating hormone (MSH), 32 in Addison’s disease, 168 in Cushing’s disease, 170

Melatonin, 4–5, 83–85, 87–102 biology of, 87 dosage of, 96, 101 effect on reproductive biology, 87 entraining effects of, 88 fad use of, 85 for jet lag, 98–99 light-dark cycles and secretion of, 87 for night-shift workers, 92–96, 94, 95 pharmacokinetics of, 101 phase resetting in humans by, 88–92, 90–92 in blind persons, 88–89 dim light melatonin onset, 89 phase response curves for, 87–88 safety of, 101–102 sleep-promoting (hypnotic) effects of, 84, 96–98, 98 interaction with chronobiotic effects, 98–100 species differences in phaseshifting effects of, 88 Melatonin analogs, 100 Memory enhancement of by dehydroepiandrosterone, 209, 220 by estrogen, 307 impairment of corticosteroid-induced, 191, 193–194, 515 in Cushing’s syndrome, 174, 176–177 hypothyroidism and, 432, 432, 433 progesterone metabolite–induced, 319 in thyrotoxicosis, 424 role of hippocampus in learning and, 517 MEN (multiple endocrine neoplasia) syndromes, 122, 123, 125

Index Menopause, 246–247, 305, 489. See also Postmenopausal women average age at onset, 265 gonadal hormone levels after, 305, 491 Menstrual cycle, 6, 245–246 behavioral effects of hormone changes during, 245 modulation of preexisting psychopathology by, 259–262, 263 normal, 246 recrudescence of previously experienced psychiatric illness triggered by, 262 Menstrual cycle–related mood disorders (MRMD), 248–259, 489. See also Premenstrual syndrome association with abnormal physiological events, 252–253, 254–255 case example of, 248 definition of, 248 luteal phase–specific mood disturbances, 250, 251 necessity of luteal phase for occurrence of, 253–259, 257, 258 research diagnostic criteria for premenstrual dysphoric disorder, 249 thyroid function in premenstrual dysphoric disorder, 389–390 Mental retardation, opioid antagonists for self-injurious behavior in, 42 Mesterolone, antidepressant effect of, 333 Metabolic alkalosis, in Cushing’s syndrome, 172 Methimazole, 366 Methionine-enkephalin (metenkephalin), 40, 41 3-Methoxy-4-hydroxyphenylglycol, corticosteroid effects on cerebrospinal fluid levels of, 197

573

Methyltestosterone with estrogen for hormone replacement therapy, 309–310 psychiatric effects of, 333 high-dose laboratory studies of, 341 Methysergide, 47 Metyrapone, for depression, 152 Mifepristone (RU 486), 253, 257–258 depression and adrenocorticotropic hormone response to, 522–523 for psychotic depression, 153 Minnesota Multiphasic Personality Inventory (MMPI), 335, 424, 426 Mitotane, for Cushing’s syndrome, 178, 180 MK-869, 56, 60 MMPI (Minnesota Multiphasic Personality Inventory), 335, 424, 426 Monoamine oxidase, estrogen inhibition of, 305, 306 Monoamine oxidase inhibitors (MAOIs) effect on glucose regulation, 118 effect on thyroid function, 377–378 neuroendocrine pathophysiology and actions of, 31 use in hyperthyroidism, 378, 428 Mood stabilizers. See also specific drugs for postpartum psychosis, 295 for steroid-induced psychopathology, 195–196, 198 MRMD. See Menstrual cycle–related mood disorders MSH (melanocyte-stimulating hormone), 32 in Addison’s disease, 168 in Cushing’s disease, 170 Mueller, Johannes, 12

574

PSYCHONEUROENDOCRINOLOGY

Multidimensional Anger Inventory (MDAI), 337 Multidimensional Personality Questionnaire, 337 Multiple endocrine neoplasia (MEN) syndromes, 122, 123, 125 Multiple sclerosis effects of dehydroepiandrosterone treatment in, 216 neuropsychiatric effects of adrenocorticotropic hormone for, 192 lithium prophylaxis for, 195–196 Murray, George, 13 Muscle dysmorphia, induced by anabolic-androgenic steroids, 343 Muscular dystrophy, anabolicandrogenic steroids for, 333 Myocardial infarction, serotonergic hypoactivity and, 521 Myxedema, 13, 16. See also Hypothyroidism Myxedema coma, 429, 435 “Myxedematous madness,” 420, 431 Nalmefene, in schizophrenia, 42 Naloxone, 42 provocative test for adrenocorticotropic hormone and cortisol response, 477 in schizophrenia, 42 for self-injurious behavior, 42 Naltrexone, for self-injurious behavior, 42–43 Nandrolone decanoate, 335 Narcolepsy, delta sleep–inducing peptide in, 57 Neodynorphin, 41 Neurodegenerative disorders arginine vasopressin in, 45 hypothalamic-pituitary-adrenal axis activity in, 37, 38–39 Neuroendocrine testing, 7, 469–494 appropriate use of, 471–472 in basal (nonstimulated) state, 470

