Bipolar Psychopharmacotherapy: Caring for the Patient

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Bipolar Psychopharmacotherapy

Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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Bipolar Psychopharmacotherapy Caring for the Patient Editors

Hagop S. Akiskal International Mood Center, University of California at San Diego, La Jolla, CA, USA

and

Mauricio Tohen Lilly Research Laboratories, Indianapolis, IN and McLean Hospital, Harvard Medical School, Belmont, MA, USA

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Copyright © 2006

John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777

Email (for orders and customer service enquiries): [email protected] Visit our Home Page on www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher. Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England, or emailed to [email protected], or faxed to (+44) 1243 770620. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The Publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the Publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103–1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 33 Park Road, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02–01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 22 Worcester Road, Etobicoke, Ontario, Canada M9W 1L1 Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Library of Congress Cataloging in Publication Data Bipolar psychopharmacotherapy : caring for the patient / editors, Hagop S. Akiskal and Mauricio Tohen. p. cm. Includes bibliographical references and index. ISBN-13 978-0-470-85607-9 (cloth : alk. paper) ISBN-10 0-470-85607-6 (cloth : alk. paper) 1. Manic-depressive illness—Chemotherapy. 2. Lithium—Therapeutic use. 3. Antipsychotic drugs. 4. Psychopharmacology. [DNLM: 1. Bipolar Disorder—drug therapy. 2. Anticonvulsants—therapeutic use. 3. Antimanic Agents—therapeutic use. 4. Antipsychotic Agents—therapeutic use. 5. Bipolar Disorder—prevention & control. WM 207 B6176 2006] I. Akiskal, Hagop S. II. Tohen, Mauricio. RC516.B529 2006 616.89′5061—dc22 2005013978 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN-13 978-0-470-85607-9 (HB) ISBN-10 0-470-85607-6 (HB) Typeset in 11/13pt Times by Integra Software Services Pvt. Ltd, Pondicherry, India Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.

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Dedication This book is dedicated to bipolar patients and their families, for the privilege of caring for them.

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Contents

List of Contributors Preface Chapter 1

ix xiii

The Scope of Bipolar Disorders Hagop S. Akiskal

Chapter 2 Lithium Treatment: Focus on Long-Term Prophylaxis Mogens Schou and Paul Grof Chapter 3 Valproate: Clinical Pharmacological Profile Charles L. Bowden and Vivek Singh

1

9

27

Chapter 4 Pharmacological Profile and Clinical Utility of Lamotrigine in Bipolar Disorders David J. Muzina, Joseph R. Calabrese

43

Chapter 5 Carbamazepine, Other Anticonvulsants and Augmenting Agents Heinz Grunze

63

Chapter 6 Olanzapine in Treatment for Bipolar Disorder Mauricio Tohen, Giedra Campbell, and Daniel Lin Chapter 7 Haloperidol and Risperidone in Mania John Cookson Chapter 8 A Comparison of “Second Generation Antipsychotics” in the Treatment for Bipolar Disorder: Focus on Clozapine, Quetiapine, Ziprasidone and Aripiprazole Paul E. Keck, Jr. and Susan L. McElroy

85

105

125

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viii Chapter 9

Contents Complex Combination Therapy: The Evolution Toward Rational Polypharmacy in Lithium-Resistant Bipolar Illness Robert M. Post, Andrew M. Speer and Gabriele S. Leverich

Chapter 10 The Primacy of Mania Athanasios Koukopoulos Chapter 11 Diagnostic and Clinical Management Approaches to Bipolar Depression, Bipolar II and Their Comorbidities Giulio Perugi, S. Nassir Ghaemi and Hagop S. Akiskal Chapter 12 Bipolarity in Women: Therapeutic Issues Susan L. McElroy, Lesley M. Arnold and Lori L. Altshuler Chapter 13 Pediatric Bipolar Disorder: The Promise of Psychopharmacotherapy Joseph Biederman Chapter 14 Treatment for Bipolar Disorder in Older Adults Kenneth I. Shulman

135

169

193

235

279

301

Chapter 15 Psychosocial Interventions in Bipolar Disorders: Rationale and Effectiveness David J. Miklowitz

313

Chapter 16 The Pivotal Role of Psychoeducation in the Long-Term Treatment of Bipolar Disorder Francesc Colom and Eduard Vieta

333

Chapter 17 The Role of Treatment Setting in the Pharmacotherapy of Bipolar Disorder Jean-Michel Azorin

347

Chapter 18 Suicide Prevention Zoltán Rihmer

353

Chapter 19 Principles of Caring for Bipolar Patients Hagop S. Akiskal and Kareen K. Akiskal

367

Index

389

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List of Contributors

Hagop S. Akiskal, International Mood Center, Department of Psychiatry at the University of San Diego and Veterans Administration Medical Center, 3350 La Jolla Village Dr. (116-A), San Diego, CA 92161, USA Kareen K. Akiskal, International Mood Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA Lori L. Altshuler, UCLA Mood Disorders Research Program, UCLA, USA Lesley M. Arnold, Women’s Health Research Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA Jean-Michel Azorin, Department of Psychiatry, Ste Marguerite Hospital, 13274 Marseille Cedex 9, France Joseph Biederman, Pediatric Psychopharmacology Unit (ACC 725), Massachusetts General Hospital, 15 Parkman Street, Boston, MA 02114-3139, USA Charles L. Bowden, Department of Psychiatry, Mail Code 7792, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio TX 78229-3900, USA Joseph R. Calabrese, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106, USA Giedra Campbell Lilly, Research Laboratories, Eli Lilly & Co, 525 S. Meridian Street, Indianapolis, IN 46225, USA Francesc Colom, Bipolar Disorders Program, Stanley Research Center, IDIBAPS, Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain John Cookson, Royal London Hospital, St Clement’s, 2A Bow Road, London E3 4LL, UK

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x

List of Contributors

S. Nassir Ghaemi, Bipolar Disorder Research Program, Cambridge Hospital, Department of Psychiatry and Harvard University, Cambridge, MA 02139, USA Paul Grof, Deparmtent of Psychiatry, University of Ottawa, Royal Ottawa Hospital, 1145 Carling Avenue, Ottawa, Ontario K2E 7L2, Canada Heinz Grunze, Psychiatrische Klinik und Poliklinik LMU München, Ludwig Maximilians Universität München, Nussbaumstrasse 7, D-80336 Munich, Germany Paul E. Keck, University of Cincinnati College of Medicine, Department of Psychiatry, 231 Albert Sabin Way, ML 559, Cincinnati, OH 45267-0559, USA Athanasios Koukopoulos, Centro Lucio Bini, Via Crescenzio 42, 00193 Rome, Italy Gabriele S. Leverich, Biological Psychiatry Branch, National Institute of Mental Health, Bldg. 10, 10 Center Drive MSC 1272, Bethesda, MD 20892-1272, USA Daniel Lin Lilly, Research Laboratories, Eli Lilly & Co, 525 S. Meridian Street, Indianapolis, IN 46225, USA Susan L. McElroy, Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA David J. Miklowitz, Department of Psychology, Davie Hall CB#3270, University of North Carolina, Chapel Hill, NC 27599-3270, USA David Muzina, Department of Psychiatry and Psychology, Desk P-57, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA Giulio Perugi, Institute of Psychiatry, Via Roma 67, 56100 Pisa, Italy Robert M. Post, Biological Psychiatry Branch, National Institute of Mental Health, Bldg. 10, Rm. 3s239, 10 Center Drive MSC 1272, Bethesda, MD 20892-1272, USA Zoltán Rihmer, National Institute for Psychiatry and Neurology, Budapest 27, POB 1, 1281 Hungary Mogens Schou, The Psychiatric Hospital, Skovagervej 2, DK-8240 Risskov, Denmark

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List of Contributors

xi

Kenneth I. Shulman, Department of Psychiatry, Sunnybrook & Women’s College Health Sciences Center, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada Vivek Singh, Department of Psychiatry, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio TX 78229-3900, USA Andrew Speer, Biological Psychiatry Branch, National Institute of Mental Health, Bldg. 10, 10 Center Drive MSC 1272, Bethesda, MD 20892-1272, USA Mauricio Tohen, McLean Hospital, Harvard Medical School, Belmont, MA and Lilly Research Laboratories, Eli Lilly & Co, 525 S. Meridian Street, Indianapolis, IN 46225, USA Eduardo Vieta, Clinical Institute of Psychiatry and Psychology, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain

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Preface Bipolar disorder has emerged as a major public health problem. Its prevalence, phenomenology, subtypes, treatment and outcome are all under reevaluation. A burgeoning research-based literature has appeared and continues to grow. New therapeutic modalities, both psychopharmacologic and psychosocial, have been introduced. The clinical and scientific challenges presented by this condition have created the psychiatric subspecialty for bipolar disorders. One of the major challenges for this subspecialty is to integrate the emerging clinical science of bipolar treatments. The idea for this book was born in October 1998 at the ECNP Congress in Paris. One of the topics discussed at that meeting was the fact that clinicians in both Europe and the United States used antipsychotics in bipolar disorder, yet US guidelines gave priority to lithium or anticonvulsants. The two editors decided to hold an international conference in Paris, France, on bipolar disorder at the 50th anniversary of the introduction of chlorpromazine in the same city in 1952. It would be recalled that the first patients treated with this agent suffered from bipolar mania. For a variety of logistic reasons, the conference was held in Monte Carlo instead of Paris in February 2002. Presided by the present editors and supported by an unrestricted educational grant from Eli Lilly, the conference covered the clinical psychopharmacology and related topics dealing with all agents available at that time for the treatment of bipolar disorder. With a roster of 24 of the top experts in the field and over 500 opinion leaders and researchers from all over the world in attendance, to the best of our knowledge, it was the largest freestanding conference on bipolar disorder. As we were editing the book on the material presented at the Monte Carlo conference, the field of bipolar psychopharmacology virtually exploded into a revolution. With so many new agents approved for bipolar disorder between 2002 and 2005, we had to revise the plans for this book in a radical way. The 19 chapters of the present book now overlap no more than 20% with the original conference in Monte Carlo. All chapters have been independently peer reviewed and updated through April 2005. We have endeavored – and we believe we have succeeded – in recruiting contributors who are the pioneers in bipolar psychopharmacotherapy and its clinical applications in children, the elderly and women. Special attention

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xiv

Preface

is also given to bipolar depression, which has emerged as a major clinical and therapeutic challenge. The book goes beyond pharmacotherapy to cover innovative psychoeducational and psychosocial interventions, managing the patients in the hospital and subsequent long-term care in the community. Questions about the health care climate, advocacy organizations for bipolar disorder and social parameters impacting it are also addressed. Finally, suicide prevention is given special consideration. This book, then, provides a broad integrative philosophy of caring for bipolar patients and their families. Hagop S. Akiskal and Mauricio Tohen

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CHAPTER

1 The Scope of Bipolar Disorders Hagop S. Akiskal International Mood Center University of California at San Diego, USA

DIAGNOSTIC AND PUBLIC HEALTH ASPECTS Recent advances in the epidemiology, psychopathology and pharmacotherapy of bipolar disorders have led to a greater recognition of this illness in all of its varieties (Akiskal et al., 2000). The lifetime risk for bipolar conditions is about 1% for the core (bipolar I) phenotype, making it at least equal in prevalence to schizophrenia. A higher percentage of acute psychiatric hospital admissions is now being assigned to the category of mania, and the recognition of clinically attenuated outpatient forms of the illness (soft bipolar spectrum) is increasing. The latter (bipolar II and beyond) is now estimated to be at least 4–5 times more prevalent than bipolar I (Angst et al., 2003; Hirschfeld et al., 2003; Judd and Akiskal, 2003). Reasons for the current focus on the entire diagnosable range of bipolar conditions are several. Predominant among these is the tendency of diagnostic practice to follow the availability of effective treatment modalities (Lehmann, 1969). After the discovery of chlorpromazine, North American psychiatrists were tacitly encouraged to elicit subtle degrees of formal thought disorder from their patients so as to bring them the benefits of this new class of drugs. By the early 1970s, schizophrenia had become more or less synonymous with psychosis. With the advent of lithium carbonate treatment and its well-documented efficacy for bipolar disorders, this trend became reversed in favor of bipolar disorders. Beginning with DSM-III (American Psychiatric Association, 1980), the concept of schizophrenia has been largely restricted to a core group of deteriorating psychotic disorders, while mood disorders have been broadened to include even those with mood-incongruent psychotic features that may or may not coincide with affective episodes. This diagnostic approach reflects more than just therapeutic fashion; it is supported by familial aggregation, course and outcome (Akiskal, 2002). Available evidence indicates that mood disorders are often recurrent and, especially in bipolar conditions, Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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can lead to considerable impairment in developmental, conjugal and social spheres. The public health significance of bipolar disorder is summarized in Table 1.1. The most important of these is suicide, seen in as many as 20% of those who receive inadequate or no treatment, and must be considered a preventable complication (Khuri and Akiskal, 1983). It now appears that bipolar II may account for a disproportionately large portion of suicidal morbidity and mortality among all the affectively ill (Rihmer and Pestality, 1999), emphasizing the importance of early and accurate diagnosis. At the “softest” end of the spectrum, milder degrees of bipolar disorder – subsumed under the rubrics of cyclothymic disorder (Akiskal etal., 1977) and bipolar disorder not otherwise specified (bipolar NOS) – are now categorized as mood disorders rather than being grouped with neurotic or personality disorders. Although these seemingly attenuated and “atypical” variants may not be easily distinguishable from nonaffective personality disorders, the clinician is advised to err on the side of affective diagnosis because of treatment implications. External validating strategies – such as family history, course and inter-episodic temperamental features – are often necessary to confirm the diagnosis of the bipolar spectrum (Akiskal, 2003). The most established of bipolarity beyond classic mania and bipolar I is the bipolar II type, so-named originally by Dunner, Gershon and Goodwin (1976). Like diabetes type II, its onset is often insidious, but its ravages no less devastating than that of the psychotic forms of the illness. This is particularly true for cyclothymic depression, a variant of bipolar II we have termed “bipolar II-½” (Akiskal and Pinto, 1999). Arising from a cyclothymic temperament, it pursues an unstable course and is likely to be misdiagnosed as axis II cluster B. These patients represent the “dark side” of bipolarity (Akiskal, Hantouche and Allilaire, 2003; Hantouche, Angst and Akiskal, 2003). The American Psychiatric Association (2000) Diagnostic Manual of Mental Disorders, even in its last edition (DSM-IV), does not recognize hypomanic or Table 1.1: Public health aspects of bipolar disorder • • • • • • • • • • • • •

Lifelong cyclical illness 1–5% of population Peak onset 15–30 years 5–10-year delay in correct diagnosis Frequent hospitalization Repeated hospitalization Repeated conjugal disruption: promiscuity Repeated job change/loss Financial disasters Alcohol/substance abuse 50% nonadherence to medication Increased cardiovascular mortality Suicide (highest within 10 years of illness onset)

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3

manic switches occurring during pharmacotherapy, electroconvulsive therapy, phototherapy and sleep deprivation as indicators of bipolar disorder. These patients are obviously not unipolar major depressive disorder (MDD), nor are they classified under bipolar not-otherwise specified (NOS). Therefore, this common clinical phenomenon is voted by the DSM Committee out of existence! Since at least 1983, there has been good evidence that such switching on antidepressants requires bipolar family history (Akiskal et al., 1983, 2000, 2003). They are best regarded as less penetrant forms of bipolar disorder (bipolar III). Diagnostic status of depressive states with mood swings in the setting of multiple drug abuse, particularly that of stimulants, is controversial, but we contend that many of these individuals belong to a provisional bipolar type III-½ (Akiskal and Pinto, 1999; Maremmani et al., 2003; Camacho and Akiskal, 2005). This is relevant in a book on advances in bipolar disorder, because many of these patients respond favorably to anticonvulsant mood stabilizers. Finally, I would like to mention bipolar type IV, which refers to individuals who develop depression later in life from a lifelong background of hyperthymic temperament (hypomanic traits without clear-cut episodes); their bipolar status might be inferred from familial bipolarity (Cassano et al., 1992). In a French national study (Table 1.2), 65% of all major depressions belonged to the bipolar spectrum, of which the most prevalent were the bipolar II and II-½ phenotypes (Akiskal et al., 2005b). These considerations are important because nearly all pharmacologic treatments covered in this book – certainly those approved by regulatory bodies – pertain to bipolar I. Thus, there is a wide gap between the psychopharmacology of bipolar disorder and the public health significance of the phenotypes observed in the community and the clinic. Lithium was the first specific agent for bipolar disorder approved for clinical use. This was 35 years ago. Many other agents have been approved since then, almost all of them in the last decade. They are all covered in this book. Lithium medicalized psychiatry in bringing significant attention to the course of bipolar disorder. Its importance should not be overshadowed by these new developments. Many patients, Table 1.2: Bipolar spectrum subtypes (n=316) in the French EPIDEP study of major depression (n=493): validation by bipolar family history* N

%

Bipolar I Bipolar II Bipolar II-½ Bipolar III Bipolar IV

41 61 164 28 22

8.4 12.4 33.5 5.7 4.5

Total

316

64.5

* Akiskal et al. (2005b)

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especially those in the “core” classic form of the illness, do respond to lithium. Its judicious use, often in combination with other agents in rational polypharmacy, requires intimate knowledge of its physiological and medical characteristics. Regrettably, young psychiatrists are not having adequate experience with this agent. A summary of the medical workup of patients in preparation of lithium use (Akiskal, 1999) is given in this chapter’s appendix.

PSYCHOLOGICAL AND SOCIAL ASPECTS The long-term, essentially life-long, nature of bipolar disorder and its vicissitudes dictate continuity of treatment and long-term caring. To solve practical problems in the patients’ lives requires caring that goes beyond medications and psychotherapy, to include the family, significant others and the community. Bipolar disorder continues to be poorly understood by both the public and doctors. More often than not, a bipolar child is classified as having conduct disorder or Attention Deficit Hyperactivity Disorder (ADHD) (Dilsaver, Henderson-Fuller and Akiskal, 2003). A teenager’s suicide attempt is misattributed to problems of the heart, adolescent crisis or substance abuse; promiscuous behavior is blamed on childhood “sexual abuse.” Bipolar patients from time to time describe their parents as “monsters” or “emotionally abusive,” which some psychotherapists accept on blind faith without ever talking to the parents. Bipolar II patients are often diagnosed as unipolar and/or borderline personality (Akiskal, 2004), treated with antidepressants without mood stabilizers, resulting in tragic aggravation of the course of the illness (Akiskal and Mallya, 1987; Akiskal et al., 2005a). Excessive spending, squandering, of one’s economic resources and pathological generosity may lead to financial ruin before bipolarity is considered. Polls of members of the Depressive and Manic-Depressive Association in the U.S. have shown a latency of 10 years from the onset of symptoms until the correct diagnosis of bipolar disorder (Hirschfeld et al., 2003). Early diagnosis is critical because suicide in bipolar patients often occurs within this early period. The comfort, support, destigmatization, information and advocacy provided by such a conglomeration of patients, families and community leaders (many of whom are themselves bipolar) represents a novel approach in the rehabilitation of the bipolar patient into society. This is a humane and just cause. Given that about 10% of patients with bipolar illness have creative and leadership achievements (Akiskal and Akiskal, 1988), sophisticated clinical management of bipolar illness can potentially safeguard the adaptive capacity and contributions that gifted bipolar people provide to society. Although psychotically ill (bipolar) patients are represented in the media as being creative, this is a destigmatization campaign at best and glamorizing madness at worst. Achievement and creativity are largely attributes of the softer spectrum represented in the attenuated temperamental expressions of bipolarity involving bipolar II (Akiskal and Akiskal, 1988, 2005).

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Spanning from temperament to psychosis, bipolarity is a fascinating yet tragic human condition. Mental health professionals who treat these individuals must use pharmacotherapy and psychosocial interventions compassionately, judiciously and rigorously – only rarely “aggressively.” Severe bipolar illness is not just an ordinary illness to be medicated to “mediocrity.” The temperament of these individuals deserves all our consideration and respect. While most psychotic bipolar patients are neither leaders nor creators, they are the reservoir of the genes, which in dilute form, might serve as the seeds of genius (Akiskal, 2000).

APPENDIX: LABORATORY CONSIDERATIONS IN THE CLINICAL USE OF LITHIUM More than any other development, the introduction of lithium has emphasized the role of physicianship in psychiatry. The scientific literature and clinical wisdom on the therapeutic aspects of this salt have been well summarized in a monograph by Jefferson et al. (1983). The success of lithium treatment is dependent on the thoroughness of the initial workup, on dosage titration procedures and on appropriate monitoring throughout therapy. The type of workup depends on the age of the patient and concurrent medical conditions (Table 1.3). In young (less than 40 years), physically healthy subjects, preparation for lithium therapy should include medical history (especially focused on neurologic, renal, cardiac, gastrointestinal, endocrine and cutaneous systems), physical examination and laboratory evaluation focusing on electrolytes and thyroid. In older patients or those with a history of cardiac disease, a baseline electrocardiogram (EKG) should be obtained, and an electroencephalogram (EEG) performed if epilepsy is suspected; if there is a history of renal disease, thorough evaluation of baseline kidney function is mandatory. Given rigorous indications for lithium, major medical illness and abnormalities in laboratory indices do not necessarily contraindicate its use; they do dictate, however, greater medical vigilance, including frequent determination of blood levels and use of lower doses. Table 1.3: Recommended laboratory workup of patients considered for lithium therapy Healthy <40 years

All others: consider

Weight CBC T4/TSH FBS/serum electrolytes Urinalysis BUN/creatinine

EKG EEG TRH test 24-hour urine volume Urine concentration test Creatinine clearance

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A short-term lithium trial in the controlled environment of a hospital is relatively easy to administer and is recommended for acutely manic, medically ill or elderly subjects. In outpatient practice, the physician must make sure that the patient and significant others understand the importance of adherence with periodic laboratory procedures and monitoring of side effects. Lithium is rapidly and completely absorbed from the gastrointestinal tract and peaks in the serum in about 1.5–2.0 (standard preparation) or 4.0–4.5 hours (slow release preparation), depending on age. Its half-life varies from 24–36 hours; steady state is reached in about four days. Lithium is not protein bound and is excreted unchanged almost entirely through the kidneys. It can be safely combined with most classes of drugs except diuretics and nonsteroidal anti-inflammatory agents (other than aspirin), which tend to increase the serum lithium level. Acutely manic and possibly bipolar depressive patients have a high tolerance for lithium and preferentially retain it during the first 10 days while excreting sodium; a regular diet is recommended. Postpubertal bipolar patients, who typically have excellent glomerular function, require higher doses to achieve the same level of equilibrium in the serum. The reverse is true in the geriatric age group. Elderly subjects with adequate glomerular function can benefit considerably from judicious lithium use. However, greater medical vigilance is required for this group; initial doses should be low (150–300 mg/day), with frequent clinical and laboratory monitoring to maintain blood levels in the lower range (0.3–0.8 mEq/L). Special attention must be paid to signs of sinus node dysfunction (bradycardia) or neurotoxicity; the latter is particularly likely in patients with concurrent neurologic disease or sedative and alcohol abuse. In healthy subjects who achieve good episode prevention, quarterly serum levels (12 hours after the last dose) and serum creatinine are generally sufficient; thyroid indices must be obtained at least once a year. For elderly or medically compromised patients, laboratory tests should be repeated as dictated by the medical condition, with frequent serum lithium levels; the dosage should be kept at the lowest possible level compatible with prophylaxis.

REFERENCES Akiskal HS. Mood (Affective) Disorders, in Berkhow R (ed.). Merck Manual of Diagnosis and Therapy, 17th ed. Rathaway, NJ, Merck Sharp and Dohme, 1999, pp. 1525–44. Akiskal HS. Dysthymia, cyclothymia and related chronic subthreshold mood disorders. In Gelder M, Lopez-Ibor J, Andreasen N (eds). New Oxford Textbook of Psychiatry. London, Oxford University Press, 2000, pp. 736–749. Akiskal HS. Classification, Diagnosis and boundaries of bipolar disorders. In Maj M, Akiskal HS, Lopez-Ibor JJ, Sartorius N (eds). Bipolar Disorder. London, John Wiley & Sons, 2002, pp. 1–52. Akiskal HS. Validating “hard” and “soft” phenotypes within the bipolar spectrum: Continuity or discontinuity? J. Affect. Disord. 2003; 73: 1–5.

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Akiskal HS. Demystifying borderline personality: Critique of the concept and unorthodox reflections on its natural kinship with the bipolar spectrum. Acta Psychiatr. Scand. 2004; 110: 401–407. Akiskal HS, Akiskal KK. Re-assessing the prevalence of bipolar disorders: Clinical significance and artistic creativity. Psychiatrie et Psychobiologie. 1988; 3: 29s–36s. Akiskal KK, Akiskal HS. The theoretical underpinnings of affective temperaments: Implications for evolutionary foundations of bipolarity and human nature. J. Affect. Disord. 2005; 85: 231–239. Akiskal HS, Mallya G. Criteria for the “soft” bipolar spectrum: Treatment implications. Psychopharmacol. Bull. 1987; 23: 68–73. Akiskal HS, Pinto O. The evolving bipolar spectrum: Prototypes I, II, III, IV. Psychiatr. Clin. North Am. 1999; 22: 517–534. Akiskal HS, Hantouche EG, Allilaire J-F. Bipolar II with and without cyclothymic temperament: “dark” and “sunny” expressions of soft bipolarity. J. Affect. Disord. 2003; 73: 49–57. Akiskal HS, Djenderedjian AH, Rosenthal RH, Khani MK. Cyclothymic disorder: Validating criteria for inclusion in the bipolar affective group. Am. J. Psychiatry. 1977; 134: 1227–1233. Akiskal HS, Walker PW, Puzantian VR, King D, Rosenthal TL, Dranon M. Bipolar outcome in the course of depressive illness: Phenomenologic, familial, and pharmacologic predictors. J. Affect. Disord. 1983; 5: 115–128. Akiskal HS, Bourgeois ML, Angst J, Post R, Moller HJ, Hirschfeld RMA. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J. Affect. Disord. 2000; 59 (Suppl 1): 5s–30s. Akiskal HS, Hantouche EG, Allilaire JF, Sechter D, Bourgeois M, Azorin JM, ChatenêtDuchêne L, Lancrenon S. Validating antidepressant-associated hypomania (bipolar III): A systematic comparison with spontaneous hypomania (bipolar II). J. Affect. Disord. 2003; 73: 65–74. Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: Implications for the antidepressant-suicide controversy. J. Affect. Disord. 2005a; 85: 245–58. Akiskal HS, Hantouche EG, Allilaire JF, Akiskal KK. Validating the bipolar spectrum: Overview of the phenomenology and relative prevalence of clinical subtypes in the French national EPIDEP study. J. Affect. Disord. 2005b, in press. American Psychiatric Association. DSM-III. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Press, 1980. American Psychiatric Association. DSM-IV. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Press, 2000. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W. Toward a re-definition of subthreshold bipolarity: Epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J. Affect. Disord. 2003; 73: 133–146. Camacho A, Akiskal HS. Proposal for a bipolar-stimulant spectrum: Temperament, diagnostic validation and therapeutic outcomes with mood stabilizers. J. Affect. Disord. 2005; 85: 217–230. Cassano GB, Akiskal HS, Savino M, Musetti L, Perugi G, Soriani A. Proposed subtypes of bipolar II and related disorders: With hypomanic episodes (or cyclothymia) and with hyperthymic temperament. J. Affect. Disord. 1992; 26: 127–140. Dilsaver SC, Henderson-Fuller S, Akiskal HS. Occult mood disorders in 104 consecutively presenting children referred for the treatment of attention-deficit/hyperactivity

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disorder in a community mental health clinic. J. Clin. Psychiatry 2003; 64: 1170–1176. Dunner DL, Gershon ES, Goodwin FK. Heritable factors in the severity of affective illness. Biol. Psychiatry 1976; 11: 31–42. Hantouche EG, Angst J, Akiskal HS. Factor Structure of hypomania: Interrelationships with cyclothymia and the soft bipolar spectrum. J. Affect. Disord. 2003; 73: 39–47. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: How far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J. Clin. Psychiatry 2003; 64: 161–74. Hirschfeld RM, Holzer C, Calabrese JR, Weissman M, Reed M, Davies M, Frye MA, Keck P, McElroy S, Lewis L, Tierce J, Wagner KD, Hazard E. Validity of the mood disorder questionnaire: A general population study. Am. J. Psychiatry 2003; 160: 178–180. Jefferson J, Greist JH, Ackerman DL, Carroll JA. Lithium Encyclopedia. Washington, DC: American Psychiatric Press, 1983. Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the U.S. population: Re-analysis of the ECA database taking into account subthreshold cases. J. Affect. Disord. 2003; 73: 123–131. Khuri R, Akiskal HS. Suicide prevention: The necessity of treating contributory psychiatric disorders. Psychiatr. Clin. North Am. 1983; 6: 193–207. Lehmann HE. The impact of the therapeutic revolution on nosology. In Doucet P, Laurin C (eds). Problematique de la psychose. New York, Excerpta Medica Foundation, 1969, pp. 136–153. Maremmani I, Pacini M, Lubrano S, Lovrecic M, Perugi G. Dual diagnosis heroin addicts. The clinical and therapeutic aspects. Heroin Addict. Relat. Clin. Probl. 2003; 5: 7–98. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr. Clin. North Am. 1999; 22: 667–73.

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2 Lithium Treatment: Focus on Long-Term Prophylaxis Mogens Schou1 and Paul Grof2 1

2

Syrenvej 4, Risskov, DK-8240, Denmark Mood Disorders Center of Ottawa, Suite 301, 1929 Russell RD, Ottawa, Ontario, Canada.

INTRODUCTION It is difficult to tell the exact age of lithium treatment for mood disorders. In the 1880s lithium was used for the treatment and prevention of recurrent depressions (Lange, 1886; Schioldann, 2001), but statistics and controlled trials were not known at that time, and the observations remained clinical impressions. In the 1950s lithium treatment for mania became evidence based (Schou etal., 1954), and in 1967–1970, prophylactic lithium treatment did the same (Baastrup and Schou, 1967; Baastrup et al., 1970). There is nevertheless good reason to count the age of lithium treatment from 1949, when Cade (1949) published his paper “Lithium salts in the treatment of psychotic excitement”, for lithium has remained in psychiatric use since then. Why is lithium treatment still being used after half a century? This chapter does not aim at giving a systematic chronological exposition of the history of lithium treatment in psychiatry. This has been done in other publications to which the reader is referred, e.g. Johnson (1984), Schou (1992), and Healy (1997). An attempt will be made to answer the question by recounting briefly and commenting in detail on selected events. Methodological problems are given more attention than presentation of data. There have been many misunderstandings about lithium. Some of them will be addressed in this chapter, but it has not been possible to deal with them all.

The original version of this paper was published in the Journal of Affective, Disorders in 2001: Mogens Schou: Lithium treatment at 52. J Affect Disord 2001; 67: 21–32. The journal kindly permitted an updating by Schou and Grof in 2003. This chapter has not been updated since 2003. The authors.

Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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Since lithium is used primarily for the prevention of recurrences, this review – based on previous work by Schou (1993b, 1998c, 2001) – deals primarily with prophylactic treatment and disregards treatment for individual episodes. In collaboration with Grof (2003), this chapter has been thoroughly updated from previous contributions to address contemporaneous challenges in the long-term treatment for what the authors term “typical” bipolar disorders.

CADE’S PIONEERING STUDY It has often been claimed that the so-called “psychopharmacological era” started with the introduction of chlorpromazine in 1952. The era actually started when Cade introduced lithium as an antimanic drug in 1949. When the word “serendipity” was used about Cade’s discovery, he became annoyed and pointed out that it was based on a specific hypothesis and experimental observations. The hypothesis was that mental illnesses are caused by intoxication with an unknown compound, and that this toxic agent can be found in the patients’ urine. His hypothesis led him to inject lithium urate, the only soluble salt of uric acid, into guinea pigs, and when he saw that they became docile and lethargic, he started treating psychiatric patients with lithium carbonate after having tried it on himself without ill effects. Whereas schizophrenic and depressed patients did not show essential changes, all ten manic patients showed abatement or cessation of their symptoms. Later attempts to induce lethargy in guinea pigs with lithium showed, however, that this was possible only with high doses. Cade’s animals were presumably intoxicated rather than merely lethargic. To make therapeutic discoveries on the basis of misinterpreted experiments requires curiosity, daring, luck and compassion for patients!

DISCOVERY OF THE PROPHYLACTIC ACTION OF LITHIUM By 1964 Schou (1956), Hartigan (1963) and Baastrup (1964) had independently made observations on small groups of patients that seemed to indicate that prolonged treatment with lithium might ameliorate or prevent not only manic but also depressive recurrences. This was a new and unexpected observation, and it called for closer examination.

NON-BLIND MIRROR TRIAL A confirmation of the original observations came from a large, open study. A non-blind trial lasting six years and involving eighty-eight bipolar and unipolar patients who had suffered at least two episodes within two years provided the first systematically collected evidence of a prophylactic action of lithium against both manic and depressive episodes of manic-depressive illness (Baastrup and Schou, 1967). The average number of episodes per year decreased by 87% from the time before lithium

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treatment to the time during lithium treatment (p < 0.001). The decreases were equally large in the two groups. A Swiss–Czech–Danish collaborative trial confirmed the findings (Angst et al., 1970). Psychiatrists in other countries then initiated lithium treatment. They also observed depressive as well as manic recurrences diminish in intensity and frequency, and they were gratified by lithium’s prophylactic action. However, Blackwell and Shepherd (1968) expressed sharp skepticism. This was not based on a failure to confirm the Danish findings for they never tried treating patients with lithium; their skepticism was purely speculative. Blackwell and Shepherd contested the validity of the evidence. They felt that bias and the suggestive power of the psychiatrists accounted for the observations, and that patients selected because they had suffered frequent episodes during recent years could be expected to have fewer episodes during the following years. In their reply Baastrup and Schou (1968) pointed out that most of the patients were discharged soon after starting lithium treatment. General practitioners, who were unaware of the ongoing trial and therefore unbiased, determined when a recurrence had taken place. Moreover, rather than decrease, the frequency of episodes must be expected to increase in the way that is characteristic of recurrent affective disorders (Angst and Weis, 1969; Grof et al., 1970a). Blackwell and Shepherd were apparently not familiar with these findings, or they chose to overlook them. The discussions between Blackwell and Shepherd, and Baastrup and Schou went on for some time and created uncertainty among British and American psychiatrists, who hesitated to start prophylactic lithium treatment. Baastrup and Schou felt that no useful purpose was served by continuing a potentially interminable discussion and that double-blind observations were required.

DOUBLE-BLIND DISCONTINUATION TRIAL Baastrup, Schou and their associates therefore carried out a double-blind discontinuation trial (1970). Bipolar and unipolar patients who had been given lithium for at least a year were allocated randomly to either placebo or continued lithium treatment. Within six months the difference between the groups had reached a pre-determined significance level (p < 0.01), and sequential analysis terminated the trial. While 21 of 39 placebo-treated patients had relapsed, none of 45 lithiumtreated patients had done so. The final analysis revealed a statistical difference of p < 0.001. Later randomized, placebo-controlled trials of both discontinuation design and prospective design confirmed the findings, e.g. Melia (1970), Coppen et al. (1971), Cundall, Brooks and Murray (1972), Hullin, McDonald and Allsopp (1972), Prien, Caffey and Klett (1973) and Stallone et al. (1973). The evidence was now so strong that lithium became approved for prophylactic treatment by regulatory agencies in many countries. In 1974 the FDA approved its long-term use in bipolar disorder.

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OBSERVER BIAS, DISEASE COURSE Schou, Thomson and Baastrup (1970) tested the assumptions on which Blackwell and Shepherd had based their criticism. The effect of observer bias and psychological factors on the recording of recurrences was investigated by comparing the disease course of a group of patients in whom lithium treatment was switched double-blind to placebo, and another group who stopped taking lithium on their own initiative. When lithium is discontinued during a double-blind study, observer bias and suggestion continue to work at full force; when lithium is discontinued openly, their psychological effect ends. The percentage of patients who suffered relapse each month was the same in the two groups. The trial showed that in manic-depressive patients neither observer bias nor placebo effects were strong enough to exert significant influence on the recorded recurrence rate. In the same study a survival analysis revealed that before lithium treatment 14% of the patients relapsed each month. While the patients were in lithium treatment, the proportion of patients who relapsed was 1.5%. When lithium was discontinued, 16% of the patients relapsed each month. The low frequency of episodes during lithium treatment was accordingly not a result of ‘regression toward the mean’ as Blackwell and Shepherd had suggested.

FURTHER DOUBTS ABOUT THE EFFICACY OF LITHIUM TREATMENT Lithium prophylaxis became widely used during the following years, but occasionally doubts about its efficacy were still expressed. Dickson and Kendell (1986) found that even though long-term lithium treatment was being increasingly administered in Edinburgh during the period 1970–1981, admission rates for mania and depression were on the rise; the authors felt that this cast doubts on the efficacy of lithium treatment. Schou (1986) pointed out that drawing conclusions about the efficacy of a treatment administered to a limited number of patients from the admission rates of a much larger number is a dubious procedure. Prophylactic lithium treatment is given only to manic-depressive patients with frequent recurrences, so even if lithium treatment were 100% effective, it could only be expected to prevent a small fraction of re-admissions. Grof (1987) drew attention to the many other factors that could have led to a rise in the number of admissions, for example a shift in diagnostic practice. In other hospitals rises in admissions for comparable reasons were observed. In 1995 Moncrieff claimed that a prophylactic action of lithium treatment was never satisfactorily demonstrated. She found it likely that development of side effects had compromised the blindness of the prophylactic lithium trials, but she presented no evidence in support of that notion. The evidence available shows that the blindness had not been invalidated (Schou, 1998a).

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Basing her arguments purely on speculation Moncrieff claimed that discontinuation studies are invalid because abrupt discontinuation of lithium treatment provokes manic recurrences. This is strange logic. Even if a discontinuation design with rebound manias might inflate the size of lithium’s effect, this in itself shows that lithium is not without effect (Goodwin, 1995). Moncrieff insisted that the rise in frequency of recurrences after discontinuation of lithium was not caused by the removal of an active prophylactic drug. The cause was instead, she claimed, rebound recurrences precipitated by withdrawal of lithium. She referred to a study by Suppes etal. (1993) that reported rapid development of predominantly manic recurrences after abrupt discontinuation of lithium. These observations are impressive, but they were made in patients who differed diagnostically from those in whom lithium was originally shown prophylactically effective in 1967–1970. During the last decades the increasing use of standardized cross-sectional diagnoses (DSM) has led to a widening of the indications for lithium use (Grof, 1998). Patients with, for example, excessive motor activity have been classified as bipolar manic and given lithium, and many of them benefitted somewhat from the anti-aggressive and anti-psychotic effects lithium also has in bipolar patients (Kingsbury and Garver, 1988). In the early prophylactic trials the patients were diagnosed according to ICD criteria and had classical manic-depressive illness, and in these patients discontinuation of lithium led to re-emergence of recurrences at a rate that did not exceed their experiences before they started lithium treatment (Grof, Cakuls and Dostal, 1970b; Schou, Thomsen and Baastrup, 1970; Rifkin, Quitkin and Howard, 1975; Fyrö and Petterson, 1977; Sashidharan and McGuire, 1983; Mendlewicz, 1984; Berghöfer, Kossman and Müller-Oerlinghausen, 1996). Moncrieff had extrapolated from one group of patients to another group that was diagnosed differently. The principal argument in Moncrieff’s “case” against prophylactic lithium treatment failed.

DEBATE There are few psychiatric treatments that have been debated as hotly as prophylactic treatment with lithium. The reasons for this are difficult to understand. Perhaps the treatment was so effective that psychiatrists who had not themselves used it for their patients found the observations utterly unlikely and refused to believe the evidence.

METHODOLOGICAL ISSUES The debate raised by Blackwell and Shepherd revealed two different attitudes toward clinical trials. Shepherd himself had worked with randomized, placebo-controlled trials and was convinced that valid evidence could be obtained only with this procedure;

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any other evidence had to be rejected. The 1967 trial by Baastrup and Schou was not randomized and placebo controlled, the reason being that it had started more or less on an exploratory basis and then had gradually grown. The authors felt, however, that data collected in an open prophylactic study of mirror-design need not necessarily be disregarded. The marked and long-lasting change produced by lithium in the course of the disease of patients having had a median of nine episodes prior to lithium treatment coincided with the start of that treatment and was unlikely to be fortuitous.

PERSONAL ISSUES Perhaps it may at this point be appropriate to correct an error that started with Shepherd’s description of Schou as an “enthusiastic advocate”. This is an ambiguous compliment. The term “enthusiast” might refer to someone who is strongly engaged in their work, but in the given context the term “advocate” can hardly have been meant as a compliment. In British English an advocate is someone who gathers evidence exclusively for or exclusively against a particular case or person. A clinical scientist, on the other hand, is someone who gathers all relevant evidence and then weighs it carefully before drawing a conclusion. The latter is usually in the form of a hypothesis that may later be rejected, by the scientist himself or by others. A conversation between Healy and Schou (Healy, 1997) revealed that Shepherd used his epithet with a more special meaning. Healy: “I happen to know that there are people at the Maudsley who explain your position by hinting that you yourself had manic-depression and are on lithium and that therefore you have a vested interest in seeing things one way . . . Did you know that?” Schou: “This is entirely new to me. Perhaps it explains why Shepherd always referred to me as an enthusiast, clearly meaning an uncritical person whose opinions couldn’t be trusted. Well, I am not manic and never was in lithium treatment. But what difference does it make? Baastrup’s and my data, arguments and conclusions are there for anyone to assess. Should data, arguments and conclusions presented by insane persons be disregarded rather than judged on their merits?” This may appear to be a personal grudge without wider implications. It involves, however, an important question of principles. A reader may pay attention to the author’s assumed motives and his mental state. But should this, apart from perhaps sharpening the reader’s critical sense, lead him to reject totally the data, arguments and conclusions of a person whose motives the reader does not find sufficiently noble or whose mental state he does not deem sufficiently sane? If that were so, science and the patients might be deprived of potentially valuable information.

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CONCERNS ABOUT SIDE EFFECTS AND RISKS Pharmaceutical companies have regarded lithium as a competitor with their own products, and claims about lithium’s many and severe side effects have been repeated again and again. Lithium does have side effects, and sometimes they are so troublesome that treatment must be discontinued. However, if lithium treatment is carried out competently, most of the side effects are mild and a small price to pay for the emotional stability obtained.

EFFECT OF THE SERUM LITHIUM CONCENTRATION The frequency and severity of side effects depends primarily on the serum lithium concentration being kept low and competently tailored to each patient. At the psychiatric hospital in Risskov, Denmark, the range of serum lithium concentrations was lowered from 0.8–1.0 mmol/L to 0.5–0.8 mmol/L (Schou, 1988; Vestergaard and Schou, 1988; Schou and Vestergaard, 1988; Vestergaard, Poulstrup and Schou, 1988). The average serum lithium concentration decreased by about 30%, and the proportion of patients not having side effects rose from 10 to 40%. Lithium-induced tremor and diarrhea were markedly less pronounced during treatment with low serum concentrations than with high; so were lithium-induced increase of urine volume and reduction of renal concentrating ability. It is worth noting that the claims of many and severe side effects of lithium are made primarily in the United States. In 1989 a group from Boston (Gelenberg etal., 1989) compared doses leading to what they called “standard” serum lithium levels, 0.8–1.0 mmol/L, with doses leading to low levels, 0.4–0.6mmol/L. The trial showed that the higher levels were not only more effective but also associated with a higher incidence of side effects than the lower. There was more non-compliance in the highlevel group; the authors nevertheless chose to recommend the high levels. They did not examine effects and side effects of the levels in between 0.6 and 0.8 mmol/L. In Europe the recommended serum lithium range has for several years been 0.4–0.8 mmol/L, to be exceeded at each end in particularly sensitive and particularly resistant patients respectively (Birch etal., 1993). A single American author has recommended serum lithium concentrations between 0.3 and 0.8mmol/L (Akiskal, 1999).

LITHIUM EFFECTS ON THE KIDNEYS Owing to its important clinical implications this issue has been investigated systematically in thousands of patients. Critical data come from studies testing the kidney function of patients both before and during lithium treatment. Long-lasting lithium treatment does not lead to a gradual deterioration of the kidney function. The urine volume and the renal concentrating ability do not change over treatment

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periods from 1 to 30 years. In investigations by European authors (Povlsen et al., 1992; Kallner and Petterson, 1995; Bendz, Sjödin and Aurell, 1996) the glomerular filtration rate of patients maintained at serum lithium concentrations between 0.3 and 0.9 mmol/L decreased only corresponding to the patients’ increasing age. In an American study (Gitlin, 1993) 3 out of 82 patients showed gradual rises of the serum creatinine concentration. Gitlin’s patients were maintained at serum lithium concentrations between 0.6 and 1.2 mmol/L.

PREVENTION OF LITHIUM INTOXICATION Patients undergoing lithium treatment rarely commit suicide by taking overdoses of lithium but lithium intoxications can develop under various unfortunate circumstances. Intoxication does not develop randomly. Lithium is eliminated through the kidneys, and the mechanisms governing the excretion have by now been unraveled through animal experiments and clinical experiences over many years. This knowledge has led to precautionary guidelines (Thomsen and Schou, 1999). Situations to be avoided during lithium treatment include overdose, kidney disease, dehydration, sodium deficiency and interaction with various drugs. It is useful for physicians and patients to keep such conditions in mind.

USE DURING PREGNANCY AND LACTATION Early experiments on primitive aquatic animals had shown that exposure to high concentrations of lithium in the surrounding fluid led to malformations of the offspring. After lithium came into use for the treatment of manic-depressive patients in 1949, a “Register of Lithium Babies” was established (Schou, 1969) in order to reveal whether malformed children would be born to mothers having been in lithium treatment during pregnancy. The register was based on voluntary reports, and it indicated an increased frequency of congenital malformations of the heart. However, these findings exaggerated the risk because congenitally malformed babies were more likely to be reported than normal babies, and the retrospective register was closed in 1990 (Schou, 1990). When the lithium baby register was started, psychiatrists were not used to thinking along teratogenic lines, and the register’s estimate of maximum teratogenic risk was taken as a measure of the true teratogenic effect of lithium. That gave lithium a “bad press”. Later investigations without the bias of the register have given reassuring results and found no relationship between malformations and lithium given during pregnancy. Lithium can be given safely during the last six months of the pregnancy, and if the risk of recurrence is high, it can also be given during the first three months. The risk of fetal changes is minimal (Jacobson et al., 1992; Schou, 1998b).

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BREASTFEEDING DURING LITHIUM TREATMENT Small amounts of lithium pass from the mother’s blood to her milk and hence to the nursing child. However, breastfeeding plays an important role for both mother and child, physically and psychologically, and it is today doubtful whether it is advisable to abstain from breastfeeding during lithium treatment. One can today measure the lithium concentration in the mothers’ milk, and it is still lower than in the blood of the fetus.

‘NATURALISTIC’ TRIALS In some ‘naturalistic’ or ‘outpatient’ or ‘clinical practice’ trials the prophylactic effectiveness of lithium has been found to be lower than it was in the early trials. The explanation of this discrepancy is hardly that lithium has changed its properties. What may have changed is treatment adherence and patient selection. In these trials the patients may have been supervised insufficiently to keep non-compliance under control (Schou, 1993a). Poor compliance is the major cause of the difference between efficacy, the potential of a treatment, and effectiveness, the result obtained under clinical conditions (Guscott and Taylor, 1994), and efforts should be made to improve compliance and increase effectiveness also when lithium treatment is given under naturalistic or outpatient or clinical practice conditions (Schou, 1997). In some of the ‘naturalistic’ trials lithium treatment was given to patients with atypical features and co-morbid psychopathology and to patients who previously had been found refractory to lithium (Schou, 1998a). The indications for lithium treatment had been influenced by the introduction of new diagnostic criteria (Gershon and Soares, 1997; Gitlin and Altshuler, 1997). The effectiveness of lithium prophylaxis is a question of carefully monitored lithium treatment given on indications where it has been shown efficacious. Optimum results of lithium treatment are obtained only when well-informed and conscientious physicians administer it to well-informed and conscientious patients.

ARE NEW AND BETTER PROPHYLACTIC AGENTS ABOUT TO OUST LITHIUM? Lithium treatment has side effects, and it would be welcome if something better were forthcoming and its advantages convincingly demonstrated (Schou, 1998a). However, the search for other prophylactic drugs has faced certain obstacles. Since lithium prophylaxis is so effective (Goodwin and Jamison, 1990), it might be difficult to obtain permission from ethical committees and informed consent from patients to compare new drugs of unproved prophylactic efficacy with placebo or

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with lithium. The investigators have employed two approaches to be able to use drugs other than lithium. The first was to emphasize the shortcomings of lithium treatment, real or alleged. The second was to treat patients who were refractory to lithium treatment or had troublesome side effects.

CRITICISMS OF LITHIUM The claim that lithium has many and severe side effects, notably on the kidneys, was discussed in an earlier section. It has also been claimed that lithium is not effective in rapid cycling and mixed states. That is only partly true. Lithium can be efficacious in some of these disorders (Baastrup and Schou, 1967; Hanna et al., 1972), but it is often ineffective, and it would be welcome if other drugs could be proved better.

THE DRUG A/DRUG B FALLACY It is sound and responsible practice to switch to another drug when lithium is not effective or not tolerated. One must, however, realize that observations made under these circumstances are biased in favor of the new drug; the trial cannot show whether the new drug is prophylactically efficacious also when given as first treatment, let alone more efficacious than lithium. When a patient is switched from drug A to drug B because the former was ineffective or not tolerated, then drug B must necessarily come out as good as or better than drug A, for it cannot come out worse. Since many studies have had this design, the evidence of a prophylactic effect of new drugs must be assessed with caution.

ANTICONVULSANTS In bipolar disorder it is primarily the anticonvulsant drugs carbamazepine, valproate and lamotrigine for which a prophylactic action has been claimed. When these and similar drugs are compared with lithium, experience from recent decennia has shown it important to distinguish between typical and atypical bipolar disorder (Schou, 1998a). Patients with typical, classical bipolar disorder have an episodic course, mood-congruent symptoms and often present with full manias (bipolar I). Patients with atypical bipolar disorder have an incompletely remitting, non-episodic course and often include mood-incongruent symptoms, rapid cycling, dysphoric mania and comorbidity. In two prospective randomized double-blind studies (Placidi et al., 1986; Greil et al., 1997, 1998; Greil and Kleindienst, 1999) the prophylactic efficacies of lithium and carbamazepine were compared. Whereas lithium was consistently superior to carbamazepine in patients with typical bipolar disorder, carbamazepine

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had the same efficacy as lithium or showed an edge to be better in patients with atypical bipolar disorder. Valproate is used extensively as a mood stabilizer. However, in a prophylactic study by Bowden et al. (2000) only mildly ill patients were treated, and neither valproate nor lithium differed significantly from placebo. The trial was accordingly invalid. Lamotrigine has been tested extensively and been shown to be an efficacious treatment for preventing bipolar episodes, particularly bipolar depression and rapid cycling (Calabrese et al., 2000; Bowden et al., 2003).1 Studies by Canadian researchers from Halifax and Ottawa compared lamotrigine and lithium and were primarily patient oriented rather than drug oriented. Passmore et al. (2003) studied 164 subjects from 21 families of bipolar probands, 14 responders to lithium and 7 responders to lamotrigine. There were differences between the drugs with respect to clinical course (episodic in the lithium group, rapid cycling in the lamotrigine group) and comorbidity (panic attacks and substance abuse in the lamotrigine group). The relatives of lithium responders had significantly higher risk of bipolar disorder, and the relatives of lamotrigine responders had higher prevalence of schizoaffective disorder, major depression and panic attacks. Replication of the Canadian study would be of great clinical and public health relevance. Grof (2003) discussed more broadly the principle and the execution of longterm monotherapy in bipolar patients. A current and quite widespread practice is to add further mood stabilizers already when the first mood stabilizer has been given for only a short time. It has, however, been found by the Canadian researchers that many patients can be successfully stabilized on monotherapy if the drug is initially selected according to the patients’ clinical characteristics. Likely to respond well to lithium are patients with typical bipolar disorder, an episodic and fully remitting disease course and a family history of remitting bipolar disorder with an episodic course and usually the absence of comorbidity. Likely to respond to lamotrigine and olanzapine are patients with atypical symptoms, a non-episodic course with residual symptoms, comorbidity and a family history of other psychiatric disorders and substance addiction.2

PROPHYLAXIS IN RECURRENT DEPRESSIVE DISORDER Long-term lithium treatment exerts a recurrence-preventive action not only in bipolar disorder but also in depressive disorder (Baastrup and Schou, 1967; Angst et al., 1970; Baastrup et al., 1970). This observation did not then have, and has not later had, any noticeable effect on the prophylactic treatment for depressive disorder. 1

This topic is further discussed in Chapter 4. As discussed throughout this book, these “atypical” patients are prevalent in clinical practice, and their clinical management represents a formidable challenge.