of gonadotropins and sex steroids, 489–493, 490 estrogen and progesterone, 491–492 follicle-stimulating hormone and luteinizing hormone, 490–491 growth hormone, 492–493 prolactin, 493 testosterone, 491 of hypothalamic-pituitary-adrenal axis activity, 33–34, 139–144, 472–484 basal activity, 474–477 to differentiate depression from Cushing’s syndrome, 476–477 plasma adrenocorticotropic hormone and cortisol, 142, 474–475, 475 in refractory depression, 477 salivary cortisol, 141–143, 476 urinary free cortisol, 142, 143, 475, 475–476 methods and problems in, 482–484 provocative tests, 477–482 adrenocorticotropic hormone stimulation test, 169, 480–481 arginine vasopressin infusion, 480 corticotropin-releasing hormone stimulation test, 34, 478–480 dexamethasone suppression test, 33–34, 139–144, 153–154, 481–482 dexamethasone–corticotropin-releasing hormone test, 36, 143 exercise, 477–478 insulin-induced hypoglycemia, 477

Index naloxone administration, 477 of hypothalamic-pituitary-thyroid axis activity, 362–363, 419, 484–489 antithyroid antibodies, 485–486 assays for thyroid-stimulating hormone, 486–487 assays for thyroxine, 487–489, 488 basal hormone measurements, 485, 486 during lithium treatment, 377 provocative tests, 486 principles of, 470–471 provocative tests, 470–471 Neuroendocrine window strategy, 29, 31, 59 Neurokinin A, 56 Neurokinin B, 56 Neuroleptics. See Antipsychotics Neuronal atrophy, corticosteroidinduced, 197–198 Neuropeptide Y, 50, 54–56 anatomical distribution of, 55 in appetitive behaviors and anorexia, 55 corticotropin-releasing hormone and, 55 in depression and suicide victims, 55 receptors for, 55 Neuropeptide Y receptor agonists, 56 Neuropeptide Y receptor antagonists, 56 Neuropeptides, 4, 29. See also specific neuropeptides cholecystokinin, 50–52 clinical implications of alterations of, 58–60, 59 delta sleep–inducing peptide, 57–58 diazepam-binding inhibitor, 57 endogenous opioids, 40–43

575

neuropeptide Y, 54–56 neurotensin, 52–54 somatostatin, 47, 49–50 substance P, 56 Neurotensin, 52–54 in Alzheimer’s disease, 54 brain distribution of, 52–53 effects of antipsychotics on level of, 53 as endogenous neuroleptic, 53 in Huntington’s disease, 54 in schizophrenia, 53–54 antipsychotic effects on, 53 postmortem studies of, 53–54 Neurotensin receptor agonists, 54 Neurotensin receptor antagonists, 54 Neurotransmitters, 17–18, 29–30, 30 corticosteroid effects on, 181, 197 effects on glucose regulation, 118 endogenous opioid peptides as, 40 estrogen effects on, 287 prolactin regulation by, 108 stimulation of corticotropinreleasing hormone release by, 472 stress and, 519–522, 520 norepinephrine, 519–521 serotonin, 521–522 thyroid hormone effects on, 438 Night-shift work maladaptation, 83, 84 melatonin for, 92–96, 94, 95 Norepinephrine, 18, 29, 30 corticosteroid effects on cerebrospinal fluid levels of, 197 estrogen effects on receptors for, 287 modulation of hippocampal responsiveness by, 517 stimulation of corticotropinreleasing hormone release by, 472 stimulation of growth hormone release by, 47 stress and, 519–521, 520

576

PSYCHONEUROENDOCRINOLOGY

Norethindrone acetate, 311 Norplant. See Levonorgestrel Obesity arginine vasopressin in, 44 in binge-eating disorder, 394 in Cushing’s syndrome, 172 glucocorticoid elevation and, 515 Obsessive-compulsive disorder (OCD) depression and, 114 aminoglutethimide for, 153 growth hormone in, 114 hypothalamic-pituitary-adrenal axis activity in, 37, 38 prolactin in, 111 thyroid function in, 388, 389 17a-OH-pregnenolone, 473 17a-OH-progesterone, 473 Olanzapine for psychiatric symptoms of thyrotoxicosis, 426 for steroid psychosis, 195 Oliver, George, 14–15, 17 Opioid abuse/dependence, anabolicandrogenic steroid use and, 345 Opioid agonists, 42 Opioid antagonists, 42 in schizophrenia, 42 for self-injurious behavior, 42–43 Opioid peptides, endogenous, 40–43 classes of, 41 effect on thyrotropin secretion, 368 as neurotransmitters, 40 precursors of, 40–41 prolactin regulation by, 108 role in psychiatric disorders, 41 depression, 41–42 self-injurious behaviors, 42–43, 59 Oral contraceptives, 6, 303, 304, 315–317 modes of administration for, 315 mood and behavioral effects of, 315–316

pyridoxine deficiency and, 311 for women with history of depression, 311 Organotherapy, 13–14 Osmolality, plasma, 44 Osteoporosis, postmenopausal, 305 Ovariectomy, 16 Ovulation, 246, 247 clomiphene for induction of, 318 premenstrual syndrome and, 313 suppression of, 265, 313–314 Oxytocin, 44 Panhypopituitarism, 125–126 causes of, 125–126 clinical features of, 126 diagnosis of, 126 psychiatric effects of, 126 Panic disorder cholecystokinin in, 51–52 Cushing’s syndrome and, 176 dehydroepiandrosterone sulfate in, 213 growth hormone in, 114 hypothalamic-pituitary-adrenal axis activity in, 37, 38 during premenstrual phase, 262 prolactin in, 111 relationship between hypoglycemia and, 120 thyroid function in, 388, 389 thyroid hormone treatment for, 459, 460 Paranoia, hypothyroidism and, 432, 433 Parathyroid adenoma, 123 Parathyroid hormone, 123–125 factors affecting secretion of, 123 psychiatric effects of hyperparathyroidism, 123–124 psychiatric effects of hypoparathyroidism, 124–125 Parkinson’s disease arginine vasopressin in, 45

Index hypothalamic-pituitary-adrenal axis activity in, 37, 38 PD. See Psychotic depression Pentagastrin, 52 Perimenopause, 6, 246–247, 265–272 age window for, 265–266 behavioral effects of hormone changes during, 245 definition and characterization of, 265–266 occurrence of mood disturbances during, 266–267 relationships between mood disturbances and, 267–269 causal relationship, 269–271 symptoms of depression during, 267, 268 treatment of mood and behavioral disturbances during, 271–272 Personality disorders, insulin responses in, 121–122 Phencyclidine, 30 Phenelzine, effect on glucose regulation, 118 Phenothiazines. See also Antipsychotics for psychiatric symptoms of hypothyroidism, 435 for steroid-induced psychopathology, 195 use in hyperthyroidism, 429 Phentolamine, inhibition of growth hormone release by, 47 Pheochromocytoma, 123, 125, 169 Phototherapy, effect on thyroid function, 381 Pigmentation changes in Addison’s disease, 168 in Cushing’s disease, 170 Pituitary adenoma, thyrotropinsecreting, 421 Pituitary gland in alcoholism, 506 in eating disorders, 504–505

577

enlargement of, in depression, 34, 503–504, 506–507 magnetic resonance imaging of, 503–504 normal size and weight of, 503 Pituitary hormones, 18–19, 30 arginine vasopressin, 43–47, 472–473 growth hormone, 47–48, 111–115, 492–493 oxytocin, 44 panhypopituitarism, 125–126 prolactin, 108–111, 493 PMS. See Premenstrual syndrome POMC (pro-opiomelanocortin), 40–41, 167 in Addison’s disease, 168 POMS (Profile of Mood States), 336–339 Porteus maze, 425 Positron emission tomography, 60 studies of thyroid system and brain activity, 437 Postmenopausal women anabolic-androgenic steroids for, 334 dehydroepiandrosterone sulfate levels in, 212–213 depression in, 305, 306 hormone replacement therapy for, 6, 271–272, 303–312 (See also Hormone replacement therapy) osteoporosis in, 305 Postpartum psychiatric disorders, 6, 281–296 blues, 282, 290–291 consequences of, 291 endocrine factors in etiology of, 290 nonendocrine factors in etiology of, 290 treatment of, 290–291 classification of, 281

578

PSYCHONEUROENDOCRINOLOGY

Postpartum psychiatric disorders (continued) dehydroepiandrosterone supplementation and, 212 depression, 267, 282–283, 291–294 consequences of, 294 duration of, 283 endocrine factors in etiology of, 291–292 premenstrual syndrome and, 262 prevalence of, 282 psychotic vs. nonpsychotic, 282 recurrence of, 294 risk factors for, 282–283, 283, 292 severity of, 282 symptoms of, 282 thyroiditis and, 433 treatment of, 292–294 historical perspectives on, 281 menstrual cycle and, 262 psychosis, 262, 283–284, 294–296 bipolar disorder and, 283–284, 295 consequences of, 295–296 endocrine factors in etiology of, 294–295 incidence of, 283 nonendocrine factors in etiology of, 295 onset of, 283 recurrence of, 295–296 symptoms of, 283 treatment of, 295 role of endocrine changes in pregnancy and puerperium in etiology of, 281, 284–289 androgens, 288 corticosteroids, 289 b-endorphin, 286 estrogen, 286–288 follicle-stimulating hormone and luteinizing hormone, 285–286