2

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The antidepressant drugs had been introduced in the late 1950s, and they have later dominated both the acute and the prophylactic treatments for this disorder. It should, however, be noted that many patients are treated with antidepressants who according to present-day international classifications have, or must be suspected of having, bipolar disorder. They are patients with bipolarity in the family, patients whose depressive disorder started in childhood or puberty, patients about whom there is information about at least one episode with hypomanic symptoms and patients with antidepressant-induced hypomania (Akiskal etal., 2003; Chun and Dunner, 2004). Such patients may with advantage be treated with lithium instead of with antidepressants. These observations are in good agreement with the conclusion of recent extensive epidemiological studies suggesting that many depressive patients may in fact have bipolar propensity (Angst et al., 2003; Judd and Akiskal, 2003).3

COMBINATION TREATMENT There is mounting clinical evidence that in patients who do not tolerate lithium or in patients who are refractory to long-term lithium, the addition of an antiepileptic or of atypical neuroleptics may in some cases be of use (Grof, 2003; Yatham, Calabrese and Kusumakar, 2003). There has, however, until now been a relative scarcity of controlled trials demonstrating superiority of the combination over either drug given alone. Such studies are described elsewhere in this book. It is noteworthy that in nearly all of them lithium is considered the gold standard to be augmented. While giving two drugs together might achieve better results by reaching two subgroups of bipolar patients in a heterogeneous population, the real question that needs to be answered is whether such a side effect-prone combination works better than the tailoring of each drug to appropriately selected patients. During unsatisfactory maintenance treatment for recurrent major depressions with antidepressant drugs, augmentation with lithium is frequently useful. In patients who respond to antidepressants plus augmentation with lithium it may be worth trying to discontinue the antidepressant after some time. The patients may then remain stabilized on long-term lithium alone.

THE EFFECT OF LITHIUM ON THE PATIENTS’ SUICIDAL BEHAVIOR In the 1980s it was noted that among about 9000 lithium-treated patients in three major mood disorder clinics in the United States the frequency of suicides was conspicuously low (Jamison, 1986). In the 1990s systematic investigations on very large groups of patients revealed that the frequencies of suicides and of 3

Such data have been published from clinical settings (See review by Akiskal et al., 2000; Akiskal, 2003).

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suicide attempts were about 10–15 times lower in patients given prophylactic lithium treatment than in patients not given such treatment (Coppen et al., 1991; Müller-Oerlinghausen et al., 1992; Tondo et al., 1997; Kallner et al., 2000; Schou, 2000; Baldessarini, Tondo and Hennen, 2001; Goodwin et al., 2003). It would, however, be wrong to claim that an antisuicidal effect of lithium has been definitively proved. Such proof is in principle not possible for any kind of antisuicidal intervention because there is no matching patient group to compare with. One cannot, after all, keep suicide-threatened patients on placebo or deprived of psychological and social support merely to observe if and when they will commit suicide. Nor can one determine by throwing a die when and in whom an ongoing and possibly effective intervention should be discontinued. But the studies reviewed are not incompatible with the assumption that lithium has a striking antisuicidal effect. As scientists we must concede that the investigations merely indicate such a possibility. As responsible clinicians we owe it to patients and relatives alike not to disregard that possibility. No other prophylactic agent in mood disorders has shown a similar evidence of antisuidal action.

BENEFITS OF PROPHYLACTIC LITHIUM TREATMENT The discovery and implementation of prophylactic lithium treatment have had far-reaching results. (1) The efficacy of lithium therapy and prophylaxis has established that recurrent mood disorders are treatable conditions and psychiatry is a medical discipline. (2) Lithium was the first psychotropic drug for which a recurrence-preventive action in mood disorders was demonstrated. This paved the way for other medications to be studied on this indication. Lithium prevents recurrences not only in bipolar disorder but also in recurrent unipolar depressions. Such a double action has not been seen with other drugs. (3) During the last fifty years lithium has stimulated research in numerous fields – clinical, pharmacological, physiological, biochemical, genetic, etc. (4) Mood disorders place a heavy burden on the economy of individuals, the health system and society at large (Wyatt and Henter, 1995). Since lithium treatment is effective and inexpensive, its widespread use has reduced such costs substantially (Reifman and Wyatt, 1980). (5) Last but not least, prophylactic lithium treatment has changed the lives of millions of people for the better. After years in the shadow of fear it may be difficult to hope again, but gradually patients and their families experience how the course of the disease has been altered, and how fear loses its grip. Patients feel that life once more becomes safe and predictable, and that normal friendships can be established or re-established. Prophylactic lithium treatment can

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CONCLUSION Prophylactic lithium treatment for mood disorders was introduced more than thirty years ago, and in spite of being an inexpensive drug, unsupported by powerful pharmaceutical industries, lithium is still used all over the world. Lithium is, with the exception of the USA where valproate has overtaken it, the prophylactic agent most widely used in bipolar disorder. Lithium unquestionably produces the most dramatic benefits of any medication used in psychiatry if it is used correctly. It is clearly the treatment of choice for many patients who suffer from “classic” bipolar disorder, effectively preventing both the manic and the depressed phases of the disorder. This has happened in spite of the fact that few psychiatric treatments have been debated so hotly. Trial strategies, the selection of patients and diagnostic criteria for giving lithium to patients have been commented upon. Misunderstandings and misstatements about lithium have abounded, and this chapter attempts to rectify the most common ones. Competition from pharmaceutical companies trying to replace lithium with new prophylactic medications has been fierce. All this might have meant a short life for lithium. But prophylactic lithium treatment is still widely in use, waiting for something indisputably better to replace it.

REFERENCES Akiskal, H.S. (1999) Affective disorders. In: Berkow, R. (ed.), Merck Manual of Diagnosis and Therapy. 14th edn Rathaway, NJ., Merck, Sharp and Dohme Research Laboratories, pp. 1525–1544. Akiskal, H.S., Bourgeois, M.L., Angst, J., Post, R., Moller, H.J., Hirschfeld, R.M.A. (2000) Reevaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J. Affect. Disord. 59 (Suppl. 1): 5s–30s. Akiskal, H.S., Hantouche, E.G., Allilaire, J.F., Sechter, D., Bourgeois, M.L., Azorin, J.M., Chatenet-Duchene, L., Lancrenon, S. (2003) Validating antidepressant-associated hypomania (bipolar III): A systematic comparison with spontaneous hypomania (bipolar II). J. Affect. Disord. 73: 65–74. Angst, J., Weis, P. (1969) Zum Verlauf depressiver Psychosen. In: Schulte, W., Mende, W. (eds), Melancholie in Forschung, Klinik und Behandlung. Stuttgart, Thieme. pp. 2–9. Angst, J., Weis, P., Grof, P., Baastrup, P.C., Schou, M. (1970) Lithium prophylaxis in recurrent affective disorders. Brit. J. Psychiatry 116: 604–614. Angst, J., Gamma, A., Benazzi, F., Ajdacic, V., Eich, D., Rössler, W. (2003) Toward a re-definition of subthreshold bipolarity: Epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J. Affect. Disord. 23: 133–146. Baastrup. P.C. (1964) The use of lithium in manic-depressive psychosis. Compr. Psychiatry 5: 396–408.

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Baastrup, P.C., Schou, M. (1967) Lithium as a prophylactic agent: Its effect against recurrent depressions and manic-depressive psychosis. Arch. Gen. Psychiatry 16: 162–172. Baastrup, P.C., Schou, M. (1968) Prophylactic lithium. Lancet I: 1419–1422. Baastrup, P.C., Poulsen, J.C., Schou, M., Thomsen, K., Amdisen, A. (1970) Prophylactic lithium: Double-blind discontinuation in manic-depressive disorders. Lancet II: 326–330. Baldessarini, R.J., Tondo, L., Hennen, J. (2001) Treating the suicidal patient with bipolar disorder. Reducing suicide risk with lithium. Ann. N.Y. Acad. Sci. 932: 24–38. Bendz, H., Sjödin, I., Aurell, M. (1996) Renal function on and off lithium in patients treated with lithium for 15 years or more: A controlled, prospective lithium withdrawal study. Nephrol. Dial. Transplant. 11: 457–460. Berghöfer, A., Kossman, A.B., Müller-Oerlinghausen, B. (1996) Course of illness and pattern of recurrences in patients with affective disorders during long-term lithium prophylaxis: A retrospective analysis over 15 years. Acta Psychiatr. Scand. 93: 349–354. Birch, N.J., Grof, P., Hullin, R.P., Kehoe, R.F., Schou, M., Srinivasan, D.P. (1993) Lithium prophylaxis: Proposed guidelines for good clinical practice. Lithium 4: 225–230. Blackwell, B., Shepherd, M. (1968) Prophylactic lithium: Another therapeutic myth? An examination of the evidence to date. Lancet I: 968–971. Bowden, C.L., Calabrese, J.R., McElroy, S.L., Gyulai, L., Wassef, A., Petty, F., Pope, A.C. Jr., Chou, J.C., Keck, P.E., Rhodes, L.J., Swann, A.C., Hirschfeld, R.M., Wosniack, P.J. (2000) A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch. Gen. Psychiatry 57: 481–489. Bowden, C.L., Calabrese, J.R., Sachs, G., Yatham, L.N., Asghar, S.A., Hompland, M., Montegomery, P., Earl, N., Smoot, T.M., DeVeaugh-Geiss, J. (2003) A placebocontrolled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch. Gen. Psychiatry 60: 392–400. Cade, J.F.J. (1949) Lithium salts in the treatment of psychotic excitement. Med. J. Aust. 36: 349–352. Calabrese, J.F., Suppes, T., Bowden, C.L., Sachs, G.S., Swann, A.C., McElroy,S.L., Kusumakar, V., Ascher, J.A., Earl, N.L., Green, P.L., Monaghan, E.T. (2000) A double-blind, placebo-controlled prophylactic study of lamotrigine in rapid-cycling bipolar disorder. Lamotrigine 614 Study Group. J. Clin. Psychiatry 61: 841–850. Coppen, A., Noguera, R., Bailey, J., Burns, B.H., Swani, M.S., Hare, E.H., Gardner, R., Maggs, R. (1971) Prophylactic lithium in affective disorders: Controlled trial. Lancet II: 275–279. Coppen, A., Standish-Barry, H., Bailey, J., Houston, G., Silcocks, P., Hermon, C. (1991) Does lithium reduce the mortality of recurrent mood disorders? J. Affect. Disord. 23: 1–7. Cuhn. B.J. D.H., Dunner, L.D. (2004) A review of antidepressant-induced hypomania in major depression: Suggestions for DSM-V. Bipolar Disord. 6: 32–42. Cundall, R.L., Brooks, P.W., Murray, L.G. (1972) A controlled evaluation of lithium prophylaxis in affective disorders. Psychol. Med. 2: 308–311. Dickson, W.E., Kendell, R.E. (1986) Does maintenance lithium therapy prevent recurrences of mania under ordinary clinical conditions? Psychol. Med. 16: 521–530. Fyrö, B., Petterson, U. (1977) A double blind study of the prophylactic effect of lithium in manic-depressive illness. Acta Psychiatr. Scand. 269 (Suppl.): 17–22. Gelenberg, A.J., Kane, J.M., Keller, M.B., Lavori, P., Rosenbaum, J.F., Cole, K., Lavalle, J. (1989) Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. New Engl. J. Med. 321: 1489–1493.

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Gershon, S., Soares, J.C. (1997) Current therapeutic profile of lithium. Arch. Gen. Psychiatry 54: 16–20. Gitlin, M.J. (1993) Lithium-induced renal insufficiency. J. Clin. Psychopharmacol. 13: 276–279. Gitlin, M.J., Altshuler, L.L. (1997) Unanswered questions, unknown future for one of our oldest medications. Arch. Gen. Psychiatry 54: 21–23. Goodwin, G.M. (1995) Lithum revisited. A reply. Brit. J. Psychiatry 167: 573–574. Goodwin, F.K., Jamison, K.R. (1990) Manic-Depressive Illness. Oxford University Press, New York. Goodwin, F.K., Fireman, B., Simon, G.E., Hunkeler, E.M., Lee, J., Revicki, D. (2003) Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA 290: 1467–1473. Greil, W., Kleindienst, N. (1999) Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified. Int. Clin. Psychopharmacol. 14: 283–285. Greil, W., Ludwig-Mayerhofer, W., Erazo, N., Engel, R.R., Czernik, A., Giedke, H., MüllerOerlinghausen, B., Osterheider, M., Rudolf, G.A., Sauer, H., Tegeler, J., Wetterling, T. (1997) Lithium vs carbamazepine in the maintenance treatment of schizoaffective disorder: A randomised study. Eur. Arch. Psychiatry Clin. Neurosci. 247: 42–50. Greil, W., Kleindienst, N., Erazo, N., Müller-Oerlinghausen, B. (1998) Differential response to lithium and carbamazepine in the prophylaxis of bipolar disorder. J. Clin. Psychopharmacol. 18: 455–460. Grof, P. (1987) Admission rates and lithium therapy. Brit. J. Psychiatry 150: 264–265. Grof, P. (1998) Has the effectiveness of lithium changed? Impact of the variety of lithium’s effects. Neuropsychopharmacol. 19: 183–188. Grof, P. (2003) Selecting effective long-term treatment for bipolar patients: Monotherapy and combination therapy. J. Clin. Psychiatry 64 (Suppl.5): 53–61. Grof, P., Schou, M., Angst, J., Baastrup. P.C., Weis, P. (1970a) Methodological problems of prophylactic trials in recurrent affective disorders. Brit. J. Psychiatry 116: 599–603. Grof, P., Cakuls, P., Dostal, T. (1970b) Lithium drop-outs: A follow-up study of patients who discontinued prophylactic treatment. Int. Pharmacopsychiatry 5: 162–169. Guscott, R., Taylor, L. (1994) Lithium prophylaxis in recurrent affective illness: Efficacy, effectiveness and efficiency. Brit. J. Psychiatry 164: 741–764. Hanna, S., Jenner, A., Pearson, I., Thompson, E. (1972) The effect therapeutic effect of lithium carbonate on a patient with a forty-eight hour periodic psychosis. Brit. J. Psychiatry 121: 271–280. Hartigan, G.P. (1963) The use of lithium salts in affective disorders. Brit. J. Psychiatry 109: 810–814. Healy, D. (ed.) (1997) Lithium. Interview with Mogens Schou. In The Psychopharmacologists II. Chapman & Hall, London. pp. 259–284. Hullin, R.P., McDonald, R., Allsopp, M.N.E. (1972) Prophylactic lithium in recurrent affective disorders. Lancet I: 1044–1046. Jacobson, S.J., Jones, K., Johnson, K., Ceolin, L., Kaur, P., Sahn, D., Donnenfeld, A.E., Rieder, M., Santelli, R., Smythe, J., Einarson, T. Koren,G. (1992) Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 339: 530–533. Jamison, K.R. (1986) Suicide and bipolar disorders. Ann. N.Y. Acad. Sci. 487: 301–315. Johnson, F.N. (1984) The History of Lithium Treatment. Mcmillan, London.

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Judd, L.L., Akiskal, H.S. (2003) The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases. J. Affect. Disord. 73: 123–31. Kallner, G., Petterson, U. (1995) Renal, thyroid and parathyroid function during lithium treatment: laboratory tests in 207 people treated for 1–30 years. Acta Psychiatr. Scand. 91: 48–51. Kallner, G., Lindelius, R., Petterson, U., Stockman, O., Tham, A. (2000) Mortality in 497 patients with affective disorders attending a lithium clinic or after having left it. Pharmacopsychiatry 33, 8–13. Kingsbury, S.J., Garver, D.L. (1988) Lithium and psychosis revisited. Prog. Neuropharmacol. Biol. Psychiatry 22: 249–263. Lange, C. (1886). Bidrag til Urinsyrediatesens Klinik. Hospitalstidende 5, 1–15, 21–38, 45–63, 69–83. Melia, P.I. (1970) Prophylactic lithium: A double-blind trial in recurrent affective illness. Brit. J. Psychiatry 116: 621–624. Mendlewicz, J. (1984) Lithium discontinuation in bipolar illness: A double-blind prospective controlled study. In Corsini, G.U. (ed.), Current Trends in Lithium and Rubidium Therapy. Stuttgart, MTP Press. pp. 125–141. Moncrieff, J. (1995) Lithium revisited: A re-examination of the placebo-controlled trials of lithium prophylaxis in manic-depressive disorder. Brit. J. Psychiatry 167: 569–574. Müller-Oerlinghausen, B., Ahrens, B., Grof, E., Grof, P., Lenz. G., Schou, M., Simhandl, C., Thau, K., Volk, J., Wolf, R., Wolf, T. (1992) The effect of long-term lithium treatment on the mortality of patients with manic-depressive or schizo-affective illness. Acta Psychiatr. Scand. 86: 218–222. Passmore, M.J., Garnham, J., Duffy, A., MacDougall, M., Munro, A., Slaney, C., Teehan, A., Alda, M. (2003) Penotypic spectra of bipolar disorder in responders to lithium versus lamotrigine. Bipolar Disord. 5: 110–114. Placidi, G.F., Lenzi, A., Lazzerini, F., Cassano, G.B., Akiskal, H.S. (1986) The comparative efficacy and safety of carbamazepine versus lithium: A randomized, double-blind, 3-year trial in 83 patients. J. Clin. Psychiatry 47: 490–494, 1986. Povlsen, U.J., Hetmar, O., Ladefoged, J., Bolwig, T.B. (1992) Kidney functioning during lithium treatment: A prospective study of patients treated with lithium for up to ten years. Acta Psychiatr. Scand. 85: 56–60. Prien, R.F., Caffey, E.M., Klett, C.J. (1973) Prophylactic efficacy of lithium carbonate in manic-depressive illness. Arch. Gen. Psychiatry 28: 337–341. Reifman, A., Wyatt, R.J. (1980) Lithium: A brake in the rising cost of mental illness. Arch. Gen. Psychiatry 37: 355–388. Rifkin, A.F., Quitkin, F., Howard, A. (1975) A study of abrupt lithium withdrawal. Psychopharmacol 44: 157–158. Sashidharan, S.P., McGuire, R.J. (1983) Recurrence of affective illness after withdrawal of long-term lithium treatment. Acta Psychiatr. Scand. 68: 126–133. Schioldann, J. (2001) In commemoration of the century of the death of Carl Lange. The Lange theory of ‘Periodical Depressions’. A landmark in the history of lithium therapy. Adelaide Academic Press. Schou, M. (1956) Lithiumterapi ved mani: Praktiske retningslinier. Nord. Med. 55: 790–794. Schou, M. (1969) The ‘Scandinavian Register of Lithium Babies’. In: Diding, N., Ottosson, J.O., Schou, M. (eds), Lithium in Psychiatry. Acta Psychiatr. Scand. Suppl. 207: 97. Schou, M. (1986) Admission rates and lithium therapy. Brit. J. Psychiatry 149: 798–799. Schou, M. (1988) Effects of long-term lithium treatment on kidney function: An overview. J. Psychiatr. Res. 22: 287–296.

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Schou, M., Vestergaard, P. (1988) Prospective studies on a lithium cohort. 2. Renal function. Water and electrolyte metabolism. Acta Psychiatr. Scand. 78: 427–433. Schou, M. (1990) Lithium treatment during pregnancy, delivery, and lactation. An update. J. Clin. Psychiatry 51: 410–413. Schou, M. (1992) Phases in the development of lithium treatment in psychiatry. In: Samson, F. and Adelman, G. (eds), The Neurosciences: Paths of Discovery II. Birkhäuser, Boston. pp. 147–166. Schou, M. (1993a) Lithium prophylaxis: About ‘naturalistic’ or ‘clinical practice’ studies. Lithium 4: 77–81. Schou, M. (1993b) Lithium Treatment of Manic-Depressive Illness: A Practical Guide, 5th edn, Karger, Freiburg, London, New York. Schou, M. (1997) The combat of non-compliance during prophylactic lithium treatment. Acta Psychiatr. Scand. 95: 361–363. Schou, M. (1998a) Has the time come to abandon prophylactic lithium treatment? A review for clinicians. Pharmacopsychiatry 31: 210–215. Schou, M. (1998b) Treating recurrent affective disorders during and after pregnancy: What can be taken safely? Drug. Saf. 18: 143–152. Schou, M. (1998c) The effect of prophylactic lithium treatment on mortality and suicidal behavior: A review for clinicians. J. Affect. Disord. 50: 253–259. Schou M. (2000) Suicidal behavior and prophylactic lithium treatment of major mood disorders: A review for clinicians. Suicide and Life-Threatening Behavior 30: 289–293. Schou, M. (2001) Lithium treatment at 52. J. Affect. Disord. 67: 21–23. Schou, M., Thomsen, K., Baastrup, P.C. (1970) Studies on the course of recurrent endogenous affective disorders. Int. Pharmacopsychiatry 5: 100–106. Schou, M., Juel-Nielsen, N., Strömgren, E., Voldby, H. (1954) The treatment of manic psychoses by the administration of lithium salts. J. Neurol. Neurosurg. Psychiatry 17: 250–260. Stallone, F., Shelley, E., Mendlewicz, J., Fieve, R.R. (1973) The use of lithium in affective disorders, III. A double-blind study of prophylaxis in bipolar illness. Am. J. Psychiatry 130: 1006–1010. Suppes, T., Baldessarini, R.J., Faedda, G.I., Tondo, L., Tohen, M. (1993) Discontinuation of maintenance treatment of bipolar disorder: Risks and implications. Harv. Rev. Psychiatry 1: 131–144. Thomsen, K., Schou, M. (1999) Avoidance of lithium intoxications: Advice based on knowledge about the renal lithium clearance under various circumstances. Pharmacopsychiatry 32: 83–86. Tondo, L., Jamison, K.R., Baldessarini, R.J. (1997) Effect of lithium maintenance on suicidal behavior in major mood disorders. Ann. N.Y. Acad. Sci. 836: 339–351. Vestergaard, P., Poulstrup, I., Schou, M. (1988) Prospective studies on a lithium cohort. 3. Tremor, weight gain, diarrhea, psychological complaints. Acta Psychiatr. Scand. 78: 343–441. Vestergaard, P., Schou, M. (1988) Prospective studies on a lithium cohort. 1. General features. Acta Psychiatr. Scand. 78: 434–441. Wyatt, R.J., Henter, I. (1995) An economic evaluation of manic-depressive illness. Soc. Psychiatry Psychiatr. Epidemiol. 30: 213–219. Yatham, L.N., Calabrese, J.R., Kusumakar, V. (2003) Bipolar depression: Criteria for treatment selection, definition of refractoriness, and treatment options. Bipolar Disord. 5: 85–97.

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3 Valproate: Clinical Pharmacological Profile Charles L. Bowden and Vivek Singh Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Valproate has a unique history, current importance, mechanism and profile of action in bipolar disorder, and several other conditions in psychiatry and other areas of medicine. We review the development of this information for bipolar disorders, the current guidelines for effective clinical use of valproate, and provide a commentary on possible future developments with this molecule. Valproic acid was developed as an organic solvent in 1881 (Burton, 1881), recognized serendipitously as an anticonvulsant in the 1960s, then in its French formulation (valpromide) found to have behavioral benefits in bipolar patients (Lambert et al., 1966; Puzynski and Klosiewicz, 1984). Two pivotal studies, the first a small single center trial in treatment of refractory patients (Pope Jr. et al., 1991), the other a large multicenter study published in 1994 (Bowden et al., 1994), led to regulatory approval in the U.S. (in its divalproex formulation) for treatment of mania in 1995, and at the present throughout most of the world. Valproate has had a large and continually evolving impact on the treatment for bipolar disorders, and circa 2005 is the most widely prescribed treatment for the disorder in the United States. This article focuses on the main dimensions of valproate’s development over the past decade, and their implications for current treatments in bipolar disorder.

MANIA Valproate was significantly superior to lithium in the subset of patients with mixed mania (Bowden, 1995) and among patients with more than 2 lifetime episodes of depression (Swann et al., 1990). In a double-blind randomized study versus carbamazepine, valproate yielded significantly greater improvement in

Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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manic symptomatology, earlier improvement, significantly greater for elevated mood, irritability, speech and thought disturbance, required less use of rescue medications, and was associated with fewer adverse effects (17% vs 67%). Valproate was similarly effective to haloperidol in patients with psychotic mania (McElroy et al., 1996) and in two studies compared with olanzapine, although dosing differences in the comparisons with olanzapine limit interpretation of results (Tohen et al., 1994; Zajecka and Weisler, 2000); divalproex was associated with fewer adverse effects than olanzapine, specifically weight gain, sedation, changes in low density lipoproteins and cholesterol (Zajecka etal., 2002). Intravenous valproate infused as 600 mg over 20 minutes yielded rapid improvement in 4 of 5 manic patients (Grunze et al., 1999). In an open randomized study of adolescents experiencing mania, divalproex yielded non-significantly higher rates of response than did lithium or carbamazepine (Kowatch et al., 2002). These studies of the past decade extend the evidence of the efficacy of valproate as equivalent or superior to other approved treatments for mania in bipolar disorder, and the breadth of circumstances in which it can be effectively employed. No methodologically adequate studies have been conducted in patients with hypomania or cyclothymic disorder, though open clinical case material showing utility on clinical grounds has been published (Jacobsen, 1993; Deltito etal., 1994). The same considerations apply to the open data in rapid cycling patients (Calabrese etal., 1992).

COMBINATION TREATMENT Several studies indicate that valproate is effective when combined with other drugs used in the treatment for mania. Each of the studies reviewed below has utilized a randomized, double-blind, placebo-controlled design. Three of the reports studied addition of an antipsychotic drug to either valproate or lithium, and reported results combining patients who received either mood stabilizer. The reports suggest that similar results occurred with the subsets of patients treated with valproate and with lithium. The studies consistently showed that when combined with antipsychotic drugs, lower doses of the antipsychotic drug are needed than when an antipsychotic drug is used as monotherapy for the same type manic condition (Sachs et al., 2002; Tohen et al., 2002; Yatham et al., 2003). Addition of valproate to haloperidol resulted in significantly greater improvement than did haloperidol alone, and in lower dosage of haloperidol than in patients treated with haloperidol alone (Muller-Oerlinghausen et al., 2000). Addition of risperidone (Yatham, 2000; Sachs et al., 2002) or olanzapine (Tohen et al., 2002) to valproate or lithium resulted in a greater response rate than did continuation of the mood stabilizers as monotherapy. The Sachs et al. study allowed patients to enroll who had received treatment with either valproate or lithium at an adequate dose for two weeks or longer and were still manic, or patients who were manic

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without treatment, in which case both risperidone and either lithium or valproate were started concurrently. No advantage for the combination treatment occurred in the cotherapy group, whereas the subset of patients who had demonstrated unresponsiveness to valproate or lithium showed the advantage of the add-on therapy. Each of the other studies required some degree of failure on the first treatment. Therefore, the studies indicate that in most circumstances combination therapy should be limited to patients who fail to respond to a relatively short period of adequate treatment with a first drug before adding a second. One maintenance study with similar enrollment of manic patients who continued to have manic symptoms despite valproate or lithium treatment has been completed. Among the subset of patients who achieved remission of mania with olanzapine plus valproate or lithium, those then randomized to combination treatment had longer time to manic relapse, but not depressive relapse, than did those treated with valproate or lithium as monotherapy. Rates of earlier discontinuation and weight gain were higher in the combination group (Tohen etal., 2004).

FACTORS ASSOCIATED WITH ACUTE RESPONSE TO VALPROATE Mania with depressive features has been associated with greater responsiveness to divalproex than lithium in manic patients (Freeman et al., 1992; Bowden, 1995). In contrast, patients with mania without any depressive features had equivalent acute responses to divalproex and lithium. Irritability in manic patients has been associated with greater likelihood of response to divalproex than to lithium (Swann etal., 2002), and even versus carbamazepine (Vasudev etal., 2000). Irritability has been the most consistently differentiating symptom favoring divalproex benefit in patients with disorders other than bipolar disorder (Hollander etal., 2001; Frankenburg and Zanarini, 2002; Casey etal., 2003). The first of the latter studies was among schizophrenic patients; the latter two studies included bipolar patients “comorbid” with borderline personality disorder. In one double-blind study, manic patients with a history of prior poor response to lithium had superior responses to divalproex than to lithium (Bowden, 1994). Manic patients with a higher number of lifetime episodes of mania or depression (≥8) and, especially, with more than two lifetime depressive episodes were more likely to respond to divalproex than to lithium (Swann et al., 1999). Open studies have suggested that patients with atypical manic states, e.g., associated with other neurological conditions, substance abuse, later age at onset were generally more likely to respond to valproate than to lithium (Kahn, Stevenson and Douglas, 1988). No randomized, double-blind data have been presented on these points. One study of behavioral components in manic patients found that patients with “hyperactivity” as a predominant feature of mania were equally responsive to divalproex and lithium, with both superior to placebo (Swann et al., 2002). The

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same study also found that for patients whose manic episodes were marked by psychosis or by core depressive features neither divalproex nor lithium was more efficacious than placebo over a three-week period. The foregoing analyses of symptom and illness course features consistently suggest that divalproex’s efficacy is broader, particularly in more severe and complicated presentations of mania, than is the efficacy for lithium or, although less extensively studied, carbamazepine. There are insufficient controlled comparisons with other antimanic drugs to draw conclusions about response patterns.

DEPRESSION One small-blinded randomized study showed divalproex and paroxetine added to lithium to be equivalently efficacious in patients with bipolar depression, with fewer patients treated with paroxetine plus lithium requiring early discontinuation than those treated with VPA plus lithium (Young et al., 2000). Two small studies reported trends for superiority of valproate compared with placebo in treatment for bipolar depression (Winsberg etal., 2001; Petty etal., 2002; Davis etal., 2004). These studies suggest that acute effectiveness of valproate in depression is modest.

MAINTENANCE TREATMENT FOR BIPOLAR DISORDER One large, double-blind, placebo monotherapy study has been published (Bowden et al., 2000). Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to one year of maintenance treatment with divalproex, lithium or placebo. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any full mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores. The divalproex group did not differ significantly from the placebo group in time to any mood episode, in part because substantially lower rates of relapse into mania occurred with placebo than had occurred in early lithium studies, thereby reducing study power from 0.8 to under 0.3. On other planned analyses which were not affected by the lower rate of relapse into mania, which was in part consequent to tapering of lithium at the time of randomization, rather than abruptly discontinuing lithium as had occurred in early lithium maintenance studies, divalproex was significantly more efficacious than placebo. Divalproex was superior to placebo in terms of lower rates of early discontinuation for either a recurrent mood episode or depressive episode or drop out for any reason (Bowden, 2003). Divalproex was superior to lithium in longer

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duration of successful prophylaxis in the study, and displayed less deterioration in depressive symptoms and Global Assessment Scale scores. A post hoc relative risk analysis (Macritchie et al., 2000) of the study reported that patients treated with divalproex were significantly less likely than those treated with placebo to have prematurely left the study for a mood episode (R2 = 0.63, 95% CI 0.44–0.90).

FACTORS ASSOCIATED WITH RESPONSE IN MAINTENANCE TREATMENT In this section, a series of findings uniquely related to maintenance and prophylactic treatment effectiveness with valproate (and in some cases the comparator treatment regimen studied) are summarized. Almost all studies regarding predictors of response other than the ones reviewed here for valproate, as well as other mood stabilizing drugs, have been on acute treatment effects. However, although the earlier section on predictors of response in mania is important, one should not extrapolate findings in that section to maintenance treatment decisions. Several of the subjects covered here can only apply in maintenance, e.g. whether a drug’s acute efficacy is predictive of its maintenance efficacy or whether an acute symptom presentation is predictive of maintenance responsiveness. In the authors’ view, these considerations will prove to be the most important set of predictors in the care of bipolar patients.

CONTINUATION OF ACUTE TREATMENT INTO MAINTENANCE During the open phase of the large divalproex, lithium, placebo maintenance study, approximately half of the patients were treated by psychiatrist choice with divalproex and the other half with lithium to bring their manic symptoms under control. A small number of patients received no mood stabilizer treatment during the open phase, as either their required manic episode had resolved without intervention, or the drug treatment had been discontinued. Among the patients initially treated with divalproex, those then randomized to divalproex had wider advantages compared to placebo for time to mania or depression (p = .05), time to depression (p = 0.03) and the proportion of patients who completed the trial and did not have either a manic or depressive episode (Div = 41%, Pla = 13%, Li = 27%, Div > Pla, p = 0.002) (Bowden et al., 2000). The divalproex to divalproex group continued in the maintenance phase for a significantly longer period of time (mean = 208.9 days) compared to subjects treated initially with lithium and randomized to lithium (mean = 130.3 days; p = 0.019), while subjects treated acutely with no mood stabilizer and randomized to placebo demonstrated an intermediate response (mean = 175.9 days). Among patients who were treated in the open phase with lithium, there was no significant advantage on any of the analyses for those subsequently randomized to lithium compared to those randomized to

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placebo or divalproex. This is the only study published to date that has allowed a statistical test of the relationship between acute episode response and maintenance treatment outcomes (Bowden, 2004). The results are particularly informative, as the patients prescribed open divalproex treatment were generally experiencing a more severe form of bipolar illness than those selected for open lithium treatment. For example, the duration of the open phase was significantly shorter for the no mood stabilizer group (16.0 days) than the lithium group (35.3 days; p<0.001) and the divalproex group (48.2 days; p<0.001), and for the lithium group compared to the divalproex group (p<0.001). Similarly, the time from the start of the index episode to randomization was also significantly shorter for the no mood stabilizer group (59.5 days) compared to the lithium group (74.1 days; p<0.001) and the divalproex group (81.7 days; p <0.001), than for the lithium group. The mean age of the first manic episode was significantly younger in the divalproex group (23.3 years) compared to the lithium group (25.7 years; p= 0.04), and the mean number of days since the last manic episode was longer for the lithium group (447.2 days) compared to either the no mood stabilizer (334.4 days; p =0.007) or divalproex (343.6 days; p=0.01) group.

DYSPHORIC VS EUPHORIC MANIA In contrast to evidence in acute mania, patients whose acute manic episode included significant dysphoric symptoms (dysphoric mania, n = 249) had equivalent maintenance outcomes with divalproex or lithium treatment, with overall outcomes equivalent for patients with dysphoric and euphoric features, e.g. the likelihood of premature discontinuation from maintenance therapy among patients with initial dysphoric mania and euphoric mania was similar: 63.4% vs 71.1%; p = 0.154. Unexpectedly, the rate of discontinuation for intolerance during maintenance treatment was higher for initially dysphoric manic patients than euphoric patients (15.7% vs 7.3% respectively; p = 0.032), whether treated with lithium (23.2%) or valproate (17.1%). These findings indicate that some component of the more complex symptomatology of dysphoric mania increases subjective distress from adverse effects independent of treatment, and has implications for dosing and treatment selection in long-term care of mixed or dysphoric mania (Bowden et al., 2005). Conversely, among initially euphoric manic patients, randomized treatment with divalproex was associated with significantly less discontinuation due to intolerance than treatment with lithium (7.1% vs 18.2%; p = 0.03). The rate of discontinuation due to intolerance in euphoric manic patients was similar for divalproex and placebo. Additionally, treatment with divalproex was significantly (p = 0.05) more effective than lithium in delaying time to a depressive episode in the initially euphoric manic patients. Additionally, among euphoric manic patients, mean depressive symptomatology during maintenance treatment increased significantly more with lithium than with either divalproex or placebo. Also, GAS scores among euphoric manic patients worsened significantly more with lithium

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treatment than with either divalproex or placebo. Whether for overall efficacy, prophylaxis of depression or tolerability among initially euphoric manic patients, those randomized to lithium treatment fared less well than did those randomized to divalproex. Thus, where divalproex works acutely, it seems to outperform lithium in the long term.

SERUM-LEVEL RELATIONSHIPS TO MAINTENANCE OUTCOMES Whereas both for valproate and lithium, serum level-response relationships are well established for treatment of mania, minimal systematic study has been conducted regarding optimally effective maintenance serum levels. In this study, the daily dose was adjusted upward from the starting dose to maintain target serum through drug concentrations of 71–125μg/mL for valproate or 0.8–1.2mmol/L for lithium, as tolerated. In a post hoc analysis, four ranges of serum levels were defined for both divalproex and lithium (Keck et al., 2005). For divalproex, the valproate serum level ranges used to define these categories were: nontherapeutic, <49.9 μg/mL; low therapeutic, 50.0–74.9 μg/mL; medium therapeutic, 75.0–99.9 μg/mL; and high therapeutic, >100.0 μg/mL. For lithium, the corresponding serum level ranges were: nontherapeutic, <0.49 mmol/L; low therapeutic, 0.50–0.79 mmol/L; medium therapeutic, 0.80–1.00 mmol/L; high therapeutic, >1.00 mmol/L. Significant differences between divalproex at the medium range (75–99.9 μg/mL) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; p < 0.05) (Figure 3.1) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, p=0.003). No lithium serum level range differed significantly from another, nor from placebo. A smaller sample of patients were treated with lithium in the study, therefore the results for lithium should be seen as suggestive, not definitive (Table 3.1). 100% 80% Survival

Placebo Nontherapeutic

60%

Low therapeutic 40%

Medium therapeutic High therapeutic

20% 0% 0

1

2

3

4

5

6

7

8

9

10 11 12

Months of Study

Figure 3.1: Survival analysis: Discontinuation for any reason divalproex-treated patients

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Bipolar Psychopharmacotherapy Table 3.1: Median survival time: Discontinuation for protocol-defined mania or depression Treatment Group (N) Placebo (88) Lithium Nontherapeutic (5) Low Therapeutic (16) Medium Therapeutic (37) High Therapeutic (16) Divalproex Nontherapeutic (11) Low Therapeutic (45) Medium Therapeutic (85) High Therapeutic (28)

Median Survival Time, months (95% Confidence Limit) 3.5 (2, 5) 1 (1, 3) 4 (2, 10) 4 (2, 9) 3 (1, 5) 5 (1, NC) 5 (4, 10) 8 (5, 12) 2 (1, 3)

NC = not calculable

TOLERABILITY Overall, tremor and reported weight gain were the only symptoms more commonly seen with divalproex than placebo (Bowden et al., 2000). Patients treated acutely with divalproex had significantly fewer premature discontinuations due to intolerance when randomized to maintenance treatment with divalproex (7.1%) than did patients randomized to lithium. The results from this large, randomized, blinded study are re-enforced by similar results regarding overall effectiveness of valpromide versus lithium in an earlier, randomized open study conducted by Lambert and Venaud (1992). A retrospective analysis of 38 patients with bipolar disorder treated with lithium or divalproex in a university outpatient psychiatry clinic sample for over one year adds perspective to the above studies. Mean duration of follow-up was 90 weeks. Lithium and divalproex were equally effective and tolerated in the total sample. Divalproex monotherapy (24%) was more common than lithium monotherapy (7%, p = 0.07) and was significantly more effective in treating depressive symptoms, with improvement on the HDRS (14.8 ± 9.2 vs 7.6 ± 7.8, p = 0.003) (Ghaemi and Goodwin, 2001). It is clinically noteworthy that cognitive dulling may be reversed by switching patients to divalproex (Stoll et al., 1996). The side-effect profile of valproate is generally well characterized, including from studies conducted in epileptic and migraine patients. Several recent randomized studies with placebo or active treatment comparator groups add relevant new information, and are reviewed here.

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None of the studies of the past decade has indicated evidence of hepatic dysfunction, or significant worsening of hepatic indices, as compared with results seen in placebo- or comparator-treated patients (Bowden etal., 2000). This finding suggests that some of the earlier evidence was associated with dosing factors, or patient selection, that are not relevant in current practice. High serum levels, particularly above 125 μg/ml, are associated with reductions in platelet count and WBC, increased appetite and sedation (Bowden et al., 2000). Studies in migraine employing doses of 500–1000 mg/day have reported no adverse effects compared with placebo, including for weight gain, indicating that patients who are able to achieve benefits from relatively lower doses are likely to be free of even the more common side effects associated with valproate. Immediate release formulations are more likely to cause these adverse events when compared to the extended or enteric coated formulations (Zarate et al., 2000). Extended release formulations (DepakoteER, Depakine Chrono, Orfiril Long) have much flatter peak to trough relationships, and thereby lessen the frequency of adverse effects that are associated with high serum levels (Wilder et al., 1983; Zarate et al., 2000). Recent studies have shown that valproate reduces cholesterol and LDL levels, may increase HDL levels, and protects against effects of some antipsychotic drugs to worsen lipid function (Zajecka et al., 2002). In schizophrenic patients treated for 12 weeks, adjunctive valproate significantly reduced cholesterol increases observed among patients receiving only olanzapine or risperidone (Casey et al., 2003). PCOS has been associated with valproate taken in combination with other drugs in retrospective analyses of epileptic and bipolar patients (Rasgon, 2004). PCOS did not occur across a sectional study of bipolar patients treated with valproate, although menstrual irregularities were seen in a large proportion of the patients (Rasgon et al., 2000). A study evaluating four groups of women with epilepsy: an untreated group, a carbamazepine-treated group, a valproate-treated group and a group receiving more than one antiepileptic, found no evidence of a causative role for valproate in the development of PCOS. Valproate did not alter endocrine measures indicative of PCOS in a 12–15-month study in rhesus monkeys. Studies suggest that obesity may be a mechanistic pathway whereby valproate, and potentially other drugs, increase androgenic compounds. It therefore seems advisable to treat weight gain as a risk factor for possible development of PCOS and intervene as needed to avoid clinically significant weight gain.

EFFECTS ON SUICIDALITY A retrospective study of patients with bipolar disorder who had at least one filled prescription for lithium, divalproex or carbamazepine found a higher risk of

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suicide attempts and death with divalproex than with lithium treatment (Goodwin et al., 2003). A second retrospective study found no difference in suicide attempt rates among lithium-, valproate- or carbamazepine-treated patients (Yerevanian, Koek and Mintz, 2003). Rates of suicidal behavior in bipolar disorder were reduced significantly by treatment with lithium, valproate or carbamazepine, compared to patients in treatment, but not taking a mood stabilizer, with no differences among the three drugs. The study suggests that treatment with a mood stabilizer, which likely reduced illness symptomatology, may be more important than the specific mood stabilizer in reducing suicidal risk in bipolar disorders (11.6 vs 22.9 events/100 patient years).

MECHANISMS OF ACTION Recent studies indicate substantially overlapping, but also distinct mechanisms on signal transduction for valproate and for lithium, nearly always at tissue concentrations that are achieved with therapeutic doses of either valproate or lithium. In general, when other psychotropic drugs have been studied in these paradigms, no comparable results have emerged.

INHIBITION OF GSK-3 Both valproate and lithium inhibit glycogen synthase kinase 3 (GSK-3) at concentrations obtained therapeutically, whereas carbamazepine had no effects (Gould, Chen and Manji, 2004). The effect of valproate in reduction of GSK-3 activity may be indirect, linked to its capability to up-regulate gene expression through inhibition of histone deacetylase (Harwood and Agam, 2003). Histone deacetylase is a target of valproate that results in gradual increases in the phosphorylation of Akt and GSK-3 beta. Although chronic lithium treatment increased the Ser-9 phosphorylation of GSK-3 beta, it did not alter the phosphorylation of Akt. Although valproate and lithium each increased inhibitory phosphorylation of Ser-9-GSK-3 beta, this appears to be directly by phosphorylation following lithium administration, in contrast to the effects of valproate which are mediated by inhibition of histone deacetylase (DeSarno, Li and Jope, 2002). GSK-3 is associated with functional roles in neuroprotection and circadian rhythms. Bipolar patients have altered circadian rhythm activity in relationship to motor activity, interests and sleep, therefore this action constitutes a possible functional pathway by which valproate and lithium control manic systems (Gray et al., 2003). GSK-3 beta is a key enzyme of the Wnt signaling pathway, which is critical for proper embryonic development. One may speculate that inhibition of GSK-3 could contribute to the mechanisms by which valproate and lithium can cause fetal abnormalities (Gould and Manji, 2002).

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ACTIVATION OF ERK KINASE Both valproate and lithium also stimulated the extracellular signal-regulated kinase (ERK) pathway in the rat hippocampus and frontal cortex (Einat et al., 2003). An ERK kinase inhibitor, SL327, induced qualitatively similar effects to amphetamine, which can cause relapse in remitted manic patients and mood elevation in normal subjects. The results suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers (Gould and Manji, 2002).

INCREASE OF BCL-2 EXPRESSION Lithium and valproate increase the expression of the cytoprotective protein B-cell lymphoma/leukemia-2 gene (bcl-2) in the CNS in vivo and in cells of human neuronal origin (Gray et al., 2003). VPA concurrently increased the expression of genes regulated by the ERK pathway, including growth cone-associated protein 43 and bcl-2 promoted neurite growth and cell survival, and enhanced norepinephrine uptake and release. These data link VPA activation of the ERK pathway with production of neurotrophic effects (Yuan et al., 2001).

INHIBITION OF PKC Chronic administration of lithium and valproate results in reduction in protein kinase C (PKC) isozymes in rat frontal cortex and hippocampus. Although VPA reduces the activity of PKC and reduces the protein levels of different PKC isoforms, the effect of VPA appears to be largely independent of myoinositol (Brunello and Tascedda, 2003). Lithium and VPA increase the DNA binding of the activator protein 1 (AP-1) family of transcription factors for PKC in cultured cells in vitro, and in rat brain ex vivo and increase (Chen, Masana and Manji, 2000). Additionally, both omega 3 fatty acids DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 μmol, suggesting that this group of compounds that has been putatively suggested to have mood stabilizing properties share a similar mechanism with valproate (Seung Kim et al., 2001). Valproate is incorporated into neuronal membranes in an active, saturable process at concentrations found clinically, and appears to substitute for naturally occurring phospholipids involved in neuronal membrane and ion channel integrity (Siafaka-Kapadai et al., 1998).

ACTIVATION OF MARCKS PROTEIN Two prominent substrates for PKC in the brain, MARCKS and GAP-43, which have been implicated in actin-membrane plasticity and neurite outgrowth during neuronal differentiation respectively, and are essential to normal brain development,

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are activated by valproate within as little as one day at therapeutically relevant concentrations. Valproate reduced MARCKS protein expression and demonstrated increased GAP-43 protein expression, with concomitant alterations in cellular morphology, including an increase in the number and length of neurites and accompanied by a reduction in cell growth rate. The reduction in MARCKS protein expression and increased GAP-43 protein expression were associated with concomitant alterations in cellular morphology, including an increase in the number and length of neurites and a reduction in cell growth rate.

ATTENUATION OF CRF Valproate reduced CRF mRNA expression and reduced CRF1 receptor binding, suggesting that one of valproate’s effects in brain is to dampen tone in this pathway that is associated with stress linked psychopathology, including mixed mania (Watterson et al., 2002). Some neurochemical actions of valproate are not shared with lithium. Valproate, but not lithium or carbamazepine, dose-dependently inhibited substance P (SP)-induced IL-6 synthesis (seen with pre-incubation periods of 30 minutes, 3, 7 and 14 days). The inhibitory effect of valproate was not mediated by inhibition of the stress-regulated kinases p38 and p42/44 (Erk1/2) but by inhibition of PKC epsilon activation. Furthermore, valproate down-regulated the expression of the substance P receptor (neurokinin(NK)-1) (Lieb et al., 2003).

SUMMARY The central role of valproate in the treatment for bipolar disorders is accounted for by the large effect sizes of its benefits in mania and maintenance treatment. It benefits relatively severe bipolar disorders and behavioral components, particularly irritability, in ways that appear to differentiate it from other currently available treatments for bipolar disorders. Studies of the last decade provide more practical guidelines for selection of valproate as monotherapy, or as a component of combination treatment. Serum level monitoring is a helpful guide to efficacious use and dosing to avoid adverse effects in both acute and maintenance treatment. Valproate has some adverse risks that warrant its discontinuation on occurrence, e.g. pancreatitis; or risks for offspring, e.g. neural tube defects in the first trimester of pregnancy. Patients sometimes wish to discontinue it when they experience severe hair loss. Expanding knowledge of its molecular mechanisms may lead to a role for valproate in other disease states, new specific treatments for bipolar disorders, and productive studies on the neurobiological bases of bipolar disorders.

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Yatham L. Safety and efficacy of risperidone as combination therapy for the manic phase of bipolar disorder: Preliminary findings of a randomized, double-blind study (Abstract). Presented at the 13th European College of Neuropsychopharmacology Congress, Munich, Germany, 2000. Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A. Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial. Br. J. Psychiatry. 2003; 182: 141–147. Yerevanian BI, Koek RJ, Mintz J. Lithium, anticonvulsants and suicidal behavior in bipolar disorder. J. Affect. Disord. 2003; 73: 223–228. Young LT, Joffe RT, Robb JC, MacQueen GM, Marriott M, Patelis-Siotis I. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am. J. Psychiatry. 2000; 157: 124–126. Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G. The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J. Biol. Chem. 2001; 276: 31674–83. Zajecka J, Weisler RSKW. Divalproex Sodium Vs. Olanzapine for the Treatment of Mania in Bipolar Disorder. Presented at the 39th Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 2000. Zajecka J, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. A comparison of the efficacy, safety and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J. Clin. Psychiatry. 2002; 63: 1148–1155. Zarate CA Jr., Tohen M, Narendran R, Tomassini EC, McDonald J, Sederer M, Madrid AR. The adverse effect profile and efficacy of divalproex sodium compared with valproic acid: A pharmacoepidemiology study. J. Clin. Psychiatry. 2000; 60: 232–236.

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CHAPTER

4 Pharmacological Profile and Clinical Utility of Lamotrigine in Bipolar Disorders David J. Muzina1, Joseph R. Calabrese2 1

Department of Psychiatry and Psychology, Cleveland Clinic Foundation, Cleveland, Ohio, USA 2 Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, Ohio, USA

INTRODUCTION There remains a pressing need for additional treatment options for affective illnesses, particularly those refractory or difficult to treat mood disorders such as bipolar disorder. Estimates of the prevalence of bipolar I disorder across diverse cultures and ethnic groups are consistent, ranging between 0.4 and 1.6% in adults (Weissman et al., 1996). Recent estimates of the overall prevalence of bipolar disorder (types I and II) in the general Unites States population suggest that 4–6% of American adults may suffer from this debilitating mental disorder (Hirschfeld et al., 2003; Judd and Akiskal, 2003). Bipolar disorder carries a high burden, negatively affecting lives in many areas, most notably the performance of work-related, leisure and interpersonal activities (Calabrese et al., 2003b). The greatest need exists in the treatment for depressive episodes associated with bipolar disorder as symptoms of depression are much more commonly experienced and more difficult to treat than manic symptoms (Judd et al., 2002; Post et al., 2002). Reports of lamotrigine’s beneficial effects on mood in epilepsy patients led to its use and study in affective disorders. Studies involving bipolar patients suggested that lamotrigine possessed a broad spectrum of therapeutic activity in bipolar disorder, with later descriptions of greater efficacy for depressive than for manic symptoms. Given the significant burden, prevalence and recurrent nature of bipolar disorder – especially bipolar depression – lamotrigine Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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appears to begin to address an area of serious unmet public health need (Calabrese et al., 2003b). We will review the pharmacological profile of this structurally unique anticonvulsant that has become a critical component in the treatment for bipolar disorder. The clinical applications for lamotrigine in mood disorders will be discussed by initially reviewing research evidence supporting its use and then outlining particular clinical scenarios in which lamotrigine can be best utilized as an effective mood stabilizer in acute and chronic therapy. Issues surrounding dosing, drug interactions, rash and use in women of child-bearing age with bipolar disorder will also be discussed. Although the most robust data for lamotrigine is in its prophylactic activity in bipolar I depression, extrapolation of its use for bipolar II (via secondary analyses) will also be undertaken.