gonadotropin-releasing hormone, 285 human chorionic gonadotropin, 285 human placental lactogen, 285 postpartum blues, 290 postpartum depression, 291–292 postpartum psychosis, 294–295 progesterone, 288 prolactin, 286 thyroid hormones, 288–289 Posttraumatic stress disorder (PTSD), 535–536 dexamethasone suppression test in, 38, 148 hippocampal atrophy in, 526, 536 hypothalamic-pituitary-adrenal axis activity in, 37, 38, 147–148 stress, 38, 148 thyroid function in, 388–389 Prednisone abuse potential for, 193 dehydroepiandrosterone cotreatment with, 196 neuropsychiatric effects of, 173, 190 in asthmatic children, 193 cognitive disturbances, 193 dosage and, 191 in multiple sclerosis patients with family history of depression, 192 sensory flooding, 191 Pregnancy. See also Postpartum psychiatric disorders dehydroepiandrosterone in, 212 depression during, 282–283 endocrine changes in, 284–289 androgens, 288 corticosteroids, 289 b-endorphin, 286 estrogen, 286–288

Index follicle-stimulating hormone and luteinizing hormone, 285–286 gonadotropin-releasing hormone, 285 human chorionic gonadotropin, 285 human placental lactogen, 285 progesterone, 288 prolactin, 286 thyroid hormones, 288–289, 488 use of antidepressants in, 293 5a-Pregnane-3,20-dione, 320 Pregnanolone, 319 premenstrual syndrome and, 252 Pregnenolone, 320, 473 Pregnenolone sulfate, 319–320 Premarin. See Hormone replacement therapy Premenstrual dysphoric disorder, 248 prevalence of, 313 research diagnostic criteria for, 249, 250 thyroid function in, 389–390 Premenstrual syndrome (PMS), 248–259. See also Menstrual cycle–related mood disorders Daily Rating Form for, 264 depression self-ratings in, 250, 251 etiology of, 313 evaluation of patient with, 264 menstrual cycle–related hormone changes and, 252–253, 254–255 mood side effects of hormone replacement therapy in women with history of, 310–311 mood side effects of oral contraceptives in women with history of, 316 operational definition of, 250 postpartum behavioral changes and, 262, 290

579

prevalence of, 250, 312–313 role of ovulation in pathophysiology of, 313 treatment of, 264–265 antidepressants, 315 estrogen, 314 gonadotropin-releasing hormone analogs and estrogen, 313–314 leuprolide, 256, 260–261, 314 progesterone, 264, 320 symptomatic, 315 Pro-opiomelanocortin (POMC), 40–41, 167 in Addison’s disease, 168 Prodynorphin, 41 Proenkephalin, 41 Profile of Mood States (POMS), 336–339 Progesterone, 247, 492 brain receptors for, 319 in hormone replacement therapy, 303–304, 310–311 (See also Hormone replacement therapy) measurement of, 492 after menopause, 246, 305 metabolites of, 288, 319 mood and behavior effects of progestins and, 318–320 in normal menstrual cycle, 246, 318, 320, 492 normal values of, 490 in oral contraceptives, 310, 315–316 in pregnancy and puerperium, 288 postpartum blues and, 290 postpartum depression and, 291 for premenstrual syndrome, 264, 320 premenstrual syndrome and, 252, 254, 256 protein binding of, 492 Proglumide, 51

580

PSYCHONEUROENDOCRINOLOGY

Prolactin, 108–111, 493. See also Hyperprolactinemia in anxiety, 111, 286 in bipolar disorder, 111 deficiency of, 109 in depression, 109, 110, 286 dopamine regulation of, 108, 286, 493 fenfluramine-induced increase in, 110 galactorrhea and plasma levels of, 493 measurement of, 493 in pregnancy and puerperium, 286 role in inducing psychiatric symptoms, 108–109 role in lactation, 286, 493 in schizophrenia, 110–111 secretion of, 108, 362, 493 Prolactinoma, 108, 109 Propranolol, for psychiatric symptoms of thyrotoxicosis, 425 combined with propylthiouracil, 426 Propylthiouracil combined with propranolol for mania in thyrotoxicosis, 426 effects in alcoholic patients with liver disease, 385 Provera. See Medroxyprogesterone acetate Provocative tests, 470–471. See also Neuroendocrine testing of growth hormone release, 493 of hypothalamic-pituitary-adrenal axis activity, 477–482 of thyroid function, 486 Psychoneuroendocrinology clinical importance of, 3 history of, 4, 9–22, 10 paths of investigation in, 4 Psychopharmacologic bridge technique, 31, 59 Psychosis. See also Schizophrenia

corticosteroid-induced, 139, 173, 190, 191 dosage and, 192 treatment of, 195 hyperparathyroidism and, 123 hypoparathyroidism and, 125 hypopituitarism and, 126 hypothyroidism and, 431–433, 432 treatment of, 435 induced by anabolic-androgenic steroids, 336 postpartum, 262, 283–284, 294–296 bipolar disorder and, 283–284, 295 consequences of, 295–296 endocrine factors in etiology of, 294–295 incidence of, 283 menstrual cycle and, 262 nonendocrine factors in etiology of, 295 onset of, 283 recurrence of, 295–296 symptoms of, 283 treatment of, 295 in thyrotoxicosis, 424, 425 Psychostimulants, 30 Psychotherapy, for postpartum depression, 293 Psychotic depression (PD), 21, 33 antiglucocorticoid strategies for, 152–153 dexamethasone suppression test in, 141, 144–145 postpartum, 282, 283 PTSD. See Posttraumatic stress disorder Public Law 101-647 (Anabolic Steroids Control Act of 1990), 332 Public Law 103-417 (Dietary Supplement Health and Education Act of 1994), 207 Pyridoxine deficiency, 311