CLINICAL PHARMACOLOGY OF LAMOTRIGINE PHARMACODYNAMICS Lamotrigine is an antiepileptic drug of the phenyltriazine class that has demonstrated efficacy as add-on treatment for partial seizures (Matsuo et al., 1993; Mikati et al., 1989) and as maintenance treatment for bipolar I disorder to delay the time of occurrence of mood episodes (Bowden et al., 2003; Calabrese et al., 2003a). Although its mechanism of therapeutic action in humans is not definitively understood, lamotrigine is thought to possess modulatory and protective effects on neurotransmission and intracellular signal transduction processes. Structurally distinct from other antiepileptic drugs, lamotrigine interacts preferentially on the slow inactivated state of presynaptic neuronal sodium and calcium channels to prolong inactivation of the neuron and promote stabilization of the neuronal membrane (Xie and Hagan 1998). This effect is augmented by a use-dependent action in which further inhibition by the drug develops during rapid, repetitive stimulation (i.e. epileptiform bursts). Consequently, the release of the excitatory amino acid glutamate is antagonized (Fitton and Goa, 1995; Li, Ketter and Frye, 2002). Lamotrigine has also been observed to inhibit cortical and amygdaloid kindling (Leach, Marden and Miller, 1986; Gilman, 1995; Xie et al., 1995). Lamotrigine has no substantial in vitro affinity for adenosine, adrenergic, dopaminergic, muscarinic and opioid receptors at clinically applicable concentrations and binds only weakly to inhibit serotonin 5HT3 receptors (Leach, Baxter and Critchley, 1991). Lamotrigine lacks clinically meaningful activity at the 5HT1A receptor, where changes in 5HT1A receptor-mediated cyclic adenosine monophosphate pathway have been implicated in affective disorders (Shiah et al., 1998; Vinod and Subhash, 2002). In early epilepsy studies with lamotrigine it was noted that many patients reported improvement in mood and psychological well-being independent from

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reduction in seizure frequency, which led to its investigation for use in affective disorders (Smith et al., 1993a,b; Jacoby et al., 1996). Significantly, lamotrigine has minimal negative effects on cognitive, memory or psychomotor function and is not associated with sedative effects or weight gain (Cohen et al., 1985; Goa, Ross and Chrisp, 1993; Ginsberg, Sachs and Ketter, 2003).

PHARMACOKINETICS Lamotrigine is extensively absorbed demonstrating linear kinetics, resulting in 98% bioavailability (Garnett, 1997). Peak plasma concentrations are attained after 1–3 hours with mean plasma protein binding of 55–68% (Cohen et al., 1987; Ramsay et al., 1991; Rambeck and Wolf, 1993). Lamotrigine readily crosses the placental barrier causing fetal blood concentrations similar to maternal levels and passes into breast milk reaching 40–80% of the maternal lamotrigine concentration (Ohman, Vitols and Tomson, 2000; Pennell, 2003). The rate-limiting step in the elimination of lamotrigine is N-glucoronidation by the liver with a plasma elimination half-life of 25 + 10 hours (Cohen et al., 1987). Autoinduction of its own metabolism does not occur and there are no active metabolites. Pregnancy increases lamotrigine clearance by more than 50% early during pregnancy and reverts quickly after delivery (Tran et al., 2002). Clearance may be reduced in the elderly and in patients with moderate to severe hepatic dysfunction.

DRUG INTERACTIONS Lamotrigine administration does not affect the serum concentrations of other drugs. However, enzyme-inhibiting drugs such as divalproex sodium increase lamotrigine concentrations by significantly competing for metabolism through glucoronidation effectively increasing the mean half-life of lamotrigine to about 70 hours (Yuen et al., 1992; Anderson et al., 1996). Enzyme-inducing drugs, such as phenytoin, carbamazepine and phenobarbital, reduce lamotrigine’s mean elimination half-life to about 12 hours and decrease lamotrigine concentrations (Hachad et al., 2002). A recently completed but unpublished study shows that there is no clinically significant drug–drug interaction between oxcarbazepine and lamotrigine, and although there is a need for lamotrigine dosage adjustment when co-prescribed with carbamazepine, this is not necessary for oxcarbazepine (data on file, GlaxoSmithKline 2003). Lamotrigine does not significantly affect the pharmacokinetics of lithium (Chen, Veronese and Yin 2000). Table 4.1 summarizes lamotrigine drug interaction information.

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Table 4.1: Lamotrigine drug interactions Lamotrigine has no known effects on levels of: Increased levels of lamotrigine caused by: (estimated % increase LTG) Decreased levels of lamotrigine caused by: (estimated % decrease LTG)

Lithium Carbamazepine Divalproex

Phenytoin Phenobarbital Mesuximide

Antidepressants Benzodiazepines Antipsychotics

Divalproex/Valproate (−100%) Carbamazepine (40%) Phenytoin (50%)

Phenobarbital (40%) *Oxcarbazepine <30%

Bold indicates interaction with clinically significant importance. * No dosage adjustment appears necessary for lamotrigine with oxcarbazepine

LAMOTRIGINE AND AFFECTIVE DISORDERS The observations of Smith and colleagues (1993a,b) that patients treated with add-on lamotrigine for partial seizures experienced improved mood apart from effects on epilepsy stimulated investigations of lamotrigine’s efficacy to treat mood disorders. Early case reports involving bipolar patients suggested that lamotrigine possessed a broad spectrum of therapeutic activity in bipolar disorder, including rapid cycling and mixed states (Weisler et al., 1994; Calabrese, Fatemi and Woyshville, 1996; Walden et al., 1996). A subsequent open-label study provided preliminary data that lamotrigine was effective for patients with refractory bipolar disorder, with 68% of depressed patients and 84% of manic/ hypomanic/mixed patients showing moderate to marked response (Calabrese et al., 1999a). Lamotrigine was used as an add-on therapy in 60 of these patients and as monotherapy in 15. Later studies focused on the ability of lamotrigine to prevent mood episodes associated with bipolar I disorder, for which it received a US-FDA approved indication in 2003.

ACUTE MOOD DISTURBANCES: DEPRESSION An open naturalistic study of 22 depressed bipolar patients who were refractory to treatment with a combination of divalproex sodium and another mood stabilizer or divalproex sodium and an antidepressant for 6 weeks were treated with add-on lamotrigine. By the end of week 4, 16 out of 22 (72%) responded, suggesting that lamotrigine may be useful in bipolar depression (Kusumakar and Yatham, 1997). In a double-blind placebo-controlled study of lamotrigine monotherapy in outpatients

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with non–rapid-cycling bipolar I depression, treatment with lamotrigine over 7 weeks (50 or 200 mg/day) resulted in significant improvements from baseline depression scores (HAM-D, HAM-D Item 1, MADRS), particularly in the 200mg group, compared with placebo (Calabrese etal., 1999b). Improvements were observed as early as week 3. Figure 4.1 demonstrates the percentage of patients showing a response to treatment at endpoint. Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover study of three 6-week monotherapy evaluations including lamotrigine, gabapentin and placebo. Using the Clinical Global Impressions (CGI) Scale for Bipolar Illness as the primary outcome variable, this study reported a 52% response rate (CGI-I as much or very much improved) for lamotrigine, compared to 26% for gabapentin and 23% for placebo-treated patients (Frye et al., 2000). A placebo-controlled, double-blind study of lamotrigine as adjunct to paroxetine in acute depression did not find a significant difference in HAM-D total score at the endpoint of the study for the paroxetine plus lamotrigine group when compared with paroxetine alone (Normann et al., 2002). However, lamotrigine appeared to accelerate the onset of action of the antidepressant and improved core depressive symptoms as reflected by HAM-D items 1 (depressed mood), 2 (guilt feelings) and 7 (work and interest) and the CGI-Severity of Illness scale (p < 0.0001). Lamotrigine-treated patients had fewer days on treatment with benzodiazepines and fewer withdrawals for treatment failure. A recently completed double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with HAM-D-17

MADRS

CGI-I

60% 54%*

51%

50%

51%*

48%*

45%

x Responders

41%** 40%

37% 29%

30%

26%

20% 10% 0% HAM-D-17

MADRS

CGI-I

Figure 4.1: Lamotrigine vs placebo in bipolar I depression. Reprinted by permission from J Clin Psychiatry (Calabrese et al., 1999b) * p < 0.05 vs. placebo ** p < 0.1 vs. placebo

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fluoxetine for resistant major depressive episodes produced mixed results concerning lamotrigine’s antidepressant efficacy (Barbosa, Berk and Vorster, 2003). Twenty-three patients with a resistant major depressive episode (unipolar N = 15, bipolar II N = 8) were treated with fluoxetine 20 mg/day and concomitantly randomly assigned to receive either lamotrigine (N = 13) or placebo (N = 10) over 6 weeks. Lamotrigine was initiated at 25 mg/day and titrated to 100 mg/day. Although lamotrigine was statistically superior to placebo on the CGI scale at endpoint (absolute score and responder analysis) for both unipolar and bipolar II patients, it failed to separate statistically from placebo on the Hamilton Rating Scale for Depression and Montgomery-Asberg Depression Rating Scale. The authors suggested that this negative study may have been the result of artifact from the small sample size used and the limited power of the study. The brief duration of the study (6 weeks), the need to titrate lamotrigine slowly to minimize rash risk, and the use of relatively low dose lamotrigine (maximum of 100 mg/ day) also contributed to the observed findings. Two unpublished studies (data on file, GlaxoSmithKline, 2003) of patients with bipolar I depression (study GW40910) or bipolar I or II depression (study GW603) reportedly found no significant differences between lamotrigine and placebo treatments over the 8–10 weeks study duration on primary endpoints of the MADRS and 17-item Ham-D scores (Goldsmith et al., 2003). The longer duration of these studies, higher dosing for lamotrigine used (200 mg/day in GW40910 and 100–400 mg/day in GW603) and larger numbers of subjects studied (458 total) raises doubts about the acute antidepressant effects of lamotrigine monotherapy in bipolar disorder. Reviews of recent placebo-controlled acute trials in bipolar depression and the use of antiepileptic drugs in psychiatry confirm that the greatest unmet need in bipolar disorder is depression (Muzina, El-Sayegh and Calabrese, 2002; Muzina and Calabrese, 2003).

ACUTE MOOD DISTURBANCES: MANIA/MIXED STATES The 1999 open-label study by Calabrese and colleagues observed a robust response to lamotrigine (primarily as add-on therapy) in 84% of manic/ hypomanic/mixed patients (Calabrese et al., 1999a). In the first double-blind, randomized, controlled study of lamotrigine in acute mania lamotrigine titrated to 100 mg/day over three weeks was as effective as lithium 800 mg/ day (mean blood level 0.77 mmol/L) in reducing manic symptoms (Ichim, Berk and Brook, 2000). However, lamotrigine has not shown anti-manic activity in placebo-controlled studies (Bowden, 2003). Unpublished studies (data on file, GlaxoSmithKline, 2003) in patients with acute manic or mixed exacerbations of bipolar I disorder have found no significant difference from baseline in the 11-item Mania Rating Scale (MRS) between lamotrigine and placebo (Goldsmith et al., 2003).

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PREVENTION OF MOOD DISTURBANCES: MAINTENANCE THERAPY The initial lamotrigine maintenance study was a double-blind, placebo-controlled study in rapid cycling bipolar disorder (Calabrese etal., 2000). Open label lamotrigine added to the treatment regimens of 324 patients meeting DSM-IV criteria for rapid cycling bipolar disorder resulted in 182 stabilized patients stabilized who were then randomly assigned to the double-blind maintenance phase after being stratified for bipolar I or II disorder. Other psychotropic agents were tapered and patients randomly assigned to either lamotrigine monotherapy or placebo in a 1:1 ratio for the six-month maintenance phase. Overall 49 placebo-treated patients (56%) and 45 lamotriginetreated patients (50%) required treatment for an emerging mood episode with additional pharmacotherapy. Although there was no statistical significance between these two treatment groups on the primary outcome measure of time to additional pharmacotherapy (median of 12 weeks for placebo versus 18 weeks for lamotrigine), lamotrigine was significantly more effective than placebo in the survival in study analysis (median of 8 weeks for placebo versus 14 weeks for lamotrigine). In the subanalysis according to disease type, lamotrigine was significantly more effective than placebo in delaying time to additional pharmacotherapy for bipolar II patients than bipolar I patients. Forty-six percent of bipolar II patients on lamotrigine monotherapy were stable without relapse after 6 months compared to only 18% of placebo-treated bipolar II patients. Figure 4.2 depicts survival curves indicating length of study participation for

Survival Estimate

Bipolar I 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Bipolar II

A. Additional Pharmacotherapy

C. Additional Pharmacotherapy

p = 0.073

p = 0.738 B. Survival in Study

PBO LTG

D. Survival in Study

p = 0.426

p = 0.015

0 2 4 6 8 10 12 14 16 18 20 22 24 26 0

2

4

6

8 10 12 14 16 18 20 22 24 26

Week Calabrese et al., 2000

Figure 4.2: Lamotrigine in rapid cycling bipolar I and II disorders. Reprinted by permission from J Clin Psychiatry (Calabrese et al., 2000)

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bipolar I versus bipolar II subtypes treated with lamotrigine compared with placebo (Calabrese etal., 2000). In an unpublished study (data on file, GlaxoSmithKline, 2003), these findings were not replicated. However, significantly fewer lamotriginetreated rapid cyclers required intervention for a depressive episode. Collectively, these results suggest that lamotrigine may be a useful treatment for rapid cycling bipolar patients, especially for type II and for the prevention of depressive relapses. Two 18-month maintenance studies (Bowden et al., 2003; Calabrese et al., 2003) comparing lamotrigine, lithium and placebo provided further support for the use of lamotrigine as a mood stabilizer and led to its approval by the US FDA in June 2003 as a maintenance treatment for bipolar I disorder. These complementary studies enrolled patients in a double-blind phase of maintenance therapy after a recent depressed, hypomanic or manic episode remitted (CGI-S score of <3 for 4 consecutive weeks) during open-label stabilization during which lamotrigine was initiated as adjunctive or monotherapy and other psychotropics discontinued. In both studies, 50% of patients achieved stabilization criteria allowing for progression into double-blinded maintenance therapy with lamotrigine (50–400 mg/day), lithium (0.8–1.1 mEq/L) or placebo. The primary efficacy endpoint used was time to intervention for any mood episode. In both of these studies, lamotrigine and lithium demonstrated effective prophylaxis against any emerging mood episode compared with placebo. There were statistically fewer relapsing mood episodes and longer median survival in lamotrigine- and lithium-treated patients compared with placebo. Median survival before intervention for any mood episode for lamotrigine-treated patients ranged from 118 to 256 days, significantly better than placebo (85–93 days). Lithium also outperformed placebo with a median survival of 170–292 days. However, there were important differences in the spectra of maintenance efficacy. In both studies, lithium, but not lamotrigine was superior to placebo at delaying the time to intervention for a manic or hypomanic episode. In total for both studies 123 manic/hypomanic events emerged during maintenance, with 25% of placebotreated patients experiencing a manic hypomanic/mixed episode (47 of 188); 21% of the lamotrigine group relapsed (58 of 273), but only 11% of patients in the lithium-treatment arm had breakthrough mania or hypomania (18 of 164). Lithium was clearly more effective than placebo and lamotrigine in preventing manic and hypomanic relapse in recently symptomatic bipolar I patients. In contrast, lamotrigine appears to be more effective than lithium in the prevention of depressive relapse in bipolar I patients. In both studies, lamotrigine but not lithium, was significantly better than placebo at prolonging time to intervention for a depressive mood episode. There were 209 depressive relapses in the patients observed in the two studies, with a higher rate of relapse in the placebo (68 of 188, or 36%) and lithium treatment groups (56 of 164, or 34%); lamotrigine was better at preventing recurrence of depression with a 31% rate of depressive relapse and a longer median survival before treatment of depression was necessary. The difference

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was particularly evident in the treatment of recently manic or hypomanic patients in whom only 14% of those receiving lamotrigine (8 of 58) needed intervention for emergent depression compared with 23% of patients receiving lithium (10 of 44) and 30% receiving placebo (21 of 69). A combined analysis of these two pivotal maintenance studies confirms that lamotrigine delays time to intervention of mood episodes in recently stabilized bipolar I patients. Figure 4.3 shows that the percentage of lamotrigine-treated patients that remained free from the need for intervention for any mood episode was significantly greater than placebo (37% vs 22%). Figures 4.4 and 4.5 demonstrate lamotrigine’s bimodal preventative efficacy over 18 months of treatment. Lamotrigine was effective at delaying depressive episodes compared with placebo, with a 39% increase in the percent of patients who remained intervention-free for depression (Figure 4.4). Lamotrigine was also superior to placebo at prolonging the time to intervention for mania, with a 22% increase in the percent of patients who remained intervention-free at 18 months (Figure 4.5) Goodwin et al., 2004.

RASH Rashes requiring hospitalization and discontinuation of treatment have been reported with lamotrigine. A German registry that documents the incidences of serious rash has been in place since 1990 and ascertains hospitalized cases of

Estimated % of pts intervention-free

100

Lamotrigine 100– 400 mg (n = 223) Placebo (n = 188)

90 80 70 60 50 40 30 20

LTG vs PBO, p < 0.001

10 0 1 2 3

4

5 6 7

8 9 10 11 12 13 14 15 16 17 18 Month

Figure 4.3: Time to intervention for any mood episode combined analysis*. Adapted by permission from J Clin Psychiatry (Goodwin et al., 2004) * Bowden et al., 2003, Calabrese et al., 2003 and Goodwin et al., 2004

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Bipolar Psychopharmacotherapy Estimated % of pts intervention-free

52 100

Lamotrigine 100– 400 mg (n = 233) Placebo (n = 188)

90 80 70 60 50 40 30 20

LTG vs PBO, p = 0.009

10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Month

Figure 4.4: Time to intervention for a depressive episode combined analysis*. Adapted by permission from J Clin Psychiatry (Goodwin et al., 2004) * Bowden et al., 2003, Calabrese et al., 2003 and Goodwin et al., 2004

Estimated % of pts intervention -free*

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) related to antiepileptic drug use (Rzany et al., 1996). Reported cases are confirmed by a registry physician and reviewed by a dermatological expert committee ensuring high diagnostic accuracy. The incidence of serious rash rising to the level of SJS/TEN diagnosis in the German registry was 0.02% from 1993 to 2001 (Messenheimer, 2002).

100 Lamotrigine 100– 400 mg (n = 223) Placebo (n = 188)

90 80 70 60 50 40 30 20

LTG vs PBO, p = 0.034

10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Month

Figure 4.5: Time to intervention for a manic episode combined analysis*. Adapted by permission from J Clin Psychiatry (Goodwin et al., 2004) * Bowden et al., 2003, Calabrese et al., 2003 and Goodwin et al., 2004

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The rate of lamotrigine-associated rash in patients with mood disorders has been reported in a retrospective analysis conducted of rates of lamotrigine-related rash in 12 multicenter studies of lamotrigine for mood disorders (n=955) (Calabrese et al., 2002). These studies included 1 open study, 7 randomized controlled acute trials and 4 randomized controlled maintenance trials from 1996 to 2001. Overall, benign rash was observed in 8.3% of patients receiving lamotrigine compared with 6.4% receiving placebo. Serious rash rate was 0.1% in lamotrigine-treated patients (one in 1000) across all controlled and open-label trials. There were no observed cases of serious rash observed with lamotrigine during the controlled phases of these trials, including the three maintenance studies with duration up to 76 weeks. Risk of rash is noted to be higher in pediatric patients, and is increased by coadministration of divalproex sodium or exceeding the recommended initial dose or dose escalation schedule for lamotrigine. Dose escalation of lamotrigine when co-administered with divalproex should be at 50% of the recommended rate, and the same is true for the target dose. Women may be at increased risk for rash compared with men, with a relative risk of 1.8 (Wong, Mawer and Sander, 1999). The clinical management of rash begins initially with the prescription of clear instructions to the patient to follow the recommended dosing schedule to minimize the risk of rash occurring. Rash occurring during the first 5 days of initial lamotrigine therapy is probably non-drug related, however patients should be monitored closely by holding lamotrigine and observing the course of rash. A benign rash typically peaks within days and is spotty, not confluent and non-tender; no systemic features are present and the rash does not involve any mucosal surfaces. In these cases, lamotrigine dosage should be lowered and the titration slowed with a warning to the patient to discontinue the medication if the rash worsens or systemic signs arise (headache, fever, malaise, pharyngitis). Serious rashes tend to be confluent and widespread, cause tenderness and appear hemorrhagic. Systemic signs of illness are often present and careful assessment of internal organ functioning must be performed promptly to exclude hepatic, renal or hematologic system involvement. Patients may require hospitalization and discontinuation of other medications that may contribute to rash progression, such as other anticonvulsants, sulfonamides and penicillins. Progression of erythematous rash with fever and mucosal involvement, or SJS, may be halted by early discontinuation of the causative agent. Patients with a history of serious rash should not be rechallenged with lamotrigine (Calabrese et al., 2002).

OTHER SIDE-EFFECTS AND TOLERABILITY Lamotrigine is known to be generally well tolerated in the treatment for epilepsy (Choi and Morrell, 2003). A great deal of data generated by the 18-month lamotrigine maintenance trials (Bowden et al., 2003; Calabrese et al., 2003) confirm clinical experience and epilepsy management reports of lamotrigine’s favorable side-effect

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Bipolar Psychopharmacotherapy Table 4.2: Adverse events observed during randomized phase of lamotrigine maintenance studies (in %)*. Reprinted by permission from J Clin Psychiatry (Goodwin et al., 2004) Event Nausea Insomnia Somnolence Back pain Fatigue Rhinitis Benin rash Abdominal pain Dry mouth Constipation Vomiting Cough exacerbation Pharyngitis

Lamotrigine n = 227

Placebo n = 190

14 10 9 8 8 7 7 6 6 5 5 5 5

11 6 7 6 5 4 5 3 4 2 2 3 4

* Adverse events listed had incidence >5% and were numerically greater than placebo. (Bowden et al., 2003; Calabrese et al., 2003a; Goodwin et al., 2004)

profile in the treatment of bipolar patients. In 280 patients on maintenance lamotrigine during double-blinded treatment in both trials combined, only 23 (8.2%) discontinued study participation prematurely due to an adverse event; 7.9% of placebo-treated patients experienced adverse events that led to end of study (15 of 191). Over the 18 months randomized phase, lamotrigine treated patients exhibited a 4.9 pound mean decrease in body weight, compared to a 2.6 pound mean weight gain in the placebo group. In a combined analysis of both studies, the incidence of manic/hypomanic/ mixed episodes reported as adverse events was 5% for patients treated with lamotrigine, 4% for patients treated with lithium and 7% for patients treated with placebo. In general, lamotrigine exhibits placebo level rates of treatment-emergent adverse events and is better tolerated than lithium (Calabrese, Vieta and Shelton, 2003). Table 4.2 lists treatment-emergent adverse events for the combined maintenance studies during randomized phase.

CLINICAL APPLICATIONS FOR LAMOTRIGINE IN MOOD DISORDERS ACUTE MOOD DISTURBANCES: DEPRESSION With the wealth of available pharmacotherapies for the treatment of unipolar major depressive disorder and the relative paucity of data to support its use for acute depression, lamotrigine remains a distant option in any medication algorhythm

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to manage unipolar illness. However, there is sufficient available literature and clinical experience to suggest a possible adjunctive role for lamotrigine in some patients only partially responsive to traditional antidepressants or suffering with treatment refractory depression. Based on preliminary evidence (Barbosa Berk and Vorster, 2003; Normann et al., 2002), patients experiencing ongoing depressive symptoms despite adequate antidepressant medication dosing may benefit from augmentation with lamotrigine titrated to 100–200 mg/day. A minimum of 6–9 weeks of adjunctive lamotrigine should be considered an adequate trial when used as an off-label add-on therapy in these cases. For the management of acute bipolar depression, APA Practice Guidelines recommend lamotrigine as a first-line option with moderate clinical confidence (Hirschfeld etal., 2003). Only lithium carries a higher degree of confidence in these guidelines for the initial treatment of acute bipolar depression. In patients experiencing persistent bipolar depression despite adequate lithium or other first-line treatment, lamotrigine can be recommended as add-on therapy with clinical confidence. However, these 2002 APA Practice Guidelines were created and published prior to the completion of the two pivotal lamotrigine maintenance studies (Bowden etal., 2003; Calabrese et al., 2003). As of November 2003, lamotrigine has been approved for long-term use in bipolar disorder in 25 countries worldwide. In the authors’ clinical experiences (Calabrese and Muzina, 2004), acute bipolar II depression can be treated initially with lamotrigine monotherapy. Dosing should follow published titration schedules to minimize the risk of rash, with a minimum dose of 50 mg/day and a target dose of 200 mg/day for most patients (Table 4.3). In bipolar II patients experiencing a breakthrough depression or rapid cycling on other pharmacotherapy, lamotrigine may be considered for augmentation, keeping in mind potential drug interactions that may affect dosing. In type I bipolar depression, lamotrigine should not be used as monotherapy due to a relatively modest efficacy against potential manic relapse. British guidelines suggest lamotrigine be used for acute bipolar depression as a monotherapy only “where depressive symptoms are less severe” (Goodwin, 2003). We suggest

Table 4.3: Recommended lamotrigine dosing schedule Concomitant medication? Week 1&2 Week 3&4 Week 5 Not on divalproex or carbamazepine On divalproex On carbamazepine or phenytoin

Week 6

Week 7

25 mg qd

50 mg qd

100 mg qd 200 mg qd 200 mg qd

25 mg qd 50 mg qd

25 mg qd 100 mg qd

50 mg qd 100 mg qd 100 mg qd 200 mg qd 300 mg qd 300 mg qd

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initial lithium monotherapy or lithium–lamotrigine combination for bipolar I depression to improve acute antidepressant activity and to provide greater bimodal prophylactic efficacy in the long-term management of the disorder. Severe acute bipolar I depression can be treated with a combination of lithium and lamotrigine, although combination with other mood stabilizers, atypical antipsychotics or traditional antidepressants may be necessary. Comorbid catatonic or psychotic features should merit consideration of ECT. Patients with a history of rapid cycling or activation on antidepressants should be prescribed traditional antidepressants only after other options have failed and only carefully in combination with known mood stabilizers to minimize the risk of manic switch or cycling. Rapid cycling bipolar I patients most certainly will require combination therapy and may benefit from lamotrigine in tandem with other mood stabilizers, particularly to address below baseline mood disturbances.

ACUTE MOOD DISTURBANCES: MANIA/MIXED STATES Lamotrigine monotherapy is not recommended for the acute management of mania or mixed states associated with bipolar I disorder. Despite limited case reports and early data suggesting that lamotrigine may possess anti-manic properties, further study has led to the conclusion that lamotrigine has only mild to moderate efficacy in mania and should not be reliably used as monotherapy in these urgent above baseline mood disturbances. The addition of lamotrigine to other first-line antimanic agents, such as lithium, divalproex, olanzapine or quetiapine, may hasten or complete recovery from acute manic or mixed states. Lamotrigine should definitely be considered as an initial adjunctive treatment for these bipolar I patients to address the need to prevent future mood episodes after recovery from the current manic or mixed episode. Again, dosing guidelines should be followed as indicated previously and in the package insert to avoid increased risk of rash. In bipolar II patients experiencing hypomanic relapse with disruptive irritability, lamotrigine can be used as a monotherapy or, preferably, in conjunction with another mood stabilizer such as lithium. Another useful strategy is the prescription of lamotrigine plus a short-term atypical antipsychotic. This combination rapidly provides relief of such hypomanic symptoms as irritability, lack of sleep, racing thoughts (we submit via the atypical antipsychotic acutely and longer-term prophylaxis of future mood disruptions via lamotrigine). This is critical given the known predominance of the depressive state in bipolar II disorder, to which lamotrigine’s therapeutic profile best lends itself as an effective mood stabilizer. Lamotrigine is particularly effective in the management of rapid cycling bipolar II disorder, although these patients often require the addition of a second or even third medication.

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PREVENTION OF MOOD DISTURBANCES: MAINTENANCE THERAPY Lamotrigine is indicated by the US FDA for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes. It should therefore be considered in the treatment of all bipolar patients due to the inherent natural tendency for the illness to be chronic and recurrent. Maintenance monotherapy with lamotrigine can be considered on clinical grounds in those individuals with non-bipolar I illness, “milder” forms of bipolar II disorder with predominant depressive course, and in other bipolar spectrum disorders such as cyclothymic disorder with disruptive effects on the patients’ social and occupational life. In theory, lamotrigine monotherapy could also be considered as a maintenance therapy after successful ECT for either unipolar or bipolar depression and there are early studies in the planning stages to investigate lamotrigine’s potential in these clinical situations. In most patients, lamotrigine should be part of a combined pharmacological strategy to prevent relapse. Although lamotrigine has been demonstrated an effective maintenance treatment for bipolar I disorder, its ability to prevent manic episodes was considerably less robust than its antidepressant ability. A comprehensive bipolar maintenance medication treatment plan must address prevention of depressive and manic phases, and lamotrigine is only moderately effective in the delay of manic episodes necessitating use of other mood stabilizers with a complementary efficacy profile, such as lithium or divalproex. To date there are still no known pharmacologic agents with true and complete “bimodal” efficacy able to deal with the acute and chronic manifestations of this serious mental illness.

USE IN WOMEN AND THE RISK OF MALFORMATIONS IN PREGNANCY There have been reports of lamotrigine serum concentrations decreasing in women after starting oral contraceptives and increasing after oral contraceptives were discontinued. Dosage adjustments may have to be made in women taking lamotrigine during times of oral contraceptive initiation or termination, although no known link existence between blood levels and therapeutic effects for affective disorders. Lamotrigine carries a Category C FDA warning for use during pregnancy. Pregnant women maintained on lamotrigine during pregnancy should have blood levels of lamotrigine checked monthly as its clearance increases significantly as pregnancy progresses. A preconception determination of lamotrigine blood level in a stable bipolar woman may provide a target dose range to maintain during pregnancy. Clearance of lamotrigine drops quickly after delivery, requiring dosage reduction in most postpartum patients. Breast-feeding is not recommended to nursing mothers on lamotrigine since significant levels of lamotrigine are present in breast milk and long-term effects of exposure to neonates is unknown.

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While there are no lamotrigine interactions with progesterone-only oral contraceptives (Crawford 2002), Sabers and colleagues (2001) have reported have reported decreased plasma lamotrigine levels (mean 49%, range 41–64%) in seven patients taking oral contraceptives containing ethinylestradiol. More recently, these findings have been replicated in an open-label, non-randomized, non-placebo-controlled, single sequence design conducted in 22 healthy women (see GSK Revisions to Prescribing Information 2005). An ethinylestradiol-containing oral contraceptive administered in combination with lamotrigine significantly decreased levels of lamotrigine (on average, 52% decrease in AUC and 39% decrease in Cmax. Based on these new data, when lamotrigine is started in a woman currently taking an estrogen-containing oral contraceptive, the titration schedule remains unchanged whereas the maintenance dose may need to be increased as much as twofold in women starting or currently taking oral contraceptives. Conversely, the maintenance dose of lamotrigine may need to be decreased by as much as 50% below the maintenance dose if oral contraceptives are stopped. According to the most recent interim report of the Lamotrigine Pregnancy Registry issued July 2003, during the period September 1, 1992 through March 31, 2003, 593 pregnancies with lamotrigine exposure were reported in 29 countries (USA 193). In the prospective reports with lamotrigine monotherapy exposure during first trimester in 302 outcomes, there were 9 major birth defects (3% rate). In lamotrigine exposure, 7 of 67 outcomes (10.4%) with polytherapy including valproate had major birth defects, while only five major malformations were observed in 148 outcomes when lamotrigine was part of a polytherapy not including valproate (3.4%). There appears to be a higher frequency of major birth defects when lamotrigine and valproate are used together during first trimester pregnancy (data on file, GlaxoSmithKline, 2003). More recently, Cunnington and colleagues (2005) have reported on the frequency of major congenital malformations (MCM) in lamotrigine-exposed pregnancies from September 1, 1992 through March 21, 2004, in the International Lamotrigine Pregnancy Registry. Healthcare professional throughout the world voluntarily enrolled lamotrigine-exposed pregnancies in this observational study of women with epilepsy. Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with MCM were reported (2.9%; 95% CI 1.6% to 5.1%). Among 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with MCM were report (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with MCM were reported (2.7%; 95% CI 1.0% to 6.6%). No distinctive pattern of MCMs was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy. At the time of the analysis, the Registry had the power to detect a 1.79 to 2.00-fold increase in the risk of MCM, assuming a baseline rate of 2 to 3%. The authors concluded that the risk of all MCM after first-trimester exposure to lamotrigine montotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%).

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SUMMARY The discovery of lamotrigine’s positive effects on mood in epilepsy patients led to its investigations in and eventual approval for treating bipolar affective disorder. Although the exact mood stabilizing mechanism of action for this novel anticonvulsant is unknown, it is thought to work by inhibiting voltage-sensitive sodium currents, in this manner stabilizing neuronal membranes and as a result modulating the presynaptic transmitter release of excitatory amino acids such as glutamate. Although there is some suggestion that lamotrigine may have some beneficial effect in the treatment for unipolar depression, available evidence points to a primary role as a mood stabilizer in bipolar disorders that has moderate to marked acute and prophylactic antidepressant efficacy, only modest antimanic prophylaxis and no acute antimanic efficacy. Lamotrigine is very well tolerated, requires careful dose monitoring in certain clinical situations and offers significant potential benefit as monotherapy or in combination with other mood stabilizers in the acute and long-term management of bipolar disorder. Current data are strongest for bipolar I disorder. Its role in bipolar II is in need of further systematic studies. Our discussion was meant to enrich rational clinical considerations.

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5 Carbamazepine, Other Anticonvulsants and Augmenting Agents Heinz Grunze Department of Psychiatry, LMU Munich, Germany

INTRODUCTION Despite the fact that a multitude of well established and extensively studied medications for bipolar disorder is nowadays available, a fair proportion of patients need treatment with additional drugs. This includes very often older anticonvulsants, e.g. carbamazepine or its off-spring, oxcarbazepine, other older agents with so far limited scientific evidence or which only became available recently, and drugs which appear useful only for one pole of the illness, e.g. antidepressants. However, as described in greater detail in Chapter 9, a concomitant use of these agents is rather the rule than the exception. This chapter will focus on three different classes of medication: 1. Anticonvulsants (other than valproate and lamotrigine, already covered in Chapters 3 and 4) 2. Antidepressants 3. Nutritional supplements and thyroid hormone.

ANTICONVULSANTS CARBAMAZEPINE Starting with the first studies of Okuma etal. (1973) the efficacy of carbamazepine for the acute treatment of mania has been demonstrated in several, mostly small studies, both by the group of Okuma and by others investigators (e.g. Ballenger and Post, 1980; Müller and Stoll, 1984; Emrich, Dose and von Zerssen, 1985; Post etal., 1987). Comparative studies have been conducted as well with conventional antipsychotics as with lithium (Okuma et al., 1979, 1990; Klein et al., 1984; Stoll et al., 1986; Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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Lerer et al., 1987; Brown, Silverstone and Cookson, 1989). The impression of these studies was that carbamazepine was overall equally effective as the comparators, with a probably slightly slower onset of response compared to antipsychotics, but still slightly faster acting than lithium (Small et al., 1996). In a recent comparative trial with valproate (Vasudev, Goswami and Kohli, 2000) both carbamazepine and valproate were found to be efficacious as first-line antimanic agents. However, advantages for valproate were observed both for time to onset of action and tolerability. Summarizing these trials, antimanic efficacy of carbamazepine appears apparent despite the relative absence of methodological unambiguous controlled studies. Looking into specific sub-groups of patients carbamazepine may be especially helpful in patients with incomplete response to lithium in acute mania, rapid cycling (Denicoff et al., 1997; Greil et al., 1998), patients with co-morbid organic (neurological) disorders (Schneck, 2002) and schizoaffective patients (Elphick, 1985; Goncalves and Stoll, 1985; Greil et al., 1997a). For the depressed phase of bipolar disorder, unequivocal evidence for the usefulness of carbamazepine is missing. Small, mainly open, studies (reviewed by Brambilla, Barale and Soares, 2001) suggest that carbamazepine may be useful in the treatment of both unipolar and bipolar depression. But again, in the absence of randomized placebo-controlled studies, this statement remains questionable. There have been two new trials of carbamazepine in acute mania which addresses the foregoing methodological problems. These are a large multicenter randomized double-blind placebo-controlled trial of an extended release formulation of carbamazepine (ERC-CBZ) for monotherapy for bipolar, manic and mixed patients (Weisler et al. 2004, 2005). They included 204 and 239 patients, respectively, with acute manic or mixed states. Both studies initiated treatment at 400 mg/day and increased as necessary and tolerated up to 1600mg/day. In the first study, ERC-CBZ started showing significantly greater improvement than placebo as of week two, and in the second already as of week one. The main side effects in both studies that were higher than placebo were dizziness, nausea and somnolence. These studies finally provided clear and unambiguous evidence for the efficacy of carbamazepine in acute mania. A main disadvantage of carbamazepine is the induction of different members of the cytochrome P 450 family. This may cause an increased metabolism of different antidepressants leading to reduced effectiveness. Thus, carbamazepine has not been recommended as a first-line treatment for bipolar depression. First evidence for a prophylactic efficacy of carbamazepine in bipolar disorder was established by five randomized controlled trials in the 1980s and early 1990s. Four of these studies compared carbamazepine with lithium (Placidi et al., 1986; Watkins et al., 1987; Lusznat, Murphy and Nunn, 1988; Coxhead, Silverstone and Cookson, 1992), and one with placebo (Okuma et al., 1981). A meta-analysis of the four lithium trials concluded that carbamazepine’s efficacy as a prophylactic

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agent could not be established on a basis of these trials because of the heterogeneity in design, differences in statistical power and sensitivity of outcome measures (Dardennes et al., 1995). More convincing evidence for prophylactic efficacy of carbamazepine is now available with three new maintenance studies. Denicoff et al. compared carbamazepine, lithium and the combination of both in 52 bipolar I patients. Patients were randomized either to carbamazepine or lithium treatment for the first year, then switched over to the alternative treatment for the second year and finally to combination treatment for the third year. Whereas the prophylactic efficacy of both monotherapies was disappointing, combination treatment with both lithium and carbamazepine was clearly superior to each monotherapy. Greil et al. (1997b) and Greil and Kleindienst (1999) compared carbamazepine and lithium in an open-label, but randomized parallel group study, lasting for 2.5 years and involving 144 patients with bipolar I, II and not otherwise specified bipolar disorders. No significant difference was observed between both treatments based on survival analysis with time to hospitalization or episode recurrence. However, when combining different outcome-measures (recurrence and need for additional medication and/or adverse events) lithium was significantly better than carbamazepine. Additionally, less suicide attempts and completed suicides were observed in the lithium group (Thies-Flechtner et al., 1996); this finding is also supported by a recent chart analysis by Yerevanian, Koek and Mintz (2003) showing a trend toward better antisuicidal properties for both lithium and valproate compared to carbamazepine. The impression that lithium may be overall more efficacious than carbamazepine in the prophylactic treatment for bipolar disorders is also backed up by a recent study of Hartong et al. (2003) comparing 94 patients in a randomized, two-year double-blind study. Out of 44 patients on lithium, 12 patients developed a new episode compared with 21/50 on carbamazepine treatment. Significant superiority for lithium was shown in those patients who were not previously treated with any other mood stabilizer. Interestingly, relapse with lithium occurred almost exclusively within the first three months of the trial while carbamazepine patients carried a constant risk of an episode of about 40% per study year. This may hint to different intracellular effects and modes of action of these two drugs. In conclusion, carbamazepine appears to be an effective drug in bipolar disorder, especially in the treatment for acute mania, but not of special utility. There is no strong evidence for an antidepressant efficacy, and in long-term treatment the general impression is that it is less efficacious than lithium and lacks special antisuicidal properties. Additionally, in combination treatment, induction of the cytochrome P 450 metabolism complicates combination treatments both with other mood stabilizers and with several antipsychotics and antidepressants.

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OXCARBAZEPINE Oxcarbazepine is the 10-keto-analog of carbamazepine and uses a different pathway of metabolism. It avoids the formation of the 10,11-epoxide metabolite of carbamazepine which is thought to be responsible for the majority of neurological side effects. Instead, oxcarbazepine is reduced by a cytosolic reductase to its 10-mono-hydroxy derivative (MHD). Avoiding the metabolism by cytochrome P 450 3A4, oxcarbazepine does not induce its own metabolism and has only a few clinically significant drug interactions. As a drawback, the scientific evidence for efficacy in bipolar disorder is considerably less than for carbamazepine. Most of the work on oxcarbazepine in bipolar disorder, especially in acute mania, was performed by Emrich et al. in the early 1980s (Emrich, Dose and von Zerssen, 1984; Emrich, 1994). The antimanic effect of oxcarbazepine appeared comparable to the one of valproate in these early studies. In a double-blind comparative trial with haloperidol by Müller and Stoll (1984) no difference in efficacy was observed between oxcarbazepine and haloperidol. This impression was also supported by another study by Emrich (1990). With similar efficacy, the tolerability of oxcarbazepine was significantly better, with the incidence of side effects 3.5 times higher in the haloperidol group compared to the oxcarbazepine group. These studies are also comprehensively reviewed by Dietrich, Kropp and Emrich (2001). More recently, a study by Hummel et al. (2002) supplied further supporting evidence for antimanic efficacy of oxcarbazepine, using an on–off–on design. Oxcarbazepine monotherapy was effective in patients with mild to moderate mania (Young Mania Rating Score <25) but not in severely manic patients. So far, no controlled studies are available for oxcarbazepine in bipolar depression. A retrospective chart review by Ghaemi, Ko and Katzow (2002) suggests that oxcarbazepine may possess mild to moderate efficacy in bipolar depressed patients. However, this impression has not been verified by controlled studies so far. Considering prophylactic treatment we also have to refer to case series and open studies. Munoz (2002) investigated the mood stabilizing effect of oxcarbazepine as adjunctive treatment over 12 weeks. Improvement according to pre-defined criteria was observed after 3 weeks in 71% of patients entering this study manic and all patients entering this study depressed, with 60% of the responders of the manic group remaining euthymic through the remaining 9 weeks of the study, and all of the responders in the depressed group remaining stable for the remainder of this study. Nasr and Casper (2002) conducted a further open, but prospective review in 87 patients with mood disorders including 28 patients with bipolar disorder. With the addition of oxcarbazepine, a significant improvement in the CGI severity of illness score was observed in all patients. The greatest improvement was seen in bipolar II patients with predominant hostility. In the study of Reinstein (2001) 42 patients with bipolar or schizoaffective disorder were stabilized with valproate. Half of them were switched to oxcarbazepine after 10 weeks

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of treatment and followed up for another 10 weeks. Compared to patients remaining on valproate, mood stability was maintained to a similar degree. As a secondary outcome, it was noted that 47% of patients on valproate gained weight compared to only 26% of patients on oxcarbazepine and a substantial proportion (70%) of patients lost weight after being switched from valproate to oxcarbazepine. In conclusion, there is some evidence for acute antimanic effects of oxcarbazepine, at least in mild to moderate manic patients, but probably not in severely ill patients. Data on the treatment for bipolar depression and prophylactic efficacy are sparse (for further review: Grunze and Walden, 2002; Hellewell, 2002). However, oxcarbazepine may be a potential candidate drug for patients who previously responded well to carbamazepine, but had problems with tolerability or drug interactions in combination treatment.

PHENYTOIN Although phenytoin has been a first choice treatment for epilepsies since the 1940s, it has never been studied in a thorough way in bipolar disorder until recently. Mishory et al. (2000) were the first who published a placebo-controlled add-on trial with phenytoin in acute mania. Patients entering the study were started on haloperidol in a dose of the physician’s discretion and then randomly assigned to receive either phenytoin or placebo as an add-on treatment. The improvement for the phenytoin group was significantly better starting from week 3 until the end of the study (week 5). In general, phenytoin was well tolerated, except for one patient developing tachycardia at 500 mg/day at week 4 and another patient developing dizziness at study initiation which responded to reduction of the dose. The same group also investigated the acute antimanic effect of fosphenytoin in a small open trial, observing no antimanic effects after one hour despite using doses which are effective in status epilepticus (Applebaum, Levine and Belmaker, 2003). In a recent study the same group looked into prophylactic efficacy of phenytoin (Mishory, Winokur and Bersudsky, 2003) Phenytoin or placebo were randomly added to ongoing and not changed prophylactic treatment in stabilized bipolar patients. After six months patients who had not relapsed were crossed over to the other drug without breaking the blind. There were only three patients (21.4%) who had a relapse on phenytoin, nine (56.3%) relapsed on placebo. This effect was significantly in favor of phenytoin. However, with the small size of the study, further conclusive trials have to be awaited before a more extensive use of phenytoin in bipolar disorder can be recommended.

CLONAZEPAM AND LORAZEPAM These two benzodiazepam derivatives are quite frequently used in bipolar disorder. However, they are generally not considered as primarily mood stabilizing

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agents, but are used as add-on treatment to calm down the patient and relieve anxiety. This is especially true for lorazepam. Nevertheless, there are some studies supporting mood stabilizing effects of these two drugs. Clonazepam is a high-potency 1,4-benzodiazepine derivative. Besides acting on the GABA A receptor (Haefely, 1983) clonazepam may also modulate the central serotonergic metabolism (Lima, 1991). Several open trials and case series support antimanic efficacy (Chouinard, Young and Annable, 1983; Chouinard, 1985; Adler, 1986; Pande, 1988; Chouinard etal., 1993; Bottai etal., 1995; Morishita and Aoki, 1999). For treating the depressed phase of the illness, evidence for efficacy of clonazepam appears less convincing. In a study of Kishimoto etal. (1988) 27 patients with major depression, among them 9 with bipolar depression, were treated openly with clonazepam. The authors report marked or moderate improvement to be obtained in 84% of the patients with a rapid onset of the antidepressive effect of clonazepam. For maintenance treatment diverging results have been reported. Sachs et al. (Sachs, Rosenbaum and Jones, 1990a; Sachs, Weilburg and Rosenbaum, 1990b; Sachs, 1990) describe positive effects of add-on clonazepam for maintenance treatment. This is also in line with previous results of the study of Chouinard (Chouinard, 1987) where clonazepam was administered as an adjunct to lithium or combined lithium/tryptophane treatment. However, the most recent study of Winkler et al. (2003) could not establish prophylactic efficacy for clonazepam in bipolar patients. Interestingly, they saw a prophylactic efficacy of clonazepam in recurrent unipolar depression. Summarizing these results most evidence points toward antimanic efficacy of clonazepam whereas data for the treatment of bipolar depression and maintenance treatment are either missing or ambiguous. As for lorazepam, it is often used as a standard rescue medication in controlled mania studies, but it may by itself influence the outcome of the trial when not applied in a controlled and restricted manner. Several studies point toward an antimanic efficacy of lorazepam which may even be comparable to the one of haloperidol (Lenox et al., 1992). Used as an add-on medication to haloperidol, lorazepam was less efficacious than lithium add-on treatment (Chou et al., 1999). In a double-blind randomized comparison with clonazepam, however, lorazepam appeared more efficacious for treating acute mania (Bradwejn et al., 1990). Recently, parenteral administration of lorazepam was also studied in comparison to olanzapine and placebo in 201 acutely manic patients. At endpoint after 24 hours, lorazepam injections were significantly superior to placebo in several outcome parameters measuring agitated behavior, although the study was not powered to show differences between lorazepam and placebo (Meehan et al., 2001). Due to the imminent danger of dependency, long-term use of lorazepam cannot be recommended. Thus, prophylactic efficacy has not been studied in a controlled manner so far.

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LEVETIRACETAM Levetiracetam is a pyrrolidine derivative which has been approved for add-on treatment of refractory partial epilepsy in adults. Its mechanisms of action appear different from those known from other classic antiepileptic drugs (Hovinga, 2001). In an animal model of mania, levetiracetam appeared efficacious (Lamberty, Margineanu and Klitgaard, 2001). A first case report (Goldberg and Burdick, 2002) and an open add-on study applying an on–off–on design (Grunze et al., 2003) are supportive of antimanic efficacy in men, but double-blind randomized controlled trials for mania have still to be conducted. A case report suggests also efficacy in long-term mood stabilization in rapid cycling patients (Bräunig and Krüger, 2003). Further data on long-term maintenance treatment or on the treatment for bipolar depression are currently not available.

ZONISAMIDE Zonisamide has recently been approved in several countries for the adjunctive treatment of refractory epilepsies. With classical antiepileptic drugs it shares several mechanisms of actions, such as sodium and T-type calcium channel blocker properties. Additionally, zonisamide also exerts effects on serotonine and dopamine turnover (Okada etal., 1995, 1999; Oommen and Mathews, 1999). Zonisamide also binds to the GABA A receptor and inhibits carbonic anhydrase which, in turn, effects both extra- and intracellular pH-dependent neurotransmitter systems. In 1994, Kanba et al. presented evidence of antimanic effects of zonisamide in an open study with a responder rate of 80%. These findings were recently followed up in a study of the Stanley Foundation Bipolar Network where 63 bipolar outpatients received zonisamide adjunctive open treatment in mania, bipolar depression or continuous cycling. In all phases of the illness, the addition of zonisamide appeared helpful (Leverich et al., 2003). In addition, zonisamide seems to have a potentially beneficial side-effect profile in terms of weight loss. With currently more controlled data lacking zonisamide may be a future choice as add-on treatment in patients who are not sufficiently responsive to standard therapy, especially, if weight gain constitutes an additional problem.

TOPIRAMATE Several open studies favored topiramate as a potential antimanic agent (Marcotte, 1998; McElroy, Kmetz and Keck, 1998; Normann etal., 1999; Calabrese etal., 2001; Grunze et al., 2001) reporting also about the beneficial weight loss properties in some patients. However, this positive first impression could not hold true in rigorous randomized, placebo-controlled trials (which to the best of our knowledge

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remain unpublished). For the depressed phase of the illness, an open trial with adjunctive topiramate by McElroy et al. (2000) showed no improvement. However, McIntyre et al. (2002) found in an eight week, single-blind, randomized comparator trial with bupropione similar efficacy of topiramate in patients with bipolar I or II depression. Clearly, more controlled data are needed, not only for bipolar depressed patients but also for long-term treatment in order to give any advice on topiramate’s use in bipolar disorder.

GABAPENTIN Although several open trials have favored gabapentin treatment in acute mania, the two double-blind controlled studies of Pande et al. (2000a) and Frye et al. (2000) could not prove antimanic efficacy of this drug. Controlled data for bipolar depression are missing. As gabapentin appears to have also mild anxioloytic properties (Pande et al., 1999, 2000b) it may still be helpful in selected bipolar patients with anxiety comorbidity or mixed depression and anxiety (Carta et al., 2003). In line with these findings, an open systematic prospective study demonstrated that the utility of this agent in refractory bipolar disorder was accounted for by its anxiolytic effects in patients with comorbid alcohol problems.

TIAGABINE Only open studies exist so far for tiagabine in bipolar disorder. No antimanic effect was observed in an open study by Grunze et al. (1999). Convincing effects were also not seen in a case series of Suppes et al. (2002). In the studies of both Grunze and Suppes significant adverse events (provocation of seizures) were observed. The clinical utility of tiagabine, however, may be different when used in low doses for long-term treatment. Case reports of Schaffer and Schaffer (1999) showed some degree of stabilization in outpatients previously not responding satisfactorily to standard medication. With the severe side effects which may be provoked by tiagabine, however, it appears unlikely that further controlled studies will be conducted in bipolar disorder.