Index Raloxifene, 318 Reserpine, 30 Reverse triiodothyronine (rT3), 362, 484 in anorexia nervosa, 393 in depression, 365 Rheumatoid arthritis, 525 Risperidone, for psychiatric symptoms of thyrotoxicosis, 426 Rosenzweig Picture-Frustration Study, 336 rT3 (reverse triiodothyronine), 362, 484 in anorexia nervosa, 393 in depression, 365 RU 486 (mifepristone), 253, 257–258 depression and adrenocorticotropic hormone response to, 522–523 for psychotic depression, 153 Rush, Benjamin, 16 S20098, 100 SAD. See Seasonal affective disorder Salivary cortisol test, 141–143, 476 Scale for Assessment of Negative Symptoms (SANS), 149 Schäfer, Edward A., 15, 17 Schedule for Affective Disorders and Schizophrenia, 267 Schizoaffective disorder, ketoconazole for, 153 Schizophrenia. See also Psychosis arginine vasopressin in, 46–47 cholecystokinin in, 51 dehydroepiandrosterone and dehydroepiandrosterone sulfate levels in, 213–214 depression and, 148–149 ketoconazole for, 153 endogenous opioid peptides in, 41 growth hormone in, 114–115 hypothalamic-pituitary-adrenal axis activity in, 38, 148–150 dexamethasone suppression test, 141, 145, 148–150

581

relationship between hypercortisolemia and outcome, 151 negative symptoms of, 149 neurotensin in, 53–54 opioid antagonists in, 42 prolactin in, 110–111 suicidality and, 148–149 thyroid function in, 363, 364, 395–396 antithyroid antibodies, 372 cerebrospinal fluid studies, 376 early studies, 395 effects of somatic treatments, 396 peripheral thyroid hormones, 395–396 thyrotropin and antithyroid antibodies, 396 SCID (Structured Clinical Interview for DSM-III), 336, 338, 339 SCL-90 (Symptom Checklist–90), 337, 339 SCN (suprachiasmatic nucleus), circadian rhythms and, 85–87, 86, 166 melatonin effects on, 88 Scopolamine, 209 Seasonal affective disorder (SAD), 83 insulin responses in, 121 thyroid function in, 367, 375 effects of phototherapy, 381 Secretin, 15 Sedative-hypnotics, use in hypothyroidism, 436 Seizures, in hypoparathyroidism, 124 Selective serotonin reuptake inhibitors (SSRIs) effects on glucose regulation, 118 estrogen augmentation of, 306 lithium augmentation of, 461 for premenstrual syndrome, 265, 315 for steroid-induced psychopathology, 198

582

PSYCHONEUROENDOCRINOLOGY

Selective serotonin reuptake inhibitors (SSRIs) (continued) use in Addison’s disease, 170 use in hyperthyroidism, 379 use in with Cushing’s syndrome, 179 Self-injurious behavior, opioid antagonists for, 42–43 Selye, Hans, 7–8, 20 Semon, Felix, 13 “Sensory flooding,” corticosteroidinduced, 191 Serotonin (5-HT), 29, 30 effect on glucose regulation, 118 glucocorticoid regulation of, 521 glucose metabolism in low serotonin syndrome, 122 modulation of hippocampal responsiveness by, 517 premenstrual syndrome and luteal phase decreases in platelet uptake of, 253 prolactin regulation by, 108 psychiatric effects of serotonergic hypoactivity, 521–522 receptors for estrogen effects on, 287 hippocampal, corticosteroid effects on, 197 stimulation of corticotropinreleasing hormone release by, 472 stress and, 520, 521–522, 535 Sertraline effect on thyroid function, 366, 379 for postpartum depression, 293 use in diabetic patients, 118 Sex hormone–binding globulin (SHBG), 491, 492 Sexual dysfunction Cushing’s syndrome and, 176 diabetes mellitus and, 116 SHBG (sex hormone–binding globulin), 491, 492

Sheehan’s syndrome, 125–126, 293 Simmonds’ disease, 125 Simple phobia, prolactin in, 111 Sleep deprivation, effect on thyroid function, 366, 381 Sleep disturbances circadian rhythm disorders, 83–84, 84 melatonin for, 98–100, 99 in Cushing’s syndrome, 174, 176 delta sleep–inducing peptide in, 57 postpartum, 282 Social phobia growth hormone and, 112, 114 prolactin and, 111 Social withdrawal, in Cushing’s syndrome, 175 Somatostatin, 47, 49–50, 492 in Alzheimer’s disease, 50, 59 brain distribution of, 47 corticosteroid effects on cerebrospinal fluid levels of, 197 in depression, 49, 50 functions of, 49 secretion of, 47 Spinocerebellar degeneration, hypothalamic-pituitary-adrenal axis activity in, 39 SSRIs. See Selective serotonin reuptake inhibitors Starling, Ernst, 15 Stress, 7–8, 513–536. See also Posttraumatic stress disorder Addison’s disease and, 168, 170 allostasis and, 513, 516, 518–519, 523, 524 allostatic load, 513, 514, 516, 523 vs. homeostasis, 19–20, 513, 518–519 anxiety and, 513 arginine vasopressin modulation of response to, 480 brain as controller of and target for, 515–518

Index chronic, 513 connections between disease and, 513, 514 contributors to experience being interpreted as stressful, 514, 516 Cushing’s disease and, 171 definition of, 518 dehydroepiandrosterone and dehydroepiandrosterone sulfate levels and, 208, 212 depression and, 525–526, 535 diabetes and, 116, 525 “general adaptation syndrome” to, 20 glucocorticoid effects on dendritic branching and neurobiology of, 527–532, 529 Graves’ disease and, 421, 422, 525 heightened sympathetic reactivity, glucocorticoid increase, insulin hypersecretion, insulin resistance and, 523–524 human studies of changes in hippocampal volume, cognitive function and, 533–534 hypothalamic-pituitary-adrenal axis response to, 32, 32, 472 adrenal steroids and adaptation to stress, 518 containment of, 519, 520, 522–523 glucocorticoid secretion, 514, 519, 535 immune function and, 524–525 individual differences in aging and risk for dementia and, 526–527, 528 as individualized response, 514, 518 neurogenesis in adult dentate gyrus and, 531–533 noradrenaline and, 519–521, 520 perceived, 518

583

rheumatoid arthritis and, 525 serotonin and, 520, 521–522, 535 Structured Clinical Interview for DSM-III (SCID), 336, 338, 339 Substance P, 56 brain distribution of, 56 in depression, 56 functions of, 56 Substance P antagonists, 56 Suicidality adrenal gland enlargement and, 35, 501 corticosteroid-induced, 190 corticosteroid-withdrawal, 194 corticotropin-releasing hormone receptor density and, 34 cortisol level and, 181 Cushing’s syndrome and, 174, 502 neuropeptide Y and, 55 postpartum, 282 premenstrual, 259 among schizophrenic patients, 148–149 serotonergic hypoactivity and, 521 Suprachiasmatic nucleus (SCN), circadian rhythms and, 85–87, 86, 166 melatonin effects on, 88 “Sympathico-adrenal medullary system,” 19 Symptom Checklist–90 (SCL-90), 337, 339 Systemic lupus erythematosus effects of dehydroepiandrosterone treatment in, 216 neuropsychiatric effects of steroids for, 190 differentiation from lupus cerebritis, 190–191 Systen. See Estradiol, transdermal patch T3. See Triiodothyronine T4. See Thyroxine Tachykinins, 56

584

PSYCHONEUROENDOCRINOLOGY

Takamine, Jokichi, 15 Tamoxifen, 304, 317–318 for breast cancer, 317–318 depression related to, 317–318 effect on bone mineral density, 317 mood and behavior effects of, 317–318 TBG. See Thyroxin-binding globulin TBPA (thyroxine-binding prealbumin), 361 TCAs. See Antidepressants, tricyclic Testosterone, 331, 491 androgen receptor binding of, 331 androgenic effects of, 331 antidepressant effects of, 333 chemical structure of, 331 clinical studies of psychiatric effects of, 332–333 in Cushing’s syndrome, 182 effects of dehydroepiandrosterone treatment on, 225, 226 with estrogen for hormone replacement therapy, 309–310, 334 measurement of, 491 metabolism to estradiol, 331 normal values of, 490 ovarian failure and deficiency of, 309 for perimenopause-related depression, 272 in pregnancy and puerperium, 288 postpartum depression and, 291 protein binding of, 491 secretion of, 491 synthetic analogs of, 331 (See also Anabolic-androgenic steroids) Testosterone cypionate, 341 Testosterone decanoate, 335 Testosterone enanthate, 335 Testosterone/estradiol–binding globulin, 491 Tetany, in hypoparathyroidism, 124 3a-5a-Tetrahydrodeoxycorticosterone, 289