ANTIDEPRESSANTS IN BIPOLAR DISORDER Antidepressants in the bipolar context can be viewed as augmenting agents on ongoing mood stabilizers, or vice versa (when a patient on antidepressants has failed to respond and is deemed bipolar or otherwise worthy of a trial with a mood stabilizer). The discussion in this section pertains to their use as augmenting agents in a patient protected against mania by a mood stabilizer.

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During recent years, one of the main points of discrepancy between treatment recommendations was the role of antidepressants in bipolar disorder (Möller and Grunze, 2000). In the absence of large, rigorously controlled trials, the role of antidepressants was interpreted very differently, depending whether someone considered bipolar depression as a unique pathophysiology very different from unipolar depression, or a more syndrome and symptom orientated view was applied. The pros and cons for antidepressants have been discussed in a reasonable number of recent review papers (Montgomery et al., 2000; Thase and Sachs, 2000; Grunze and Möller, 2002; Keck and McElroy 2003; Thase, Bhargava and Sachs, 2003). Despite having different opinions about treatment, all experts agree that bipolar depression is the greater challenge compared to mania. As pointed out by recent articles by the San Diego group (Judd et al., 2002, 2003), Bipolar I patients suffer three times as many days per years from depression than from mania; in Bipolar II patients, the relation is even thirty-seven to one comparing the number of depressed and hypomanic days. Besides the longer illness duration, bipolar depression constitutes also a high risk factor for suicide, exceeding even the risk in unipolar depression (Bottlender et al., 2000). Thus, a most efficacious treatment is demanded, but keeping in mind that the patient should not be exposed unnecessarily to the risk of a switch into mania or cycle acceleration. For the effectiveness of antidepressants in bipolar depression, the best evidence so far is the large cohort study by Möller et al. (2001) in 2032 hospitalized depressed patients. Comparing unipolar and bipolar depressed patients no difference was observed between these two groups looking at treatment success, captured by CGI ratings, and the duration of hospitalization. At the time of data collection, bipolar depressed patients of this cohort were almost exclusively treated with antidepressants only and mood stabilizers were added after stabilization was achieved. Most of these patients received tricyclic antidepressants, and only a minority were treated with selective serotonin reuptake inhibitors. Secondary analysis revealed a significant difference in switch rates between these different antidepressants which is in line with several other studies (e.g. Peet, 1994; Boerlin et al., 1998; Calabrese et al., 1999). For most antidepressants, proof of placebo-controlled efficacy or superiority compared to other antidepressants is still sparse. A study by Cohn etal. (1989) compared fluoxetine to imipramine and placebo in 89 patients with bipolar depression. Fluoxetine appeared superior to both placebo and imipramine. Retrospective analysis of one of the few large-scale placebo-controlled phase III studies, allowing also bipolar II patients to be recruited, also favored fluoxetine over placebo (Amsterdam et al., 1998). Subgroup analysis also showed that response in bipolar II patients was not different from matched unipolar patients. Similar to a subgroup analysis of the study of Möller (Bottlender et al., 2002), this is supportive of the argument that antidepressants do not treat specific disease entities but just a syndrome. Similar efficacy to fluoxetine has also been reported for tianeptine, a new antidepressant

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which increases both serotonin and dopamine uptake in the brain (Loo etal., 1999). Similar to SSRIs, tianeptine showed also a low switch rate in this study. Two studies including also bipolar patients have been reported for venlafaxine. In a retrospective analysis of a randomized study, venlafaxine was similarly effective for both unipolar and bipolar II depression (Amsterdam, 1998; Amsterdam and Garcia-Espana, 2000). However, conclusions from these studies are limited by their retrospective nature and the small sample size. A further randomized trial compared venlafaxine and paroxetine showing a trend toward a better response for venlafaxine but also a clearly higher switch rate (Vieta et al., 2002). Nevertheless, at least in severely ill bipolar patients the efficacy of modern antidepressants alone seems to be not satisfactory. In a double-blind randomized trial of the Stanley Foundation Bipolar Network, three modern antidepressants (bupropion, sertraline, venlafaxine) were administered as add-on treatment to ongoing mood stabilizer in bipolar depression. In a blinded intermediate analysis of 175 patients an overall response rate of 49.7% was observed after 10 weeks of treatment (Post et al., 2002). Thus, bipolar depression is not only a very prominent but also difficult-to-treat phase of the illness. Several open and small double-blind trials also exist for bupropion, monoamine oxidase inhibitors (MAOI) and, of course, tricyclic antidepressants. Due to the small number of patients all trials appear not very conclusive. Some studies show that the MAOI tranylcypromine, compared with the tricyclic imipramine, is less likely to be associated with disruptive hypomanic switches; this is a distinct clinical advantage. Likewise, Bupropion appears to be less prone to induce a switch into mania than tricyclic antidepressants, and thus should be preferred. In any case, treatment with antidepressants in bipolar patients should always be accompanied by a mood stabilizer, not only to minimize the switch risk but also to maintain continuous control of the long-term course of illness (Grunze et al., 2002). Another point of controversy is the duration of antidepressant treatment. Most recommendations today emphasize, if at all, only the intermittent use of antidepressants instead of continuous treatment (Nolen and Bloemkolk, 2000; Sachs et al., 2000; el Mallakh and Karippot, 2002). Analysis of seven small controlled trials could not supply sufficient information to support the long-term use of antidepressants in bipolar patients (Ghaemi, Lenox and Baldessarini, 2001). However, a recent analysis comparing patients in the Stanley Foundation Bipolar Network who decided (on their own wish) to discontinue antidepressants after relief of depressed symptoms with those who continued on the antidepressants showed a statistically significant advantage for treatment continuation (Altshuler et al., 2003). Patients continuing were less likely to suffer from a depressive relapse within one year (41% compared to 71%, median time to relapse 532 and 159 days respectively). Even more surprisingly, at one year post-treatment 29% of the medication discontinuer group compared to 13% of the medication continuer group had a relapse into mania. Thus, the general rule to discontinue

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antidepressants as early as possible may not hold true in a significant minority of bipolar patients; subgroup analysis is still pending to find out which patients have the most profit of continuation of antidepressants, and which patients are exposed to additional risks by not stopping antidepressant treatment. There remains, nonetheless, a subgroup of bipolar patients, possibly those with cyclothymic temperament who appear at risk for switching and cycle acceleration. These are the patients where antidepressants are likely to be problematic, even when covered with mood stabilizers. Without confirmation from double-blind randomized studies, all the foregoing considerations are tentative. The exception is a doubleblind randomized study by Tohen et al. (2003), which demonstrated that fluoxetine added to olanzapine was more effective than olanzapine alone, both of which were significantly better than placebo in bipolar I depression. In conclusion, antidepressants will remain part of the treatment portfolio of bipolar disorder especially as long as the evidence for antidepressant properties of both lithium (Grunze, 2003) and anticonvulsants (Ernst and Goldberg, 2003) is not convincing, with the exception of lamotrigine (covered in Chapter 4). Considering the potential suicide risk of bipolar depression, an optimized and sometimes maximized treatment is mandatory. Nevertheless, there is clearly a demand for more controlled data to inform current clinical practice.1

OTHER POTENTIALLY USEFUL AGENTS IN BIPOLAR DISORDER OMEGA 3 FATTY ACIDS Omega 3 fatty acids are essential polyunsaturated fatty acids. The general interest of psychiatry stems from the fact that supplementing animal diets with omega 3 fatty acids leads to significant changes in the content of major brain neurotransmitters (Chalon et al., 1998). In addition, omega 3 fatty acids are able to modulate brain gene expression (Kitajka et al., 2002) and possess neuroprotective properties (Lauritzen et al., 2000). The special interest for affective disorders originates in the concept that omega 3 fatty acid deficiency may be one of the yet unrecognized risk factors (Coryell et al., 1999) that predispose patients to both affective disorders and cardiovascular disease (Hibbeln, 1998). In a first double-blind, placebo-controlled trial of omega 3 fatty acids, prophylactic antidepressive and mood stabilizing properties were observed in thirty patients with unstable bipolar disorder (Stoll et al., 1999). These findings were also confirmed in a twelve week, randomized, double-blind placebo-controlled study comparing one or two grams ethyl-EPA to placebo in addition to standard treatments in 75 patients with acute depression (Frangou and Lewis, 2002). Opposite to these findings, a large randomized and 1

Further discussion of suicidal patients is covered in Chapter 18.

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placebo-controlled study of the Stanley Foundation (Keck et al., manuscript in preparation) could not find any difference between omega 3 fatty acids (preparation containing 6 gram ethyl-EPA) and placebo in bipolar depressed or cycling patients. The assumption had been made that a bell-shaped curve of efficacy may be the underlying reason for these different findings, but clearly further controlled studies are needed to establish omega 3 as an effective treatment in bipolar disorder.

CHROMIUM Chromium picolinate was effective in a small open trial in eight patients with refractory depression (McLeod and Golden, 2000). These preliminary findings were also supported by a small placebo-controlled study in atypical depression (Davidson et al., 2003). Studies in bipolar depression are currently ongoing but first case reports suggest that chromium may be a helpful add-on treatment in instable and cycling patients (Amann et al., 2002).

CALCIUM ANTAGONISTS Calcium fluxes across the membrane and altered intracellular calcium levels may play a role not only in epilepsies but also in the pathophysiology of affective disorders (Dubovsky and Franks, 1983). Different calcium antagonists like verapamil and diltiazem were found to be effective in manic patients in open and small controlled clinical studies; however, they may exert intolerable orthostatic side effects in higher dosages. The dihydropyridine L-type calcium channel blocker nimodipine is highly lipid soluble and penetrates the blood–brain barrier already in concentrations where peripheral side effects are negligible. Nimodipine showed efficacy in open trials in both acute mania (Brunet et al., 1990; Grunze et al., 1996) and depression (Walden et al., 1995) and treatment refractory rapid cycling disorder (Pazzaglia et al., 1993, 1998). However, its use appears not very practical due to its short half life time and the consequent need of multiple dosing. Nevertheless, it may be still an alternative in patients unsatisfactorily responsive to standard treatment.

THYROID HORMONES As many patients do not respond adequately to standard medications alone, augmentation strategies have been developed. The interest in using thyroid hormones to treat affective disorders originates from the observed association between psychiatric symptoms and thyroid disease states (Whybrow, Prange and Treadway, 1969). Since then, a series of open and controlled clinical trials have been conducted on the therapeutic use of thyroid hormones in mood disorders (Bauer and Whybrow, 2001). Whereas tri-iodothyronin (T3) has been investigated

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in earlier years, Levothyroxin (T4) became increasingly the drug of interest due to a better tolerability, especially in high, supra-physiological doses. Several open studies in both bipolar depression and rapid cycling patients suggest efficacy of T4 (for an overview, see Bauer et al., 2003). Randomized, double-blind studies are currently under way. Thus, T4 may become an additional option for augmentative treatment in refractory bipolar patients.

CONCLUDING REMARKS In this chapter, the author has attempted to provide a comprehensive review about additional pharmacological treatment options in bipolar disorder. Treatment options not covered in this chapter (e.g. magnesium, mexiletine, clonidine, pramipexol, etc.) have only been evaluated in small case series or open studies. Others, like tamoxifen, with an interesting mechanism of protein kinase inhibition, have even been evaluated in double-blind controlled studies showing positive effects in acute mania, but due to tolerability problems and toxicity are unlikely to become an acceptable treatment in bipolar patients. With the increasing portfolio of treatment options in bipolar disorder, every review is incomplete, leaving out some treatment options that other authors would consider as promising. Thus, in a subsequent edition of this book some years from now, this chapter is likely to be substantially revised.

REFERENCES Adler LW (1986). Mixed bipolar disorder responsive to lithium and clonazepam. J. Clin. Psychiatry, 47, 49–50. Altshuler L, Suppes T, Black D, Nolen WA, Keck PE, Jr., Frye MA, McElroy S, Kupka R, Grunze H, Walden J, Leverich G, Denicoff K, Luckenbaugh D, and Post R (2003). Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am. J. Psychiatry, 160, 1252–1262. Amann B, Forsthoff A, Matzner N, Dargl S, and Grunze H (2002). Chromium as antidepressant and mood stabilizer in refractory cycling patients: A case report. Bipolar Disord., 4, 123. Amsterdam J (1998). Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J. Clin. Psychopharmacol., 18, 414–417. Amsterdam JD and Garcia-Espana F (2000). Venlafaxine monotherapy in women with bipolar II and unipolar major depression. J. Affect. Disord., 59, 225–229. Amsterdam JD, Garcia-Espana F, Fawcett J, Quitkin FM, Reimherr FW, Rosenbaum JF, Schweizer E, and Beasley C (1998). Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J. Clin. Psychopharmacol., 18, 435–440. Applebaum J, Levine J, and Belmaker RH (2003). Intravenous fosphenytoin in acute mania. J. Clin. Psychiatry, 64, 408–409. Ballenger JC and Post RM (1980). Carbamazepine in manic-depressive illness: A new treatment. Am. J. Psychiatry, 137, 782–790.

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6 Olanzapine in Treatment for Bipolar Disorder Mauricio Tohen1,2, Giedra Campbell1, and Daniel Lin1 1

2

Lilly Research Laboratories, Indianapolis, IN, USA McLean Hospital, Harvard Medical School, Belmont, MA, USA

Over the past several decades, significant advances have been made in the pharmacological treatment for bipolar disorder. Yet a significant proportion of patients with this condition are not responsive or only partially responsive to existing treatments, and among those who do obtain symptomatic relief, the majority subsequently experience relapse. This unmet medical need is being addressed by the introduction of novel medications and adjunctive treatment strategies. Typical antipsychotic agents such as haloperidol have been used extensively, either alone or in combination with other agents, for the treatment for bipolar disorder. In a metaanalysis of published reports through the year 2000, Tohen et al. (2001) found that 89% of hospitalized manic patients and 64% of outpatients with mania were treated with typical antipsychotics. While the efficacy of conventional antipsychotic agents for this condition has been well established, considerable concerns have been raised regarding their associated side effects, especially the long-term ones (Kane and Smith, 1982). The most prominent of these are extrapyramidal symptoms (EPS), of which tardive dyskinesia is the most serious. More importantly, recent studies have reported an increased risk of relapse into depression and higher rates of discontinuation in patients with mania who received mood stabilizer combined with typical antipsychotic, compared with mood stabilizers alone (Zarate, Jr. and Tohen, 2004). Thus, the clinical benefits of typical antipsychotic use in bipolar disorder are frequently offset by poor tolerability and the risk of noncompliance. The development of clozapine as an antipsychotic agent for both schizophrenic (Naber and Hippius, 1990; Hippius, 1999; Meltzer et al., 2003) and bipolar disorder (Calabrese et al., 1996; Shulman, Singh and Shulman, 1997; Frye et al., 1998) heralded a major change in the treatment for psychosis and was the first of a new generation of antipsychotic drugs. Despite the unfavorable side-effect profile and Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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the need for blood monitoring for aganulocytosis, clozapine showed efficacy in refractory schizophrenic and bipolar disorders. In addition, it was often effective in reversing tardive dyskinesia. But all of these findings came from open clinical reports. Nonetheless, it served as a model for the development of better tolerated atypical antipsychotics. The term “atypical” was first used to describe clozapine, since its pharmacological properties were very different from those of older typical antipsychotic drugs. According to Lieberman and Duncan (2000), as a broad class, atypical antipsychotic drugs are characterized by: (a) lower incidence of extrapyramidal symptoms and tardive dyskinesia; (b) superior antipsychotic efficacy and a broader sprectrum of efficacy; (c) minimal chronic elevation of prolactin levels; (d) low potential to cause catalepsy in preclinical animal studies; and (e) lower dopamine (D2) receptor affinity and higher serotonin (5-HT) receptor affinity. Atypical antipsychotic agents offer distinct advantages over typical agents in the treatment for bipolar disorder with respect to tolerability, reduced adverse-event liability and, in turn, improved treatment compliance and response to medication. However, atypical antipsychotic drugs also carry a higher risk of weight gain and hyperlipidemia (Meyer, 2001; Koponen et al., 2002). Olanzapine was the first atypical antipsychotic drug to be approved in the United States and in the European Union for the treatment of acute bipolar mania and, more recently, bipolar maintenance/relapse prevention. In common with clozapine, olanzapine has a broad pharmacology and binds with high affinity to dopaminergic, serotonergic, adrenergic, muscarinic and histaminergic receptors. The binding characteristics of olanzapine to dopamine D2 receptors is consistent with the hypothesis that functional D2 receptor antagonism is an important factor in antipsychotic efficacy (Seeman and Kapur, 2000). Olanzapine’s higher dissociation constant at the D2 receptor, relative to haloperidol and other typical antipsychotic drugs, may account for its lower propensity to induce EPS or tardive dyskinesia (Seeman and Kapur, 2000). The unique pattern of binding of olanzapine to other receptor sites may provide multiple potential mechanisms of therapeutic action and may account for its efficacy in the complex symptoms of bipolar disorder (Bymaster et al., 1996). This chapter reviews the rationale behind the study design and the data from double-blind randomized controlled trials that have evaluated the efficacy for olanzapine monotherapy and olanzapine combination therapy in the treatment for bipolar disorder. The safety and tolerability of olanzapine is also briefly reviewed.

RATIONALE BEHIND THE CLINICAL TRIAL DEVELOPMENT OF OLANZAPINE Considering the complex nature of bipolar disorder, it is essential to evaluate the potential therapeutic value of new treatments in all phases of the illness-mania,

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depression and maintenance of euthymia. The approach adopted in the evaluation of olanzapine was to establish first the safety and efficacy of the drug for treatment of acute mania. The value of adjunctive therapy to improve efficacy for the treatment of acute mania was also explored using olanzapine in combination with existing treatments, such as lithium or valproate. This was followed by the evaluations of efficacy and safety for the treatment of acute bipolar depression with olanzapine and olanzapine–fluoxetine combination. Once efficacy and safety were determined for the acute phases of the disorder, olanzapine was studied for relapse prevention or maintenance of response. Thus, a comprehensive evaluation of olanzapine, both as monotherapy and in combination therapy, has led to regulatory approvals for all phases of bipolar disorder, and has increased the number of options available to physicians for the treatment of this disorder.

EFFICACY IN THE TREATMENT FOR ACUTE MANIA Two randomized, double-blind, placebo-controlled trials of 3 and 4 weeks’ duration compared olanzapine with placebo in 139 and 115 patients respectively, with a DSM-IV diagnosis of bipolar I disorder (Tohen et al., 1999, 2000, 2001). In both studies, patients treated with olanzapine showed significantly greater mean improvements in Young Mania Rating Scale (YMRS) total score, the primary efficacy measure, compared with placebo-treated patients (olanzapine vs placebo: −10.3 vs −4.9; p < 0.019 (Tohen et al., 1999) and −14.8 vs −8.1; p < 0.001 (Tohen et al., 2000)). Based on clinical response criteria, defined as an improvement of ≥50% in YMRS total score from baseline to endpoint and an endpoint YMRS total score ≥12, significantly more olanzapine-treated patients responded compared with placebo-treated patients (olanzapine vs placebo: 49% vs 24%; p < 0.004 (Tohen et al., 1999) and 65% vs 43%; p = 0.02 (Tohen et al., 2000)). In both trials the mean modal dose was similar (14.9 mg and 16.4 mg), even though the starting dose was 10 mg in the trial from Tohen et al. (1999) and 15 mg for the trial from Tohen et al. (2000). There were no statistically significant differences with respect to the measures of Parkinsonism, akathisia and dyskinesia between olanzapine- and placebo-treated patients in either study. The results from these two studies suggest that relative to placebo, olanzapine had superior efficacy for the treatment of acute mania symptoms and was generally well tolerated. As noted above, the two trials differed in the starting dose of olanzapine; 10 mg/day in the first, and 15 mg/day in the second study. Statistically significant differences in mania symptoms relative to placebo were observed at week 3 in the first study, and at week 1 in the second. The benefits of early response to treatment may be partially reflected in a significantly lower rate of premature discontinuation due to lack of efficacy in the second study (26% olanzapine vs 48% placebo during 4 weeks; p = 0.02). Notably, there were no clinically meaningful differences in adverse events between the two studies. Based on the observations of an earlier

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onset of action and the lack of increased adverse event risk, subsequent acute mania studies used a starting dose of 15 mg/day. The efficacy of olanzapine for the treatment of acute mania has also been examined in relation to other psychotropic agents. Efficacy, safety and quality-of-life measures were assessed in a direct comparison between olanzapine (5–20 mg/day, n = 234) and haloperidol (3–15 mg/day, n = 219) in a randomized controlled trial consisting of two successive, 6-week, double-blind periods in patients with bipolar mania (Tohen et al., 2003b). In addition to the assessment of mania symptoms, this trial also included scales to assess symptoms of depression to evaluate the potential risk of depressogenic effects associated with these treatments. Rates of remission, defined as YMRS scores ≤12 and Hamilton Rating Scale for Depression scale-21 item (HAMD-21) scores ≤8 at week 6 of treatment, were similar for olanzapine- and haloperidol-treated patients (52.1% vs 46.1% respectively; p=0.15), suggesting a similar efficacy for both agents. However, for a subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for olanzapine-treated patients relative to the haloperidol group (56.7% vs 41.6%; p = 0.04). For the subset of patients who entered the study nondepressed but became depressed during the course of the trial, haloperidol treatment was associated with a statistically significantly shorter time to switch into depression (p = 0.04) (Figure 6.1). Moreover, olanzapine compared favorably with haloperidol on two dimensions of the quality-of-life scale (Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]), namely general health and role limitations due to emotional problems. On all measures assessing EPS, both patient-reported and scale-defined, significantly more haloperidol-treated patients experienced a worsening of symptoms. Divalproex, an anticonvulsant, has been shown to have efficacy in the treatment for acute bipolar mania (Pope, Jr. et al., 1991; Bowden et al., 1994). Olanzapine was compared with divalproex in a randomized, double-blind trial with patients hospitalized for acute bipolar manic or mixed episodes (Tohen et al., 2002a). This trial consisted of a 3-week acute phase, followed by a 44-week phase to assess maintenance of response and relapse prevention. The results of the 44-week extension phase will be discussed at a later point in this chapter. The primary efficacy measure was baseline to endpoint change in total YMRS score at 3 weeks. Relative to divalproex (500–2500 mg/day, n = 123), olanzapine treatment (5–20 mg/day, n = 125) was more effective in reducing the symptoms of mania. On the primary efficacy measure, YMRS total score, the mean change was −13.4 points for olanzapine-treated patients and −10.4 points for divalproex-treated patients (p =0.03). With respect to treatment response, as defined by an improvement of ≥50% in YMRS score from baseline to endpoint, more patients in the olanzapine group responded than did in the divalproex group (54.4% vs 42.3% respectively), although this difference did not reach statistical significance (p=0.06). However, a significantly greater number of olanzapine-treated patients achieved remission, as

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89 1.00

Probability of Not Switching to Depression

0.80

0.60

0.40 p = 0.04 Olanzapine, n = 12 Haloperidol, n = 22

0.20

0.00 0

10

20

30

40

50

60

70

80

90

100

Time to Switching to Depression (Days)

Figure 6.1: Time to switch to depression for patients who were not clinically depressed at baseline (HAMD-21 ≤8). Time to switch to depression (HAMD-21 ≥15) was significantly longer (log-rank test χ21 = 4.1; p = 0.04) for the olanzapine group compared with the haloperidol group. During the 12-week period, 22 haloperidol- and 12 olanzapinetreated patients switched to depression. The number of patients who experienced a switch to depression by days 15, 30 and 60 were 3, 9 and 18 for the haloperidol group and 1, 3 and 8 for the olanzapine group (Tohen et al., 2003b). Reprinted by permission from Archives of General Psychiatry (JAMA) (Tohen et al., 2003b) Abbreviations: HAMD-21, Hamilton Depression Rating Scale-21 item.

defined by an endpoint YMRS total score ≤12, compared with the divalproex group (47.2% vs 34.1% respectively; p = 0.04). Patients treated with olanzapine also achieved remission in a statistically significantly shorter period of time than did divalproex-treated patients (estimated 25th percentile for time to remission was 3 days for olanzapine patients and 6 days for divalproex patients; p < 0.04). In a separate randomized, 12-week, double-blind study, olanzapine (5–25 mg/ day, n = 57) was compared with divalproex (750–3250 mg/day, n = 63) in patients with bipolar disorder hospitalized for acute mania (Zajecka et al., 2002). YMRS total scores decreased from baseline to day 21 of treatment in both treatment groups (−17.2 for olanzapine and −14.8 for divalproex). This difference between groups, however, was not statistically significantly different (p = 0.210). Historically, antipsychotic agents have been used in combination with mood stabilizers for the treatment of acute mania, and the accumulated evidence supports the contention that adjunctive therapy with these two classes of compounds yields greater efficacy and more rapid onset of response (Klein et al., 1984; Muller-Oerlinghausen et al., 2000). The use of olanzapine in combination with either lithium or valproate for the treatment of acute mania was examined in 344 patients in a 6-week, double-blind, randomized, placebo-controlled study (Tohen

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et al., 2002b). Patients diagnosed with bipolar disorder presenting with manic or mixed episodes who were inadequately responsive to at least 2 weeks of lithium or valproate treatment alone were randomized to receive “olanzapine cotherapy” (n=229) (olanzapine, 5–20mg/day+lithium or valproate) or “monotherapy” (n=115) (placebo + lithium or valproate). It should be noted that this group of patients would not be considered treatment resistant, since they failed to respond only to one agent at a therapeutic blood level for at least 2 weeks. The design of this study was intended to address a common treatment dilemma faced by practitioners. Namely, should a physician continue treatment with the original therapeutic agent under careful observation, even if patients do not demonstrate a response within the first two weeks, or should another drug be added? Patients who received olanzapine cotherapy had significantly greater mean improvements in YMRS total scores than those who received monotherapy (−13.1 vs −9.1 respectively; p = 0.003). Rates of clinical response, defined as ≥50% improvement in YMRS total scores from baseline to endpoint, were also significantly higher with cotherapy (68% vs 45%, p < 0.001). In addition, time to response was significantly shorter for cotherapy (p = 0.002), with a median response time of 18 days for cotherapy versus 28 days for monotherapy. The results of this study also demonstrated substantial efficacy of olanzapine plus lithium or valproate cotherapy in treating depressive symptoms present at randomization. For the study population as a whole, olanzapine cotherapy improved HAMD-21 total scores significantly more than did monotherapy with lithium or valproate (5.0 vs 0.9 points, p < 0.001). Furthermore, in a subset of patients presenting with moderate-to-severe depressive symptoms (DSM-IV mixed episode and HAMD-21 ≥20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.3 points compared with 1.6 for monotherapy (p < 0.001). Also, within this subset of patients, more than four times as many patients in the cotherapy group showed at least a 50% improvement in depressive symptoms (43% vs 10%, p = 0.006). EPS, as assessed by the Simpson–Angus, Barnes Akathisia and Abnormal Involuntary Movement scales, were not significantly changed from baseline to endpoint in either treatment group. Compared with the use of lithium or valproate alone, addition of olanzapine provided superior efficacy in the treatment for manic or mixed bipolar episodes. Patients who suffer from mania with severe agitation are in need of immediate treatment in order to avoid harm to themselves or others. For pharmacokinetic reasons, the intramuscular administration of a molecule provides a faster onset of action than the oral use of the drug. For this reason, the efficacy and safety of intramuscular injections of olanzapine for the treatment of acutely agitated patients with bipolar mania were examined in a double-blind randomized study (Meehan et al., 2001). In this study, 201 agitated patients with bipolar mania were randomly assigned to receive one to three injections of olanzapine (n = 99), lorazepam (n = 51) or placebo (n = 51) within a 24-hour period. The doses of

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olanzapine for the first and second injections were 10 mg and for the third injection, 5 mg. The doses of lorazepam for the first and second injections were 2 mg and for the third injection, 1 mg. For placebo-treated patients, the first and second injections were placebo and the third injection was olanzapine, 10 mg. Agitation was measured at baseline, every 30 minutes for the first 2 hours, and at 24 hours after the first injection using the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) subscale as the primary scale, and two additional scales: the Agitated Behavior Scale (ABS) and the Agitation-Calmness Evaluation Scale (ACES). At 2 hours after the first injection, patients treated with olanzapine showed a statistically significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo (PANSS-EC, ABS, ACES; p < 0.001) or lorazepam (PANSS-EC, ABS, ACES; p < 0.01) (Figure 6.2). At 24 hours after the first injection, olanzapine remained statistically significantly superior to placebo in reducing agitation in patients with acute mania (PANSS-EC, p = 0.025), whereas such improvements in patients treated with lorazepam were not statistically significantly different from those treated with placebo or olanzapine (PANSS-EC, lorazepam vs placebo, p = 0.08; lorazepam vs olanzapine, p = 0.81). There were no statistically significant differences among the three treatment groups in safety measures, including treatment-emergent EPS, the incidence of acute dystonia or QTc interval changes.

Olanzapine

Lorazepam

Placebo

Change in PANSS-EC Score

0 –2 –4 2 hrs –6

‡

24 hrs

–8 –10

* †

–12

Figure 6.2: Mean change in PANSS-EC scores at 2 and 24 hours after the first intramuscular injection (LOCF) (*olanzapine vs placebo, p<0.001; †olanzapine vs lorazepam, p=0.001; ‡ olanzapine vs placebo, p = 0.025) Abbreviations: PANSS-EC – Positive and Negative Syndrome Scale-Excited Component; LOCF – last observation carried forward.

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EFFICACY IN THE TREATMENT FOR BIPOLAR DEPRESSION In the treatment for bipolar disorder, the major challenge is perhaps not the management of manic episodes, but rather the management of episodes of depression. To date there is no pharmaceutical product with a regulatory approval for this phase of the illness. Bipolar depression, or the depressive phase of bipolar disorder, is a particularly difficult condition to treat and is often inadequately managed with currently available therapeutics. Thus, there is a great need to develop alternative strategies that ameliorate the depressive symptoms of bipolar disorder without inducing mania or hypomania, or accelerating cycling. As reviewed above, olanzapine has demonstrated efficacy in the treatment for acute bipolar mania (Tohen et al., 1999, 2000, 2002a,b, 2003b; Zajecka et al., 2002), and has also been found to improve depressive symptoms in patients with schizophrenia (Tollefson et al., 1998). The potential efficacy of olanzapine monotherapy or combination therapy with the antidepressant fluoxetine for the treatment for bipolar depression was therefore explored in a randomized, double-blind, placebo-controlled study (Tohen et al., 2003d). In this 8-week trial, olanzapine (5–20 mg/day) was compared with placebo and an olanzapine/fluoxetine combination (OFC; olanzapine and fluoxetine: 6 and 25; 6 and 50; or 12 and 50 mg/day) in 833 patients with bipolar depression (baseline Montgomery–Asberg Depression Rating Scale [MADRS] scores of ≥20). Starting at week 1, both olanzapine- and OFC-treated patients showed statistically significant improvements in depressive symptoms compared with placebo, and the treatment effect was also statistically significantly larger with OFC therapy compared with olanzapine monotherapy beginning at week 4 through the end of 8 weeks (Table 6.1 and Figure 6.3). The mean changes in MADRS total score between baseline and endpoint were −18.5 for OFC and −15.0 for olanzapine, both of which were significantly greater than placebo (−11.9; p < 0.001). The response rate, defined as a ≥50% reduction in MADRS total score, was significantly higher for the OFC treatment group (56%) relative to both olanzapine (39%, p=0.006) and placebo (30%, p<0.001). Similarly, the rate of remission, as defined by a MADRS total score ≤12 at endpoint and completion of at least 4 weeks of study, was significantly higher for OFC (49%) relative to olanzapine (33%, p = 0.007) and placebo (25%, p < 0.001). Time to remission was significantly shorter for the olanzapine group compared with the placebo group (p = 0.02) and again significantly shorter for the OFC group compared with placebo (p < 0.001) and olanzapine (p = 0.01) groups. In the Tohen et al. (2003d) study, the incidence of treatment-emergent mania was low, and there were no statistically significant differences among the three treatment groups (6.4% OFC, 5.7% olanzapine and 6.7% placebo). Thus, neither olanzapine nor OFC induced switches to mania or hypomania, an effect known to occur with some antidepressant drugs when they are given alone (Wehr and Goodwin, 1987; Altshuler et al., 1995). The results of this study suggest that

6.

5.

4.

3.

2.

Treatment

Placebo Olanzapine OFC Reported Sadness Placebo Olanzapine OFC Inner Tension Placebo Olanzapine OFC Reduced Sleep Placebo Olanzapine OFC Reduced Appetite Placebo Olanzapine OFC Concentration Difficulties Placebo Olanzapine OFC

1. Apparent Sadness

Items 3.5 ± 0.1 3.8 ± 0.1 3.6 ± 0.1 4.0 ± 0.1 4.1 ± 0.1 3.8 ± 0.1 3.3 ± 0.1 3.4 ± 0.1 3.2 ± 0.1 3.1 ± 0.1 3.2 ± 0.1 3.2 ± 0.2 1.8 ± 0.1 2.0 ± 0.1 1.6 ± 0.2 3.4 ± 0.1 3.4 ± 0.1 3.3 ± 0.1

−1.3 ± 0.1 (−1.5, −1.1) −1.5 ± 0.1 (−1.7, −1.3) −2.1 ± 0.2 (−2.4, −1.7) −1.5 ± 0.1 (−1.8, −1.3) −1.8 ± 0.1 (−2.0, −1.5) −2.2 ± 0.2 (−2.6, −1.8) −1.0 ± 0.1 (−1.2, −0.8) −1.4 ± 0.1 (−1.5, −1.2) −1.7 ± 0.2 (−2.0, −1.4) −1.3 ± 0.1 (−1.6, −1.0) −2.0 ± 0.1 (−2.3, −1.8) −2.3 ± 0.2 (−2.8, −1.9) −0.7 ± 0.1 (−1.0, −0.5) −1.4 ± 0.1 (−1.6, −1.1) −1.2 ± 0.2 (−1.7, −0.8) −1.4 ± 0.1 (−1.7, −1.2) −1.7 ± 0.1 (−1.9, −1.5) −1.6 ± 0.2 (−2.0, −1.2)

Mean Baseline ± SE Mean Change ± SE; (95% CI) NA −1.74 −3.69 NA −1.48 −2.98 NA −2.56 −3.46 NA −4.05 −3.83 NA −3.98 −2.09 NA −1.59 −0.72

t NA 2439 2122 NA 550 537 NA 2522 2240 NA 2298 1986 NA 1938 1643 NA 554 538

df

p NA .08 <.001 NA .14 .003 NA .01 <.001 NA <.001 <.001 NA <.001 .04 NA .11 .47

vs Placebo

NA NA −2.56 NA NA −2.01 NA NA −1.75 NA NA −1.12 NA NA 0.55 NA NA 0.36

t

NA NA 2034 NA NA 532 NA NA 2153 NA NA 1903 NA NA 1577 NA NA 533

df

NA NA .01 NA NA .045 NA NA .081 NA NA .26 NA NA .58 NA NA .72

p

vs Olanzapine

Table 6.1: Baseline-to-week-8 mean change in MADRS items (MMRM). Reprinted by permission from Archives of General Psychiatry (JAMA) (Tohen et al., 2003d)

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Placebo Olanzapine OFC Placebo Olanzapine OFC Placebo Olanzapine OFC Placebo Olanzapine OFC

7. Lassitude

3.5 ± 0.1 3.5 ± 0.1 3.7 ± 0.1 3.6 ± 0.1 3.6 ± 0.1 3.5 ± 0.1 3.3 ± 0.1 3.3 ± 0.1 3.2 ± 0.1 1.9 ± 0.1 2.0 ± 0.1 1.8 ± 0.1

−1.5 ± 0.1 (−1.7, −1.2) −1.5 ± 0.1 (−1.7, −1.2) −2.1 ± 0.2 (−2.5, −1.6) −1.6 ± 0.1 (−1.9, −1.4) −1.6 ± 0.1 (−1.9, −1.4) −2.3 ± 0.2 (−2.7, −1.9) −1.3 ± 0.1 (−1.5, −1.1) −1.4 ± 0.1 (−1.6, −1.2) −2.0 ± 0.2 (−2.3, −1.6) −0.9 ± 0.1 (−1.1, −0.7) −1.1 ± 0.1 (−1.3, −0.9) −1.2 ± 0.2 (−1.5, −0.9)

Mean Baseline ± SE Mean Change ± SE; (95% CI) NA −0.01 −2.48 NA −0.13 −3.13 NA −1.07 −3.35 NA −1.68 −1.69

t

p

NA NA 2388 .99 2063 .01 NA NA 2469 .90 2157 .002 NA NA 2471 .29 2140 <.001 NA NA 2149 .09 1830 .09

df

vs Placebo

NA NA −2.51 NA NA −3.10 NA NA −2.67 NA NA −0.57

t

NA NA 1976 NA NA 2069 NA NA 2050 NA NA 1753

df

NA NA .01 NA NA .002 NA NA .008 NA NA .57

p

vs Olanzapine

The MMRM analysis used a banded Toeplitz structure for the within-patient error covariance structure based on maximum Schwartz’s Bayesian criterion for items 1, 3, 4, 5, 7, 8, 9 and 10 and a heterogeneous banded Toeplitz structure for the within-patient error covariance structure based on maximum Schwartz’s Bayesian criterion for items 2 and 6. Abbreviations: MADRS – Montgomery–Asberg Depression Rating Scale; MMRM – mixed-effects model repeated measures; SE – standard error; CI – confidence interval; OFC – olanzapine/fluoxetine combination (Tohen et al., 2003d).

10. Suicidal Thoughts

9. Pessimistic Thoughts

8. Inability to Feel

Treatment

Items

Table 6.1: (Continued)

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Olanzapine

95

MADRS Total Score Mean Change from Baseline

0 Olanzapine (n = 351) Placebo (n = 355) OFC (n = 82)

–5

–10

–15

–20 0

1

2

3

4

5

6

7

8

Week

Figure 6.3: Least-squares mean change in MADRS scores during the 8-week study period. Improvement in MADRS scores with olanzapine and olanzapine/fluoxetine combination was significantly greater than that with placebo throughout the study period (p < 0.001). Improvement in MADRS with olanzapine/fluoxetine combination was significantly greater than that with olanzapine at weeks 4–8 (p < 0.02) (Tohen et al., 2003d). Reprinted by permission from Archives of General Psychiatry (JAMA) (Tohen et al., 2003d) Abbreviation: MADRS – Montgomery–Asberg Depression Rating Scale.

although olanzapine appears to be effective in the treatment of patients with bipolar depression, cotherapy with fluoxetine greatly enhanced its therapeutic effects. Importantly, the enhanced efficacy of olanzapine/fluoxetine combined therapy was not associated with a greater risk of treatment-emergent mania.

EFFICACY IN BIPOLAR MAINTENANCE/RELAPSE PREVENTION Until recently, the long-term efficacy and relapse prevention of most pharmacotherapies used in bipolar disorder was poorly studied. Yet, there is an acute need for prophylactic treatments to minimize the risk of relapse because bipolar disorder is a chronic recurring condition. Repeated relapses into either manic, mixed or depressive phases of bipolar disorder have negative implications for disease progression and patients’ responsiveness to subsequent treatments: essentially, patients with a history of multiple relapses are likely to be less responsive to pharmacotherapeutics. Several studies have been performed to explore the role of olanzapine in long-term prophylactic treatment for bipolar disorder (Tohen et al., 2003a,c).

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In a randomized double-blind study, described previously, the long-term efficacy of flexibly dosed olanzapine (5–20 mg/day) was compared with divalproex (500–2500 mg/day) in 251 patients with bipolar disorder during 47 weeks (Tohen et al., 2003c). Relative to divalproex-treated patients, olanzapine-treated patients had a significantly greater mean improvement at endpoint in YMRS total score, the primary efficacy measure (p = 0.03). The median time to symptomatic remission of mania (YMRS total score ≤12) was significantly shorter for olanzapine-treated patients than for those treated with divalproex (14 vs 62 days respectively; p = 0.05). However, no statistically significant differences occurred between treatments in the rates of remission during the 47 weeks (56.8% olanzapine and 45.5% divalproex respectively) or subsequent rates of relapse into mania or depression (42.4% olanzapine and 56.5% divalproex respectively). Olanzapine’s efficacy in relapse prevention has also been assessed when given in combination with mood stabilizers. The relative efficacy of olanzapine cotherapy (olanzapine in combination with lithium or valproate) versus monotherapy (either lithium or valproate alone) in preventing relapse was evaluated in an 18-month, double-blind study (Tohen et al., 2004). Patients who had previously achieved syndromic remission (DSM-IV) after 6 weeks’ treatment with olanzapine cotherapy (Tohen et al., 2004) were re-randomized to either olanzapine cotherapy or monotherapy (lithium or valproate) and followed for up to 18 months. No statistically significant differences occurred between the treatment groups for time to relapse into an affective episode (based on DSM-IV criteria) or for rates of relapse into either mania or depression when relapse was defined using a symptom-rating scale. However, in a subset of patients who met both symptomatic and syndromic remission criteria (the latter defined as YMRS ≤12 and HAMD-21 ≤8) at the outset of the study, the time to symptomatic relapse into either mania (YMRS ≥15) or depression (HAMD-21 ≥15) was significantly longer for the olanzapine cotherapy group relative to the monotherapy group (median times 163 vs 42 days respectively; p = 0.023). For over 30 years, lithium has been the “gold standard” for relapse prevention in bipolar disorder. To demonstrate a clear value for new treatments, comparisons to lithium are essential. Olanzapine was compared with lithium in a randomized, double-blind study of relapse prevention in bipolar disorder (Tohen et al., 2005). Patients with a diagnosis of bipolar disorder, manic or mixed type, with a history of at least two manic or mixed episodes within 6 years, and a YMRS total score ≥20 received open-label treatment with a combination of olanzapine and lithium for 6–12 weeks. By using a combination of both agents to treat the acute episode, the potential bias of including patients who were not tolerant of either treatment was avoided. Furthermore, a past history of non-tolerance or non-response to either treatment was an important exclusion criterion. Patients who achieved symptomatic remission, defined as a YMRS total score ≤12 and an HAMD-21 total score ≤8, were randomly assigned to receive monotherapy with either

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olanzapine (n = 217) (5–20 mg/day) or lithium (n = 214) (300–1800 mg/day) for 52 weeks. Relapse to an affective episode, defined as a YMRS total score ≥15 and/or an HAMD-21 total score ≥15, occurred in 30% of olanzapine-treated and 39% of lithium-treated patients (p = 0.055). Olanzapine-treated patients had a statistically significantly lower incidence of relapse into a manic episode than lithium-treated patients (14% vs 28% respectively; p < 0.001), whereas both groups had similar incidences of relapse into a depressive episode (16% vs 15% respectively; p=0.895). The incidence of hospitalization for an affective episode was significantly lower for olanzapine-treated patients compared with lithium-treated patients (14% vs 23%; p=0.026). Significantly more olanzapine-treated patients (47%) completed the 52-week trial than those on lithium (33%; p = 0.004). The rates of discontinuation due to adverse events were 19% for the olanzapine group and 26% for the lithium group (p = 0.105). The efficacy of olanzapine for relapse prevention in bipolar disorder was assessed further in a year-long randomized double-blind placebo-controlled study (Tohen et al., 2003a). Patients with acute manic or mixed episodes of bipolar disorder received open-label treatment with olanzapine (5–20 mg/day) for 6–12 weeks. Those patients who achieved symptomatic remission, defined as a YMRS total score ≤12 and an HAMD-21 total score ≤8, were randomized to receive olanzapine (n = 225) (5–20 mg/day) or placebo (n = 136) for 52 weeks. Relative to placebo, olanzapine statistically significantly increased time to relapse to an affective (manic, depressive, or mixed) episode, defined as a YMRS total score ≥15 and/or an HAMD-21 total score ≥15 and/or psychiatric hospitalization (p < .001). Relapse to an affective episode occurred in 46.7% of olanzapine-treated patients and 80.1% of placebo-treated patients (p < 0.001). Olanzapine-treated patients had a statistically significantly lower rate of relapse into a manic episode (16.4% olanzapine vs 41.2% placebo; p < 0.001), or a depressive episode (34.7% olanzapine vs 47.8% placebo; p = 0.015) compared with the placebo-treated patients. Significantly more patients in the olanzapine group completed the 52-week trial than those in the placebo group (23.6% olanzapine vs 9.6% placebo; p = 0.001) with approximately twice as many placebo-treated patients discontinuing due to lack of efficacy (28% olanzapine vs 57% placebo; p = 0.001).

SAFETY AND TOLERABILITY SHORT-TERM STUDIES In the two placebo-controlled registration trials for acute mania (Tohen et al., 1999, 2000), short-term treatment with olanzapine for acute manic or mixed episodes in bipolar disorder was generally well tolerated. Very few patients in either study discontinued due to adverse events (0/70 olanzapine-treated patients and 2/69 placebo-treated patients in one study [0%, 2.9%]; and 2/55

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olanzapine-treated patients and 1/60 placebo-treated patient in the other study [3.6%, 1.7%]). In the second study, the only adverse event that occurred statistically significantly more often in olanzapine-treated patients than in placebo-treated patients was somnolence; in the other, statistically significantly more common events included somnolence, dry mouth, dizziness and weight gain. Olanzapine-treated patients gained averages of 1.65 and 2.11kg in the two studies, whereas placebotreated patients either lost weight (0.44 kg) or gained a lesser amount (0.45 kg). In both studies, no clinically important laboratory, vital sign or ECG findings were observed, and EPS were infrequent. The safety and tolerability of olanzapine were further demonstrated in three short-term studies comparing olanzapine with other commonly used medications: a 6-week study comparing olanzapine to haloperidol (Tohen etal., 2003b), a 3-week study comparing olanzapine with divalproex (Tohen et al., 2002a) and a 12-week study comparing olanzapine with divalproex (Zajecka et al., 2002). Rates of discontinuations due to adverse events were similar across all three studies regardless of study duration or medication, suggesting similar tolerability for all of the studied medications (olanzapine vs haloperidol, 8.1% vs 11.4% (Tohen et al., 2003b); olanzapine vs divalproex, 9.6% vs 7.3% (Tohen et al., 2002a); and 8.8% vs 11.1% (Zajecka et al., 2002) respectively). In the haloperidol-controlled study, adverse events that occurred statistically significantly more often in olanzapinetreated patients than in haloperidol-treated patients included somnolence, weight gain, infection, dizziness and fever. Events that were statistically significantly more common for olanzapine-treated patients than for divalproex-treated patients in the 3-week study included dry mouth, increased appetite and somnolence; in the 12-week study, somnolence, weight gain, rhinitis, edema and slurred speech. Olanzapine-treated patients gained more weight than comparator-treated patients, with a mean gain of 2.82 kg in the haloperidol-controlled study and gains of 2.49 kg and 4.0 kg in the divalproex-controlled studies, compared with 0.02 kg for haloperidol and 0.92 and 2.5 kg in the respective divalproex treatment groups. In all three studies, there were no clinically important laboratory, vital sign or ECG findings, and EPS were infrequent for olanzapine-treated patients. The frequency of EPS was significantly lower among olanzapine-treated patients than among haloperidol-treated patients, with no differences observed between olanzapinetreated patients and divalproex-treated patients. These safety findings are consistent with a 6-week study comparing olanzapine combined with lithium or valproate (“olanzapine cotherapy”) with lithium or valproate alone (“monotherapy”) (Tohen et al., 2002b). In this study, cotherapy patients were more likely than monotherapy patients to discontinue due to adverse events (10.9% vs 1.7%). Adverse events that occurred statistically significantly more often in olanzapine cotherapy patients than in monotherapy patients included somnolence, dry mouth, weight gain, increased appetite, tremor and slurred speech. However, of these, only somnolence and weight gain occurred with sufficient severity to cause

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treatment discontinuation in the olanzapine cotherapy group (2.6% and 1.3% respectively). As in the previous studies, weight gain was higher for patients in the olanzapine cotherapy group (3.08 vs 0.23 kg). Other than a greater incidence of treatment-emergent elevated prolactin in the olanzapine cotherapy group, no clinically important differences occurred in vital signs or laboratory and ECG findings.

LONGER-TERM STUDIES Olanzapine’s safety and tolerability were assessed in four long-term studies of relapse prevention. In a 47-week comparison of olanzapine and divalproex (Tohen etal., 2003c), patients receiving olanzapine experienced a higher incidence of dry mouth, somnolence, increased appetite, weight gain, akathisia and abnormal liver function tests than those on divalproex. Olanzapine and divalproex treatment groups did not differ in dropout rates due to adverse events. Based on the last-observation-carried forward analysis, patients in the olanzapine group gained significantly more weight than those in the divalproex group (3.44 vs 1.72kg; p=0.045). Based on the observed-case analysis for patients who completed the 47 weeks, weight increase did not differ for those completing 19 weeks or more of treatment (Figure 6.4). WEIGHT CHANGE FROM BASELINE (OC) 6

Change in Weight (kg)

5 4 3 2 Olanzapine Divalproex

1 0 –1 0

5

10

15

20 25 30 Weeks in Treatment

35

40

45

Olanzapine-treated patients gained significantly more weight than divalproex-treated patients from day 3 to week 15. By weeks 19 to 47, weight gain did not differ by treatment group.

Figure 6.4: Mean change in weight (observed case analysis) in a study of olanzapine versus divalproex (Tohen et al., 2003c). Reprinted by permission from American Journal of Psychiatry (Tohen et al., 2003c)

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In an 18-month comparison of olanzapine cotherapy with lithium or valproate monotherapy in patients who had completed 6 weeks’ treatment with cotherapy (Tohen et al., 2004), the only adverse event observed statistically significantly more often in cotherapy patients than in monotherapy patients was weight gain (19.6% vs 6.3%). There were no common or clinically important differences in vital signs, ECGs or laboratory evaluations in either study. In a year-long comparison of olanzapine and placebo in patients who had achieved remission while receiving 6–12 weeks of olanzapine therapy (Tohen etal., 2003a), patients receiving olanzapine experienced a statistically significantly higher incidence of weight increase, fatigue and akathisia than those on placebo. While a slightly higher proportion of olanzapine-treated patients than placebo-treated patients discontinued due to adverse events, the difference was not statistically significant. Conversely, placebo-treated patients were statistically significantly more likely to discontinue due to lack of efficacy. In the one-year-long relapse prevention study that compared olanzapine with lithium (Tohen et al., 2003a), slightly more lithium-treated patients than olanzapine-treated patients discontinued due to adverse events, although the difference was not statistically significant. Weight gain across the double-blind therapy phase was statistically significantly greater in the olanzapine group compared with the lithium group (1.79 vs −1.38 kg respectively; p < 0.001).

SUMMARY In summary, data based on randomized double-blind controlled trials suggest that olanzapine has efficacy in the treatment for acute mania, bipolar depression and relapse prevention. The data, however, suggest more robust efficacy in the treatment for acute mania than bipolar depression and in the prevention of mania compared to the prevention of depression. The adverse events that were seen most commonly in olanzapine-treated patients at significantly greater rates than in comparator-treated patients were events related to somnolence (somnolence, fatigue or hypersomnia) and weight gain (weight gain, increased weight or increased appetite). Moreover, a larger proportion of olanzapine-treated patients than comparator-treated patients experienced clinically important weight gain.

REFERENCES Altshuler, L. L., Post, R. M., Leverich, G. S., Mikalauskas, K., Rosoff, A., Ackerman, L., 1995. Antidepressant-induced mania and cycle acceleration: A controversy revisited. Am J Psychiatry. 152, 1130–1138. Bowden, C. L., Brugger, A. M., Swann, A. C., Calabrese, J. R., Janicak, P. G., Petty, F., Dilsaver, S. C., Davis, J. M., Rush, A. J., Small, J. G., 1994. Efficacy of divalproex vs

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lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA. 271, 918–924. Bymaster, F. P., Calligaro, D. O., Falcone, J. F., Marsh, R. D., Moore, N. A., Tye, N. C., Seeman, P., Wong, D. T., 1996. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 14, 87–96. Calabrese J. R., Kimmel S. E., Woyshville M. J., Rapport J. D., Faust C. J., Thompson P. A., Meltzer H. Y., 1996. Clozapine for treatment-refractory mania. Am J Psychiatry. 153, 759–64. Frye, M. A., Ketter T. A., Altshuler, L. L., Denicoff K., Dunn R. T., Kimbrell, T. A., Cora-Locatelli, G., Post, R. M., 1998. Clozapine in bipolar disorder: Treatment implications for other atypical antipsychotics. J Affect Disord. 48, 91–104. Hippius, H., 1999. A historical perspective of clozapine. J Clin Psychiatry. 60 (Suppl. 12), 22–3. Kane, J. M., Smith, J. M., 1982. Tardive dyskinesia: Prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry. 39, 473–481. Klein, E., Bental, E., Lerer, B., Belmaker, R. H., 1984. Carbamazepine and haloperidol v placebo and haloperidol in excited psychoses. A controlled study. Arch Gen Psychiatry. 41, 165–170. Koponen, H., Saari, K., Savolainen, M., Isohanni, M., 2002. Weight gain and glucose and lipid metabolism disturbances during antipsychotic medication: A review. Eur Arch Psychiatry Clin Neurosci. 252(6), 294–298. Lieberman, J. A., Duncan, G., 2000. What Makes Olanzapine an Atypical Antipsychotic? In: Tran, P., Bymaster, F. P., Tye, N. C., Herrera, J. M., Breier, A., Tollefson, G.(eds), Olanzapine (Zyprexa): A Novel Antipsychotic. Lippincott Williams and Wilkins, Philadelphia, xxiii–xxvii. Meehan, K., Zhang, F., David, S., Tohen, M., Janicak, P., Small, J., Koch, M., Rizk, R., Walker, D., Tran, P., Breier, A., 2001. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol. 21, 389–397. Meltzer H. Y., Alphs L., Green A. I., Altamura A. C., Anand R., Bertodi A., Bourgeois M., Chouinard G., Islam M. Z., Kane J., Krishman R., Lindenmayer J. P., Potkin S., 2003. International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 60, 82–91. Meyer, J. M., 2001. Effects of atypical antipsychotics on weight and serum lipid levels. J Clin Psychiatry. 62, Suppl. 34. Muller-Oerlinghausen, B., Retzow, A., Henn, F. A., Giedke, H., Walden, J., 2000. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. J Clin Psychopharmacol. 20, 195–203. Naber, D., Hippius, H., 1990. The European experience with use of clozapine. Hosp Community Psychiatry. 41, 886–90. Pope, H. G., Jr., McElroy, S. L., Keck, P. E., Jr., Hudson, J. I., 1991. Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry. 48, 62–68. Seeman, P., Kapur, S., 2000. What Makes Olanzapine an Atypical Antipsychotic? In: Tran, P., Bymaster, F. P., Tye, N. C., Herrera, J. M., Breier, A., Tollefson, G. (eds), Olanzapine (Zyprexa): A Novel Antipsychotic. Lippincott Williams and Wilkins, Philadelphia, 3–24.

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Shulman, R.W., Singh, A., Shulman, K.I., 1997. Treatment of elderly institutionalized bipolar patients with clozapine. Psychopharmacol Bull. 33, 113–8. Tohen, M., Baker, R. W., Altshuler, L. L., Zarate, C. A., Suppes, T., Ketter, T. A., Milton, D. R., Risser, R., Gilmore, J. A., Breier, A., Tollefson, G. A., 2002a. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry. 159, 1011–1017. Tohen, M., Bowden, C., Calabrese, J., Chou, J., Jacobs, T. G., Baker, R. W., Williamson, D., Evans, A. R., 2003a. Olanzapine’s efficacy for relapse prevention in bipolar disorder: a randomized double-blind placebo-controlled 12-month trial. Bipol Disord. 5 (Suppl. 1), 89. Tohen, M., Calabrese, J. R., Sachs, G. S., Banov, M. D., Detke, H. C., Risser, R., Baker, R. W., Chou, J. C. Y., Bowden, C. L. (In Press). A randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute olanzapine treatment. Am J Psych. Tohen, M., Chengappa, K. N., Suppes, T., Baker, R. W., Zarate, C., Bowden, C., Sachs, G., Kupfer, D. J., Ghaemi, S. N., Feldman, P. D., Risser, R., Evans, A. R., Calabrese, J., 2004. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry. 184, 337–345. Tohen, M., Chengappa, K. N., Suppes, T., Zarate, C. A., Jr., Calabrese, J. R., Bowden, C. L., Sachs, G. S., Kupfer, D. J., Baker, R. W., Risser, R. C., Keeter, E. L., Feldman, P. D., Tollefson, G. D., Breier, A., 2002b. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 59, 62–69. Tohen, M., Goldberg, J. F., Gonzalez-Pinto Arrillaga, A. M., Azorin, J. M., Vieta, E., Hardy-Bayle, M. C., Lawson, W. B., Emsley, R. A., Zhang, F., Baker, R. W., Risser, R. C., Namjoshi, M. A., Evans, A. R., Breier, A., 2003b. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry. 60, 1218–1226. Tohen, M., Greil, W., Calabrese, J., Sachs, G. S., Yatham, L. N., Oerlinghausen, B. M., Koukopoulos, A., Cassano, G. B., Grunze, H., Licht, R. W., Dell’Osso, L., Evans, A. R., Risser, R., Baker, R. W., Crane, H., Dossenbach, M. R., Bowden, C. L., 2005. Olanzapine versus Lithium in the maintenance treatment of bipolar disorder: A 12-month, randomized, double-blind, controlled clinical trial. Am J Psych. 162, 1281–1290. Tohen, M., Jacobs, T. G., Grundy, S. L., McElroy, S. L., Banov, M. C., Janicak, P. G., Sanger, T., Risser, R., Zhang, F., Toma, V., Francis, J., Tollefson, G. D., Breier, A., 2000. Efficacy of olanzapine in acute bipolar mania: A double-blind, placebo-controlled study. Arch Gen Psychiatry. 57, 841–849. Tohen, M., Ketter, T. A., Zarate, C. A., Suppes, T., Frye, M., Altshuler, L., Zajecka, J., Schuh, L. M., Risser, R. C., Brown, E., Baker, R. W., 2003c. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study. Am J Psychiatry. 160, 1263–1271. Tohen, M., Marneros, A., Greil, W., Calabrese, J. R., Sachs, G., Yatham, M. B., Muller-Oerlinghausen, B., Koukopoulis, A., Cassano, G. B., Grunz, H., Licht, R. W., Dell’Osso, L., Evans, A. R., Risser, R., Baker, R. W., Crane, H., Dossenboch, M. R., Bowden, C., 2005. Olanzapine versus lithium in maintenance of response in bipolar disorder: a randomized double-blind controlled 12-month clinical trial. Am J Psychiatry. 162: 1–10. Tohen, M., Sanger, T. M., McElroy, S. L., Tollefson, G. D., Chengappa, K. N., Daniel, D. G., Petty, F., Centorrino, F., Wang, R., Grundy, S. L., Greaney, M. G., Jacobs, T. G., David, S. R., Toma, V., 1999. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry. 156, 702–709.

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Tohen, M., Vieta, E., Calabrese, J., Ketter, T. A., Sachs, G., Bowden, C., Mitchell, P. B., Centorrino, F., Risser, R., Baker, R. W., Evans, A. R., Beymer, K., Dube, S., Tollefson, G. D., Breier, A., 2003d. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 60(11), 1079–1088. Tohen, M., Zhang, F., Taylor, C. C., Burns, P., Zarate, C., Sanger, T., Tollefson, G., 2001. A meta-analysis of the use of typical antipsychotic agents in bipolar disorder. J Affect Disord. 65(1), 85–93. Tollefson, G. D., Sanger, T. M., Lu, M. K., Thieme, M. E., 1998. Depressive signs and symptoms in schizophrenia – a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry. 55, 250–258. Wehr, T. A., Goodwin, F. K., 1987. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 144(11), 1403–1411. Zajecka, J. M., Weisler, R., Sachs, G., Swann, A. C., Wozniak, P., Sommerville, K. W., 2002. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry. 63(12), 1148–1155. Zarate, C. A., Jr., Tohen, M., 2004. Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in remitted manic patients. Am J Psychiatry. 161(1), 169–171.

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7 Haloperidol and Risperidone in Mania John Cookson The Royal London Hospital, London, UK

INTRODUCTION In 1958 the creative genius of Paul Janssen, the Belgian clinician and chemist, and founder of the Janssen pharmaceutical company, led to the introduction of haloperidol, a butyrophenone with antipsychotic properties. This had been synthesized as a variant of the pethidine molecule and it was observed to antagonize the effects of amphetamines in animals. The fact that amphetamines were associated with psychotic reactions in cyclists, who were taking them to enhance their performance, led Janssen to study the effects of haloperidol in schizophrenia and mania. The occurrence of neurological (Parkinsonian) side effects with the phenothiazines such as chlorpromazine (discovered in 1952) had indicated that these drugs affected neurones, and the name “neuroleptic” (“seizes neurones”) was used to describe the phenothiazines and later haloperidol; the term “antipsychotic” is now preferred. Later, newer drugs called “atypical,” “second generation” or “new generation” antipsychotics were developed to avoid these side effects. Risperidone is an atypical antipsychotic that was developed by Janssen pharmaceuticals.

ACUTE TRANQUILLIZATION IN MANIA The acutely manic patient presents an immediate challenge to medical and nursing staff, and usually requires medication to reduce aggressive or violent behavior, agitation and the behavioral consequences of psychotic thinking. The violent patient presents the most extreme challenge to the psychiatrist of how to combine psychology and pharmacology, compassion and safety in effective proportion. Drugs are used both to treat the underlying manic state and to reduce aggression and arousal (Royal College of Psychiatrists, 1998; Cookson, Taylor and Katona, 2002a). The aim of acute tranquillization is to calm or sedate the Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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patient sufficiently to minimize the risk posed to the patient and to others. Often it is used for sedation, but sometimes it addresses also the underlying illness, particularly mania. When an antipsychotic is used, haloperidol is often the drug of first choice, especially if intramuscular administration is necessary – 5–10 mg may be given intramuscularly for the first injection and repeated. In some countries, a lower dose is started. A combination of haloperidol with a benzodiazepine such as lorazepam, which may also be given intramuscularly (1–2 mg), has been the commonest approach for rapid tranquillization of acutely disturbed patients, many of whom have mania. There is little evidence concerning the optimal dose of haloperidol for this use. Mania may improve rapidly following parenteral haloperidol. Ratings of mania improved by 30% within 20 minutes after intravenous injection of 2.5–5mg, and such improvement was seen before patients slept (Cookson et al., 1983).

SEDATION IS NOT REQUIRED FOR ANTIPSYCHOTICS TO IMPROVE MANIA Chlorpromazine was the most widely investigated antipsychotic in early comparative trials in mania, but drugs with more specific dopamine-receptor blocking actions have antimanic properties, although these drugs – such as pimozide and haloperidol – are less sedative, being without blocking actions at histamine receptors. The efficacy of these non-sedative drugs in mania highlights the importance of dopamine (DA) receptor blockade in the antimanic effects of antipsychotic drugs (Post et al., 1980), and indicates that antimanic activity can occur independently of sedation (Cookson, Silverstone and Wells, 1981).

HALOPERIDOL IN MANIA In the 1990s, the preference of American (New York) psychiatrists for high potency antipsychotics such as haloperidol in mania was illustrated in a study by Chou etal. (1996) of 528 manic patients in New York state hospitals in 1990. During the first three weeks of hospitalization for mania, 92% received antipsychotic medication, 61% lithium, 54% both and 22% benzodiazepines – mainly lorazepam. Haloperidol (38% of prescriptions) was the most widely used antipsychotic drug, followed by fluphenazine (20%) and chlorpromazine (18%). Since haloperidol was the most commonly prescribed antipsychotic in mania, the study by Shopsin et al. (1975) is important. This compared haloperidol (up to 36 mg/day) with chlorpromazine (up to 1800 mg/day) and lithium in a three-week study with only ten patients in each treatment group. Lithium appeared to produce a broader improvement in manic symptoms than the antipsychotics; seven patients were well enough to be discharged after treatment with lithium compared to only

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one patient on chlorpromazine and two patients on haloperidol. However, the clinical ratings (Clinical Global Impression) showed almost identical levels of improvement at three weeks for lithium and haloperidol, both of which were superior to chlorpromazine. The authors described haloperidol as more effective than lithium in reducing hyperactivity, while lithium produced greater effects on mood and ideation; however, the Brief Psychiatric Rating Scale did not show significant differences in individual items for the three treatments. Haloperidol had a more pronounced antimanic effect than chlorpromazine and this was not accompanied by sedation. The authors argued that the control of symptoms by haloperidol was “a suppressive lid,” as opposed to the “more total normalization of affect, ideation and behavior” on lithium. An alternative view was expressed as early as 1972 by Prien et al., who found “no evidence the treatments worked differently on the underlying manic process” and were “unable to confirm . . . the claims that lithium treats the underlying manic process while chlorpromazine controls . . . behaviour through sedation without affecting underlying mood and ideation.” The high rate of remission within three weeks on lithium in this study by Shopsin et al. (1975) is in contrast to the lower rates seen in more recent studies such as that by Bowden et al. (1994). Conversely, the very low rate of remission on haloperidol contrasts with the dose-finding study of 47 severely ill manic patients by Rifkin et al. (1994), in which 45% of patients, treated with haloperidol, remitted within six weeks. The latter study was important in failing to show a significantly greater improvement with doses of haloperidol above 10 mg/day and up to 80 mg/day. However, the numbers involved were small and the confidence limits overlapped in all three dose ranges. There was a distinct trend for patients on 30 mg/day or more to do better than those on only 10 mg/day. Further studies are needed to identify the optimal doses for haloperidol in mania. In the largest randomized comparative study of haloperidol (Tohen et al., 2003), the drug was compared with olanzapine over 6–12 weeks. Among patients on haloperidol (up to 15 mg/day, mean dose at sixth week 7 mg/day), the proportion responding (50% reduction in YMRS score) at 6 weeks was 74%; the proportion showing syndromal remission (according to DSM-IV) was 44%, a figure similar to that found by Rifkin et al. (1994). In patients who had low levels of depressive symptoms at commencement on haloperidol, a total of 16.8% switched into depression within 12 weeks. However, as there was no placebo group, it is not known whether this represents the natural history of the patients’ mood cycles, perhaps accelerated by effective treatment for mania, or some additional depressant effect of haloperidol. In patients who remain disturbed on standard doses of haloperidol, additional sedation may be achieved by benzodiazepines, especially lorazepam, a practice that carries less risk of cardiotoxicity than using higher doses of antipsychotics

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(Lenox et al., 1992; Busch, Miller and Weiden, 1989). However, a combination of two antimanic drugs from different classes should also be considered, for example an antipsychotic with lithium.

COMBINATION TREATMENT WITH LITHIUM AND HALOPERIDOL If, as Shopsin etal. (1975) found, lithium is superior to haloperidol, and acts through different mechanisms to exert its antimanic effect, one would expect that patients treated with a combination of lithium and haloperidol would respond significantly better than patients treated with either drug alone. One small study (with seven patients in each group and therefore not sufficiently powered to explore the question conclusively) addressed this comparison in mania (Garfinkel, Stancer and Persaud, 1980). Haloperidol appeared superior to lithium alone, and the combination gave no additional advantage during three weeks of treatment. One of the recent combination studies of atypical antipsychotics plus “mood stabilizers” included haloperidol as an active comparator (which will be discussed later in this chapter; see Table 7.2).

HORMONE CHANGES AND MECHANISMS OF ANTIMANIC EFFECTS OF ANTIPSYCHOTICS CORTISOL Elevated serum cortisol levels are found in mania. During treatment with haloperidol, there is dissociation between an early normalization of cortisol levels within three days and a more gradual clinical improvement during two weeks of treatment (Cookson et al., 1985). This may occur because haloperidol blocks noradrenaline alpha-1 receptors in humans (Szabadi, Gaszner and Bradshaw, 1981). Alpha-1 receptor blockade is also thought to contribute to transient sedative effects of antipsychotics (Peroutka and Snyder, 1980). It may account for the early transient sedative effects seen in mania with haloperidol (Cookson et al., 1983).

PROLACTIN Dopamine (DA-2) receptors in the prolactin-secreting cells of the anterior pituitary gland are blocked by classical antipsychotic agents, and by risperidone. The resulting elevation of serum prolactin levels provides a biological marker of this dopamine receptor blockade; it may also have clinical consequences including side effects such as galactorrhea, amenorrhea, reduced libido and reduced bone density. During treatment with haloperidol, prolactin levels increase in the plasma

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over the course of 14 days, with a pattern of rise similar to the timecourse of clinical improvement. However, more detailed analysis using intravenous “test doses” of haloperidol, shows an initial rise in serum prolactin levels, which is partly transient after the first intravenous dose and cannot be exceeded by giving larger doses of haloperidol (Cookson et al., 1983). This is followed by a gradual rise during the following 2–4 weeks. Within two weeks, prolactin secretion by the pituitary becomes sensitive over a wider range of doses of haloperidol than in the drug-naive patient. These compensatory changes, in the control of prolactin secretion, are thought to include changes in the level of dopamine in the portal pituitary blood supply during prolonged treatment with haloperidol. If similar compensatory changes occur in the DA pathways of the limbic system, doses of haloperidol that are effective in the drug-naive manic patient may not be sufficient to control patients in later stages of mania, who have received prolonged treatment with antipsychotic drugs.

ANTIPSYCHOTICS AS MOOD STABILIZERS Antipsychotic drugs are used extensively in the maintenance treatment of bipolar patients (Sernyak et al., 1994; Sernyak and Woods, 1998; Cookson and Sachs, 1999; Cookson, 2001). For patients who are unresponsive to lithium (and anticonvulsants), and particularly for those whose compliance with oral medication is poor, depot formulations of antipsychotic drugs including haloperidol decanoate have the advantage of providing a sustained and reliable delivery of a drug for periods of weeks. For rapid cycling bipolar patients, the depot antipsychotic haloperidol decanoate stabilized mood swings (Lowe and Batchelor, 1990). In a minority of bipolar outpatients, depot antipsychotic medication is used and can reduce the time spent in both manic and depressed phases (Littlejohn, Leslie and Cookson, 1994).

RISPERIDONE Atypical antipsychotic drugs may be classified according to the breadth of their pharmacological activity. The term “Serotonin and Dopamine Receptor Antagonist” (SDRA) is used to describe risperidone, ziprasidone and sertindole. All three are structurally similar to haloperidol with its central ringed (piperidine) nitrogen. 5HT-2A receptors facilitate excitatory effects on cortical and other neurones. Risperidone is an antagonist as are many other atypical antipsychotics including clozapine, olanzapine, zotepine and ziprasidone, but not sulpiride or amisulpride. 5HT-2A antagonists increase slow-wave sleep and decrease paradoxical (REM) sleep; they may also reduce anxiety. They have interesting effects to restore DA cell firing

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and increase dopamine release; this may lead to less EPSE, less cognitive impairment and less reduction of drive as compared with the classical antipsychotics.

PHARMACOLOGY Risperidone (Risperdal) is a benzizoxazole. It resembles clozapine in that it is a potent 5HT-2A and D2 antagonist, but differs in that it has less affinity for D3 and D4 receptors. It also blocks H1, NA alpha-1 and alpha-2 but not ACh receptors. It is effective in schizophrenia, with a much lower incidence of extrapyramidal side effects than haloperidol. With oral risperidone, doses of 2–6 mg/day occupy 65–80% of the D2 receptors in the basal ganglia visualized by raclopride; higher doses occupy more than 80% of the receptors and are liable to produce EPSE. Using labeled setoperone to visualize 5-HT-2 receptors, it is known that even the lowest therapeutic doses, such as 2 mg of risperidone, produce substantial blockade of 5-HT-2 receptors in the brain, approaching saturation.

PHARMACOKINETICS Risperidone is metabolized partly by liver hydroxylase (CYP IID6) and has an active metabolite hydroxyrisperidone with similar pharmacological properties that is excreted by the kidneys. The combined half-life is said to be about 24 hours. About 7–10% of Caucasians have low levels of this enzyme and are slow metabolizers of risperidone. They can be detected by their slow metabolism of debrisoquine or dextromethorphan. Some drugs inhibit the hydroxylase enzymes – for instance phenothiazines, fluoxetine and paroxetine – leading to increases in the level of risperidone but lower levels of hydroxyrisperidone. However, carbamazepine induces liver enzymes and reduces serum levels of many commonly employed drugs, including haloperidol and risperidone (Yatham et al., 2003).

RISPERIDONE LONG ACTING INJECTION Although the metabolite could be esterified to produce a depot formulation, this has not been developed. Instead there is a long acting intramuscular injection (Risperdal Consta), based on encapsulation of risperidone in microspheres of a biodegradable polymer, glycolic acid-lactate, that is also used for sutures. Gradual hydrolysis of the polymer at the site of injection gives a slow release of risperidone, beginning three weeks after the first injection, achieving optimal blood levels between 4 and 6 weeks. A dose of up to 50 mg is given as an aqueous suspension, every two weeks, being equivalent to up to 4 mg oral risperidone daily. However, as the injected form

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avoids first-pass metabolism in the liver it is difficult to state a bio-equivalent dose with confidence.

CLINICAL EFFECTS OF RISPERIDONE In chronic schizophrenia with persistent symptoms it provides a slightly greater overall improvement than older antipsychotics. However, these advantages are greatest in a narrow range of doses, 1–8 mg daily (Marder and Meibach, 1994; Peuskens et al., 1995). The advantage over haloperidol on negative symptoms in schizophrenia is due in part to the lesser incidence of extrapyramidal side effects, and greater improvement in depression. Comparisons with haloperidol have also shown that risperidone produces greater cognitive improvement, so that attention and working memory improve. It is also associated with less severe depressive symptoms during short-term follow-up. Risperidone produces less impairment of working memory than haloperidol, but longstanding deficits remain. Risperidone is associated with less depression than haloperidol, during follow up in schizophrenia.

ADVERSE EFFECTS Postural hypotension and mild sedation can be avoided by increasing the dose gradually. Reports of cerebrovascular events in elderly patients on risperidone have led to a special warning by the FDA. At doses above 6mg/day there is an increasing incidence of EPSE. Weight gain occurs to a greater extent than with haloperidol, and occasionally impairment of ejaculation or orgasm, and blurred vision. Risperidone blocks D2 receptors in the pituitary and increases prolactin levels to a slightly greater extent than haloperidol. There is a correlation between raised prolactin levels and reduced libido (Kleinberg etal., 1999). Risperidone produces less tardive dyskinesia than classical antipsychotics in the elderly. A slight increase in the incidence of diabetes in patients with schizophrenia under the age of 40 treated with risperidone has been observed (Sernyak et al., 2002). It remains to be seen whether weight gain and metabolic changes including hyperglycemia are also problems to the same extent in the treatment for bipolar disorder.

RISPERIDONE IN MANIA AND HYPOMANIA Interest in antipsychotics in mania includes their ability to not only improve and control mania and hypomania but also avoid subsequent ‘post-manic’ depression, as well as their ability to maintain improvement after remission of mania and prevent further recurrences of mania or of depression. It is also important to know how their profile of side effects compares with older antipsychotics,

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particularly regarding acute extrapyramidal side effects but also later tardive dyskinesia. Evidence for the use of risperidone in bipolar disorder is available from open series, double-blind comparative trials, and – most revealingly of all – from placebo-controlled comparisons. Risperidone improves mania in patients with AIDS, who are particularly sensitive to developing extrapyramidal side effects with typical antipsychotics (Singh, Golledge and Catalan, 1997). Several open series attest to the efficacy of risperidone in mania (Tohen et al., 1996; Licht, Bysted and Christensen, 2001; Vieta et al., 2002). In a comparative trial in mania, in which additional lorazepam was permitted, risperidone was of similar efficacy to haloperidol or lithium (Segal, Berk and Brook, 1998). An open study of 44 bipolar II patients with hypomania followed them for 6 months; it found an improvement in mania, and only 4% had a relapse of hypomania, but 14% had a depressive recurrence (Vieta et al., 2001).

PLACEBO-CONTROLLED DESIGN To prove the efficacy of a drug in a psychiatric condition, it is essential to conduct randomized double-blind placebo-controlled trials. The challenges of conducting such trials in mania have only been met in recent years, and in the course of developing novel anticonvulsant and atypical antipsychotic treatments. These recent trials are therefore providing answers to questions that have long remained unresolved about the treatment for bipolar disorder. Analysis of the results of these trials requires attention not only to the statistical significance of differences in special rating scales, but also to the size of the effect, and to the generalizability of results based on highly selected patients in clinical trial centers to other groups of patients with mania in routine practice. It is also important to consider how dropouts from the studies may have biased the interpretation of results.

PLACEBO-CONTROLLED MONOTHERAPY TRIALS OF RISPERIDONE There have been three parallel-group randomized placebo-controlled trials of risperidone in mania (Hirschfeld et al., 2004; Smulevich et al., 2005; Khanna et al., 2005). Table 7.1 displays these studies using a “Number Needed to Treat” (NNT) analysis and showing the dropouts rates for reasons of adverse events, lack of efficacy and other reasons. The NNT is calculated by dividing the difference in response rate of active drug and placebo into 100 and correcting to the next highest integer. It represents the number of patients who must be treated in order for one patient to achieve the defined response (usually a 50% reduction in rating scale score) as a result of the pharmacological effect of the drug. The NNT thus provides a measure of the

2.1 4

14.6 3

50% reduction YMRS

DSM-IV Manic 3 weeks Extended to YMRS ≥ 20 12 weeks without placebo Smulevich et al. MADRS ≤ 20 (2005) International LZP, chloral or diazepam for 10 days

3.4

4.8

DSM-IV Manic or mixed YMRS ≥ 20

Risperidone N = 154 Mean modal 4.2 mg/day

6

36

50% reduction in YMRS

3 weeks Khanna et al. (2005) India LZP for 10 days

8

14

3 weeks Hirschfeld et al. DSM-IV Manic (2004) USA YMRS ≥20 LZP for 10 days MADRS ≤ 20

4

12.5

2.8

16

22

48

36

73

24

43

15

37

19

7 (4–26)

3 (2–4)

6 (4–13)

Difference Other Dropouts Inclusion criteria Dropouts for Inefficacy for Adverse Dropouts Response from Criterion for placebo Number-Needed-To-Treat % % events % % Response

Risperidone N = 146 Mean modal 5.6 mg/day Placebo N = 144

Risperidone N = 134 Mean modal 4.1 mg/day Placebo N = 125

Treatment Mean Dose/day Numbers Duration Authors for ITT Sites Extra drugs

Table 7.1: Placebo-controlled parallel-group randomized trials of monotherapy with risperidone or haloperidol in mania

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10.1

10.1

5.9

28.7

Haloperidol N = 98 Mean day 21: 5.2 mg/day

4.9

17.6

Quetiapine N = 102 Responders day 21: Mean 559 mg/day Placebo N = 100 DSM-IV Manic YMRS ≥ 20 50% reduction YMRS

3

1

Haloperidol N = 144 Mean modal 8 mg/ day

3 weeks extended to 12 weeks) McIntyre et al. (ECNP), 2005 LZP for 10 days Hypnotics for insomnia

5

6

25.3

23.9

23.5

6

8 (4–36)

3/52: 7 3/52: NSD 15 (−16 to +5) 12/52: 21 12/52: 5 (3–14)

14

3/52: 55 3/52: 20 3/52: 5 (3–16) 12/52: 70 12/52: 31 12/52: 4 (3–6)

3/52: 35 12/52: 39

3/52: 42 12/52: 60

47

33

50% reduction YMRS

Placebo N = 140 4

Difference Other Dropouts Inclusion criteria Dropouts for Inefficacy for Adverse Dropouts Response from Criterion for placebo Number-Needed-To-Treat % % events % % Response

Treatment Mean Dose/day Numbers Duration Authors for ITT Sites Extra drugs

Table 7.1: (Continued)

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size of effect that can be expected of the drug in a clinical situation. For a drug to be useful monotherapy as a first-line treatment in a common and severe disorder such as mania, the NNT for 50% improvement in severity should be in the order of 2–4 (Cookson, Taylor and Katona, 2002b). All three studies were of 3 weeks duration and there was a placebo response rate of 24–36%, reflecting the effects of a variety of possible non-specific factors such as hospitalization, extra medication with benzodiazepines or chloral allowed during the first 10 days, and bias in the raters. In the trial of Hirschfeld et al. (2004), the dose of risperidone was increased gradually over 4 days to a maximum of 6 mg/day, and was effective compared with placebo from day 3. However, the NNT was 6 (95% confidence interval 4–13). Side effects on risperidone were somnolence (28% vs 7% on placebo) and hyperkinesias (Parkinsonism) in 16% vs 5%. The study by Khanna et al. (2005) was conducted in India, and was distinguished by relatively high YMRS scores on entry (about 10 points higher than in most other studies of atypical antipsychotics in mania), and by a high rate of study completion on risperidone with low dropout rates particularly for lack of efficacy. Although having the same protocol for increase in dose, the mean modal dose in this study was higher (5.4 mg/day). The rate of response on risperidone was highest in this study and the NNT was impressively low at 3 (95% confidence interval 2–4). Initial depression scores were already low but improved further, the change being greater on risperidone than placebo even by day 3. Extrapyramidal side effects occurred in 35% of those on risperidone, and 6% on placebo. The study by Smulevich et al. (2005) was conducted at international centers and allowed a slightly slower dosing schedule reaching a maximum of 6 mg/day by day 5. This study also had a haloperidol comparator group with a mean modal dose of 8mg/day (Table 7.1). Both active drugs were effective compared with placebo from day 7. By day 21 the NNT for 50% improvement was 7 (95% confidence interval 4–26) for risperidone and similar for haloperidol at 8 (95% confidence interval 4–36). MADRS depression scores, low at the start, fell more on risperidone than on placebo from week 1, and on haloperidol only at week 2. Side effects on risperidone included extrapyramidal symptoms (17% compared with 40% on haloperidol). In all three of these studies, the improvement in mania occurred in patients with or without psychotic symptoms. In the studies of Khanna et al. and of Smulevich et al., the improvement on active treatments was continuing to develop during the third week of treatment; the extension to 12 weeks in the Smulevich study demonstrated further improvement in YMRS scores with active treatment up to 12 weeks, suggesting that the dose initially administered may not have been sufficient to achieve maximum improvement. On the other hand, in the study of Hirschfeld et al., the improvement appeared to be complete within 2–3 weeks. Risperidone, possibly in a dose-related manner (Aubrey, Simon and Bertsky, 2000), has been described as worsening or precipitating mania in predisposed

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patients, mainly those with schizophrenia, schizoaffective disorder or organic brain disease. No evidence of such exacerbation of mania was found in these placebo-controlled trials of risperidone.

PLACEBO-CONTROLLED MONOTHERAPY TRIALS OF HALOPERIDOL IN MANIA Two of the recent monotherapy studies of atypical antipsychotics in mania have included haloperidol as an active comparator (see Table 7.1): the risperidone study of Smulevich et al. (2005), and the quetiapine study of McIntyre et al. (2005). In the study of Smulevich etal. (2005) reviewed, the haloperidol dose started at 4mg/day and was adjusted to 2–12mg/day by day 5. The timecourse of improvement was similar to that with risperidone, and by day 21 the NNT was 8 (95% confidence interval 4–36), far larger than one would usually associate with the most commonly used antimanic drug of the previous decade; this might be because the mean modal dose of haloperidol was only 8mg/day or because the patients in the trial were in some way not typical of routine clinic patients and more resistant to treatment. Finally, a comparator group on haloperidol (up to 8 mg/day) was included in the study reported by McIntyre etal. (2005) of quetiapine (up to 800mg/day) and placebo, analyzed at 3 and 12 weeks. At 3 weeks the response rate (50% reduction in YMRS score) on haloperidol, on a mean dose of only 5.2mg/day, was 55% compared with 35% on placebo, giving an NNT of 5 (95% confidence interval 3–16). There were more dropouts on placebo than on haloperidol or quetiapine, so that the analysis using last observations carried forward was biased in favor of the active drugs, and especially so after three weeks when more patients on placebo or haloperidol than on quetiapine dropped out. By 12 weeks the response rate on haloperidol was 70% and on placebo 39%, giving an NNT of 4 (3–6). Depression scores (MADRS) improved by day 21 on both quetiapine and haloperidol more than on placebo. On the other hand, the switch rates into depression were similar for haloperidol (8.1%) and placebo (8.9%), and tended to be lower for quetiapine (2.9%). Side effects in the form of extrapyramidal symptoms were much more common on haloperidol (59.6%) than on placebo (15.8%), as was akathisia (33.3% on haloperidol and 5.9% on placebo). Somnolence occurred more often with haloperidol (9.1%) than placebo (5%).

TRIALS OF COMBINATION THERAPY USING RISPERIDONE OR HALOPERIDOL WITH A “MOOD STABILIZER” (LITHIUM, VALPROATE OR CARBAMAZEPINE) Two studies of risperidone (1–6 mg daily) added for 3 weeks to treatment with lithium or valproate (or carbamazepine in one study) have demonstrated an

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advantage of risperidone over placebo (Sachs et al., 2002; Yatham et al., 2003). The NNTs for the combination of risperidone or haloperidol with “mood stabilizers” (lithium or valproate) are tabulated in Table 7.2. These large studies included 156 and 150 patients respectively and the former included a group on haloperidol (2–12 mg/day). In both studies, the antipsychotics (risperidone or haloperidol) were effective in patients with or without psychotic features. There was no evidence of worsening of mania by risperidone. In the study of Sachs et al. (2002), response rates based on a Clinical Global Impression (CGI-I) of much or very much improvement were 30% on mood stabiliser plus placebo and 53% on combination of mood stabilizer with risperidone (in a mean modal dose of only 3.8 mg/day); this difference corresponds to an NNT of 5 (95% confidence interval 3–23) for response to risperidone. Combination with haloperidol (mean modal dose 6.2 mg/day) and lithium or valproate showed an NNT of 5 (95% confidence interval 3–64). The higher total dropout rate on haloperidol (53%) than on risperidone (35%) or placebo combination (49%) would bias the analysis of efficacy against this drug. Of all the patients, 63% had already received lithium or valproate before randomization to risperidone or placebo, and might therefore be considered non-responders to the mood stabilizer; the rest commenced on lithium or valproate at the same time as being randomized to start on risperidone or placebo. The benefit of additional antipsychotic medication was much less apparent in the latter group. Significant improvement in response to either risperidone or haloperidol was limited to patients with pure mania and was not evident in those with mixed manic states, who comprised 21% of patients. No patients achieved a CGI rating of very much improved on lithium or valproate plus placebo, but 25% of those receiving additional risperidone did so, as did 16% of those receiving additional haloperidol. A rating scale for depression was not used. Although dropouts due directly to side effects were few in all groups (2–4%), among patients receiving haloperidol plus lithium or valproate, 28% reported extrapyramidal side effects and 38% received antiparkinsonian medication, compared with 13% and 17% on risperidone in combination, and 4% and 8% on placebo in combination with lithium or valproate. Weight gain was greater on risperidone than on haloperidol or placebo, plus mood stabilizer. Somnolence was slightly more common on haloperidol (30%) than on risperidone (25%) or on placebo (12%), plus mood stabilizer. The international study of Yatham et al. (2003) used a similar design, but allowed carbamazepine as one of the “mood stabilizers.” The mean modal dose of risperidone was 4 mg/day. Unfortunately, carbamazepine was associated with a 40% reduction in blood levels of risperidone and its active metabolite, thus reducing the overall power of the study to detect benefits of risperidone. Nevertheless, the proportion of patients (59%) responding (with a 50% improvement in YMRS) on risperidone plus lithium, valproate or carbamazepine was greater than for mood stabilizer plus placebo (41%), with an NNT of 6 (95% confidence interval 3–56).

Manic or mixed YMRS ≥ 20 CGI much or very much improved

Combination with Valproate N = 69 50% less antipsychotics 3 weeks Placebo N = 67 Y-MRS Muller-Oerlinghausen et al. (2000)

Haloperidol 6.2 mg/day N = 53 Placebo N = 51 Risperidone 3.8 mg/day N = 52

Sachs et al. (2002) Combination with Li or valproate 3 weeks USA Benzodiazepines for sleep, LZP 4 mg/day for 7 days 9 13

4 4

10 6 1 3

2

6

36 (all reasons) 52 (all reasons)

35 25

45

70 46

30 53

50

41

59

24

23

20

18

5 (3–13)

5 (3–23)

5 (3–64)

6 (3–56)

Inclusion criteria Dropouts Dropouts Other Difference Number-Needed-to-Treat Criterion of for for Adverse Dropouts Response from Response Inefficacy % Events % % % placebo % (95% C.I.) Manic or mixed YMRS ≥ 20 50% less Y-MRS

Treatments Mean modal dose Numbers

Risperidone Yatham et al. (2003) 4.0 mg/day N = 69 Combination with Li, valproate or Placebo N = 73 carbamazepine 3 weeks International Benzodiazepines, LZP 4 mg/day for 7 days

Authors Treatment Duration Sites Extra drugs

Table 7.2: NNTs for combination of risperidone or haloperidol with “mood stabilizer” (lithium or valproate)

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The advantage of risperidone over placebo was far more evident in those who had already been on a mood stabilizer for at least two weeks before randomization, than in those who started the mood stabilizer shortly before starting risperidone or placebo. Response to risperidone was independent of the presence or absence of psychotic symptoms. Side effects related to extrapyramidal symptoms were commoner on risperidone plus mood stabilizer (21%) than on placebo plus mood stabilizer (8%). Conversely, in a 3-week study with 136 patients, the addition of valproate to classical antipsychotics (mainly haloperidol) has been shown to produce greater improvement than addition of placebo (Muller-Oerlinghausen et al., 2000), where 70% improved (at least 50% reduction in Y-MRS score) compared with 46% on antipsychotic plus placebo (NNT = 5; 95% CI 3–13).

RAPID CYCLING There is no mention of rapid cycling in any of the placebo-controlled studies of risperidone reviewed earlier. However, open studies suggest risperidone may be of benefit (Vieta et al., 1998), and a chart review suggested that risperidone, usually as augmentation to lithium or valproate, was beneficial in a group of 25 patients (Coconcea et al., 2003).

PHARMACOECONOMICS McGarry etal. (2003) conducted a cost-effectiveness analysis of atypical antipsychotics and competing treatment strategies in the treatment for mania, employing published costs and probabilities of outcomes, and the standard-gamble method to estimate total quality-adjusted life-years (QALY). Although haloperidol plus mood stabilizer was the least costly treatment strategy, risperidone plus mood stabilizer cost an additional £1000 per QALY. This compares with the customary threshold of £30 000 per QALY to justify new treatments.

CONCLUSIONS There is now overwhelming evidence from clinical trials that risperidone has antimanic properties, and that these are of a similar order of magnitude to the antimanic action of haloperidol but entail a much lower rate of extrapyramidal side effects. Although the trials do not show that patients on haloperidol are more likely to drop out through recognized adverse events than patients on risperidone, troublesome extrapyramidal side effects occur in the majority of patients on haloperidol and require treatment with additional anticholinergic medication. Risperidone is associated with greater weight gain than haloperidol, but whether

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this is clinically important in bipolar disorder, as it can be in schizophrenia, remains to be seen. The trials showed that the antimanic effects of both risperidone and haloperidol were independent of whether the patients had psychotic symptoms. Therefore the trials justify the conclusion that these drugs are “antimanic” as well as antipsychotic (Cookson, 2001). Only one of the trials (Khanna et al., 2005) demonstrated a size of effect for risperidone that would be desirable for a first-line monotherapy in mania with NNT of 3 (95% confidence interval 2–4). However, in these studies, the “gold standard” antimanic drug haloperidol had a rather small effect size with NNTs of 5 and 8, perhaps reflecting that the patients taking part in the trials were resistant to treatment, or that inadequate doses of haloperidol were used in the trials. Many patients with mania will require combination treatment with an antipsychotic and lithium or valproate. The trials of such combination therapy with risperidone indicate that for patients who have not responded to two weeks treatment with lithium or valproate, additional treatment with risperidone conveys further efficacy. The NNT for this improvement is rather large (about 5), but the trials include patients who started on the antipsychotic and mood stabilizer at the same time. These trials did not provide evidence to support commencing patients with mania on a combination of antipsychotic with lithium or valproate, if their responsiveness to individual drug treatments is not already known. There is no evidence that treatment for mania with risperidone leads to less post-manic depression than treatment with haloperidol, but this phenomenon has not been fully explored. Further clinical trials are needed to elucidate a role for risperidone beyond the phase of acute mania. Studies, with a more pragmatic or naturalistic design, are needed to establish the role of risperidone in routine clinical practice.

REFERENCES Aubrey, A. M., Simon, A. E. and Bertsky, C. (2000) Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. Journal of Clinical Psychiatry, 61, 649–655. Batchelor, D. H. and Lowe, M. R. (1990) Reported neurotoxicity with the lithium/ haloperidol combination and other neuroleptics – a literature review. Human Psychopharmacology, 5, 275–280. Bowden, C. L., Brugger, A. M., Swann, A. C., et al. (1994) Efficacy of Divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. Journal of the American Medical Association, 271, 918–924. Busch, F. N., Miller, F. T. and Weiden, P. J. (1989) A comparison of two adjunctive treatment strategies in acute mania. Journal of Clinical Psychiatry, 50, 453–455. Chou, J. C., Zito, J. M., Vitrai, J., et al. (1996) Neuroleptics in acute mania: A pharmacoepidemiologic study. Annals of Pharmacotherapy, 30, 1396–1398.

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Coconcea, C, Shelton, M. D., Delgado, P., Amawi, L., and Calabrese, J. R. (2003) Risperidone augmentation in rapid cycling bipolar disorder. Poster presentation: Fifth International Conference on Bipolar Disorder, Pittsburg. Cookson, J. C. (2001) Use of Antipsychotic Drugs and Lithium in Mania. British Journal of Psychiatry, 178, Suppl. 41: s148–s156. Cookson, J. C. and Sachs, G. S. (1999) Lithium: Clinical use in mania & prophylaxis of affective disorders. In: Schizophrenia and Mood Disorders: The New Drug Therapies in Clinical Practice, eds P. F. Buckley and J. L. Waddington, Butterworth-Heinemann, Oxford. Cookson, J. C., Silverstone, T. and Wells, B. (1981) A double-blind comparative clinical trial of pimozide and chlorpromazine in mania: A test of the dopamine hypothesis. Acta Psychiatrica Scandinavica, 64, 381–397. Cookson, J. C., Moult, P. J. A., Wiles, D., et al. (1983) The relationship between prolactin levels and clinical ratings in manic patients treated with oral and intravenous test doses of haloperidol. Psychological Medicine, 13, 279–285. Cookson, J. C., Silverstone, T., Williams, S., et al. (1985) Plasma cortisol levels in mania: Associated clinical ratings and change during treatment with haloperidol. British Journal of Psychiatry, 146, 498–502. Cookson, J. C., Taylor, D., Katona, C. (2002a) Chapter 14. Violence: Assessing Risk And Acute Tranquillisation. In Use of Drugs in Psychiatry: The Evidence From Psychopharmacology, pp. 117–131. Gaskell Press, London. Cookson, J. C., Taylor, D., Katona, C. (2002b) Chapter 5. Placebo Effects, Evaluating Evidence, And Combining Psychotherapy. In Use of Drugs in Psychiatry: The Evidence From Psychopharmacology, pp. 117–131. Gaskell Press, London. Garfinkel, P. E., Stancer, H. C. and Persaud, E. (1980) A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania. Journal of Affective Disorders, 2, 279–288. Hirschfeld, R., Keck, P. E., Karcher, K., Kramer, M., Canuso, C., Eerdekens, M. and Grossman, F. (2004) Rapid antimanic effect of risperidone monotherapy: A 3-week multicenter, double-blind, placebo-controlled trial. American Journal of Psychiatry, 161, 1057–1065. Khanna, S., Vieta, E., Lyons, B., Grossman, F., Eerdekens, M. and Kramer, M. (2005) Risperidone in the treatment of acute mania: Double-blind, placebo-controlled study. British Journal of Psychiatry, 187, 229–234. Kleinberg, D. C., Davis, J. M., De Coster, R. et al. (1999). Prolactin levels and adverse events in patients treated with risperidone. Journal of Clinical Psychopharmacology, 19, 57–61. Lenox, R. H., Newhouse, P. A., Creelman, W. L., et al. (1992) Adjunctive treatment of manic agitation with lorazepam versus haloperidol: A double-blind study. Journal of Clinical Psychiatry, 53, 47–52. Licht, R. W., Bysted, M. and Christensen, H. (2001) Fixed-dose risperidone in mania: an experimental trial. International Clinical Psychopharmacology, 16, 193–110. Littlejohn, R., Leslie, F. and Cookson, J. (1994) Depot antipsychotics in the prophylaxis of bipolar affective disorder. British Journal of Psychiatry, 165, 827–829. Lowe, M. R. and Batchelor, D. H. (1990) Lithium and neuroleptics in the management of manic-depressive psychosis. Human Psychopharmacology, 5, 267–274. Marder, S. R. and Meibach, R. C. (1994) Risperidone in the treatment of schizophrenia. American Journal of Psychiatry, 151, 825–835.

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McGarry, L., Bird, A. P., Thompson, D., Cookson, J., Martin, S. C., and Weinstein, M. C. (2003) Cost-effectiveness of atypical antipsychotics for treatment of acute mania in the UK. Poster 1.203 at European College of Neuropsychopharmacology (ECNP) Meeting, Prague. McIntyre, R. S., Brecher, M., Paulsson, B., Huizar, K. and Mullen, J. (2005) Quetiapine or haloperidol as monotherapy for bipolar mania: A 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. European Neuropsychopharmacology, 15, 573–585. Muller-Oerlinghausen, B., Retzow, A., Henn, F. A., Giedke, H., Walden, J. (2000) Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: A prospective, randomized, double-blind, placebo-controlled, multicentre study. Journal of Clinical Psychopharmacology, 20, 195–203. Peroutka, S. J. and Snyder, S. H. (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency. American Journal of Psychiatry, 137, 1518–1522. Peuskens, J. and the Risperidone Study Group (1995) Risperidone in the treatment of patients with chronic schizophrenia: A multi-national, multi-centre, double-blind, parallelgroup study versus haloperidol. British Journal of Psychiatry, 166, 712–726. Post, R. M., Jimerson, D. C., Bunney, W. F., et al. (1980) Dopamine and mania: Behavioural and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmacology, 67, 297–305. Prien, R. F., Caffey, E. M. and Klett, C. J. (1972) Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Archives of General Psychiatry, 26, 146–153. Rifkin, A., Doddi, S., Karajgi, B., et al. (1994) Dosage of haloperidol for mania. British Journal of Psychiatry, 165, 113–116. Royal College of Psychiatrists (1998) Management of Imminent Violence. Clinical practice guidelines to support mental health services. Occasion paper OP41. London: The Royal College of Psychiatrists. Sachs, G. S., Grossman, F., Ghaemi, S. N., Okamoto, A. and Bowden, C. L. (2002) Combination of a Mood Stabilizer With Risperidone or Haloperidol for Treatment of Acute Mania: A Double-Blind, Placebo-Controlled Comparison of Efficacy and Safety. American Journal Psychiatry, 159, 1146–1154. Segal, J., Berk, M. and Brook, S. (1998) Risperidone compared with both lithium and haloperidol in mania: a double blind randomized controlled trial. Clinical Neuropharmacology, 21, 176–180. Sernyak, M. J. and Woods, S. W. (1998) Chronic neuroleptic use in manic-depressive illness. Psychopharmacology Bulletin, 29, 375–381. Sernyak, M. J., Griffin, R. A., Johnson, R. M., et al. (1994) Neuroleptic exposure following inpatient treatment of acute mania with lithium and neuroleptic. American Journal of Psychiatry, 151, 133–135. Sernyak, M. J., Leslie, D., Alarcon, R. D., Losonczy, M. F. and Rosenheck, R. (2002) Association of Diabetes Mellitus With Use of Atypical Neuroleptics in the Treatment of Schizophrenia. American Journal of Psychiatry, 159, 561–566. Shopsin, B., Gershon, S., Thompson, H., et al. (1975) Psychoactive drugs in mania: a controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. Archives of General Psychiatry, 32, 34–42. Singh, A. N., Golledge, H. and Catalan, J. (1997) Treatment of HIV-related psychotic disorders with risperidone: A series of 21 cases. Journal of Psychosomatic Research, 42, 489–493.

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Smulevich, A. B., Khanna, S., Eerdekens, M., Kramer, M. and Grossman, F. (2005) Acute and continuation risperidone monotherapy in bipolar mania: A 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. European Neuropsychopharmacology, 15, 75–84. Szabadi, E., Gaszner, P. and Bradshaw, C. M. (1981) An investigation of the alphaadrenoceptor blocking properties of neuroleptics in the human iris in vivo. British Journal of Clinical Pharmacology, 11, 416–417. Tohen, M., Zarate, C. A., Centorrino, Hegarty, J. I., Froeschl, M. and Zarate, S. (1996) Risperidone in the treatment of mania. Journal of Clinical Psychiatry, 57, 249–253. Tohen, M., Goldberg, J. F., Gonzalez-Pinto, A. M., Azorin, J. M., Vieta, E., Hardy-Bayle, M. C., Lawson, W. P., Emsley, R. A., Baker, R. W., Risser, R. C., Namjoshi, M. A., Evans, A.R., Breier, A. (2003) A 12-week double-blind comparison of olanzapine versus haloperidol in the treatment of acute mania. Archives of General Psychiatry, 60, 1218–1226. Vieta, E., Gasto, C., Colom, F. et al. (1998) Treatment of refractory rapid cycling bipolar disorder with risperidone. Journal of Clinical Psychopharmacology, 18, 172–174. Vieta, E., Gasto, C., Colom, F., Reinares, M., Martinez-Aran, A., Benabarre, A. and Akiskal, H.S. (2001) Role of risperidone in bipolar-II: An open 6-month study. Journal of Affective Disorders, 67, 213–219. Vieta, E., Herraiz, M., Parramon, G. et al. (2002) Risperidone in the treatment of mania: Efficacy and safety results from a large, multicentre, open study in Spain. Journal of Affective Disorders, 72, 15–19. Yatham, L. N., Grossman, F., Augustyns, I., Vieta, E. and Ravindran, A. (2003) Mood stabilisers plus risperidone or placebo Mood stabilisers plus risperidone or placebo in the treatment of acute mania in the treatment of acute mania: International, double-blind, randomised controlled trial. British Journal of Psychiatry, 182, 141–147.