3a,5a-Tetrahydroprogesterone (3a,5a-THP), 320 Tetraiodothyronine. See Thyroxine THBR (thyroid hormone binding ratio), 487–488 3a,5a-THP (3a,5a-tetrahydroprogesterone), 320 Thyroid adenoma, 421 Thyroid carcinoma, 123, 125 Thyroid function, 6–7, 361–398, 484. See also Hyperthyroidism; Hypothyroidism; Thyrotoxicosis in alcoholism, 376, 383–387 abstinent patients with liver disease, 385–386 abstinent patients without liver disease, 384 during acute alcohol withdrawal, 383–384 cerebrospinal fluid studies, 386–387 effects of ethanol administration, 383 subjects at risk for developing alcoholism, 386 in anxiety disorders, 376, 388–389 cerebrospinal fluid studies, 389 panic disorder, 388, 389 peripheral thyroid hormones, 388–389 thyrotropin and antithyroid antibodies, 389 in bipolar disorder, 366–367, 372–375, 383 antithyroid antibodies, 372, 373 cerebrospinal fluid studies, 376 rapid cycling and, 374–375 brain, behavior and, 419–438, 484 early studies of, 419–420 in hyperthyroidism and thyrotoxicosis, 420–429 in hypothyroidism, 429–436 in vivo brain imaging of, 436–437

Index in depression, 363, 364, 365–366, 368–372, 381–382 abnormal circadian thyrotropin rhythm, 368, 369 antithyroid antibodies, 372, 373 cerebrospinal fluid studies, 375, 376 peripheral thyroid hormones, 363, 364, 365–366 subclinical hypothyroidism, 368–372, 370–371 thyrotropin sources of variance, 372 in eating disorders, 390–395 anorexia nervosa, 390–393, 391 binge-eating disorder, 394 bulimia nervosa, 393–394 effects of somatic treatments on, 377–381 carbamazepine and valproic acid, 379–380 electroconvulsive therapy, 380 lithium, 377 monoamine oxidase inhibitors, 377–378 neuroleptics, 396 phototherapy, 381 sleep deprivation, 381 tricyclic antidepressants, 378–379 in general psychiatric population, 363–365, 364, 420 physiology of, 361–362 in pregnancy and puerperium, 288–289, 488 postpartum depression, 291–292 in premenstrual dysphoric disorder, 389–390 prevalence of disorders of, 420 in schizophrenia, 395–396 early studies, 395 effects of somatic treatments, 396 peripheral thyroid hormones, 395–396

585

thyrotropin and antithyroid antibodies, 396 in seasonal affective disorder, 367, 375 Thyroid function tests, 362–363, 484–489 antithyroid antibodies, 485–486 assays for thyroid-stimulating hormone, 486–487 assays for thyroxine, 487–489, 488 basal hormone measurements, 485, 486 during lithium treatment, 377 provocative tests, 486 Thyroid hormone binding ratio (THBR), 487–488 Thyroid hormone treatment, 398, 445–461. See also specific thyroid hormones for anxiety disorders, 446, 459, 460 for bipolar disorder, 374–375, 446, 456–460 for depression, 372, 446–456, 460–461 approaches to, 446 thyroid-stimulating hormone, 448 thyrotropin-releasing hormone, 446–448 combined with electroconvulsive therapy, 447–448 monotherapy, 447 thyroxine, 448–449 triiodothyronine, 449–456 to accelerate antidepressant response, 450–451 for antidepressant augmentation, 451–456, 452, 456, 460–461 combined with electroconvulsive therapy, 450 monotherapy, 449–450 side effects and tolerability of, 453–454

586

PSYCHONEUROENDOCRINOLOGY

Thyroid hormone treatment (continued) history of, 13, 14, 16 for hypothyroidism, 434–435 rationale for use in psychiatric disorders, 445–446 thyrotoxicosis induced by, 421 Thyroid hormones, 361–398, 484. See also specific hormones neuroregulatory role of, 362, 363 normal values for, 486 Thyroid-stimulating hormone (TSH), 361, 484 abnormal circadian rhythm of, 368, 369 abnormal responses to thyrotropinreleasing hormone in psychiatric disorders, 419 in alcoholism, 387 abstinent patients with liver disease, 385–386 abstinent patients without liver disease, 384 during acute alcohol withdrawal, 384 subjects at risk for developing alcoholism, 386 in anorexia nervosa, 368, 391, 392–393 in anxiety disorders, 389 assays of, 362, 367, 425, 485–487, 486 biosynthesis and release of, 361, 484 hypothyroidism due to diminished release, 431 in bulimia nervosa, 394 in depression, 365, 382 abnormal circadian rhythm, 368, 369 sources of variance, 372 in hypothyroidism, 367, 367, 429, 433–434 normal values for, 486 in pregnancy and puerperium, 289

in premenstrual dysphoric disorder, 390 in rapid-cycling bipolar disorder, 374 in schizophrenia, 396 in seasonal affective disorder, 375 in thyrotoxicosis, 421, 425 in treatment of psychiatric disorders, 446 depression, 448 Thyroidectomy, 362 Thyrotoxicosis. See also Graves’ disease; Hyperthyroidism causes of, 421 definition of, 421 differentiation from hyperthyroidism, 421 due to exogenous thyroid hormone administration, 421 factitia, 421 interactions between psychotropic drugs and, 428–429 antidepressants, 378–379, 428 antipsychotics, 428–429 lithium, 428 laboratory diagnosis of, 425 lithium-induced, 377 neuropsychiatric symptoms and signs of, 423–425 treatment of, 425–426 onset of, 421, 422 psychological coping and course of, 422 recovery of psychiatric function after treatment of, 425–426, 427 subclinical, 421, 425 Thyrotropin. See Thyroid-stimulating hormone Thyrotropin-releasing hormone (TRH), 361–362, 484 in brain, 419 cerebrospinal fluid concentrations in alcoholic patients, 386–387