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CHAPTER

8 A Comparison of “Second Generation Antipsychotics” in the Treatment for Bipolar Disorder: Focus on Clozapine, Quetiapine, Ziprasidone and Aripiprazole Paul E. Keck, Jr. and Susan L. McElroy Department of Psychiatry, University of Cincinnati College of Medicine, USA

INTRODUCTION The term “second generation antipsychotics” in this chapter refers to antipsychotics introduced after the classical neuroleptics. The concept as to what is an “atypical antipsychotic” is not without controversy. As these agents exert more than antipsychotic action for these disorders, the term “antipsychotic” in the rubric of “atypical antipsychotic” has been questioned. These are clearly agents with broad efficacy, and in the absence of better terminology, we are using “second generation atypical antipsychotics” to classify the three agents reviewed in this chapter – beyond the classic neuroleptics – with evidence for clinical utility in bipolar disorders. In the early 1990s, several reports suggested that the prototypical atypical antipsychotic, clozapine, had therapeutic efficacy in patients with treatmentrefractory bipolar disorder (McElroy et al., 1991; Banov et al., 1994; Kimmel et al., 1994; Zarate et al., 1995a,b). In these reports, clozapine appeared to be exerting mood-stabilizing effects with sustained treatment, beyond the unimodal antimanic effects which were commonly observed with typical antipsychotics (neuroleptics). Moreover, favorable responses to clozapine were reported across a spectrum of presentations of bipolar disorder, including in nonpsychotic, Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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mixed and rapid cycling patients (Suppes et al., 1992, 1994). Subsequent reports have continued to suggest that clozapine may be efficacious in patients with treatmentrefractory bipolar disorder (Calabrese et al., 1996; Mahmood et al., 1997; Ciapparelli et al., 2000, 2003; Green et al., 2000). Since these observations, there has been considerable interest in the thymoleptic profiles and potential therapeutic role of subsequently developed atypical or second generation antipsychotics (SGAs) in bipolar disorder (McElroy and Keck, 2000). In addition to these initial observations regarding clozapine’s efficacy, two other lines of evidence supported the examination of SGAs in bipolar disorder: (1) their distinct pharmacological properties predictive thymoleptic activity; and, (2) reports of improvement in mood symptoms in clinical trials of these agents in patients with schizophrenia and schizoaffective disorder (Hillert, Maier and Wetzel, 1992; Keck et al., 1994, 2001; Frye et al., 1998; Muller-Siecheneder et al., 1998; Janicak et al., 2001; Sajatovic et al., 2002). In this chapter, we review the pharmacological mechanisms of SGAs associated with thymoleptic activity and the evidence of their efficacy from randomized, controlled clinical trials in acute bipolar mania, depression, and as maintenance therapy for bipolar disorder. In this chapter, we focus on the last three second generation antipsychotics approved for mania by the FDA, as well as the classical prototype “atypical” clozapine, extensively used in refractory bipolar disorders which has not been submitted for FDA approval for this indication.1

PHARMACOLOGICAL MECHANISMS ASSOCIATED WITH THYMOLEPTIC ACTIVITY ANTIMANIC ACTIVITY In a small number of randomized, controlled trials, all typical antipsychotics exerted antimanic efficacy in addition to their antipsychotic effects (Keck and McElroy, 2003a). Central dopaminergic hyperactivity has long been implicated as a mechanism in mania (Gerner, Post and Bunney, 1976). Thus, typical and SGAs are presumed to exert antimanic effects by their actions, at least in part, as dopamine D2 receptor antagonists. These effects do not distinguish SGAs from typical agents, but rather suggest that both groups of medications should have antimanic activity. Aripiprizole, in contrast, presumably exerts its antimanic efficacy via its partial dopamine D2 receptor agonist activity, diminishing excess dopamine neurotransmission via this mechanism (Keck and McElroy, 2003). A related mechanism has been described for quetiapine: Kapur and Seeman (2001) have proposed the hypothesis that quetiapine, in its fast dissociation from the D2 receptor, 1 Since olanzapine and risperidone are covered extensively elsewhere in this book (see Chapters 7 and 8), the focus of this chapter is on a comparative analysis of the four other second-generation antipsychotics – clozapine, quetiapine, ziprasidone and aripiprazole – Eds.

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exerts a “flexible” antipsychotic action – and possibly, by extension, antimanic action – in that dopamine blockage is dissipated when such action is no longer needed. Thereby, so goes the reasoning, extrapyramidal and hyperprolactinemia are largely avoided.

ANTIDEPRESSANT ACTIVITY Second generation antipsychotics, individually and as a group, differ considerably from typical antipsychotics in their interactions with serotonergic and noradrenergic systems (Frye et al., 1998). All SGAs are antagonists at the 5HT2 receptor, a mechanism associated with antidepressant activity (Aprison, Takahashi and Tachiki, 1978). Ziprasidone and aripiprazole exert partial or full agonist activity at the 5HT1A receptor which may be associated with improvement in depression, anxiety and cognition (Frye et al., 1998; Keck and McElroy, 2003b; Keck et al., 2001a). Ziprasidone is an 5HT1D receptor antagonist; inhibiting this presynaptic autoreceptor increases serotonin release. Ziprasidone and aripiprazole are moderate inhibitors of the serotonin transporter, thereby blocking serotonin reuptake (Keck et al., 2001a; Keck and McElroy, 2003b). In addition, ziprasidone is also a moderate inhibitor of the norepinephrine transporter, blocking norepinephrine reuptake (Keck et al., 2001a). Clozapine and quetiapine are alpha2 adrenergic antagonists, an action that predicts increased presynaptic noradrenergic release (Frye et al., 1998). These various effects on serotonin and norepinephrine receptors and transporters among SGAs predict antidepressant activity lacking in typical antipsychotics.

RANDOMIZED CONTROLLED TRIALS IN ACUTE BIPOLAR MANIA The randomized, controlled trials of four SGAs in acute bipolar mania described below are summarized in Table 8.1 (McElroy and Keck, 2000).

CLOZAPINE Barbini et al. (1997) reported the only randomized, controlled trial of clozapine in acute bipolar mania. This 3-week trial compared clozapine (mean dose 166 mg/ day) with chlorpromazine (mean dose 310 mg/day) in 30 hospitalized patients. Although there were no significant differences in efficacy between the two agents at the study endpoint, patients receiving clozapine displayed significantly greater reductions in manic symptoms (mean YMRS total score) by the second week of the trial, suggesting a possibly more rapid rate of onset despite a relatively low mean dose of clozapine. This study was also not adequately powered to find a significant difference in efficacy at study endpoint.

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Table 8.1: Randomized, controlled trials of Clozapine, Quetiapine, Ziprasidone and Aripiprazole in acute bipolar mania Study Clozapine Barbini et al., 1997 Quetiapine DelBello et al., 2002 Mullen, Devine and Sweitzer 2003a Mullen and Paulsson 2003b Brecher and Huizar 2003 Paulsson, 2003 Ziprasidone Keck et al. 2003a Segal et al. 2003 Weisler, 2003 Aripiprazole Keck et al. 2003b Bourin et al. 2003a Bourin et al. 2003b

Duration (weeks)

N

Mean dose (mg/d)

Results

Response Rates (%)

3

30

Clz 166 Cpz 310

Clz ≥ Cpz

ND

6 3

30 191

Qtp 435 Qtp 580

Qtp > P Qtp > P

Qtp 80; P 50 Qtp 54; P 33

3

402

Qtp 492

Qtp > P

Qtp 56; P 42

12

302

Qtp 559

Qtp > P

Qtp 42; P 34

12

302

Qtp 586

Qtp > P

Qtp 52; P 28

3 3 3

210 202 205

Zpr 133 Zpr 112 ND

Zpr > P Zpr > P Zpr = P

Zpr 50; P 35 Zpr 46; P 29 ND

3 3 12

245 272 347

Ari 28 Ari 28 Ari 22

Ari > P Ari > P Ari = Hal

Ari 40; P 19 Ari 51; P 31 Ari 50; Hal 28

Key: Clz = clozapine; Cpz = chlorpromazine; P = placebo; Qtp = quetiapine; Zpr = ziprasidone; Ari = aripiprazole; ND = no data.

QUETIAPINE Three studies examined the efficacy of quetiapine in combination with lithium or divalproex (DelBello et al., 2002; Mullen, Devine and Sweitzer, 2003a; Mullen and Paulsson, 2003b) and two studies examined quetiapine monotherapy in acute bipolar mania (Paulsson, 2003; Brecher and Huizar, 2003). DelBello et al. (2002) compared the combination of quetiapine and divalproex loading with placebo plus divalproex loading in hospitalized adolescents with bipolar mania. Patients in the combination therapy group displayed significantly greater response rates and mean reductions in YMRS total scores from baseline to endpoint compared with patients in the placebo/divalproex group. Notably, this is the only placebocontrolled, randomized combination drug trial conducted to date in a pediatric group of acutely manic patients. These findings were replicated in two combination therapy trials in adults (Mullen et al., 2003a,b). Jones and Huizar (2003) presented pooled data from the 12-week two placebo-controlled monotherapy trials (Brecher and Huizar, 2003; Paulsson, 2003) and found that quetiapine (mean dose 575 mg/day)

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produced significant reductions in YMRS total scores compared with placebo. Superior efficacy for quetiapine was evident by day 4 of treatment and was sustained through the 12 week trials. Each trial included an active comparator for assay sensitivity, haloperidol (Brecher and Huizar, 2003) and lithium (Paulsson, 2003) respectively. Although these trials were not powered to find significant differences in efficacy between active treatments, quetiapine produced comparable improvement in manic symptoms compared with haloperidol and lithium monotherapy. Common side effects associated with quetiapine in these trials included somnolence, dizziness and modest weight gain.

ZIPRASIDONE In a post hoc analysis of mood symptom improvement in patients with schizoaffective disorder, Keck et al. (2001b) found significant dose-related improvement in BPRS manic items in patients receiving ziprasidone compared with placebo. These initial findings were confirmed in a 3-week, placebo-controlled, monotherapy trial in patients with acute bipolar mania (Keck et al., 2003a). Patients received ziprasidone 80 mg/day on day 1 and 160 mg/day on day 2 with a mean dose of 130 mg/day on days 15–21. The ziprasidone group displayed significantly greater reductions in total MRS scores compared with the placebo group beginning at day 2 and extending through the remainder of the study. Not surprisingly, ziprasidone-treated patients also had significantly greater improvement in measures of psychosis and global ratings compared with patients receiving placebo. Segal et al. (2003) recently reported on the results of a second placebo-controlled trial of ziprasidone in acute bipolar mania. Dose titration proceeded more slowly than in the first trial (80 mg/day on day 1, with adjustment upward by 40 mg/day thereafter). Nevertheless, significant differences in efficacy in favor of ziprasidone were again evident by the end of day 2 and sustained throughout the 3-week trial. Response rates were significantly higher in the ziprasidone group (46%) compared with the placebo group (29%) at the end of three weeks. Weisler (2003) presented the results of a 3-week, placebo-controlled trial of ziprasidone in combination with lithium in acute 205 patients with acute bipolar I mania. Patients receiving ziprasidone in combination with lithium displayed significantly greater reductions in mean total MRS, CGI and HAMD scores at day 4 compared with patients receiving lithium and placebo. Patients in the ziprasidone arm also displayed significantly greater reductions in PANSS total, and PANSS positive and negative subscale scores at day 21. However, there was no significant difference in reduction of MRS total score between the ziprasidone and placebo groups at day 14 or 21, presumably because the therapeutic effect of lithium had become manifest by then. Common side effects associated with ziprasidone in these studies included somnolence, hypertonia, akathisia, headache and GI complaints.

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ARIPIPRAZOLE Three randomized, controlled trials examined the efficacy of aripiprazole in acute bipolar mania (Keck et al., 2003b; Bourin et al., 2003a,b). In the first placebo-controlled monotherapy trial, aripiprazole (mean dose at endpoint 27.9 mg/day) had significantly greater efficacy compared with placebo in reduction of total YMRS scores from baseline to endpoint. The second placebo-controlled monotherapy trial which also utilized an initial starting dose of aripiprazole 30 mg/day yielded comparable findings (Bourin et al., 2003). The third aripiprazole trial was a 12-week direct comparison with haloperidol without a placebo arm (Bourin et al., 2003). Patients in both treatment groups experienced significant reductions in manic symptoms which were sustained out to 12 weeks, although a significant proportion of patients receiving haloperidol dropped out of the trial due to EPS. Common side effects associated with aripiprazole in these studies included somnolence, activation, akathisia and GI complaints.

RANDOMIZED CONTROLLED TRIALS IN ACUTE BIPOLAR DEPRESSION QUETIAPINE To date, of the new SGAs covered in this chapter, only quetiapine has been studied in a randomized controlled trial in bipolar depression (Calabrese et al., 2004). This trial compared quetiapine 300 mg/day, 600 mg/day and placebo in 511 patients with bipolar I (67%) and bipolar II (33%) depression in an 8-week acute treatment study. Both quetiapine groups had significantly greater reductions in mean total MADRS scores from baseline to endpoint, beginning at week 1. There were no significant differences among the three groups in switch rates. The effect size for the quetiapine groups were large: 0.75 for 600 mg/day and 0.64 for 300 mg/day. Quetiapine-treated patients displayed significantly greater improvement in all but one item (increased appetite) of the MADRS compared with patients receiving placebo. In addition, both quetiapine groups had significantly greater improvement in mean total reductions in HAMD and HAMA scores, and significantly greater improvement in sleep quality and quality-of-life measures.

RANDOMIZED CONTROLLED LONG-TERM TREATMENT TRIALS As far as maintenance treatment for bipolar disorder is concerned, there are only two randomized, controlled trials of the new SGAs covered in this chapter.

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CLOZAPINE Suppes et al. (1999) compared clozapine with treatment as usual (TAU) in a 1-year open-label randomized of 38 patients with bipolar disorder or schizoaffective disorder, bipolar type with treatment-refractory mania. Patients receiving clozapine had significantly greater improvement on measures of positive and negative symptoms of psychosis, overall functioning and use of adjunctive medications compared with patients receiving TAU. Consistent with reports of clozapine’s efficacy in acute mania, clozapine was equally efficacious in patients with and without psychotic symptoms in this trial.

ARIPIPRAZOLE Marcus et al. (2003) reported the results of a 26-week, double-blind maintenance study of aripiprazole in 161 patients with bipolar I disorder. Patients were initially stabilized on aripiprazole 15–30 mg/day for 6–18 weeks, then randomized to aripiprazole or placebo. Time to relapse of mood symptoms was significantly longer in patients receiving aripiprazole compared with placebo. The total number of mood episodes relapses in the aripiprazole group was also significantly lower.

SUMMARY Establishing the efficacy of an agent as a mood-stabilizer usually begins with trials demonstrating antimanic effects (Keck et al., 2002). Randomized, controlled trials of SGAs have yielded convincing evidence of efficacy for these agents in the treatment for acute bipolar mania, as monotherapy and in combination with lithium or divalproex. This is true for olanzapine and risperidone (covered in Chapters 7 and 8 in this book) as well as the new SGAs quetiapine, ziprasidone and aripiprazole covered in this chapter. These agents had a rapid onset of action, efficacy in psychotic and non-psychotic patients, and where data were available, efficacy in mixed and manic, as well as rapid and non-rapid cycling patients. In combination therapy trials, combination therapy produced consistently greater and more rapid response rates compared with monotherapy with lithium or divalproex. Thus, the efficacy of SGAs in the treatment for acute bipolar mania, alone or as components of combination therapy is well established. These agents generally have superior tolerability (lower rates of EPS and risk of depressive symptom exacerbation) over typical antipsychotics. The side effect profile, among the four SGAs covered in this chapter, varies among different agents, with weight gain occurring in a significant proportion of patients receiving clozapine and, to a lesser extent, quetiapine. EPS risk appears to be least with clozapine and quetiapine. Prolactin elevation is not a clinically significant side effect with any of these agents. The effects of ziprasidone on QTc prolongation appear to be of concern

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primarily in patients with a family history of sudden death, cardiac disease, electrolyte disturbances and when co-administered with other agents that themselves have significant QTc prolonging effects. GI disturbances appear most commonly with ziprasidone and aripiprazole. Demonstration of true mood-stabilizing effects also requires evidence of antidepressant and maintenance efficacy in bipolar disorder. To date, among the new SGAs covered in this chapter, only quetiapine has demonstrated efficacy in the treatment for acute bipolar depression; only aripiprazole has efficacy data from one randomized, controlled discontinuation 6-month trial. Further studies of other second generation antipsychotics in acute bipolar depression and as maintenance treatment are needed to clarify their efficacy beyond their use in acute bipolar mania.2

REFERENCES Aprison MH, Takahashi R, Tachiki K (1978) Hypersensitive serotonergic receptors involved in clinical depression—a theory. In Neuropharmacology and Behavior, Haber B, Aprison MH (eds), Plenum, New York, pp. 23–48. Banov MD, Zarate CA, Tohen M, Scialabba D, Wines JD, Kolbrener M, Kim JW, Cole JO (1994) Clozapine therapy in refractory affective disorders: Polarity predicts response in long-term follow-up. J Clin Psychiatry, 55, 295–300. Barbini B, Scherillo P, Benedetti F, Crespi B, Colombo C, Smeraldi E (1997) Response to clozapine in acute mania is more rapid than that of chlorpromazine. Int Clin Psychopharmacol, 12, 109–112. Bourin M, Auby P, Marcus RN, Swanik R, McQuade RD, Iwamoto T, Sanchez R (2003) Aripiprazole versus haloperidol for maintained treatment effect of acute mania. American Psychiatric Association Annual Meeting, San Francisco, CA, May 17–22. Brecher M, Huizar K (2003) Quetiapine monotherapy for acute mania associated with bipolar disorder. Fifth International Conference on Bipolar Disorder, Pittsburgh, PA, June 12–14. Calabrese JR, Kimmel SE, Woyshville MJ, Rapport DJ, Faust CJ, Thompson PA, Meltzer HY (1996) Clozapine for treatment-refractory mania. Am J Psychiatry, 153, 759–764. Calabrese JR, Macfadden W, McCoy R, Minkwitz M, Wilson E, Mullen J (2004) Doubleblind, placebo-controlled study of quetiapine in bipolar depression. Abstracts of the American Psychiatric Association Annual Meeting, New York, NY, May 5, NR 756. Ciapparelli A, Dell’Osso L, Pini S, Chiavacci MC, Fenzi M, Cassano GB (2000) Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: A 24-month naturalistic study. J Clin Psychiatry, 61, 329–334. Ciapparelli A, Dell’Osso L, Bandettini di Poggio A, Carmassi C, Cecconi C, Fenzi M, Chiavacci MC, Bottai M, Ramaciotti CE, Cassano GB (2003) Clozapine in treatmentresistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: A naturalistic 48-month follow-up study. J Clin Psychiatry, 64, 451–458. DelBello MP, Schwiers ML, Rosenberg HL, Strakowski SM (2002) A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry, 41, 1216–1223. 2

Further details on this important clinical topic are covered in Chapters 7, 8, 10 and 12 – Eds.

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Frye MA, Ketter TA, Altshuler LL, Denicoff K, Dunn RT, Kimbrell TA, Cora-Locatelli G, Post RM (1998) Clozapine in bipolar disorder: Treatment implications for other atypical antipsychtoics. J Affect Disord, 48, 91–104. Gerner RH, Post RM, Bunney WE (1976) A dopaminergic mechanism in mania. Am J Psychiatry, 133, 1177–1180. Green AI, Tohen M, Patel JK, Banov M, DuRand C, Berman I, Chang H, Zarate C, Posener J, Lee H, Dawson R, Richards C, Cole JO, Schatzberg AF (2000) Clozapine in the treatment of refractory psychotic mania. Am J Psychiatry, 157, 982–986. Hillert A, Maier W, Wetzel H (1992). Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome—a functional approach. Pharmacopsychiatry 25, 213–217. Janicak PG, Keck PE, Jr, Davis JM, Kasckow JW, Tugrul KC, Dowd SM, Strong J, Sharma RP, Strakowski SM (2001). A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder. J Clin Psychopharmacol 21, 360–368. Jones M, Huizar K (2003) Quetiapine monotherapy for mania associated with bipolar disorder. Fifth International Conference on Bipolar Disorder, Pittsburgh, PA, June 12–14. Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: A new hypothesis. Am J Psychiatry, 158, 360–369. Keck PE, Jr., McElroy SL (2003a) Redefining mood stabilization. J Affect Disord 73, 163–169. Keck PE, Jr., McElroy SL (2003b) Aripiprazole: A partial dopamine D2 receptor agonist antipsychotic. Expert Opin Investig Drugs 12, 655–662. Keck PE, Jr, Wilson DR, Strakowski SM (1994). Clinical predictors of acute risperidone response in schizophrenia, schizoaffective disorder, and psychotic mood disorders. J Clin Psychiatry, 56, 466–470. Keck PE, Jr., McElroy SL, Arnold LM (2001a) Ziprasidone: A new atypical antipsychotic. Expert Opin Pharmacother 2, 1033–1042. Keck PE, Jr., McElroy SL, Strakowski SM, West SA (1994) Pharmacologic treatment of schizoaffective disorder. Psychopharmacology, 114, 529–538. Keck PE, Jr., McElroy SL, Richtand N, Tohen M (2002) What makes a drug a primary mood stabilizer? Mol Psychiatry, 7 (Suppl.), s8–s14. Keck PE, Jr., Nelson EB, McElroy SL (2003) Advances in the pharmacologic treatment of bipolar depression. Biol Psychiatry 53, 671–679. Keck PE, Jr., Reeves KR, Harrigan EP, and the Ziprasidone Study Group (2001b) Ziprasidone in the short-term treatment of patients with schizoaffective disorder: Results from two double-blind, placebo-controlled trials. J Clin Psychopharmacol, 21, 27–35. Keck PE, Jr., Versiana M, Potkin S, West SA, Giller E, Ice K (2003a) Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry, 160, 741–748. Keck PE, Jr., Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G, and the Aripiprazole Study Group (2003b) Am J Psychiatry, 160, 1651–1658. Kimmel SE, Calabrese JR, Woyshville MJ, Meltzer HY (1994) Clozapine in treatmentrefractory mood disorders. J Clin Psychiatry, 55 (Suppl. B), 91–93. Mahmood T, Devlin M, Silverstone T (1997) Clozapine in the management of bipolar and schizoaffective manic episodes resistant to standard treatment. Aust N Z J Psychiatry, 31, 424–426. Marcus R, Carson WE, McQuade RD, Sanchez R, Iwamoto T, Stock E (2003) Long-term efficacy of aripiprazole in the maintenance treatment of bipolar disorder. Abstracts of

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the Annual Meeting of the American College of Neuropsychopharmacology, San Juan, PR, December 8–11. McElroy SL, Keck PE, Jr. (2000) Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry, 48, 539–557. McElroy SL, Dessain EC, Pope HG, Jr., Cole JO, Keck PE, Jr., Frankenberg FR, Aizely HG, O’Brien S (1991) Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry, 52, 411–414. Mullen JA, Devine NA, Sweitzer DE (2003a) Quetiapine adjunctive therapy for mania associated with bipolar disorder. Fifth International Conference on Bipolar Disorder, Pittsburgh, PA, June 12–14. Mullen JA, Paulsson B (2003b) Quetiapine in combination with lithium or divalproex for the treatment of mania associated with bipolar disorder. Fifth International Conference on Bipolar Disorder, Pittsburgh, PA, June 12–14. Muller-Siecheneder F, Muller FJ, Hillert A (1998). Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. J Clin Psychopharmacol 18, 111–120. Paulsson B (2003) Quetiapine monotherapy for the treatment of bipolar mania. Fifth International Conference on Bipolar Disorder, Pittsburgh, PA, June 12–14. Sajatovic M, Mullen JA, Sweitzer DE (2002) Efficacy of quetiapine and risperidone against depressive symptoms in outpatients with psychosis. J Clin Psychiatry, 63, 1156–1163. Segal S, Reisenberg RA, Ice K, English P (2003) Ziprasidone in mania: A double-blind, placebo-controlled trial. Abstracts of the Annual Meeting of the American College of Neuropsychopharmacolgy, San Juan, Puerto Rico, December 8–11. Suppes T, McElroy SL, Gilbert J, Dessain EC, Cole JO (1992) Clozapine in the treatment of dysphoric mania. Biol Psychiatry, 32, 270–280. Suppes T, Phillips KA, Judd CR (1994) Clozapine treatment of nonpsychotic rapid cycling bipolar disorder: a report of three cases. Biol Psychiatry, 36, 338–340. Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ (1999) Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatmentresistant illness and a history of mania. Am J Psychiatry, 156, 1164–1169. Weisler RH Ziprasidone versus placebo in combination with lithium in acute mania. Abstracts of the European College of Neuropsychopharmacology Annual Meeting, September 2003. Zarate CA, Tohen M, Baldessarini RJ (1995a) Clozapine in severe mood disorders. J Clin Psychiatry, 56, 411–417. Zarate CA, Tohen M, Banov MD, Weiss MK, Cole JO (1995b) Is clozapine a mood stabilizer? J Clin Psychiatry, 56, 108–112.

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CHAPTER

9 Complex Combination Therapy: The Evolution Toward Rational Polypharmacy in Lithium-Resistant Bipolar Illness Robert M. Post, Andrew M. Speer and Gabriele S. Leverich Biological Psychiatry Branch, National Institute of Mental Health, NIH, DHHS, Bethesda, MD, USA

INTRODUCTION: PREVALENCE AND RATIONALES Twenty to thirty years ago, bipolar patients were treated largely with lithium carbonate as augmented by antidepressants, benzodiazepines and antipsychotic agents as necessary. This often complex, rapidly changing treatment was still called “monotherapy” because lithium was the basic component of the regimen and the only accepted mood stabilizer. However, this pattern has changed dramatically in the last 30 years in many academic outpatient clinics and private practice settings, wherein not only combination therapy of the type noted above, but also complex combination therapy (two or more mood stabilizers plus adjuncts), appears to be the norm in the treatment of bipolar illness. Much of this change has been accounted for by the availability of a host of new anticonvulsants, atypical antipsychotics, antidepressants and other adjunctive modalities (Table 9.1), and the recently recognized goal of attempting to treat patients to remission rather than just symptomatic improvement.

POLYTHERAPY FOR INPATIENTS An example of this change in treatment patterns is the number of medications that were required for acute mood stabilization at discharge from the National Institute of Mental Health (NIMH) following completion of formal controlled clinical trials and protocols (Frye et al., 2000). Despite the fact that patients were often admitted with lithium-refractory bipolar illness and antidepressant-refractory Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

MAOIs

tertiary tricyclics

VNS

T3, TRH, Supraphysiological T4 St. Johns Wart, O-3-Fatty Acids, cognitive/behavioral psychoeducational

rTMS

(gabapentin)

Folate

MST

valproate lamotrigine (oxcarbazepine)

RIMAs SNRIs bupropion

sleep deprivation, light therapy

buspirone

carbamazepine valpromide

SSRIs

2000s

olanzapine ziprasidone risperidone quetiapine aripiprazole

1990s

MAOIs, monoamine oxidase inhibitors; SSRIs, Serotonin-Selective reuptake inhibitors; SNRIS, Serotonin-norepinephrine reuptake inhibitors; RIMAs, reversible inhibitors of monoamine oxidase A; rTMS, repetitive transcranial magnetic stimulation; VNS, Vagus nerve stimulation; MST, magnetic seizure therapy; T4, levothyroxine; T3, triiodothyronine; TRH, thyrotropin-releasing hormone; 0–3, Omega-3; SAMe, S-adenoslmethionine; ECT, electroconvulsive therapy; PTZ, pentylene tetrazol

T4, SAMe, interpersonal

acupuncture

benzodiazepines

lithium

secondary tricyclics

clozapine

chlorpromazine haloperidol (phenothiazines) (butyrophenones) (thiothixenes)

Minor Tranquilizers bromides barbituates Physiological Approaches insulin/PTZ seizures ECT (bilat. → unilat.) Adjuncts Thyroid: extract, Others: Psychotherapy: analytic, dynamic

Mood Stabilizers

Antidepressants

reserpine

1980s atypicals

1970s

typicals

1960s

Antipsychotics/antimanics

1950s

Table 9.1: Evolution of 50 years of psychopharmacology of bipolar illness

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unipolar illness, patients were often discharged on monotherapy or close to monotherapy regimens in the 1970s. However, by the late 1990s, patients were discharged on an average of 3.3 medications and, in the most recent iterations, four or more medications. This greater number of medications (Figure 9.1) was required to achieve approximately the same 75–80% acute response rate upon discharge across all of the epochs. To explore some of the reasons for the increase in medications required upon NIMH discharge, we examined a variety of demographic variables (Frye et al., 2000). We found that there was an inverse relationship between a later date of discharge from the hospital and an earlier age of onset of affective illness (Figure 9.2; r = −0.30; n = 160; p < 0.001), an increased amount of total time depressed prior to NIMH admission, and a markedly higher incidence of rapid cyclers (those with four or more episodes per year) in those admitted for study and treatment. The same screening procedures had remained in place over the three decades, such that patients with major personality disorders or medical or substance abuse comorbidity were excluded from clinical trials. Nevertheless, it was unclear whether this reflected a general trend in the population or whether patients were more recently being more vigorously treated in the community and a more select subgroup of highly treatment-refractory patients was being referred to the NIMH. The former is likely as Lange and McInnis (2002) have documented the existence of both a year of birth, or cohort effect (decreasing age of onset) and a generational, or anticipation effect (increase in disease severity) present in most studies of bipolar illness. These population trends could be related to the general observations of earlier onset and greater treatment resistance in the community.

Number of medications

6 5

r = 0.45 p < 0.0001 N = 178

4 3 2 1

BP UP

0 1971

1976

1981

1986

1991

1996

Discharge date

Figure 9.1: Increasing polypharmacotherapy in more recent NIMH discharges. Line in middle of figure represents the mean

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Age at first symptom

60 50 40 30 20 BP UP

10 0 1971

1976

1981

1986

1991

1996

Discharge date

Figure 9.2: Earlier onset of symptoms in more recent NIMH cohorts. Line in middle of figure represents the mean

POLYTHERAPY IN OUTPATIENTS In a number of other clinics in Pittsburgh (Levine et al., 2000; Kupfer et al., 2002), New York (Goldberg, Harrow and Sands, 1996a), London (Frangou, Raymont and Bettany, 2002), Los Angeles (Gitlin et al., 1995), in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) program (Sachs et al., 2003) and at many centers across the U.S. and abroad, there is a similar trend for use of multiple medication strategies simultaneously in the treatment of outpatients with bipolar illness. We also observed this necessity in the Stanley Foundation Bipolar Network (SFBN) where 258 outpatients followed prospectively for one year were treated with an average of 4.1 medications (Post et al., 2003a). In a larger series of 539 patients, those without rapid cycling patterns (n = 333) were treated with 3.5 ± 1.8 different categories or classes of drugs, whereas the 38% of patients with rapid cycling presentations (n = 206) were treated with an average of 4.6 ± 1.8 (p < 0.01) different classes of medications (Kupka et al., 2005). Thus, while lithium monotherapy was initially touted as effective in 60–80% of bipolar patients, this high rate often included highly selected patients meeting clinical trials criteria for purer and more uncomplicated forms of the illness (Baldessarini and Tondo, 2000). Primary lithium therapy (i.e., even as supplemented by antidepressants, anxiolytics and antipsychotics) is increasingly recognized as less than optimal (Bowden, 1995; Aagaard and Vestergaard, 1990) for many patients with specific bipolar subtypes, common comorbidities, demographics, and illness course characteristics, as outlined in Table 9.2. These correlates of relatively poor response are not inconsequential, because rapid cyclers comprise 38% of our SFBN prospectively confirmed outpatient sample (Kupka et al., 2005) and 40–42% have a substance

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Table 9.2: Correlates of relative lithium non-responsiveness Factors Episode Characteristics 1. Rapid or Faster Cycling 2. Episode Contiguity 3. Sequence Pattern 4. Number of Episodes Prior to Starting Prophylaxis 5. Quality of Mania 6. Insight/Compliance Comorbidities 7. History (Hx) of Substance Abuse 8. Hx of Anxiety Disorder Genetic Background 9. Family History of Anxiety Disorder 10. Family Hx of Bipolar Illness and Especially Lithium Response

Good Response Rates Low Response Rates (About 60–80%) (About 20–40%)

Strength of Evidence

No Intermittent, i.e., with a well interval (I) Mania |Depression |I M-D-I 3 or fewer

Yes Continuous, i.e., no well interval (I) Depression |Mania |I D-M-I 4–10 or more

+++ (12) +

Euphoric Good

Dysphoric Poor

+++ (4) +

Negative

Positive

+

Negative

Positive

++

Negative

Positive

++

Positive

Negative

+++

+++ (4) +++ (9)

+, Reported by several clinician observers ++, Reported in several studies +++, Well-documented (# = approximate number of supportive studies in literature)

abuse or anxiety disorder comorbidity (Suppes et al., 2001; McElroy et al., 2001). The number of episodes prior to starting lithium is also a risk factor for poor lithium response in most (Table 9.3), but not all (Baldessarini and Tondo, 2000), studies. Table 9.3: More episodes prior to starting lithium is associated with poor prophylactic response Investigator

Correlates of Poor Response to Lithium

Prien, Caffey and Klett (1974) Sarantidis and Waters (1981) Abou-Saleh and Coppen (1986) Gelenberg et al. (1989) O’Connell et al. (1991) Goldberg et al. (1996b) Denicoff et al. (1997a) Maj et al. (1998) Swann et al. (1999) Frye et al. (2003)

↑ # of hospitalizations ↑ episodes/year ↑ episodes >3 prior episodes ≥3.8 mean episodes ≥2 prior hospitalizations ≥2 prior hospitalizations for mania ≥7.2 mean episodes ≥10 prior episodes ≥3 prior episodes (Li or LTG)

Li – Lithium; LTG – Lamotrigine

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POLYTHERAPY IN PEDIATRIC BIPOLAR ILLNESS Polytherapy is also typical in the management of childhood and adolescent bipolar illness. Biederman etal. (1998), in an academic center, noted a high incidence of the use of mood stabilizers, antipsychotics, antidepressants and psychomotor stimulants. Likewise, in the Child and Adolescent Bipolar Foundation (CABF) of Hellander and associates, multimodal pharmacotherapy is the norm (Hellander, 2003). In one retrospective chart review, 78% of children with early onset bipolar illness (average study age 9.6 ± 3.5 years) required combination drug therapy just to achieve a measure of symptomatic control, i.e., 50% improvement (Tramontina et al., 2003). In another retrospective chart review of risperidone effectiveness in juvenile mania, 96% of children were on other medications (Frazier et al., 1999). A more systematic study of the need for combination treatment in pediatric bipolar patients was done by Kowatch et al. (2000). After a 6–8-week randomization to monotherapy with valproate, lithium or carbamazepine for mania (Kowatch et al., 2000), an open extension phase of 16 weeks was performed in 35 bipolar patients (mean age 11-years old) (Kowatch et al., 2003). As summarized in Table 9.4, response rates to initial monotherapy treatment ranged from about

Table 9.4: Response to mood stabilizers in pediatric mania

Acute Phase (n = 42; 6–8 weeks) Effect Size (Cohen’s d) CGI (Score of 1 or 2) YMRS (50% improvement) Extension Phase (n = 35; 16 weeks) 1. Acute responders (n = 18) who required 2nd mood stabilizer 2. Acute non-responders (n = 17) responded to Persistent nonresponders despite

Divalproex (VPA)

Lithium (Li)

Carbamazepine (CBZ)

1.63 40%

1.06 46%

1.00 31%

53%

38%

38%

2/8

3/6

0/4

3/5 + Li 2/5 + RIS (VPA + Li)

4/5+VPA 2/2 changed to VPA 1/5 changed to VPA (Li + VPA + RIS) (VPA, VPA + Li, VPA + Li + RIS)

RIS – risperidone; CGI – Clinical Global Impression; YMRS – Young Mania Rating Scale Source: Kowatch et al. (2000, 2003).

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30–50%. Dual combination therapy was required in 58%, with a triple combination in 51%, consisting of two mood stabilizers and either a stimulant (34%), an antipsychotic (11%) or an antidepressant (6%). Expert consensus suggests that initial treatment of bipolar I, II and not otherwise specified (NOS) children with antidepressant or stimulant monotherapy is usually unsuccessful and may exacerbate the course of illness (Kowatch et al., 2005). Mood stabilizers (lithium and the anticonvulsants valproate, carbamazepine and oxcarbazepine) and atypical antipsychotics are widely used as first-line treatment with small doses of stimulants added adjunctively for residual attention-deficit hyperactivity disorder (ADHD) symptoms. Here it would appear that the sequence of treatment additions is important to a successful outcome (Kowatch et al., 2003). The lack of controlled trials and algorithms to develop systematic strategies for polytherapy is even more problematic in children than adults as the first controlled studies of monotherapy are just beginning to be performed and reported in this population. Given that many children will need complex combination therapy to achieve and maintain remission, such studies should be given very high priority. In one of the few formal combination studies, DelBello et al. (2002) found the combination of divalproex and quetiapine more effective in the treatment for adolescent mania than divalproex alone (i.e., divalproex plus placebo).

THE INADEQUACY OF TWO MOOD STABILIZERS IN COMBINATION IN SYSTEMATIC STUDIES In the studies of Denicoff and colleagues (1997a,b), relatively low response rates were observed in outpatients with bipolar illness who were treated on a double-blind basis with either lithium or carbamazepine monotherapy in the first year of study, were crossed over to the other agent in the second year, and then placed on the combination of both drugs in the third year. Open augmentation with benzodiazepines, antidepressants and antipsychotics was allowed as necessary. Despite this liberal use of rescue medicines, there was a response rate of 41.2% to lithium and 53.8% to carbamazepine. In the rapid cycling subgroup, only 28% responded to lithium, 19% to carbamazepine, but 56% of patients responded in the third year to these two agents in combination. When a fourth year on lithium and valproate was offered to nonresponders, and then a fifth year on triple combination therapy with lithium, carbamazepine and valproate (Denicoff et al., 1997b), 37% of the original cohort still had failed to have an overall much improved year on any of the five pharmacological regimens, indicating a high degree of treatment-resistance.

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The data of Calabrese et al. (2003a) for lithium and valproate are even more striking. They intended to treat a cohort of 272 rapid cycling patients to remission on the combination of lithium and valproate and then randomize individuals to either monotherapy. Surprisingly, only 24% of the 211 patients treated for four weeks and 18% of the intent-to-treat sample was sufficiently well on the combination of lithium and valproate in order to be randomized. Thus, in this highly prevalent subtype of bipolar illness, 75–80% of the outpatients failed to respond adequately to two of the best drugs for bipolar illness (lithium and valproate). Even though it may be reasonably argued that these studies are examining patients with a high degree of treatment resistance, and a form of the illness (rapid cycling) that in itself is relatively treatment resistant, it nonetheless appears that a very large segment of the bipolar population is poorly responsive to regimens of lithium plus either of two well-established mood stabilizing anticonvulsants, carbamazepine or valproate.

DEPRESSION AND CORRELATES OF POOR RESPONSE TO NATURALISTIC POLYTHERAPY In our entire cohort of patients in the SFBN, a high degree of treatment-resistance was also observed with patients remaining mildly to moderately depressed approximately 30% of the days of the year, which was three times greater an amount of time than days hypomanic or manic (Post et al., 2003a; Nolen et al., 2004; Kupka et al., 2005); these data parallel those of Judd et al. (2002). Thus, based on these large studies, the depressive phase of the illness is relatively more treatment-resistant than mania. In the SFBN study, this imbalance occurred in patients despite the use of a wide range of mood stabilizers (97%), typical (17%) and atypical antipsychotics (21%), benzodiazepines (49%), antidepressants (53%) and thyroid hormone supplementation (32%) (Figure 9.3). The recently approved anticonvulsant for prophylaxis, lamotrigine, was being used on an “as needed” basis as well. Correlates of poor response to this intensive naturalistic pharmacotherapy included adversity in childhood (physical and/or sexual abuse), earlier age of onset of illness, a prior history of a greater number of episodes and a prior history of rapid cycling (Nolen et al., 2004). In a subgroup of patients followed on a daily basis on the NIMH-Life Chart Method (LCM) for up to five years, there was a gradual reduction in the percentage of patients displaying rapid cycling from 38% in the first year of follow-up to 20.2% in the fifth year. However, a prior history of a greater number of episodes and current rapid cycling appeared to convey a relatively

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60 20.93% 50

18.22% 17.05%

Number of patients

40 12.02% 12.02% 30

20

6.59%

6.59%

3.10%

10

1.94% 0.78%

0.78% 0 0

1

2

3

4

5

6

7

8

9

10

Total number of medications

Figure 9.3: Average number of medications in 258 bipolar outpatients followed prospectively for one year

poor prognosis for shifting and staying out of the rapidly recurrent phase of the illness (Kupka et al., 2005). As noted above, rapid cyclers were treated with a significantly greater number of medications compared with those patients with nonrapid cycling presentations. These data obviously have two very different interpretations. The more likely one is that these patients with more treatment-refractory presentations were being treated more aggressively in an effort to decrease the morbidity of recurrent episodes. However, it is also possible that some of the multiple medications used (such as antidepressants in slightly more than 50% of the subjects) could have contributed to the mood destabilization. Arguing against this latter proposition are the clinical observations that with the right mix of a sufficient number of medications, a substantial group of otherwise severely ill patients with rapid recurrences will enter a remission (Frye et al., 2000; Figures 9.4 and 9.5). The vexing question as to what is “the right mix” of medications for the different illness presentations remains to be answered.

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Figure 9.4: Life chart showing response to combination therapy in a refractory bipolar patient. Bottom shows exploded view of response to five medications (T3, T4, valproic acid, bupropion and lithium) leading to remission of episodes and beginning of a persisting remission for 14 years

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MOOD STABILIZATION WITH COMPLEX COMBINATION THERAPY: 7 Medication Classes 1.5 0.5

0.5 mg/prn O

1

0.5

0.5 mg

1

0.25 1 1 0.75 O OO O O O O O O O O 1.25

0.5 0.25 OOOOO OOOOOOOO

0.5 O

0.25

0.25

0.5

5 mg

CLONAZEPAM

O O O O O O O O O O O O O O O O O O O O OO O O O OO O O O O OO O 0.5

2.5 5

2.5 Blind 50 mg

OLANZAPINE

0.25

3a 100

5 2.5 5

7.5

5 6000 mg 3000 OOOOOOOOO 5 OM3 BLIND MED 6000 OO O O O O OO O O O O OM3 OPEN

50

SERTRALINE vs. 75 mg

4800 mg

4800 900 2400

3600

2100 4500 2700 1800

150

75

1 dose O OMEGA-3

BUPROPION HCL 2400 1800

1500

25 mcg

600 2100 1200

4

Severe

2

High Moderate

25 mg 200

225 250

275

300

325 75

T TTTTTTTTT 3

CYTOMEL

GGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGG

GABAPENTIN

20 mg 30 OOOOO CITALOPRAM

100

75 50

LAMOTRIGINE GABAPENTIN D/C

Low Moderate Mild

Mild Low Moderate High Moderate

YEARLY

Severe

1997

1998

7 5 mg

2.5

5

1999

2000

CHOLINESTERASE INHIBITOR 5 mg 7.5 10 O O OO O O O O OO O O O O OO O O OO O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O OO O O O O OO O O O O OO O O O OO O O O

Donezepil

ATYPICAL

LAMOTRIGINE 50 mcg

THYROID

37.5

T TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT 3

CYTOMEL Severe

6

High Moderate

7

2.5

OLANZAPINE ANTIDEPRESSANT 30 mg 40 O O O O O O O O OO O O O OO O O O O OO O O O O OO O O O OO O O O O O O O O O O O O O O O O O O O O O O O O O O OO O O O O O O O O O O O O O O O O O O O O O OO O O O O OO O O O O OO O O O OO O O O O OO O O O O OO O O O O O O O O O CITALOPRAM ATYPICAL 20 mg 40 60 5 mg 0.125 mg O O O O O O O O O O O O O O O O O O O O O O O O O OO OO 3b ZIPRASIDONE PROCARDIA DIGOXIN BENZODIAZEPINE 0.25 mg KLONOPIN ANTICONVULSANT 50 mg

TTTTTTTTTTTTTTTTTTTTT

STIMULANT 5 mg 12.5 15 12.5 15 5 O OO O O O O OO O O O O O O O O O O O O O O O O O O O O O O O O OO O O O O O O O O O O O O O O O O O O O O O O O OO O O O O OO O O O O OO O O O OO O O O O OO O O O O O O O O O O O O O Dextroamphetamine

5 3 1 2 4 6

Low Moderate Mild

Mild Low Moderate High Moderate Severe

12-00

MONTHLY 1-01

2-01

3-01

4-01

5-01

6-01

7-01

8-01

9-01

10-01

11-01

12-01

Figure 9.5: Based on the retrospective life chart, this patient was not responsive to lithium, valproate, carbamazepine, sertraline, fluoxetine, venlfaxine, nefazodone, clonazepam and gabapentin. The patient, as seen in the life chart, was eventually responsive to the combination of: (a) clonazepam, a high-potency benzodiazepine, for sleep, anxiety and agitation symptoms; (b) lamotrigine, an anticonvulsant, for bipolar II ultra-rapid cycling and depression; (c) olanzapine, an atypical antipsychotic, for breakthrough recurrent brief hypomanias (RBHs) and ultra-rapid cycling; (d) ziprasidone, another atypical antipsychotic, with better tolerability and no weight gain; (e) triiodothyronine (T3), a thyroid hormone, as antidepressant augmentation; (f) citalopram, an antidepressant, for residual chronic depression; (g) dextroamphetamine, a psychomotor stimulant, for residual fatigue and anergia; and (h) donepezil, an acetylcholine esterase inhibitor, because of a lack of cognitive clarity. The “off” response (i.e., exacerbation of depression) upon gabapentin discontinuation in 1997 (at the dotted arrow) in retrospect suggests that gabapentin may have had a partial helpful role in preventing more severe depressions. This evidence was overlooked in the elimination of gabapentin from the regimen. An earlier antidepressant trial in late 1998 (sertraline vs bupropion) prior to addition of the atypical olanzapine resulted in re-emergence of ultra-rapid cycling

CASE EXAMPLES OF RESPONSE TO COMPLEX COMBINATION THERAPY COMPLETE RESPONSE ON FIVE DRUGS The patient’s illness and treatment course illustrated in Figure 9.4 are not unusual in the subgroup of patients requiring moderately complex combination

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therapy to achieve a more complete therapeutic response, if not a complete remission (as observed in this instance). This patient’s life chart represents the course of illness in a 30-year-old female who continuously cycled into 2–3-month periods of profound depression with psychomotor retardation, complete incapacitation including inability to perform any of the usual activities of daily living activities, a subjective sense of profound memory loss, notable speech latency, and extreme degrees of suicidal ideation alternating with brief periods of either euphoric or dysphoric (and dysfunctional) hypomania for about eight years. These incapacitating cycles of depression were not responsive to traditional antidepressants, monoamine oxidase inhibitors (MAOIs), mood stabilizers such as lithium and carbamazepine (both alone and in combination with thyroid augmentation), and benzodiazepines. Several initial periods of partial response to carbamazepine, particularly for depression, eventually resulted in loss of efficacy and resumption of severe mood cycling. At the NIMH (see insert at bottom of Figure 9.4) this patient underwent sequential double-blind clinical trials in which placebo was replaced first by nimodipine (360 mg/day, peak dose) without therapeutic success (Pazzaglia et al., 1993, 1998). The patient subjectively reported improvement in her memory, however. She was maintained on both T4 and T3 in light of her history of thyroiditis and abnormal thyroid indices and initial case reports of better response to the combination than to T4 alone by Cooke, Joffe and Levitt (1992), and the subsequent systematic study of Bunevicius et al. (1999). Treatment with valproate resulted in attenuation of only her manic episodes, and the addition of carbamazepine was without effect on her next depression. Bupropion treatment appeared to have a partial effect on her depression, but it was not until lithium was added to the four other agents (T3, T4, valproate and bupropion) that the patient began to show marked attenuation of her depressive episodes, and then stopped cycling altogether. The effect of the addition of lithium is particularly interesting, considering it was previously ineffective when used alone and in combination with multiple antidepressants, antipsychotics, and carbamazepine (Figure 9.4, top). The patient had a relatively mild side-effects burden despite these five agents, with mild to moderate tremor being the only problematic one. At discharge, she elected to remain on this combination of five agents. Not only was she able to return to work shortly after discharge for the first time in six years, but equally dramatic improvement occurred in other aspects of her life. She has remained well over the past 14 years on essentially this regimen.

CASE B: COMPLETE RESPONSE ON EIGHT MEDICATIONS This 64-year-old male had a 46-year history of bipolar-II illness with severe prolonged and incapacitating depressions and hypomanias unresponsive to traditional therapeutic modalities including the mood stabilizers, antidepressants and benzodiazepines (Figure 9.5 [see legend]). Following sequential adjunctive treatments, discontinuations

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and switching of medications for tolerability, treatment with seven different classes of medications was associated with his first persistent remission of symptoms.

SOME TREATMENT PRINCIPLES FOR COMPLEX COMBINATION THERAPY SIGNS, SYMPTOMS AND TARGETS What are the general treatment principles that may lead to such fortunate outcomes with complete and persistent remissions of the type of illness in Figures 9.4 and 9.5? Herein lies the difficulty because there is not, as yet, a systematic literature on complex combination therapy to guide the clinician. Clinicians are thus forced to adopt strategies that have some empirical backing and a modicum of support by expert opinion (Table 9.5). We suggest the utility of considering a wide variety of variables in initial and subsequent choice of medications, including: cycle pattern and frequency; the symptomatic presentation of manic, depressive and mixed episodes; concomitant Axis I, II and III comorbidities; and neurobiological findings such as endocrine or cerebrospinal fluid abnormalities. Following the use of these therapeutic targets, one must consider tolerability not only of the drug to be added, but also of the entire regimen and potential pharmacokinetic as well as pharmacodynamic factors. If one is careful in dose titration, one can use a wide range of drugs in combination and actually reduce rather than increase side-effects burden, because no one single agent has to be pushed to or above an individual’s side-effects threshold in order to achieve a complete therapeutic response.

RAPID CYCLING AND DIFFERENT TYPES OF BREAKTHROUGH SYMPTOMATOLOGY In light of the poor response to monotherapy in the case examples noted above, for the patient presenting with initial rapid cycling, we suggest the combination of lithium with either carbamazepine, valproate or lamotrigine, depending on the wave form of the illness (predominance of mania versus depression) and other clinical and familial predictors of treatment responsivity as outlined in Tables 9.6 and 9.7. To the extent that the patient continues to cycle and/or show psychotic components of their illness, an atypical antipsychotic might then be added to the regimen. If the patient had a chronic refractory depression, one might consider adding a second-generation antidepressant instead. If the patient were overweight, one might consider topiramate or zonisamide because these have been shown to be helpful in weight loss in psychiatric and neurological patients and in those with psychotropic-induced weight gain. If the patient had comorbid alcoholism or post-traumatic stress disorder (PTSD), one might choose topiramate

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Table 9.5: Some principles of rational polypsychopharmacology 1. Add one drug at a time (to distinguish individual drug efficacy and side effects) 2. Augmentation (with a new drug with a new mechanism) saves time over substitution 3. Substitution (within the same class) is appropriate in the face of drug intolerance 4. Consider drug which targets: (a) predominant symptom presentation (i.e., mania, depression, mixed state) (b) existing comorbidities (try for a two-for-one response) (c) good side effects profile and overall tolerability in combination (d) different mechanisms of action 5. Titrate toward (below) a patient’s side effects threshold (not to conventional doses and blood levels) 6. Anticipate and prevent pharmacokinetic interactions 7. Consider suicidality (lithium and psychotherapy) 8. Attend to ease of use to enhance compliance (i.e., only H.S. or A.M. dosing if possible) 9. Treat breakthrough symptoms aggressively 10. Consider the risk-to-benefit ratio in relation to both evidence and likelihood of efficacy and side effects 11. Have patient (or family) daily chart mood, sleep, comorbid symptoms, medications, and side effects 12. Monitor side effects (cognition/sedation/unsteadiness) as carefully as mood 13. Decrease dose of drug most likely associated with side effects 14. In face of good response, be conservative and maintain full-dose treatment into continuation and prophylaxis (in absence of side effects) 15. In absence of efficacy, consider augmentation strategies; changes in the major treatment strategies (i.e., the core mood stabilizers); and more experimental approaches as necessary 16. Develop a support system and the patient’s approach to: (a) an Early Warning System (EWS); identify symptoms most likely to herald onset of manic or depressive episode (b) an Emergency Action Plan (EAP, i.e., a fire drill); what to do and who to call should dangerous behavior emerge 17. Consider a sequential and evolving approach to both: (a) illness education in: (1) acute phases; (2) resolution/continuation; and (3) prophylaxis (b) type of psychotherapy: (1) cognitive behavior techniques (re: stress management/compliance); (2) interpersonal psychotherapy (re: significant other/employment); and (3) existential psychotherapy 18. Watch literature for efficacy and availability of new drug treatments and physiological approaches such as rTMS and VNS 19. Watch literature for emerging clinical, neurochemical, physiological and genetic predictors of drug response and side effects H.S., at night; rTMS – repetitive transcranial magnetic stimulation; VNS – Vagus nerve stimulation

Carbamazepine

If mania > depression Lithium

Mood stabilizer —

−

+ • Bipolar II • Family history (−) • Substance use • Schizoaffective • Paroxysmal pain (PTSD)

• Agranulocytosis (1 per million) • Aplastic anemia (5 per million) • Spina bifida (1–3%)

• Narrow therapeutic index • Irreversible cerebellar lesions in overdose • Ebstein’s anomaly

Helps Weight insomnia neutral Severe caution ±

• Bipolar I • Family history (+) • Intermittent • Euphoric • Suicide risk

+ Selection factors

Table 9.6: Initial choice of a mood stabilizer Mild caution

• Benign ↓ WBC count • Dizziness • Ataxia • Diplopia • Sedation

Tremor • Acne GI distress • Psoriasis ↑ weight Diabetes insipidus

• Hyponatremia • Severe rash • Drug–drug interactions

• • • •

Moderate caution

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• Bipolar I, II depression • Anxiety comorbidity • Family history of (+): Anxiety, Substance abuse (PTSD)

−

+

• Rash: SJS; TENs (1 in 5000 adults; 1 in 2500 children)

• Hepatic failure • Pancreatitis • Spina bifida (3–5%)

+

• Migraine • Anxiety • Dysphoria (PTSD) —

Helps Weight insomnia neutral Severe caution

+ Selection factors • • • • Tremor ↑ weight Alopecia (PCOS)

Moderate caution

• Benign rash • GI distress

• GI distress • ↑ Ammonia • ↓ Platelets

Mild caution

PTSD, post-traumatic stress disorder; WBC, white blood cell; PCOS, polycystic ovary syndrome SJS, Steven’s Johnson syndrome; TENs, toxic epidermal necrolysis; GI, gastro intestinal —, worsen; −, may worsen; ±, possibly effective; +, substantial open data Based on data and reviews of Duffy et al. (2002), Calabrese et al. (1993, 1996), Greil et al. (1998), Grof et al. (2003), Passmore et al. (2003), and Post et al. (1986, 1987, 2002)

Lamotrigine

If depression > mania

Valproate

Mood stabilizer

Table 9.6: (Continued)

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Table 9.7 Approaches to the rapid cycler with comorbid residual symptoms I. Possible Combination Treatments (in light of low response to monotherapy) A. Lithium + VPA B. Lithium + CBZ/OXC C. Lithium+LTG (Depressions (Dysphoric mania) (Schizoaffective, BPII) predominate) (Substance abuse) II. Adjunctive Treatments for co-occuring or residual symptoms A. Agitation/Anxiety/ CLONAZEPAM, LORAZEPAM, OR Insomnia ATYPICAL ANTIPSYCHOTICS (A.A) B. Psychosis ATYPICAL ANTIPSYCHOTICS (A.A) C. Persistent Cycling THIRD MOOD STABILIZER, A.A. D. Weight Loss TOPIRAMATE, ZONISAMIDE E. Alcohol Avoidance TOPIRAMATE, NALTREXONE (ACAMPROSATE); and 12-step program F. High Blood Pressure or DIHYDROPYRIDINE CALCIUM Ultradian Cycling CHANNEL BLOCKER G. Atypical Depression (SNRI + BUPROPION ≅ MAOI) H. Fatigue/Lassitude MODAFINIL, PSYCHOMOTOR STIMULANT I. Chronic Pain Syndromes GABAPENTIN, VENLAFAXINE, DULOXETINE J. Migraine VALPROATE, TOPIRAMATE K. Cognitive Dysfunction T3, CHOLINOMIMETIC (acetylcholine-esterase inhibitor), MEMANTINE (NMDA antagonist) VPA, valproate; CBZ; carbamazepine; OXC, oxcarbazepine; LTG, Lamotrigine; SNRI, serotonin and norepinephrine reuptake inhibitor; MAOI, monoamine oxidase inhibitor; T3, triiodothyronine; NMDA, N-methyl-D-aspartate; BP II, bipolar II

(Berlant, 2001; Johnson etal., 2003) over zonisamide; if one had a predominance of manic symptoms and/or sleep disorder, one might select zonisamide (at night) instead. Migraine prophylaxis can be accomplished with lithium, a calcium channel blocker, or valproate, with increasing evidence for the efficacy of topiramate for this syndrome as well. New data also support the use of topiramate in the achievement of alcohol abstinence (Johnson et al., 2003) and also possibly cocaine abstinence (Kampman et al., 2004). Comorbid anxiety symptoms are particularly important to target with focused therapy in light of their morbidity, relative resistance to lithium, and potential relationship to serious or completed suicide attempts. In this domain, the mood stabilizing anticonvulsants have much to offer over lithium carbonate, but lithium can be left in place given the evidence that it appears to possess superior antisuicide effects compared with the anticonvulsants (Baldessarini etal., 2003). For anxiety that is nonresponsive to these agents, one might consider augmentation with a high potency benzodiazepine (Beaudry etal., 1985; Charney and Woods, 1989) or with gabapentin (Pande etal., 1999, 2000; Pollack, 1993; Pollack, Matthews and Scott, 1998) since both have proven effective in many anxiety syndromes as well as in social phobia. Atypical antipsychotics may also be helpful (McIntyre and Katzman, 2003).

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To the extent that anxiety is comorbid with a depressive core, one might consider the dual action of the serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine or duloxetine. These latter two compounds are also particularly useful in those with comorbid pain syndromes (Ninan, 2000; Masand and Mago, 2005), as is gabapentin.

TREATMENT-REFRACTORY DEPRESSION If the patient continued to manifest treatment-refractory depression, a variety of augmentation approaches are available (Table 9.8). T3 augmentation of an Table 9.8: Possible approaches to acute and resistant bipolar depression that can be considered Depression breaking through ongoing MS treatment (A) Single episode; No medications

(B) Non-rapid cycling

(C) Rapid cycling to ultrarapid cycling

1a. 1b. 1c. 2.

1a. 1b. 1c. 2.

Add AD Add LTG √ √

1a. 1b. 1c. 2.

Add LTG or Li Folate Add second MS (especially LTG) or Li

3.

AD plus MS vs.LTG Start folate Li augmentation of AD if start 1a Add AD if start 1b T3 potentiation

3.

√

4.

Add AA

4.

√

3. 3a. 3b. 3c. 4.

5. 6.

Revise AD Revise MS

5. 6.

√, consider SNRI √

5. 6.

7.

7. 7a. Add serotonin and High-potency noradrenaline reuptake benzodiazepine or inhibitor plus gabapentin (Neurontin) bupropion augmentation for (Wellbutrin) insomnia or anxiety 7b. Add MAOI after 4 weeks off serotonin

T3 Add AA Add third MS Add AD Add one of two other 3a, 3b or 3c options listed previously Revise AD, MS, AA For ultradian cycling consider a dihydropyridine calcium channel blocker, such as amlodipine (Norvasc), isradipine (Dynacirc) or nimodipine (Nimotop) High-dose T4

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9. Discontinue T3 and add high-dose T4 10. ECT or repetitive transcranial magnetic stimulation or VNS (if and when available)

153

8. Gabapentin for insomnia, anxiety, restless legs and alcohol abuse 9. Carbamazepine for those with a history of alcohol abuse 10. √

AA, atypical antipsychotic; AD, antidepressant; ECT, electroconvulsive therapy; Li, lithium (Eskalith); LTG, Lamotrigine (Lamictal); MS, mood stabilizer; T3, triiodothyronine; T4, thyroxine; VNS, vagus nerve stimulation; √ = as in A; SNRI, serotonin-norepinephrine reuptake inhibitor; MAOI, monoamine oxidase inhibitor

antidepressant may enhance or speed up response, with a higher percentage of women than men responding (Altshuler et al., 2001). Folate augmentation may also be effective in light of the Coppen et al. data of folate’s superiority over placebo in augmentation strategies in lithium augmentation (Coppen, Chaudhry and Swade, 1986) and in unipolar depression (Coppen and Bailey, 2000). Attempting to target all three aminergic systems involved in depression with a combination of venlafaxine and bupropion (Fatemi et al., 1999) may be an alternative to the use of a monoamine oxidase inhibitor, with its more difficult safety profile and requirement for dietary restriction. If lamotrigine were not already in the treatment regimen, this drug would certainly be worthy of consideration at this time (Calabrese et al., 1999, 2003b). If the patient were on concomitant valproate treatment, the starting dose and rate of dose titration of lamotrigine should be at least half as slow as normally recommended because of the increased risk of serious rash on this combination and the ability of valproate to double (or more) lamotrigine blood levels (Guberman et al., 1999). If the patient continues to experience treatment-refractory depression, either of the chronic persistent variety or in rapidly recurrent phasic episodes, one might consider discontinuing T 3 augmentation and beginning superphysiologic high-dose T4 potentiation. This latter modality has been reported to be a successful augmentation strategy for both rapid cycling patients (Stancer and Persad, 1982; Bauer and Whybrow, 1990; Baumgartner, Bauer and Hellweg, 1994) and in persistent treatment-refractory depression in the studies of Bauer et al. (1998, 2001, 2002). They recommend slowly titrating the dose of T4 toward a target of 300–500 μg/day or a free thyroxin index of 150% of normal.

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EVOLVING ROLE OF ATYPICAL ANTIPSYCHOTICS The antimanic effects of the typical as well as the atypical antipsychotics have now been demonstrated in controlled studies (Strakowski et al., 2003). What is less certain is the degree of antidepressant efficacy either acutely or in long-term prophylaxis of the illness. Augmentation with these agents for refractory depression would appear to be an appropriate strategy in light of the evidence of the acute antidepressant efficacy of the olanzapine/fluoxetine combination (Tohen et al., 2003) and the likely antidepressant effects of ziprasidone and aripiprazole based on their potential special mechanisms of action. In addition to dopamine receptor blockade, ziprasidone also blocks reuptake of serotonin and dopamine (Seeger et al., 1995); aripiprazole, as a partial agonist at D1, D2, D3 and 5HT1A receptors, and a full antagonist of 5HT2 receptors (Keck and McElroy, 2003), should theoretically convey some antidepressant efficacy as well. This argument is further enhanced by the findings that the full D2, D3 agonist pramipexole has antidepressant effects in bipolar depression (Goldberg, Frye and Dunn, 1999; Zarate et al., 2004; Goldberg, Burdick, and Endick, 2004) and both 5HT1A agonism and 5HT2 blockade have been associated with antidepressant effects of other modalities (Deakin, 1991). In a naturalistic study, quetiapine had promising antidepressant effects as an open adjunct (Keck, 2001) and in a controlled clinical trial was superior to placebo in augmentation treatment for obsessive-compulsive disorder (Atmaca et al., 2002). Calabrese et al. (2005) reported robust antidepressant and antianxiety effects of quetiapine, 300 mg or 600 mg, versus placebo.

EMPIRICAL AND THEORETICAL RATIONALES FOR POLYPHARMACY As noted in the introduction, the rationale for increasingly complex combination therapy as part of the routine treatment for bipolar illness is largely driven by clinical need. When the patient does not respond to monotherapy or simple combination approaches, one must consider other options (Table 9.9).

A STANDARD APPROACH IN OTHER CHRONIC MEDICAL CONDITIONS Certainly, use of combination strategies is standard practice in many other branches of medicine, most notably in many cancer chemotherapies, treatment for congestive failure, tuberculosis, AIDS, the arthritides and others. Almost a century ago Sir William Osler noted that “The true polypharmacy is the skillful combination of remedies” (Bean and Osler, 1951). The modern question remains as to how best to achieve this goal.

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Table 9.9: Rationales for Complex Combination Therapy (CCT) • Need (failure to respond to monotherapy and dual-therapy) • Treatment of pleomorphic types, patterns and frequencies of illness (mania, depression and mixed states, rapid and ultra-ultra rapid cycling) • Wish to treat to full remission (using pharmacodynamic additive or synergistic effects) • Avoidance of breakthrough episodes (i.e., avoiding tolerance development by employing multiple neurotransmitter targets) • Targeting of comorbid conditions (anxiety disorders 40%, substance use 40%, weight gain 50–75%) • Avoidance of side effects (lower doses so that whole regimen is below side-effects threshold) • Different medications and psychotherapies for different stages of illness evolution and suicidality: – in acute treatment need for rapidity of response, crisis intervention and psychoeducation – in prevention/long-term efficacy use combinations in service of tolerability/ compliance, and education/cognitive-behavioral techniques in service of maintaining stability • CCT is a common and recommended mode in many other chronic medical conditions (i.e., AIDS, tuberculosis, congestive heart failure, rheumatoid arthritis, cancer)

COMBINATION OF AGENTS WITH DIFFERENT MECHANISMS In the absence of detailed studies, one would recommend using drugs with different mechanisms of action (Figure 9.6) rather than, for example, applying two different agents with similar mechanisms, such as two SSRIs. This approach targets a new neurochemical system potentially relevant to the patient’s residual symptoms, and adding a novel mechanism should make the late emergence of treatment resistance via a tolerance process less likely to eventually occur after an initially good response (Post and Weiss, 1996; Weiss et al., 1995).

MINIMIZING SIDE EFFECTS Certainly, a crucial therapeutic principle in complex combination therapy is minimizing the total side-effects burden. This can often be accomplished by slow titration of a given adjunctive agent so that not only it, but also the total medication burden, remains below an individual’s side-effects threshold. Under this rubric, titration to conventional target doses or blood levels is inappropriate, and one must be primarily guided by issues of tolerability. This issue is especially relevant in the psychopharmacology of bipolar disorder, because within a wide range of acceptable doses and drug levels there is relatively little evidence of a direct relationship of these variables to clinical response.

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Figure 9.6: Mechanisms of anticonvulsant action. Effects grouped and schematized as anti-excitatory (left) via inhibition of glutamate release (circles) or receptor effects, or pro-inhibitory (right) via enhancing benzodiazepine receptors (Bz-R), GABA levels (squares) or receptor activity. Glutamate is released with BDNF and zinc to act on NMDA, AMPA and kainate receptors. Sodium influx through the AMPA receptor depolarizes the cell, which releases the magnesium block at the NMDA receptor, which allows the influx of calcium ions. Benzodiazepine receptors facilitate the actions of GABA-A receptors allowing chloride influx and inhibition of cell firing. Levetiracetam facilitates GABA by inhibiting the negative modulators of the GABA receptors, zinc and β-carboline. CBZ, carbamazepine; OXC, oxcarbazepine; PHT, phenytoin; LTG, lamotrigine; VPA, valproate; TPM, topiramate; ZON, zonisamide; Na+, sodium channel; BDNF, brain-derived neurotrophic factor; K+, potassium channel; Li, lithium; NMDA R, N-methyl-D-aspartate receptor; Zn, zinc; Ca++, calcium channel; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; Mg, magnesium; NIM, nimodipine; ISR, isradipine; AML, amlodipine; GPN, gabapentin; GABA, γ-aminobutyric acid; Benzo, benzodiazepine; Cl−, chloride channel; TIA, tiagabine; BZ-R, benzodiazepine receptor

ATTENTION TO PHARMACOKINETIC INTERACTIONS One must also carefully attend to possible pharmacokinetic interactions that may directly or covertly influence the total side-effects burden. For example, if a patient is taking the combination of carbamazepine and valproate, valproate will produce a number of effects on carbamazepine that can enhance the side-effects threshold. This includes inhibition of the epoxide hydroxylase leading to a build-up of the active

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10,11-epoxide metabolite of carbamazepine (which is often not measured in routine assays) as well as valproate displacing carbamazepine from its protein-binding sites and thus adding to the level of free drug (Ketter et al., 1999). This is not to say that the combination cannot be used, but only that if one is adding valproate to a regimen with carbamazepine in place, one should consider a preventive 40–50% reduction in carbamazepine dosage in anticipation of such interactions. Similarly, if one were going to go on an erythromycin antibiotic or one of its analogs, a reduction in the dose of carbamazepine in advance of the appearance of side effects would be precautionary because of the approximate doubling of carbamazepine levels with the inhibition of the hepatic microsomal enzyme 3A4 responsible for carbamazepine metabolism.

ADVERSE PHARMACODYNAMIC INTERACTIONS Consideration of adverse pharmacodynamic interactions leading to an increased side-effects burden should also be considered. For example, while weight gain on lithium or valproate is often relatively mild and manageable, on the combination it may become excessive. If atypical antipsychotics with major weight gain liability (such as clozapine or olanzapine) are also used, the patient may be at greatly increased risk for not only problems with overweight, but also a metabolic syndrome associated with many additional medical liabilities, including hypercholesteremia, hyperlipidemia, relative insulin resistance or even overt diabetes (Nemeroff, 2003). Because depression itself is a very potent risk factor for myocardial infarction (MI) and stroke, as well as a variety of other medical syndromes (Musselman, Evans and Nemeroff, 1998), avoiding other associated and interactive risk factors such as those associated with weight gain becomes even more critical. This consideration should be factored into the initial treatment equations in the hope of preventing the development of an overweight syndrome as well as the use of weight loss modalities now that several anticonvulsant drugs used in bipolar disorder (i.e., topiramate and zonisamide) have been identified (McElroy et al., 2000, 2005; Leverich et al., 2005) as having weight loss side effects.

TARGETED PSYCHOTHERAPY IN BIPOLAR ILLNESS One of the most important treatment modalities in the use of complex combination therapy for bipolar illness is the use of psychotherapeutic techniques and their various combinations as a function of stage of treatment initiation and evolution. More than a dozen randomized controlled studies have documented the efficacy of a variety of psychotherapeutic approaches in the treatment for bipolar illness (Otto,

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Reilly-Harrington and Sachs, 2003). These range from the early studies of couples marital therapy sessions of Davenport and colleagues (1977), to: individual, family and multifamily psychoeducational approaches (Colom et al., 2003; Fristad, Goldberg-Arnold and Gavazzi 2002; Fristad, Gavazzi and Mackinaw-Koons, 2003); cognitive and behavioral approaches (Cochran, 1984; Lam et al., 2000, 2003); symptom identification and relapse prevention (Perry et al., 1999); as well as other adjunctive approaches from psychosocial and cognitive rehabilitation techniques (Craighead and Miklowitz, 2000; Miklowitz et al., 2003), to existential psychotherapy (Palmer, Tucker and Swift, 2003).

NEED FOR EARLY INTERVENTION Given the now overwhelming data that a history of a greater number of prior episodes is a prognostic factor not only for a poor response to lithium (Table 9.3), but also for lamotrigine (Obrocea et al., 2002; Frye et al., 2005) and naturalistic treatment in general (Post et al., 2003a; Nolen et al., 2004), it becomes a clinical imperative to try to intervene at the first sign of bipolar symptoms causing impairment and attempt to prevent episode recurrence and evolution. The success of this clinical intervention is very dependent on the approach and motivation of the psychotherapist and the nature of the psychoeducational package and message delivered. Psychoeducational approaches have been shown to enhance treatment adherence and lead to more stable lithium levels as well as prevent relapse. Specific instruction about techniques for symptom recognition, plans for early intervention, and building a support system and treatment team, are all critical pieces of the psychoeducational package and are exquisitely detailed in a recent book by Miklowitz (2002). To the extent that the patient can become an active co-participant (along with the physician and clinician) in concerted action against the emergence of bipolar symptoms and full-blown episodes, treatment is even more likely to be successful. We have also found that reference to underlying neurobiological mechanisms in the illness (Post et al., 2003b) as well as positive neurochemical mechanisms of action of some of the psychopharmacological agents (Post et al., 2002 a,b) – particularly when they are neurotrophic, neuroprotective or enhance neurogenesis as does lithium (Table 9.10) – can also help patients better understand the illness and the need for careful monitoring and long-term sustained intervention.

THE ELUSIVE GOAL OF LONG-TERM PROPHYLAXIS Paradoxically, wellness can be a high risk factor for endangering long-term medical health in bipolar illness. Patients may all too readily become convinced, by themselves, by friends and relatives, and even by well-meaning clinicians and

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Table 9.10: Impact of stress and psychotropic drugs on gene expression and brain structure Pathological

Adaptive

Affective Illness Stress Gluco-corticoids Lithium VPA ADs Transcription factor CREB Neurotrophic factor BDNF Anti-apoptopic factor Bcl-2 Neurite sprouting (in vitro) Neuroprotection (stroke) Neurogenesis (in vivo) Gliagenesis (in vivo) Neuronal viability (NAA by MRS in humans) Grey matter (in humans) Hippocampal volume (in humans)

↓ (↓) (↓) (↓)

↓ ↓

↓ ↓

↓ ↓ ↓ ↓ ↓

↓ ↓

↓

(↓)

↓

↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑

↑ ↑

–

↑ ↑

↑

↑ ↑

CREB, Cylic AMP response element-binding protein; BDNF, brain-derived neurotrophic factor; NAA, N-acetyl aspartate; MRS, magnetic resonance spectroscopy; VPA, valproate; AD S , antidepressants; ↑, increase; ↓, decrease; ( ), possibly

physicians, that treatment is no longer necessary. Many patients feel compelled to test this presumed reality with periods off medication, almost uniformly with disastrous consequences. The patient and family should be supplied with the appropriate statistics about the likelihood and rapidity of relapse once medications are tapered or stopped altogether. Patients should be told that after discontinuing lithium, the relapse rate is 50% within the first five months and 90% within a year and a half (Suppes et al., 1991). New evidence suggests that the rapidity of lithium taper may not be protective (Viguera, 2003), as had previously been believed (Baldessarini et al., 1996). We would still advocate a very slow taper of lithium in instances in which patients insist on such a discontinuation trial so that treatment can rapidly be reinstituted if symptoms begin to occur during the slow taper itself. Patients should be told that if relapse eventually occurs, there is no guarantee that they will either rapidly regain, or regain the full extent, of the responsivity of the previous treatment regimen. We and others have observed that about 10–15% of patients who were well for sustained periods of time, and who chose to discontinue lithium and then experienced a relapse, subsequently failed to re-respond to lithium re-institution at the same or even higher doses than those previously effective (Post etal., 1992, 1993; Bauer 1994; Koukopoulos etal., 1995; Maj, Pirozzi and Magliano, 1995; but see Berghofer and Muller-Oerlinghausen, 1996; Tondo et al., 1997). One small series that was not designed or powered to detect such an effect (Coryell etal., 1998) claimed that there was no discontinuation-induced refractoriness, although one of the patients in their study appeared to suffer from this experience,

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and the NIMH collaborative study has indicated that every occurrence of a new depression carries an approximately 16% risk of refractoriness (Solomon etal., 2000). Thus, maintaining long-term wellness with full dose pharmacoprophylaxis is a goal that often requires considerable psychotherapeutic work and education to achieve. In complex combination therapy, reducing the total pharmacological load to reduce side effects is certainly in order. However, in the absence of further guidelines, one should consider following the general rubric that the same regimen that was required to achieve acute efficacy should be continued in long-term prophylaxis. Extrapolating from prophylaxis in unipolar illness, this full dose approach is clearly supported (Frank et al., 1993; Franchini et al., 1998; Keller, 2003). Dangers from the illness alone are great, but bipolar disorder also places the patient at increased risk for other illnesses such as comorbid use and abuse of alcohol and other substances (Sonne and Brady, 1999). To the extent that these vulnerabilities can be anticipated and prevented, an enormous benefit may also be derived.

CONCLUSIONS The psychopharmacotherapy of bipolar illness is like a team sport that requires the consistent input and good performance of a great many of its members in order to achieve success. We have outlined the apparent increasing need for very complex combination therapy for adult bipolar illness that has developed over the past 50 years, without much guidance from a systematic database. The same perspective is rapidly becoming apparent for childhood onset bipolar illness as well. We have highlighted one set of approaches to polypharmacy in bipolar illness based on the literature and a good deal of personal opinion. We hope that some of the principles elucidated in this chapter will help in the further development and refinement of these approaches and their success in assisting patient’s with bipolar illness to achieve and sustain long-term remission. However, it would appear that an entirely new set of research methodologies will need to be developed to begin to make more of the critical decisions in the polypharmacy of bipolar illness based on a strong empirical database. Until that happens, careful charting of each patient’s individual course of illness, side effects and response to treatment may prove to be one of the best tools in making the complexities and choices in combination therapy as rational as possible for each patient with bipolar illness.

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CHAPTER

10 The Primacy of Mania Athanasios Koukopoulos Centro Lucio Bini, Rome, Italy

Excitement is not a mere somatic accessory but is the fundamental affection of the psyche. (Heinroth, 1818)

THE HISTORICAL CONTEXT For more than two thousand years, mania was considered the most important psychic illness – even more so than melancholia; it was the main form of madness. Like mania in Greek, follia in Latin meant mania and madness, as it does in many modern European languages (Follia, Folie, Folly). The title of the first edition of Pinel’s Handbook published in 1801 was Traité médicophilosophique sur l’alienation mentale ou la manie. Pinel considered mania the most typical and frequent mental illness. Heinroth (1818), the founder of modern clinical psychiatry, regarded excitement as the fundamental affection of the psyche. The majority of the psychic disorders described in his treatise of 1818 was of excitatory nature. Many forms of exaltation, mania and a remarkable series of mixed mood disorders (animi morbi complicati) constitute the main focus of his book. In 1845, Wilhelm Griesinger introduced the term and concept of cycle, that is, the alternation of mania and melancholia. He paid great attention to mixed states, and particularly to melancholia with destructive tendencies and melancholia with persistent excitement of the will. He had the brilliant insight that excitatory phenomena often underlie depressive states: By using the expression ‘psychic depressive states’ we did not mean to imply that the basic nature of these states is inactivity and weakness and suppression [depression] of the psychic or cerebral processes that underlie them. We have much more reason to assume that very intense states of irritation of the brain and excitation of the psychic processes are very often the cause of such states; Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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but the end result of these [psychic and cerebral] states as far as mood is concerned is a state of depression or psychic pain. (Griesinger, 1861) This is the core issue in the understanding of agitated depression (Koukopoulos and Koukopoulos, 1999), which, to this day, is not recognized as a mixed state to this date by neither by the DSM-IV TR (2000) ICD-10 (1992). Griesinger (1845) also had the intuition to compare mania to epilepsy: In other cases, the manic attacks recur every 1, 2 or 3 years; a form of true psychic epilepsy which shares with the common recurrent epilepsy the same poor prognosis. Both mania and epileptic seizures are, indeed, states of intense excitement, and the efficacy of modern antiepileptics against both disorders depends upon their anti-excitatory effect; despite this, many authors have tried to demonstrate the antidepressant properties of antiepileptics in order to explain their prophylactic action in affective disorders. Kraepelin is the last representative of this long tradition that created modern psychiatry. His broad criteria for mania, and his mixed states, which are basically conditions of excitement (depressive mania, excited depression, mania with poverty of thought, manic stupor, depression with flight of ideas and inhibited mania), denote the importance he attached to excitatory phenomena. Moreover, his fundamental states, which correspond to the four affective temperaments, are predominantly of excited and excitable nature. Among his manic-depressive patients he estimated the incidence of the following premorbid temperaments (dispositions): 12.1% depressive, 9.0% hypomanic, 12.4% irritable and 3–4% cyclothymic (Kraepelin, 1913). After Kraepelin, the clinical importance of mania diminished and that of schizophrenia expanded, due to the influence of such influential Germanophone psychiatrists as Bleuler (1911), Jaspers (1923) and Schneider (1959). Mixed states lost their clinical importance. With their new cross-sectional criteria, many psychotic manias and mixed states were diagnosed as schizophrenia. Mania, indeed, as a syndrome, is basically a psychotic condition. The criteria of Kahlbaum (1863; reviewed in Baethge, Salvatore and Baldessarini, 2003) and Kraepelin (1913), based on course and outcome, were abandoned in favor of symptom clusters present in the current episode. The motto, ‘once a schizophrenic always a schizophrenic,’ dominated the field for decades. This influence was even greater in the United States, where many psychotic manias were misdiagnosed as schizophrenic and paranoid reactions (American Psychiatric Association, 1952, 1968). The influence of psychoanalysis was also significant since mania was difficult to interpret in psychodynamic terms and impossible to treat with psychotherapy. The practice of excluding family members of the patient from the diagnostic process, especially in the United States, contributed

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significantly to the underdiagnosis of bipolar conditions by allowing hypomanic/ manic symptoms to go undetected. The introduction of chlorpromazine by the Parisian Psychiatrists Delay, Deniker and Harl (1952) could have changed this trend, but at that time the emphasis on schizophrenia was so strong that the antimanic effect of chlorpromazine was overshadowed by its anti-schizophrenic effect. This is curious, because the first patients treated by chlorpromazine at the St Anne Hospital in Paris were manic! The efficacy of neuroleptics in both schizophrenia and psychotic mania reinforced and protracted this diagnostic error. The introduction of effective antidepressants, shortly after chlorpromazine, focused psychiatrists’ attention on depression, resulting in even further neglect of mania. The largely accepted distinction between unipolar and bipolar forms of affective disorders (Angst, 1966; Perris, 1966) caused a diagnostic shift in favor of unipolar depression, termed recurrent major depressive disorder (MDD) by the DSM-III (1980). This shift was unjustified and hard to explain. Bipolar disorder was then limited to the core bipolar I phenotype with clear-cut mania and, furthermore, this disorder, for the most part, was diagnosed as schizophrenia because of its psychotic features. The more common bipolar patients with recurrent depression and hypomania, though formally recognized since at least DSM-III-R (1987), have been considered ‘atypical.’ Their recognition as genuine bipolar disorder (type II) by the DSM-IV (1994) is unfortunately lagging in practice, and many such patients are worldwide misdiagnosed as MDD (see Akiskal et al., 2000). A historic shift was brought about by the use of lithium as an antimanic and prophylactic agent in affective disorders (Baldessarini, 1970; Stoll et al., 1993). The evident antimanic effect of lithium, and the longitudinal observations in clinical practice and research trials, shed new light on the bipolar nature of many depressions and led to the rediscovery of bipolarity as described by Falret (1854), Baillarger (1854) and Kraepelin (1913). This diagnostic shift is reflected in the DSM-III (1980) by the narrowing of the definition of schizophrenia and expanding the category of major affective disorders. An important contribution to the new appreciation of bipolarity and cyclicity was the 1990 publication of Manic-Depressive Illness by Goodwin and Jamison (1990). As Schou states in his foreword, ‘the book is called Manic-Depressive Illness, but readers, especially those from Europe, should be informed that the emphasis is on bipolar disorder.’ In the present chapter, the author often uses the term ‘manic-depressive’ because it corresponds to Kraepelin’s unitarian concept of manic-depressive illness, which comprises what today are regarded by many as the recurrent unipolar and bipolar courses of the illness. It should be noted that there is nowadays a mistaken conflation of the terms ‘bipolar’ and ‘manic-depressive’ as synonymous. This misunderstanding arises out of the term ‘manic-depressive’, which in itself denotes two opposite poles, but as a clinical entity also comprises recurrent unipolar depression and, of course, the mixed states where the two poles come together.

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The work of Akiskal (1983) expanded this concept to what today is termed the bipolar spectrum. The aim of this expansion was to emphasize the fact that lessthan-manic excitements were prevalent in so-called unipolar depressions. The emphasis in the field, however, has remained primarily on depression (Ghaemi et al., 2003). This is understandable because it is more frequent than mania. Depressed individuals, moreover, have good insight into their depressive feelings and want to be understood and helped; their depressive feelings are close to normal human emotions and moods. Empathy and sympathy are easily evoked. Mania, on the contrary, is far from normal human experience. Manic patients are often aggressive, create enormous apprehension around them and are difficult to handle and treat. They have little, if any, insight into their condition and resist treatment. Furthermore, hypomanic patients deny that their behavior is abnormal and refuse treatment. A major cause of the shift of attention from mania to depression was the expansion of outpatient psychiatric practice in the second half of the 20th century, which tended to treat the milder forms of affective disorders, especially non-psychotic depression. By itself, this need not necessarily have brought about an underestimation of hypomania, but the promotion of antidepressants by the pharmaceutical industry may have played an important role. The asylum psychiatry of the 19th century brought to the forefront syndromes of excitatory nature, while the practice of prescribing antidepressant treatments on an outpatient basis in the second half of the 20th century focused the field’s attention on depressive and anxiety syndromes. Ironically, this emphasis on depression and the excessive use of antidepressant agents (Ghaemi et al., 2003) without concern for the triggering of mania or hypomania increased the number of cycling cases (Kukopulos et al., 1980, 1983) and consequently attracted new interest in bipolarity. In addition, the use and abuse of stimulating substances and caffeinated beverages appears to have had a similar effect to antidepressants on cyclothymic, hyperthymic and irritable temperaments, as well as on other forms of latent bipolarity. It is also likely that lifestyle changes, including artificial light and going to bed later, sleeping fewer hours, experiencing more sleepless nights, and a more intense and hectic lifestyle with an enormous increase of environmental stimuli contributed to a genuine increase in bipolar cases and a younger age at onset. The neglect of mania and bipolarity for so many decades also led to cyclicity being neglected, both in clinical practice and research. There were also other, more general, reasons for this neglect. Wehr (1989), for example, attributes importance to ‘a cultural shift away from a cyclical to a linear perception of time (Gould, 1987), so that psychiatrists and patients may be more likely to perceive affective recurrences as a succession of separate events than as a seasonal cycle of events’. Under such circumstances, it is natural that the intrinsic link between mania and depression would be entirely overlooked. Falret’s concept (1854) of a cercle (a cycle comprising a manic and a depressive phase and a lucid interval, all three intrinsically connected) was lost.

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Psychotropic drugs do, however, act upon the underlying process of the manicdepressive cercle: antidepressants trigger mania and hypomania, antimanic drugs may deepen depression and intervals may be shortened or lengthened under the action of treatments (Kukopulos et al., 1975). This chapter aims to present clinical facts and considerations that suggest not only that there exists an intrinsic link between mania and depression but also that the excitatory process of mania or hypomania is primary and depression secondary in the manic-depressive cycle. Metaphorically speaking, mania is the fire and depression its ash.

OBSERVATIONS FROM PHARMACOTHERAPY LITHIUM The first observations that gave rise to the idea of the primacy of mania came from the course of manic-depressive recurrences during continuous lithium treatment. Cade (1949) discovered the antimanic action of lithium and Schou et al. (1954) demonstrated it in a controlled trial. As an antimanic agent, lithium attracted little attention. One of the reasons for this neglect was the relatively narrow diagnostic range of its usefulness, that is, mania! (Schou, 1963). While testing the prophylactic action of lithium against manic recurrences, Hartigan (1961) and Baastrup (1964) observed a prophylactic action against depressive recurrences, as well Johnson (1984a). Schou fully understood the importance of these clinical observations, and performed with Baastrup the groundbreaking studies that established the prophylactic action of lithium against all the manifestations of manic-depressive illness (Baastrup and Schou, 1967; Baastrup et al., 1970). The prevention of depression by an antimanic agent came as a surprise. This surprise would occur again with antiepileptics and antipsychotics. The likely explanation was that lithium prevented depression through an antidepressant action as it prevented manic attacks through its proven antimanic action. In The History of Lithium Therapy, N.F. Johnson (1984a) writes: Perhaps lithium was also effective as an antidepressant? After all, since mania and depression occurred together in the same patient it was not implausible to suppose that even though the two states were symptomatically different there might be some common features in the control mechanisms underlying each. If lithium produced at least part of its therapeutic effect by acting on such mechanisms then it was possible that depression occurring in association with manic episodes might also be lithium-responsive. A double-blind trial was started but soon abandoned; the results were equivocal and failed to lend any clear support to an antidepressive property for lithium salts.

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The precedent set by ECT, a treatment effective against both depression and mania, rendered this explanation more plausible. An antidepressant effect of lithium, however, was never demonstrated. Actually, many patients who start lithium during their depressions feel so much more depressed that not only do they discontinue it, but they may also refuse to take it ever again. We have reported that lithium at rather high serum concentrations (close to 1.0 mEq/L) may prolong the duration of a depressive episode (Kukopulos et al., 1975). Lithium augmentation in resistant depression is still reported, but we maintain that the successfully treated cases of depression with lithium are of mixed nature; lithium is not an augmentation in these cases, but the proper treatment against the excitement buried in some resistant depressions. The proven efficacy of lithium in preventing suicide (Tondo, Hennen and Baldessarini, 2001) should be attributed not only to the prevention of depressive relapses but also to a specific action on impulsiveness and agitation, which should be considered mixed components of depression. Similar considerations may explain why the depressive phase of bipolar disorder may respond to lithium (Goodwin et al., 2003). The term mood stabilizer, coined by Kerry (Kerry and Owen, 1970), was first applied to lithium salts when it became clear that these compounds not only were effective in manic excitement, but also tended to avert both manic and depressive recurrences in bipolar patients.

RESPONSE TO LITHIUM PROPHYLAXIS The first clinical observations that gave us the idea of the cardinal role of mania in the manic-depressive cycle were the responses to lithium prophylaxis. When lithium did not act upon and suppress the manic phase, the depression took place as though lithium had not been given. When lithium attenuated and shortened the mania, depression was also attenuated. When mania was completely prevented, the depression did not occur. These observations were published in 1973 (Kukopulos and Reginaldi, 1973) with the hypothesis that lithium prevents depression by suppressing mania. Neil Johnson (1984b), in The Psychopharmacology of Lithium, supported the idea of the primacy of mania on the basis of his stimulus-processing model.

CYCLE SEQUENCE AND LITHIUM RESPONSE In the following years, my colleagues and I (Kukopulos et al., 1980) observed that patients who start the cycle with mania have a better response to prophylactic lithium than those who start with depression which is followed by mania/hypomania (Figure 10.1). This observation was confirmed in the following years by Grof et al. (1987), Haag et al. (1987), Maj, Pirozzi and Starace (1989), Faedda et al. (1991) and again by our group (Koukopoulos et al., 1995).

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Figure 10.1: Cycles

That lithium exerts a greater prophylactic effect in patients with the mania/hypomania–depression sequence is a significant observation. The most likely hypothesis is that lithium easily suppresses a manic process that develops gradually, thus preventing the subsequent depression that otherwise would have followed the mania. The onset of mania after a free interval is generally very gradual and lasts quite some time, from a few weeks to a few months. Slight changes in mood, sleep and behavior last for a long time before mania reaches, in a crescendo, its full intensity. It seems natural that prophylactic lithium, administered during the prodromal period, manages to suppress the underlying process in most cases. This process at its very beginning must be mild. The efficacy of lithium in mild excitatory processes is evidenced even by its effects on excited temperaments: hyperthymics complain of being less hyperthymic under lithium. Even in normal individuals, Judd and colleagues (1977) found that lithium caused lethargy, dysphoria and a loss of interest in interacting with others and the environment. On the other hand, lithium is much less effective on full-blown mania. Lithium as monotherapy is rarely applied in the treatment of acute mania. Mania following a depression emerges more rapidly, frequently as an abrupt switch from one state to the other, and is often activated by the antidepressant treatment administered during the depression (Kukopulos et al., 1980; Reginaldi et al., 1981). The course of rapid cyclers is typical in this regard. Continuous cycling cases with either rapid cycles or long cycles are well known to be treatment-resistant. It should be noted that the transition from depression to mania or hypomania occurs at every cycle in continuous circular cases. As an alternative explanation, Grof et al. (1987) proposed that there are likely different subtypes of bipolar disorder with different sequences of polarity, which respond differently to lithium.1 1

See Chapter 2 for further discussion of this topic – Eds.

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LITHIUM DISCONTINUATION Further evidence of the importance of the antimanic action in the prophylactic treatments came from the data of lithium discontinuation. The data of Suppes et al. (1991) show that during the first months following discontinuation, the vast majority of recurrences are manias while depression takes place later following the natural course of the illness. Our data confirm this observation (Koukopoulos et al., 1995). In other studies, the relapses were all manic and occurred from a few days to a few weeks after lithium discontinuation (Lapierre, Gagnon and Kokkinidis, 1980; Mander and Loudon, 1988). This clearly indicates that mania is a rebound phenomenon that emerges when the antimanic activity of lithium ceases abruptly. This rebound phenomenon is even clear in the gradual reduction of lithium dose, as is well described by Jamison (1995): Lowering my lithium level had allowed not only a clarity of thinking, but also a vividness and intensity of experience, back into my life; these elements had once formed the core of my normal temperament . . . I did very slowly cut back on the amount of lithium I was taking. The effect was dramatic. It was as though I had taken bandages off my eyes after many years of partial blindness . . . I felt more energetic and alive. Most significant, I could once again read without effort. In summary, the sequence of recurrences following lithium discontinuation clearly demonstrates that the recurrences are rebound phenomena: if the rebound takes the form of mania, it suggests that the therapeutic action expended had been an antimanic one. This also seems to be the case in the discontinuation of antiepileptics and antipsychotics; no systematic studies have, however, thus far been published on the matter. It is also common clinical experience that the discontinuation of depot neuroleptics, given as prophylaxis in bipolar I patients, results in a manic attack.

ANTIDEPRESSANT DISCONTINUATION While cases of mania following discontinuation of antidepressants have been reported (Goldstein et al., 1999), such cases are so rare that it is difficult to attempt an explanation. We could, however, advance the hypothesis that the excitatory process in these cases was in process, though without as yet manifesting itself clinically. The underlying neuronal processes must precede the appearance of clinical symptoms. The suspension of the antidepressant was probably insufficient to stop the excitatory process already underway. Others have resorted to pharmacologic interpretations focusing on anticholinergic rebound (Dilsaver and Greden, 1984).

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ANTIEPILEPTICS The historic development of the use of antiepileptics in affective disorders is similar to that of lithium. The antimanic effect was discovered first, and only subsequently was a prophylactic effect against both mania and depression revealed. At that point, an attempt was made to establish an antidepressant effect, but this was generally unsuccessful; the antimanic effect, however, was clear. Takezaki and Hanaoka (1971) reported that carbamazepine had an antimanic effect in nine of ten endogenous manic-depressive psychotics; they also found that it had a prophylactic effect in one of their cases. Okuma’s group (1973, 1975, 1979) reported a similar experience with the antimanic effect of carbamazepine in a larger number of cases, and their open trial revealed an antimanic effect in 55% of 90 cases and a prophylactic effect in 67% of 51 manic-depressive patients. Post et al. (2000) reported that 19 controlled studies support the efficacy of carbamazepine in acute mania; 16 of 17 partially controlled studies support its prophylactic efficacy for both manic and depressive recurrences. ‘Carbamazepine’s acute antidepressant properties are less well delineated than its antimanic properties, but the data are highly suggestive that in some treatment-refractory depressed patients, it has both acute and prophylactic efficacy’ (Post et al., 1996a,b). Again, we interpret this to mean effectiveness in the excited features of a depressive mixed state. Lambert and coworkers (1966) noticed both antimanic and antidepressant effects of valpromide, an amidation product of valproate, but subsequent studies (Emrich, Dose and von Zerssen, 1985) have confirmed its antimanic efficacy only. The percentage of responsive patients in trials of bipolar depression has been fewer than 40%, ‘suggesting that any benefits are infrequent and modest’ (Bowden, 1995). In 1996 the FDA approved valproate for the treatment of acute mania. However, in an attempt to demonstrate prophylaxis against bipolar disorder, valproate failed, though it appeared efficacious against secondary depressive measures (Bowden et al., 2003). Despite attempts by researchers to establish an antidepressant effect for pharmacological agents that appear to be mood stabilizing, such an effect has been difficult to establish. Nevertheless, the general belief persists that, in some cases, they do have an antidepressant effect. For example, although many psychiatrists were quick to assume that lamotrigine possesses antidepressant properties, the evidence for such an action is actually rather weak. The difference in improvement between patients treated with lamotrigine and those receiving placebo reported by Calabrese and colleagues (1999) (CGI response 51% and 26% respectively) could be attributed at least in part to the improvement of symptoms of agitation, anxiety and sleep disturbance, which may represent an anti-excitatory, rather than antidepressant, action. In fact, the FDA recently approved lamotrigine for maintenance treatment of bipolar I disorder (Bowden et al., 2003; Calabrese et al., 2003) and

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further stated that, ‘the effectiveness of Lamictal in the acute treatment of mood disorders has not been established’. Lamotrigine appears to be more effective in rapid cyclers (Calabrese et al., 2003), but in this case the rapid succession of states of depression and excitement confounds any putative direct effect on the depressive episodes with an indirect effect resulting from a reduction in mania or hypomania – that is, the attenuation of the depression as a secondary consequence of the attenuation of the excitement, consequent upon an anti-excitatory action of lamotrigine. Another confounding factor is the abundance, among rapid cyclers, of mixed depressions (Koukopoulos et al., 2003) which respond to the anti-excitatory effect of lamotrigine.2

ATYPICAL ANTIPSYCHOTICS The clinical use of atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) in treating affective disorders continues to expand (Ghaemi, 2000). The pattern of discovery of their efficacy in different phases of bipolar illness, however, is the same as with lithium and with the antiepileptics. Efficacy in mania was first demonstrated, and this was followed by the use of atypical antipsychotics as prophylactic agents in bipolar disorder. Antidepressant effects have been attributed to atypical antipsychotics (especially olanzapine; Tohen et al., 2003), and the term ‘atypical antidepressant’ has been proposed (Parker and Malhi, 2001). Ghaemi et al. (2000) report that, ‘accumulating evidence suggests that olanzapine, and atypical antipsychotics in general, possess mild to moderate adjunctive antidepressant properties.’ Olanzapine is indeed very effective in agitated depressions, both psychotic and non-psychotic, but as stated earlier, these syndromes should be considered mixed states, which improve with anti-excitatory agents.

TYPICAL NEUROLEPTICS One should include among the ‘mood stabilizers’ also the typical neuroleptics. At least in Italy, they have been used widely and successfully, especially in their depot preparations, in the prevention of manic attacks. They also prevent depressive episodes. Their great limitations are sedation, sexual inhibition, reduced vitality and the risk of tardive dyskinesia. Despite these limitations, they are probably the most widely used treatment for bipolar I patients in the Italian national health care system, though as in the rest of Europe, a shift to atypicals is occurring.

2

New data reported by Muzina and Calabrese in this book indicate significant antidepressive prophylaxis and promising antidepressant action – Eds.

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Robertson and Trimble (1982) in their review on the use of major tranquillizers as antidepressants found 34 double-blind trials comparing neuroleptics with tricyclics or placebo. The authors comment: ‘Results suggest that some neuroleptics have antidepressant properties, although most studies have been conducted on mixed anxiety-depressive states.’ The only way to avoid misleading results is to investigate retarded, anxious and agitated depression separately.

RECREATIONAL STIMULANT DRUGS The ‘highs’ created by recreational stimulant drugs are often followed by states of mood very similar to depression. Depressive symptoms are, moreover, considered a major component of stimulant withdrawal (Kosten, Markou and Koob, 1998). For example, MDMA (Ecstasy) is a recreational drug that stimulates the release and inhibits the reuptake of serotonin (5-HT). The acute boost in monoamine activity can generate intense feelings of elation and pleasure, as well as hyperactivity. The on-drug experience is generally followed by rebound depression and lethargy, with 80–90% of weekend Ecstasy users reporting ‘midweek blues’ (Parrott, 2001, 2002).

OTHER SOURCES OF EVIDENCE WEHR’S STUDY Further evidence of the primary importance of mania came from a study by Wehr et al. (1998) on the treatment of a rapid-cycling patient by extended bed rest and darkness. The prevention of hypomania was expected, but unexpectedly the depression was prevented as well. ‘Fostering sleep seemed to prevent not only hypomania . . . but also the depression . . . this result appears to be consistent with the hypothesis of Koukopoulos and colleagues (1980, 1983)’.

ANECDOTAL REPORTS Another source of evidence comes directly from bipolar patients and their relatives. They clearly know that their highs are inevitably followed by depression. These impressionistic convictions should not be taken too lightly by psychiatry. They have a direct and continuous experience of the evolution of the disorder. The literature on this point is vast. Jamison (1995) wrote in An Unquiet Mind, ‘it was difficult to give up the high flights of mind and mood, even though the depressions that inevitably followed nearly cost me my life’. Cioran (1992) states that, ‘although I long for luminous ecstasies, I wouldn’t ask for any, because I know they are followed by great depressions.’

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THERAPEUTIC IMPLICATIONS Hecker, in his paper on cyclothymia writes, ‘I consider the principal task of therapy the greatest possible suppression of the excitation’ (Koukopoulos, 2003). We should note that in this statement he is referring to the treatment of cyclothymia and bipolar II, and not mania. It is astonishing that Heinroth, Griesinger and Hecker could have such insights into the nature of bipolar disorder, while in modern psychiatry, despite the tools of neurophysiology and psychopharmacology, such ideas are no longer widely recognized. It was the discovery of the antimanic action of lithium, of antiepileptics and of modern atypical antipsychotics that led to a more appropriate understanding and treatment of bipolar disorders; indeed, the expanding use of antipsychotics and antiepileptics suggest that, albeit unwittingly, modern psychiatry is gradually moving toward acceptance of Hecker’s principle. In clinical practice it is an everyday experience to observe the triggering of mania by antidepressants and, alas, even to witness the administration of antidepressants to clearly excited patients. We have also frequently observed patients whose cyclicity increased considerably over years of repeated or continuous antidepressant treatments. These patients eventually became rapid cyclers (Kukopulos et al., 1983). The rule should be to prevent the emergence of excitation of any kind, and, if excitation has already risen, to suppress it as soon as possible. While this may be relatively easy to achieve during the interepisodic free interval, or at the beginning of a period of excitement, it may be extremely difficult during a depression, because any intervention with an intended antidepressive action may trigger excitement. When a bipolar patient on prophylactic mood stabilizing treatment presents with a depression, the safest approach is to first diminish the dose of the mood stabilizer. This often results in a rapid relief of the depression. This effect is analogous to the excitation that follows the withdrawal of mood stabilizers. Whatever the chosen treatment, however, every effort should be undertaken to prevent a subsequent excitement. If antidepressants are administered, they should be tapered to discontinuation as soon as improvement is manifest and, concomitantly, mood stabilizers increased. Altshuler et al. (2003) found that ‘the risk of depressive relapse in bipolar patients were significantly associated with discontinuing antidepressants soon after remission and the risk of manic relapse was not significantly associated with continuing use of antidepressants.’ Since many patients discontinued antidepressants because of a manic relapse, it is natural that they later relapsed into depression. In our view, the relapse was not associated to the antidepressant discontinuation, but to the occurrence of a manic/ hypomanic attack which inevitably was followed by depression. In difficult cases, ECT is certainly very effective and, furthermore, causes less switching than antidepressants.

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The mild hypomania of many bipolar II and cyclothymic patients and the hyperthymia of many ‘unipolar’ depressives are serious and difficult problems to solve. Patients have difficulty giving up these periods of exuberance and their advantages. It is also a problem for the treating physician to suppress such periods of exuberance during which the person could have a pleasant life and achieve important goals. The line between harmful and fruitful hypomania – dark and sunny hypomania, Akiskal would say (Akiskal, Hantouche and Allilaire, 2003) – is not always clear and, in any case, treatment decisions are difficult considering that in these patients the exuberance will be followed by depression. It is troubling that, despite the continually expanding pharmacological options for the treatment and prevention of depression, clinical outcome of the patients is not improving. Suicide rates are not diminishing (van Praag, 2002), chronic disability due to depression is increasing (Holden, 2000) and in clinical practice it seems clear that bipolarity and cyclicity are on the rise (Kukopulos et al., 1983). And yet, these modern psychopharmacological treatments have proven to be efficacious. There may be other unknown reasons for this high rate of treatment failure, but an important cause may be an inappropriate strategy in the application of psychopharmacological agents. We believe that a more appropriate therapeutic strategy should aim to prevent excitement in all its forms. As far as suicide is concerned, the lack of recognition and adequate treatment of agitated depression as a mixed state (Koukopoulos and Koukopoulos, 1999) may be a significant factor in many attempted or completed suicides.

DISCUSSION The idea that mania has primacy over depression in the manic-depressive cycle sits uncomfortably in the context of the present nosological views. From a purely practical standpoint, depression is, indeed, the more important of the two affective states, and the more difficult to treat. Depression is more frequent than mania and lasts longer. It could be, however, that undetected hypomania is as frequent as depression. Treatment-resistant depressions occur more frequently than do resistant manias; chronic depressions are more common than chronic manias; many more cases of disability arise from depression than from mania; and many more suicides occur during depression than mania. Judd et al. (2002) and Post (2003) reported that the duration of depression outweighs the duration of mania/hypomania by 3 to 4 times. In view of such observations, the idea that depression is secondary to excitatory processes may seem illogical. In this chapter we are referring to mania as the prototype of nervous excitement. Other forms of excitement such as hypomania, mixed states and hyperthymic, cyclothymic and irritable temperaments are of the same nature as mania and probably play the same role in the manic-depressive cycle, in a broad sense. The modern

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concept of the bipolar spectrum (Akiskal, 1983, 2002; Akiskal and Pinto, 1999) corresponds to Kraepelin’s conception of the entity of manic-depressive insanity with the exception of unipolar depression: Manic-Depressive insanity, as it is to be described in this section, includes on the one hand the whole domain of so-called periodic and circular insanity, on the other hand simple mania, the greater part of the morbid states termed melancholia and also a not inconsiderable number of cases of amentia (confusional or delirious insanity). Lastly, we include here certain slight and slightest colourings of mood, some of them periodic, some of them continuously morbid, which on the one hand are to be regarded as the rudiment of more severe disorders, on the other hand pass over without sharp boundary into the domain of personal predisposition. In the course of the years I have become more and more convinced that all the above-mentioned states only represent manifestations of a single morbid process. (Kraepelin, 1913) In a forthcoming paper we shall present clinical data regarding the direct link between these forms of excitement and depressive states. In this chapter, however, discussion is limited to the interpretation of the effects of pharmacological treatments on the course of the illness, and to the significance of such effects as far as the link between manic and depressive processes is concerned.