Index effects of exogenous administration of, 446 functions of, 446, 484 hypothyroidism due to diminished release of, 431 prolactin regulation by, 108, 362 in treatment of depression, 446–448 combined with electroconvulsive therapy, 447–448 monotherapy, 447 in treatment of psychiatric disorders, 446 Thyroxin-binding globulin (TBG), 361 in anorexia nervosa, 390–392, 391 in bulimia nervosa, 394 in pregnancy and puerperium, 289 Thyroxine (T4), 361–362, 484 in alcoholism, 384–385 abstinent patients with liver disease, 385 abstinent patients without liver disease, 384 during acute alcohol withdrawal, 384 in anorexia nervosa, 390–392, 391 in anxiety disorders, 388–389 assays for total or free thyroxine, 362, 485, 486, 487–489 conditions causing alterations in, 488, 488–489 biosynthesis and release of, 361, 484 in bipolar disorder, 366–367 in bulimia nervosa, 394 in depression, 365–366, 381–382 evidence for neuroregulatory role of, 362, 363 in general psychiatric population, 364 for hypothyroidism, 434–435 in hypothyroidism, 367, 367, 433–434 normal values for, 486

587

in pregnancy and puerperium, 288–289 postpartum depression and, 292 in premenstrual dysphoric disorder, 390 protein binding of, 361, 485 in schizophrenia, 395–396 in thyrotoxicosis, 421, 425 transient hyperthyroxinemia, 363–365 in treatment of psychiatric disorders, 446 bipolar disorder, 457–459 non–rapid cycling, 457–458 rapid cycling, 458–459 depression, 448–449 Thyroxine-binding prealbumin (TBPA), 361 Tourette’s syndrome, hypothalamicpituitary-adrenal axis activity in, 39 Trail Making Tests, 425 Transsexuals female-to-male, anabolicandrogenic steroids for, 334 male-to-female, effects of female hormones on, 304, 320–321 Tranylcypromine, effect on glucose regulation, 118 TRH. See Thyrotropin-releasing hormone Tricyclic antidepressants. See Antidepressants, tricyclic Triiodothyronine (T3), 361–362, 484 in alcoholism, 387 abstinent patients with liver disease, 385, 386 abstinent patients without liver disease, 384 in anorexia nervosa, 390–392, 391, 395 in anxiety disorders, 388–389 assays for free triiodothyronine, 361, 486

588

PSYCHONEUROENDOCRINOLOGY

Triiodothyronine (T3) (continued) biosynthesis and release of, 361, 484 in bulimia nervosa, 393–394 circulating, 361 evidence for neuroregulatory role of, 362, 363 in general psychiatric population, 364 for hypothyroidism, 435 in hypothyroidism, 367, 367 normal values for, 486 in pregnancy and puerperium, 289 postpartum depression and, 292 in premenstrual dysphoric disorder, 390 protein binding of, 361 regulation of brain levels of, 362 reverse (rT3), 362, 484 in anorexia nervosa, 393 in depression, 365 in schizophrenia, 395–396 in thyrotoxicosis, 421, 425 in treatment of anxiety disorders, 459 in treatment of depression, 449–456 to accelerate antidepressant response, 450–451 for antidepressant augmentation, 451–456, 452, 460–461 antidepressant class and, 454–455, 460–461 mechanism of action of, 455 precautions for use in elderly cardiac patients, 454 recommendations for, 456, 456

side effects and tolerability of, 453–454 combined with electroconvulsive therapy, 450 monotherapy, 449–450 in treatment of psychiatric disorders, 446 Triiodothyronine (T3) resin uptake test, 487 L-Tryptophan, 47 TSH. See Thyroid-stimulating hormone Tumor necrosis factor a, 223 Tyrosine hydroxylase, 519–520 Urinary free cortisol (UFC), 142, 143, 151 in Cushing’s syndrome, 476, 479 in depression, 502 measurement of, 470, 475, 475–476 Valproic acid effect on thyroid function, 380 to prevent steroid psychosis, 196 Vasopressin. See Arginine vasopressin Venlafaxine, for postpartum depression, 293 Violence/aggression dehydroepiandrosterone effects in animals, 209 induced by anabolic-androgenic steroids, 335, 337–339, 344–345, 349 insulin responses and, 121–122 von Euler, Ulf, 18 von Haller, Albert, 12 “Windows into the brain,” 3, 5 Zeitgebers, 85