PHARMACOLOGICAL ACTION All the pharmacological agents used in the prophylaxis of affective disorders have a proven antimanic and prophylactic effect against both mania and depression, while there is little unequivocal support for the view that they also exert any direct antidepressant action. Griesinger’s insight that excitatory phenomena may result in depressive suffering has not yet been appreciated by modern psychiatry. We submit that much of the confusion regarding whether or not lithium, antiepileptics and atypical antipsychotics possess antidepressant properties arises out of their efficacy in cases of mixed depressive states, which are not distinguished from pure depressive disorders by our modern nosology. The vast market potential represented by depressive states has influenced the funding policies of pharmaceutical companies (drug trials, conferences, CME courses, etc.) and this may have influenced the nosologic trends of the last forty years. However, the evolution of pharmacotherapy, as far as prevention of affective disorders is concerned, has proceeded incessantly, though very slowly and with many contrasting views, in one direction: antidepressants worsen the course of the disorder by triggering mania/hypomania and accelerating the course of recurrences (Wehr and Goodwin, 1979; Koukopoulos 1980); anti-excitatory agents, including lithium, antiepileptics and antipsychotics are useful in preventing recurrences.

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NEURONAL ANALOGY OF THE MANIC-DEPRESSIVE CYCLE AND THE PARADIGM OF EPILEPSY The idea of the primacy of excitatory over depressive processes evokes the elementary and fundamental function of the neuron: a stimulus triggers an excitation followed by a refractory period during which the neuron is unresponsive to stimuli. Mania would correspond to the excitatory phase and depression to the refractory one. As far as stimulus is concerned, we should mention all the stimulating conditions that trigger mania: stimulant substances such as narcotics, anorectics, corticosteroids and antidepressants; sleep deprivation; lithium discontinuation; summer heat and light; and psychic stressors, such as mourning and other major life events. John Brown (1795) stated, ‘There is no life without excitement and no excitement without stimulus.’ Hypomania and mania are an excess of life. Depression is, in every respect, a diminution of life. It is conceivable that excessive excitement brings about an exhaustion of nervous activity and results in what we call a ‘depression.’ Kraepelin writes at the end of the chapter on manic states: ‘Very frequently after the disappearance of manic excitement a more or less marked condition of weakness and despondency appears, which is generally regarded as exhaustion after the severe illness; however, it is obviously only the transition to depression, typical of our illness’ (Kraepelin, 1913). There is no doubt that this exhaustion/depression is typical of bipolar disorder. As Cioran (1992) puts it, ‘Sadness accompanies all those events in which life expends itself.’ This relationship is described by Aretaeus and Boerhaave (1735): ‘Once the attack of mania is over they become slowed down, docile, taciturn and sad, and when they recall the illness they have been through they feel anguish for their adversity.’ While comparison of the manic-depressive cycle to the neuronal phenomenon of excitation followed by a refractory period is suggestive of a parallelism with the manic-depressive sequence, there are nevertheless obvious dissimilarities. While the neuronal reaction to stimuli is an all-or-none phenomenon, the manic-depressive cycle consists of phases of heightened excitability (mania) and phases of reduced excitability (depression). Nevertheless, the analogy may be useful in illustrating the rationale for the notion that depression is an inevitable consequence of a preceding period of excitation. As far as mood stabilization is concerned, we maintain that a single agent cannot suppress the excitation of mania and at the same time be able to correct the reduced excitability of the depression. ECT may appear as an exception to this thesis. ECT, however, cannot be considered a single agent; convulsion is a complex phenomenon, consisting of at least two distinct phases: the excitatory phase which produces the muscular contraction and the inhibitory phase which puts an end to the excitation and the muscular contraction. Different neurobiological mechanisms underlie these two phases. Nothing similar is conceivable for pharmacological agents.

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The paradigm of epilepsy is indeed meaningful. After the intense excitation of convulsive seizures, a period of deep inhibition of the nervous system follows. Antiepileptic drugs prevent both phases. It should be noted that such seizureprovoking factors as sleep deprivation, stress, caffeine, cocaine and alcohol also trigger mania. The histories of epilepsy and manic-depressive illness are not casually interwoven. Maintaining that there is an intrinsic link between mania and depression, it follows that an action upon one phase should be reflected in an effect upon the other. The thrust of the arguments presented in this chapter is that the prevention/suppression of mania prevents the depression. This begs the question as to why the treatment of depression does not prevent mania. The answer is simple: it is obvious that if excitation does not occur, a refractory phase cannot follow. The cycle would thus be broken. The aim of treating the refractory phase (depression), however, is to increase nervous excitability, and not only does this not prevent a subsequent mania, but it can lead to an overshoot, triggering mania, and accelerating cyclicity – as is the case with essentially all antidepressant treatments.

OBJECTIONS TO THE PRIMACY OF MANIA There are certainly important objections to the idea of the primacy of mania, and these ought to be discussed. The first is historical and the others clinical. In the second century, Aretaeus of Cappadocia (Aretaeus and Boerhaave, 1735) remarked: ‘It seems to me that melancholia is the beginning and a part of mania.’ This idea reigned until modern times. In the sixth century, Alexander of Tralles (Puschmann 1878) writes, ‘...[mania is] nothing else but the mounting of melancholia towards aggressive excitation.’ Thomas Willis writes (1672) in his De Anima Brutorum, ‘Often these two (melancholia and mania) like smoke and flame mutually exclude and replace each other.’ Regarding this historically rooted idea, Esquirol (1838) comments: several great scholars, Alexander of Tralles and even Boerhaave, thought that melancholia (lypémanie) was nothing but the first stage of mania; this is true in some cases. There are indeed some individuals who, before becoming manic, are sad, morose, restless or anxious, distrustful and suspicious; some of them have a partial delusion with excitation; there are some who feel ill, they complain about headaches, aching limbs, the premonition of a severe disease that threatens them, and even the fear of becoming mad; they are anxious, tormented, they demand and receive many remedies. In these two cases the melancholic or hypochondriac symptoms are the prodromes of mania; this is the incubation period: these symptoms cannot deceive the expert; they are the signs of a manic attack ready to blow. (pp. 141–142) and

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A few hours, a few days, a few months prior to the explosion of mania, there are individuals who are hypochondriac, deeply melancholic while there are others who fall into a deep stupor . . . (p. 146) We agree with Esquirol. We have seen many patients with this course, which is probably the basis for the ancient belief. This particular course of illness also illustrates that excitatory processes may express themselves on the psychic level, as dysphoric and depressed mood. This fundamental clinical fact is also evident in the third stage of mania described by Carlson and Goodwin (1973). The first clinical objection to the concept espoused in this chapter stems from the fact that approximately 25% of bipolar cases start with depression followed by hypomania or mania (Kukopulos et al., 1980). Eighty percent of patients with this cycle sequence are bipolar II. Such patients have an excitable and labile temperament. The depression in such patients is not really the beginning of the cycle and does not come out of the blue; periods of temperamental instability, stress (including emotional excitation due to life events, both positive and negative), use of stimulants, or irregular sleep patterns, usually precede the depression. Akiskal et al. (1995) formulates the complex relationship between temperament and morbid episodes as follows: ‘Bipolar II represents the most fascinating interface between affective episodes and temperamental instability.’ The second clinical objection to the primacy of mania stems from the existence of two forms of depression: unipolar depression, in the course of which there are no evident manias/hypomanias, and depression occurring in association with states of anxiety. It could well be that these depressions are different from bipolar depressions and originate from a different process in which there is no link to excitatory phenomena. The following alternative view could be taken into consideration. Many unipolar depressions occur in people with hyperthymic temperaments and can thus be considered as belonging to the bipolar spectrum. This entity has been labeled by Cassano et al. (1992) as unipolar with hyperthymic temperament (U H-T) and by Akiskal and Pinto (1999) as bipolar IV. In many other cases, the depression is preceded by stressful life events that cause distress, nervous tension, anxiety, sleep disturbance and other neurovegetative disturbances, and the person is often involved in a flurry of tiring activities. These stressful periods must have a causal connection to the subsequent depression. It is known, for instance, that depression follows the life event several weeks or months later and this period of time is very stressful. We propose that these periods be termed hypomanic equivalents because of the nervous tension, emotional turmoil, hyperactivity and reduction in sleep that often accompany them. In predisposed people, they can bring about the same nervous exhaustion/ depression as true mania or hypomania. The basic difference between these cases and bipolar patients may be the predisposition to cyclicity of the latter.

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In many other cases, the depression follows a period of intense anxiety often accompanied by panic attacks. Anxiety, and especially a panic attack, is a phenomenon of intense nervous arousal. In this case, too, nervous exhaustion could be viewed as the cause of the depression. This type of depression could be called anxiety-associated depression. The phenomenon of nervous “exhaustion/depression” following different types of prolonged neuronal excitation evokes the more severe phenomenon of excitotoxicity following prolonged excitation and resulting in neural damage and death.

DEPRESSION AS A CONSEQUENCE OF PROLONGED NERVOUS AROUSAL According to the above-proposed hypothesis, depression would follow, and be a consequence of, states of prolonged nervous arousal, such as mania, hypomania, hypomanic equivalents and anxiety, that eventually create a state of nervous exhaustion. This hypothesis would indicate a parallelism between bipolar and unipolar depressions and would explain the efficacy of mood stabilizers in the prophylaxis of unipolar as well as of bipolar depression. The continuous presence of a mood stabilizer in the organism prevents or attenuates this nervous arousal and, by doing so, prevents the genesis of the depression. It is also clear that appropriate changes in lifestyle and sleep pattern, and the avoidance of stimulants and stressful life situations, when possible, are of crucial importance.

IMPLICATIONS FOR EVOLUTIONARY THEORY The primacy of mania would also offer a simple explanation to the evolutionary puzzle of depression. Several authors (Watson and Andrews, 2002; Nesse, 2000; Thierry et al., 1984) have recently focused their attention on the adaptive advantages of depression. According to the theory presented herein, it would not be the depression that presents adaptive advantages but the periods of excitement. Mania, or at least hypomania, offers selective advantages, providing a high level of energy, hyperactivity and aggressiveness, hypersexuality, as well as creativity of thought. High activity level is an asset throughout nature. The excitement would bring about the depression which, in itself, would not carry adaptive advantages but only disadvantages. If depression is a consequence of mania, its evident adaptive disadvantages must be less important than the advantages conferred by mania, so that the balance of selective advantage lies with mania. It was mania, therefore, and not depression, that was selected for. Even the severe disadvantages of mania are often compensated for by the advantages of the temperamental hyperthymia of bipolar I patients.

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ACKNOWLEDGEMENTS The author wishes to thank Matthew J. Albert, Gabriele Sani, Neil F. Johnson, Alexia E. Koukopoulos, Leonardo Tondo, Andreas Erfurth, Daniela Reginaldi, Luca Pani and Denis Greenan for their invaluable help in the preparation of this manuscript.

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Parrott, A. C. (2002) Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav. 71, 837–44. Perris, C. (1966) A study of bipolar (manic-depressive) and unipolar recurrent depressive psychoses. Acta Psychiatr Scand Suppl. 194, 9–189. Pinel, P. (1801) Traité médico-philosophique sur l’aliénation mentale, ou La manie, Richard Caille et Ravier, Paris. Post, R. M., Ketter, T. A., Denicoff, K., Pazzaglia, P. J., Leverich, G. S., Marangell, L. B., Callahan, A. M., George, M. S. and Frye, M. A. (1996a) The place of anticonvulsant therapy in bipolar illness. Psychopharmacology (Berl). 128, 115–29. Post, R. M., Ketter, T. A., Pazzaglia, P. J., Denicoff, K., George, M. S., Callahan, A., Leverich, G. and Frye, M. (1996b) Rational polypharmacy in the bipolar affective disorders. Epilepsy Res Suppl. 11, 153–80. Post, R. M., Weiss, S. R. B., Clark, M., Chuang, D., Hough, C. and Li, H. (2000) In Bipolar medications: Mechanisms of action, Manji, H. K., Bowden, C. L. and Belmaker, R. H. (eds). American Psychiatric Press, Washington, DC, pp. 219–48. Post, R. M., Baldassano, C. F., Perlis, R. H. and Ginsbery, D. L. (2003) Treatment of bipolar depression. CNS Spect. 8 (12), pp. 1–10. Puschmann, T. (1878) Alexander von Tralles, Wilhelm Braumüller, Wien. Reginaldi, D., Tondo, L., Floris, G., Pignatelli, A. and Kukopulos, A. (1981) Poor prophylactic lithium response due to antidepressants. Int Pharmacopsychiatry. 16, 124–8. Robertson, M. M. and Trimble, M. R. (1982) Major tranquillisers used as antidepressants. A review. J Affect Disord. 4, 173–93. Schneider, K. (1959) Clinical Psychopathology. New York, Grune and Stratton. Schou, M. (1963) Normothymotics, “Mood-Normalizers”: Are lithium and imipramine drugs specific for affective disorders? Brit J Psychiat. 109, 803–809. Schou, M., Juel-Nielsen, N., Stromgren, E. and Voldby, H. (1954) The treatment of manic psychoses by the administration of lithium salts. NJ Neurol Neurosurg Psychiatry. 17, 250–260. Stoll, A. L., Tohen, M., Baldessarini, R. J., Goodwin, D. C., Stein, S., Katz, S., Geenens, D., Swinson, R. P., Goethe, J. W. and McGlashan, T. (1993) Shifts in diagnostic frequencies of schizophrenia and major affective disorders at six North American psychiatric hospitals, 1972–1988. Am J Psychiatry. 150, 1668–73. Suppes, T., Baldessarini, R. J., Faedda, G. L. and Tohen, M. (1991) Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry. 48, 1082–88. Takezaki, H. and Hanaoka, M. (1971) The use of carbamazepine (Tegretol) in the control of manic-depressive psychosis and other manic-depressive states. Seshin-igsku. 13, 173–183. Thierry, B., Steru, L., Chermat, R. and Simon, P. (1984) Searching-waiting strategy: A candidate for an evolutionary model of depression? Behav Neural Biol. 41, 180–89. Tohen, M., Vieta, E., Calabrese, J., Ketter, T. A., Sachs, G., Bowden, C., Mitchell, P. B., Centorrino, F., Risser, R., Baker, R. W., Evans, A. R., Beymer, K., Dube, S., Tollefson, G. D., Breier, A. (2003) Efficacy of Olanzapine and Olanzapine/fluoxetine in combination in the treatment of bipolar I depression. Arch Gen Psych. 60, 1079–1088. Tondo, L., Hennen, J. and Baldessarini, R. J. (2001) Lower suicide risk with long-term lithium treatment in major affective illness: A meta-analysis. Acta Psychiatr Scand. 104, 163–72. van Praag, H. M. (2002) Why has the antidepressant era not shown a significant drop in suicide rates? Crisis. 23, 77–82.

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Watson, P. J. and Andrews, P. W. (2002) Toward a revised evolutionary adaptationist analysis of depression: The social navigation hypothesis. J Affect Disord. 72, 1–14. Wehr, T. A. (1989) In Seasonal Affective Disorders and Phototherapy, Rosenthal, N. E. and Blehar, M. C. (eds) The Guilford Press, New York, London. Wehr, T. A. and Goodwin, F. K. (1979) Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry. 36, 555–9. Wehr, T. A., Turner, E. H., Shimada, J. M., Lowe, C. H., Barker, C. and Leibenluft, E. (1998) Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep. Biol Psychiatry. 43, 822–8. Willis, T. (1672) De anima brutorum, e Theatro Sheldoniano, impensis Ric. Davis, Oxonii.

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CHAPTER

11 Diagnostic and Clinical Management Approaches to Bipolar Depression, Bipolar II and Their Comorbidities Giulio Perugi1,2, S. Nassir Ghaemi3 and Hagop Akiskal4 1

2

Institute of Behavioral Sciences “G De Lisio”, Carrara-Pisa, Italy Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, Section of Psychiatry, University of Pisa, Pisa, Italy 3 Bipolar Disorder Research Program, Emory University, Department of Psychiatry, Atlanta, MA, USA 4 International Mood Center, Department of Psychiatry at the University of California at San Diego, La Jolla, USA

INTRODUCTION The correct diagnosis of bipolar depression has major implications for clinical practice. It has emerged as a major challenge in the treatment of bipolar disorder. Hence the need for a chapter to focus on it. During the last two decades, neuropsychopharmacology has developed new relatively selective antidepressants, anticonvulsants with mood stabilizing properties and atypical antipsychotics with broad spectrum clinical effectiveness across diagnoses. Even if classical euphoric, dysphoric (mixed) and psychotic mania may be successfully treated respectively with lithium, anticonvulsants and atypical antipsychotics, the treatment of bipolar depression remains a clinical dilemma. Although the acute efficacy of various classes of antidepressants (SSRIs, SNRIs, Trycyclics, etc.) in bipolar depression is not in doubt (Pope and Hudson, 1982; Bottlender et al., 1998), there is growing concern about the possibility that these drugs might worsen the course of bipolar illness, favoring the “switch” processes and rapid cycling (Kukopulos et al., 1980; Akiskal and Mallya, 1987; Wehr and Goodwin, 1987; Ghaemi et al., 2003). Moreover, it is uncertain how best to manage agitated depression and other mixed depressive states. Finally, bipolar II depression with its multiple comorbidities is among the most misdiagnosed and mistreated conditions in psychiatry. Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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BIPOLAR DEPRESSION Misdiagnosis and inadequate treatment of bipolar depression are two of the main reasons of “pseudorefractoriness” to antidepressant drugs. The nosological approach proposed by the current international diagnostic manuals and the huge availability of a large number of safe and well-tolerated antidepressants have contributed toward an over-diagnosis of unipolar depression (Akiskal and Pinto, 1999). Both DSM-IV and ICD-10 propose criteria that are inclusive for major depression and overly restrictive for bipolar disorder. As a consequence, many patients wait a long time to receive a correct diagnosis. In a research study conducted by the Depressive and Manic-Depressive Illness National Association (Lish, Dime-Meenan and Whybrow, 1994) on a large sample of bipolar subjects, 48% were diagnosed as bipolar only after being visited by three or more psychiatrists, 57% were diagnosed otherwise, more commonly as unipolar major depression (44%), or schizophrenia (34%). A correct diagnosis was formulated only after a mean of about 8 years of other than mood stabilizer treatment. Similarly, in a research study of 48 bipolar I inpatients, 40% of them had been previously diagnosed as unipolar (Ghaemi etal., 1996) and, again, the correct diagnosis was made with a delay of about 8 years. The situation seems to be even worse in the less severe cases; in a follow-up study on 54 bipolar outpatients, including a bipolar II subgroup, the mean timeframe from the first psychiatric observation to the correct diagnosis was about 12 years (Ghaemi, Boiman and Goodwin, 2000). This is critical because suicide in bipolar illness occurs within the first decade of the illness (Guze and Robins, 1970). Lack of insight during mania is one of the most important misleading factors (Amador, Flaum and Andreasen, 1994; Michalakeas et al., 1994; Ghaemi, Stoll and Pope, 1995) in the diagnostic and therapeutic process. As insight is less impaired during depression, diagnostic evaluation based only on patient interview may lead to an underestimation of mania. For this reason, interviewing relatives may mitigate this memory bias (Akiskal et al., 2000). In fact, in a study on prodromal symptoms of mania and depression (Keitner, Solomon and Ryan, 1996), relatives reported manic symptoms twice more frequently than patients (47% vs 22%), while both relatives and patients reported similar percentages of depressive symptoms. Although gathering information from relatives or previous physicians is essential for an accurate diagnostic procedure, cross-sectional or retrospective evaluation by itself can contribute to the underdiagnosis of bipolar disorder (Sprock, 1988). Both clinical and cultural variables seem to contribute to the under-recognition of bipolar disorders in general, and bipolar depression in particular. Depressive symptomatology causes more subjective distress than mania; for this reason patients seek help mostly during depressive episodes and almost never during hypomanic episodes. Moreover, current clinical practice seems to be guided by a “depressocentric” approach (Ghaemi, Boiman and Goodwin, 2000). In the last 50 years, in fact, researchers’, clinicians’ and the public’s interest

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has been mainly focused on diagnosis and treatment of depression, while less attention has been devoted to the recognition and treatment of mania and hypomania. This attitude, at least partially, might be favored by the availability of efficacious and safe antidepressants (Baldessarini, 1994); however, among the cultural pressures that contribute to an overdiagnosis of depression and to an underestimation of (hypo)mania is the general “depressophobic” attitude in modern western society. Optimism, narcissism, dynamism, craze for activity, high energy and extroversion are considered “healthy” and positive characteristics; conversely, pessimism, selfconsciousness, slowness, irresoluteness and introversion are viewed negatively and easily attributed to a psychopathological condition. What could be considered particularly pathological in hypomania is a “dark” side characterized by irritable mood lability, impulsivity and increased consumption of drugs, and social instability which are frequently present, but often attributed to an erratic personality problem (Akiskal and Benazzi, 2003).

BIPOLAR II AND RELATED “COMORBID” DISORDERS ISSUES IN DIAGNOSING HYPOMANIA While both type I and type II bipolar conditions are often misdiagnosed, the inability to recognize past hypomania appears to be a special problem in the underestimation of bipolar depression. Although bipolar II may represent the most common bipolar phenotype (Simpson et al., 1993), it is often unrecognized, poorly researched and typically mismanaged. Hypomania is difficult to diagnose with current operational diagnostic criteria. In DSM-IV, in fact, hypomania is defined as a less severe form of mania without providing specific criteria. Mania is essentially a condition of psychomotor excitement, etc. The differential diagnosis of mania, due to its severity and impairment of functioning, has to do with schizophrenia or, with mixed states, severe depression. Hypomania, on the other hand, due to its less extreme manifestations and to its relatively unimpaired (and sometimes enhanced) functionality, has to be distinguished from “normality” and personality disorders. In the DSM-IV criteria, differences between manic and hypomanic episodes are not adequately specified. To further complicate matters, hypomania can sometimes be adaptive (Jamison et al., 1990) and by DSM-IV definition not associated with state-dependent life disruptions. Unfortunately, the statement in that latter that “in contrast to manic episode, hypomania is not severe enough to cause marked impairment in social or occupational functioning” is not only vague, but is responsible for a low diagnostic concordance (Gershon and Guroff, 1984), with the result that hypomania is often misinterpreted as “happiness,” and mania as hypomania. This often leads to bipolar I disorder frequently being diagnosed, if at

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all, as bipolar II disorder, while bipolar II disorder tends to be completely missed. Moreover, the four-day threshold of DSM-IV for the duration of the episode is unjustified and unnecessarily narrow. An extensive literature based on clinical and community samples validates the definition of hypomania at a duration threshold of two, rather than four, days (reviewed in Akiskal et al., 2000), reporting a modal duration of 1–3 days (Wicki and Angst, 1991).

ANTIDEPRESSANT-ASSOCIATED HYPOMANIA/MANIA Another important question for clinical practice pertains to hypomania that first manifests upon pharmacological treatment with antidepressants; both DSM-IV and ICD-10 have denied bipolar status to these patients. This is an unfortunate decision because an extensive literature strongly supports the inclusion of such patients within the rubric of bipolar disorders (Bunney et al., 1972; Akiskal, Khani and Scott-Strauss, 1979; Akiskal et al., 1983; Sultzer and Cummings, 1989; Altschuler etal., 1995; Benazzi, 1997b; Post etal., 1997). In prospective observations, nearly all adult patients with antidepressant-associated hypomanic episodes progress months or years later to bipolar states with spontaneous hypomania or mania (Akiskal et al., 1983); this also appears to be true for adolescent depressives (Strober and Carlson, 1982). Moreover, patients developing mood switches with antidepressants, especially at the beginning of the treatment, often present a family history of bipolar disorders and manifest a vulnerability to rapid cycling (Kilzieh and Akiskal, 1999). Hence, depressive episodes followed by pharmacological hypomania seem to represent a subtype of bipolar II pattern, which some authors describe as bipolar disorder, type III (Akiskal and Benazzi, 2003), conceptualized as a genetically “less penetrant” form of bipolar disorder requiring exogenous input from antidepressants. The same is probably generally true for phototherapy, sleep deprivation and electroconvulsive therapy. Interestingly, antidepressant-associated hypomania is not limited to major depressions. It can occur in dysthymic patients (Rosenthal et al., 1981; Rihmer, 1990), as well as social-phobic, obsessive-compulsive and other anxiety states (Himmelhoch, 1998; Perugi et al., 1999). In brief, the depressive phase of bipolar II patients can, in a significant minority of patients, be replaced by subthreshold depressive, socially anxious or obsessive inhibitions (Himmelhoch, 1998). The same is true for switches in borderline personality disorder (Akiskal et al., 1985; Levy and Brown, 1985).

THE EVALUATION OF HYPOMANIA Independently from diagnostic criteria, bipolar II diagnosis also depends on the patient’s ability to recall hypomanic episodes, and on the patient’s awareness that

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they represent part of the affective illness. In fact, in most cases, patients do not consider hypomania as an expression of the illness, but rather as a period of wellbeing. Therefore, in addition to the clinician’s skill in interviewing patients and in the interpretation of the illness manifestations, the correct diagnosis is often achieved only because of the contribution of relatives and other collateral observers. A correct diagnosis can be formulated only after an in-depth evaluation focused on hypomanic symptoms and related behavioral consequences, such as unusual hyperactivity, impulsiveness and uninhibited or inappropriate demeanor (Benazzi and Akiskal, 2003). Dunner and Tay (1993) found that clinicians specifically trained to recognize bipolar II outperformed such structured instruments as the SAD or the SCID in the diagnosis of bipolar II disorder. Although this point goes against the grain in the literature on structured interviewing, it is consistent in suggesting that the proper identification of bipolar II requires a more sophisticated clinical approach in interviewing and diagnosis. In line with earlier findings (Akiskal et al., 1977), current data indicate that intense activation in psychomotor, social and professional spheres may better define clinical hypomania than elated mood (Benazzi and Akiskal, 2003).

THE PREVALENCE OF BIPOLAR II The French Clinical Epidemiology of Depression (EPIDEP) database (Hantouche et al., 1998), deriving from a national sample of a variety of hospital and outpatient settings in France, has provided the most compelling data on the high prevalence of bipolar II among major depressive patients. At index interview 22% of nearly 500 major depressive patients could be diagnosed as DSM-IV bipolar II; a month later, upon re-interview, 40% of patients were diagnosed within the bipolar II spectrum on the basis of more in-depth evaluation and collateral information from significant others, as well as observed hypomania by the clinician. A great deal of research has been conducted on the clinical prevalence of bipolar II among patients presenting with major depressive disorder to various clinical settings worldwide. What emerges is that from 30 to 70% of all major depressions conform to the features of bipolar II or its variants (reviewed in Akiskal et al., 2000; and amplified in Akiskal and Benazzi, 2003). It is noteworthy that the data are not limited to academic centers specializing in mood disorders (Akiskal and Mallya, 1987; Cassano et al., 1992), but include at least two large outpatient psychiatric private practice settings (Kukopulos et al., 1980; Benazzi, 1997a) and one family practice clinic (Manning et al., 1997). The diagnosis of bipolar II depression is crucial not only because of its therapeutic implications but also for prognostic reasons. These patients are at high risk for relapse and for multiple episodes (Coryell et al., 1995; Vieta et al., 1997), and

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show a higher rate of suicide attempts and completed suicides than bipolar I or unipolar patients (Rihmer and Pestality, 1999). Bipolar II depressions typically have an early onset, tend to be chronic, with atypical features, and are interspersed with mild hypomanias and infrequent euthymic periods (Coryell et al., 1987; Benazzi, 1999). Although depressive symptomatology is usually mild to moderate in severity, bipolar II patients function more poorly than expected. This appears to be related to a high frequency of coexisting “non-affective” psychopathology such as panic attacks, phobias, alcohol and drug abuse, eating disorders and personality disorders (Perugi et al., 1998, 1999).

COMORBIDITY Bipolar II spectrum includes, in fact, a wide range of psychopathological manifestations and numerous behavioral disorders that suggest a bipolar diathesis which must be explored thoroughly (Perugi and Akiskal, 2002). A history of “hyperactivity” during childhood is more frequent in bipolar patients than in unipolar ones (Winokur etal., 1993), as well as a history of stimulants and alcohol abuse (Regier etal., 1990; Winokur etal., 1998; Sonne and Brady, 1999). Many cyclic, periodic or recurrent phenomena, such as seasonality, high depressive episode recurrence, recurrent irritability, recurrent neurasthenia or periodical sleep disturbances, can also be interpreted along the lines of bipolar II (Akiskal and Pinto, 1999). Furthermore, the episodic course of obsessive-compulsive disorder is often associated with bipolar II disorder (Perugi etal., 1999) and therefore a careful characterization of concurrent affective manifestations is needed. Recently, it has been suggested that some impulsive behaviors, such as explosive personality disorders, pathological gambling and some paraphilias, may belong to the bipolar spectrum (McElroy etal., 1996). Comorbidity among bipolar II, anxiety and impulse control disorders represent a complex picture, susceptible to different pathogenetic interpretations. The pathological process underlying bipolar II disorder does extend beyond euphoric and depressive dimensions, including dysphorically aroused affective states, such as anxiety, panic, irritability and impulsivity (Perugi and Akiskal, 2002). The so-called alcohol- or substance-induced mood disorders may have much in common with bipolar II spectrum disorders, in particular when mood swings outlast detoxification (Maremanni et al., 2004). Finally, many patients within the Bipolar II spectrum, especially when recurrence is high and the inter-episodic period is not free of affective manifestations, may meet criteria for personality disorders. This is particularly true for cyclothymic bipolar II patients, who are often misclassified as borderline personality disorder because of their extreme mood instability and reactivity (Akiskal et al., 1985; Perugi et al., 2003; Perugi and Akiskal, in press). Actually, mood lability of a cyclothymic nature should be considered the core characteristic of the bipolar II spectrum, and it has been prospectively validated as

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Table 11.1: Psychiatric comorbidity in bipolar disorder • • • • • • • •

Psychosis Alcohol and Stimulant Abuse ADHD Dramatic cluster PD (e.g. borderline) Bulimia Social phobia Panic attacks Obsessive-compulsive phenomena

a sensitive and specific predictor of bipolar II outcome in major depressives (Akiskal et al., 1995). The enlargement of classical bipolar II disorders to include a spectrum of conditions subsumed by a cyclothymic-anxious-sensitive disposition, with mood reactivity and interpersonal sensitivity, and ranging from mood, anxiety and impulse control disorders, will greatly enhance both clinical practice and research endeavors. In fact, viewing these constructs as related entities with a common affective temperamental diathesis will make these patients more accessible to pharmacological and psychological approaches geared to their common temperamental attributes. The common “comorbidities” of bipolar spectrum conditions are summarized in Table 11.1. Even if the comorbid conditions listed are viewed by many as distinct from bipolar disorders, the rigorous treatment of the bipolar disorder itself will often have a salutary effect on the outcome of these conditions. There are those who consider too much attention to mood lability – the presence of “mood swings” – as nonspecific and likely to lead to overdiagnosis of bipolar disorder. However, while a good deal of evidence suggests underdiagnosis of bipolar disorder, as noted earlier, no published data have provided evidence of overdiagnosis of bipolar disorder. Further, our perspective is not meant to imply that anyone with mood lability automatically has bipolar disorder, but rather that anyone with mood lability may have bipolar disorder and that the bipolar diagnosis needs to be carefully assessed in such patients. More on this will be said later in this chapter.

DEPRESSIVE MIXED STATES KRAEPELIN’S CONCEPTUAL FRAMEWORK Mixed States (MS) are characterized by the mixture of depressive and manic symptoms and, since Kraepelin (1921), have represented the main unifying element in manic-depressive illness, showing that mania and depression are different expressions of the same illness. Kraepelin observed that mixed states only rarely derive from the co-presence of full-blown manic and depressive pictures; more

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often, some depressive features are present during mania, or hypomanic features appear within depression. In Kraepelin’s systematization, at least six types of mixed states were recognized; among which, anxious or depressive mania and agitated or excited depression are the most common in contemporary psychiatric practice. Although this broad classification is accepted by prominent European psychiatrists (e.g. Berner et al., 1992), DSM-IV identifies MS as the condition in which full-blown major depression and mania are simultaneously present. The American manual does not consider cases in which expansive and depressive elements are combined without fully satisfying the criteria for one or the other type of episode (Perugi et al., 1997). Therefore, despite their clinical relevance, the depressive forms of mixed state are not included in the current official classificatory systems and, until recently, they were largely neglected in the current literature (Akiskal and Benazzi, 2003).

BIPOLAR I MIXED STATES Mixed depressive states are common in bipolar inpatients, and are associated with psychotic symptoms, a high risk of suicide and the tendency to develop a chronic course (Perugi etal., 2001). At a cross-sectional examination, perplexity, impulsivity and accelerated thinking are common (Koukopoulos et al., 1995; Koukopoulos and Koukopoulos, 1999). Unfortunately, these symptoms are not considered as possible markers of mixed states by the current classificatory systems, and the diagnosis of “unipolar” major depression is formulated. From an operational point of view, this classificatory restriction is misleading for therapeutic choices, as antidepressants would then be preferred over mood stabilizers. In order to better characterize depression with mixed features, we compared familial, demographic, clinical and course characteristics of 32 patients with depressive mixed state and those of 36 patients with major bipolar depression (Perugi et al., 2001). The two groups had close similarities in clinical and socio-demographic characteristics, including age, gender distribution, marital status, schooling, residence, age at onset, age of first treatment, age of first hospitalization, percentage of chronicity of the index episode, lifetime suicide attempts and premorbid temperamental dispositions. First-degree family history for bipolar illness and other mental disorders was also similar, except that for major depression, which was significantly more common among the relatives of depressive mixed states. These findings were in part foreshadowed in a previous Pisa study on mixed states from the female unit at our Institute (Dell’Osso et al., 1991), where an excess of depressive familial background had been observed in the entire sample (that had not been divided into depressive and manic mixed state). Patients with depressive mixed states can be distinguished from nonmixed bipolar depressives by the fact that they present fewer episodes of longer duration,

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and frequently begin their illness with a mixed episode (Perugi et al., 2001). In agreement with previous clinical observations (Akiskal and Mallya, 1987; Koukopoulos et al., 1995), the symptomatological profile of depressive mixed state is characterized by agitated, mostly psychotic, depression with irritable mood, pressured speech and flight of ideas. For instance, Akiskal and Mallya (1987) reported that 25 patients referred for treatment-resistant depression displayed subacute or chronic mixed states, apparently induced by tricyclic antidepressants; these patients were characterized by dysphoria, severe agitation, refractory anxiety, unendurable sexual excitement, intractable insomnia, suicidal obsessions and impulses and “histrionic” demeanor; they improved with antidepressant discontinuation and initiation of lithium or neuroleptics. Koukopoulos et al. (1995) observed that 45 patients with bipolar disorder, suffering from a “mixed depressive syndrome” who met DSM-III-R criteria for major depression, but not for mania, deteriorated when treated with antidepressants, experiencing increased agitation, insomnia and, in some cases, suicidal impulses; these same patients responded to low-dose neuroleptics, lithium, anticonvulsants and ECT. Koukopoulos and Koukopoulos (1999) have subsequently written a scholarly review on the clinical rationale for the validity of the concept of agitated depression as a mixed state. In light of the foregoing observations, we submit that depressive mixed states might underlie the suicidality attributed to antidepressants (Akiskal et al., 2005; Akiskal and Benazzi, 2005). In children, in particular, this issue of antidepressant induced suicidality may reflect undiagnosed bipolar disorder, since data suggest that about 50% of all depressed preadolescent children, without any evidence of mania or hypomania, will develop manic or hypomanic episodes in 10-year follow-up (Geller et al., 2001).

BIPOLAR II MIXED STATES The literature reviewed pertains largely to mixed states and agitated depression observed among hospitalized and/or psychotic patients. A high prevalence of hypomanic features has been reported (Benazzi, 2000; Benazzi and Akiskal, 2001) in depressed bipolar II and unipolar outpatients as well. Among 70 outpatients with major depression, the prevalence of full syndromal hypomania was low (2.8%), but three or more concurrent hypomanic symptoms were reported in 28.5% of the sample. About half (48.7%) of bipolar II patients had three or more concurrent hypomanic symptoms during major depression. Irritable mood, talkativeness and distractibility were significantly more common in bipolar II than in unipolar patients; racing thoughts were highly prevalent in both unipolar and bipolar II. Among the (hypo)manic symptoms reported in depressive mixed states (termed “DMX” by Benazzi and Akiskal, 2001), flight of ideas, racing thoughts and distractibility belong to the same dimension of psychic excitement. Increased mental activity (day dreaming, mental ruminations) has been reported as one of

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the fundamental features of bipolar II “depression” (Akiskal et al., 1995; Perugi etal., 1998). Other hypomanic symptoms such as grandiosity are relatively uncommon in depression and to be utilized for the selection of patients with DMX, whereas irritability and restlessness might be somewhat nonspecific. However, depressions with sexual arousal are almost always bipolar mixed states (Akiskal and Mallya, 1998; Akiskal and Benazzi, 2004). According to Akiskal and Benazzi (2001), unipolar depressives with DMX might be classified into the bipolar spectrum, and must be considered ‘pseudo-unipolar’. Two longitudinal studies indicated that intra-episodic hypomanic symptoms during a depressive episode predict a diagnostic switch from unipolar depression to bipolar disorder (Akiskal et al., 2004; Sato et al., 2004). The bipolar nature of depressive mixed states, even among “unipolar” DMX, is validated by family history of bipolar disorder (Akiskal and Benazzi, 2003). Moreover, the suicidal trends in agitated depressions are significantly related to bipolar family history (Akiskal et al., 2004, in press). These considerations may in turn be related to the suicidality risk of bipolar disorder, overt or cryptic (Rihmer and Pestality, 1999). Clinical observations suggest that unipolar DMX may not adequately respond to antidepressants, and that the use of antidepressants for unipolar depressives with intra-episodic hypomanic symptoms may be operative in treatment resistance or lead to cycling (Akiskal and Mallya, 1987; Koukopoulos et al., 1995). Welldesigned controlled trials with antidepressants versus mood stabilizers and/or other anti-manic agents should be conducted comparing unipolar depressives with and without intra-episode excitatory symptoms.

PHARMACOTHERAPY Such studies are of great importance for public health because the majority (over 90%) of bipolar patients seen in clinical practice today belong to the bipolar II spectrum (Akiskal and Mallya, 1987; Cassano et al., 1992; Benazzi and Akiskal, 2001). Yet, drug treatment of bipolar depression is surprisingly understudied, especially in comparison to mania and unipolar depression. The lack of adequate research in this area is even more astonishing considering that depressive episodes and symptoms prevail in most bipolar patients seen in clinical practice (Judd et al., 2002, 2003) and are associated with high degree of suffering and disability and with a significant risk of suicide and high mortality for different causes. Agents such as lithium, valproate and carbamazepine have been studied much more thoroughly in mania than in bipolar depression. Similarly, only a few controlled studies focused on the efficacy of antidepressants in monotherapy. The relative risk of (hypo)manic switches or of rapid cycle induction further complicates the treatment of bipolar depression. In fact, while some guidelines advise limiting the use of antidepressants, others suggest the possibility of utilizing antidepressants

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in combination with mood stabilizers. Finally, amongst new anticonvulsants and atypical antipsychotics, lamotrigine and olanzapine, respectively, have shown antidepressant properties in bipolar patients opening new opportunities in the treatment of this phase of manic-depressive illness.

TREATMENT OF THE ACUTE PHASE Only a limited number of controlled studies in the treatment of acute bipolar depression have been conducted. In a recent review of the literature, Thase and Sachs (2000) claimed that not a single antidepressant medication, nor even a particular class of antidepressant, has been demonstrated to be effective in at least two adequately powered, placebo-controlled clinical trials. This may not be entirely accurate. Among antidepressants that have been studied in the 1970s and 1980s, particular attention was devoted to tranylcypromine, an irreversible MAOI that was efficacious in two controlled studies versus placebo (Himmelhoch, Fuchs and Symons, 1982; Himmelhoch et al., 1991). While these studies demonstrate that MAOIs are better than placebo, they do not answer the clinical question whether addition of MAOI to a mood stabilizer like lithium is better than lithium alone. Amongst tricyclic antidepressants, the most studied was imipramine; which, in one study, proved to be more efficacious than placebo (57% vs 38% of responders). The drug has also been compared to several active compounds, such as fluoxetine (Cohn et al., 1989), moclobemide (Baumhackl et al., 1989), maprotiline (Kessell and Holt, 1975) and tranylcypromine (Himmelhoch et al., 1991). Response rates were similar for imipramine, moclobemide and maprotiline, but tranylcypromine was more efficacious than imipramine. While the fluoxetine study reports greater efficacy than imipramine, this result is confounded by the fact that lithium was nonrandomly given to more patients in the fluoxetine arm than the imipramine or placebo arms, making the study more of a comparison of fluoxetine plus lithium versus imipramine alone. Randomized studies on SSRIs are limited to a comparison between fluoxetine, imipramine and placebo (Cohn et al., 1989) and to two recent double blind placebocontrolled studies (Young et al., 2000; Nemeroff et al., 2001), evaluating the adjunctive efficacy of paroxetine to lithium and valproate. In the first study, fluoxetine was more efficacious than placebo (86% vs 38%); as mentioned earlier, however, a higher percentage of patients treated with the active drug were also taking lithium, compared to the percentage of patients who received placebo (17/30 vs 10/29). In the other two studies (Young etal., 2000; Nemeroff etal., 2001), paroxetine showed an additive antidepressant efficacy only in patients with a low serum level of lithium. While one of the studies (Young et al., 2000) has been criticized for small sample size, the other (Nemeroff et al., 2001) was adequately powered to demonstrate even a moderate effect size benefit with paroxetine. Patients treated with paroxetine had a low rate of switching, similar to that observed with

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placebo. In combination with data derived from other studies on SSRIs ( Kupfer etal., 2001), venlafaxine (Vieta et al., 2002) and bupropion (Sachs, Lafer and Stoll, 1994) seem to indicate that new antidepressants are as efficacious as tricyclics, but perhaps with a lower risk of inducing (hypo)manic switches (Peet, 1994). A recent meta-analysis (Gijsman et al., 2004) claimed evidence of benefit with antidepressants in bipolar disorder compared to placebo, and no risk of mania with them. This paper had a number of flaws. First, the entire meta-analysis of placebo-controlled studies came down to five reports, a relatively small number for meta-analytic techniques. Second, only one study (Nemeroff et al., 2001) was designed with equal concurrent lithium use in all arms. The other studies either had no mood stabilizers (n = 3 studies) or imbalanced lithium usage (n = 1 study, Cohn et al., 1989). Thus, to the clinical question of whether antidepressants are more effective than lithium alone, only one study (Nemeroff et al., 2001) was designed to answer the question, and it found no benefit with antidepressants, given therapeutic lithium levels. It also found some evidence of increased risk of acute mania with imipramine, though not paroxetine. Thus, we would suggest that the meta-analysis might demonstrate that antidepressants are more effective than “nothing” (placebo), but it does not demonstrate that antidepressant plus mood stabilizer is more effective than mood stabilizer alone. Further those limited studies were not powered to assess risk of acute mania, and indeed the best designed studies suggest a likely risk with TCAs. Lithium efficacy in the treatment of bipolar depression has been evaluated in eight placebo-controlled, cross-over studies (for a review see Yatham, Calabrese and Kusumakar, 2003). Amongst these, seven of the studies showed a response rate of about 76%, while all eight reported a response to lithium of 59% and to placebo of 48% respectively. In this latter case, the high placebo response, more than the lack of lithium efficacy, was the main result. Three clinical double-blind trials, comparing lithium with imipramine (Fieve, Platman and Plutchik, 1968; Watanabe, Ishino and Otsuki, 1975; Worral etal., 1979), reported a similar efficacy, even though lithium showed a higher response stability than imipramine. In both Young et al. (2000) and Nemeroff et al. (2001), the controlled and randomized trials confirmed the efficacy of lithium in the treatment of acute bipolar depression. In the first (Nemeroff et al., 2001), paroxetine, imipramine and placebo were combined with lithium. Patients with a plasma level >0.8 mEq/L of lithium did not benefit from adjunctive antidepressants; the combination with paroxetine, on the contrary, offered an advantage when lithium plasma level was lower than 8 mEq/L. Young et al. found that add-on of a second mood stabilizer (lithium or valproate) or of paroxetine to a current therapy with lithium or valproate was evaluated in bipolar patients with depressive recurrence. Differences between the combination of mood stabilizers and the combination of paroxetine plus mood stabilizers did not emerge based on depression rating scores. While this study was small (n = 30), lack of statistical power is not a major criticism one can advance

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because the effect size was tiny: the depressive scores in both groups tracked each other closely such that, with the same results, even much larger samples would not demonstrate statistical significance. All these findings indicate efficacy of lithium in the treatment of acute bipolar depression, especially at high serum levels.

ANTICONVULSANTS IN THE TREATMENT OF BIPOLAR DISORDER Valproate and Carbamazepine The antidepressant properties of valproate were initially reported in open observations (Calabrese and Delucchi, 1990). Nevertheless, valproate has not been adequately studied in bipolar depression. One randomized study with a limited sample (n = 45) (Sachs and Collins, 2001) did not show statistically significant differences between valproate and placebo, but, valproate was more effective than placebo (45% vs 27% responders), raising the problem of inadequate statistical power. A second randomized study, not yet published, found valproate more effective than placebo in acute bipolar depression (Davis, Bartolucci and Petly, 2005). Another study suggests that valproate might be more likely to work in bipolar depressives previously naïve to antidepressants (Winsberg et al., 2001). On the whole these limited studies suggest possible benefit with valproate in acute bipolar depression, contrary to common clinical assumptions. Carbamazepine has been studied only in three small controlled trials on resistant bipolar depression (Post et al., 1986). Of these patients, 68% responded to carbamazepine, while only 50% relapsed when the latter was switched to placebo.

Lamotrigine As far as new anticonvulsants are concerned, three controlled trials exploring the efficacy of lamotrigine in bipolar depression have been conducted. Frye et al. (2000) compared lamotrigine, gabapentin and placebo in resistant and rapid cycling bipolar I and II patients. Unlike gabapentin, lamotrigine proved significantly more efficacious against depressive features than placebo. Calabrese et al. (1999), in a seven-weeks double-blind study on 195 bipolar I depressive patients, compared lamotrigine at 50 or 200 mg/day with placebo, observing a significant improvement in Montgomery–Asberg Depression Rating Scale scores, in both groups. According to CGI scores, 48% and 56% of the patients taking respectively 50 mg/day and 200 mg/day of lamotrigine reported a clinical remission, versus 29% of the patients taking placebo (Calabrese et al., 1999). Subsequently, in another double-blind study (Bowden et al., 2003), lamotrigine (n = 103) has been compared to placebo (n = 103) in bipolar I and II patients. Lamotrigine was efficacious in bipolar I, but not in bipolar II; however, in the interpretation of

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these data it must be taken into account that placebo was associated with a 50% of responders. This high response to placebo complicated the interpretation of the results and made it difficult to ascertain the actual efficacy of lamotrigine. An industry-sponsored unpublished negative study did not find benefit with lamotrigine compared to placebo (GSK, data on file). Thus some positive and some negative data exist with lamotrigine for acute bipolar depression, with the possibility that acute efficacy may be limited by the need for a slow titration of this agent. In these studies, lamotrigine did not seem to induce either (hypo)manic switches or rapid cycling with high frequency, although occasional cases appeared to happen. Finally, in two open observations, lamotrigine proved efficacious in depressive schizoaffective disorder (Erfurth, Walden and Grunze, 1998) and in controlling mood instability in borderline personality disorder (Pinto and Akiskal, 1998). Both groups of patients can be considered to be resistant bipolar variants.

Gabapentin Randomized clinical trials of gabapentin are lacking. The Frye et al. study (2000) compared it with lamotrigine and placebo, and points out gabapentin’s poor efficacy in depressive symptomatology in resistant rapid cycling patients. In a double-blind placebo-controlled study on a small sample of resistant bipolar patients (n = 18), Guille (1999) did not find statistically significant differences between the two groups regarding manic symptoms; however, depressive features improved with gabapentin. According to clinical observations by our group (Perugi et al., 1999), conducted in a naturalistic setting, gabapentin augmentation proved promising in resistant-mixed bipolar patients (47% of responders) at dosages ranging from 600 to 2000 mg/day. In particular, gabapentin was effective in reducing depressive symptoms. Subsequently, we have explored predictors of response to gabapentin in a sample of 43 resistant bipolar I – DSM III R – patients (Perugi et al., 2002). Gabapentin was given in combination with other mood stabilizers, benzodiazepines, antidepressants or antipsychotics, at dosages ranging from 600 to 2400 mg/day, for a period of 8 weeks. As far as positive response predictors are concerned, logistic regression analysis showed a positive correlation when comorbid alcohol abuse, social phobia and panic disorder were present. Obviously, these data need to be confirmed in randomized trials.

Topiramate Topiramate has been also proposed in the treatment of bipolar depression (see Soares (2000) for a review). There is only one randomized study of it, which was not blinded, with topiramate appearing to be similar in efficacy to bupropion in acute bipolar depression, when added to ongoing lithium treatment (McIntyre etal., 2002).

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While this study was small, the likelihood of lack of statistical power explaining the results is lessened by the magnitude of effects observed: both topiramate and bupropion tracked each other quite closely in improvement of depressive symptoms. Observational studies suggest greater efficacy in mania than in depression (Erfurth and Kuhn, 2000), although randomized studies of mania have been negative (Janssen Pharmaceutica, data on file). Nonetheless, it is often used clinically in an augmenting mode, to help reduce weight (McElroy et al., 2003).

Olanzapine and Quetiapine Finally, amongst new atypical antipsychotics, olanzapine has also been studied in the treatment of depressive bipolar patients. Olanzapine has more randomized data, all based on industry-sponsored studies, than other antipsychotics in acute bipolar depression. In a small sample of 28 patients with refractory nonpsychotic unipolar depression, olanzapine-fluoxetine combination (OFC) was more effective than placebo, while olanzapine alone was not (Shelton et al., 2001). In two other studies of unipolar psychotic depression (n = 229 total, Rothschild et al., 2004), similar results were found: olanzapine alone was similar to placebo in both trials, but OFC was effective in one trial, though not in the other. In by far the largest study of bipolar depression ever conducted (n = 833), OFC alone was again clearly more effective than placebo, while olanzapine alone was also statistically significantly better than placebo. In very large studies, however, statistical significance can be obtained for small effect sizes (clinically trivial differences). In this study, the difference between olanzapine and placebo was a mean of about 3 points on the Montgomery Asberg Depression Rating Scale (MADRS) and most of those points involved sleep and appetite items, not core mood items. In fact, this minimal effect of olanzapine alone was the same in this study as in the previous smaller studies, the only difference being sample size. Thus, these data altogether support no meaningful clinical benefit with olanzapine alone for depressive symptoms, but likely evidence of benefit with OFC. However, since no direct comparisons have been made to fluoxetine alone, it is unclear if the OFC benefit has to do with the combination in particular, or to the use of fluoxetine. In any case, the combination appears to have an acute mania switch risk similar to placebo (about 5%), which may justify its use as opposed to fluoxetine alone. In contrast, a recent study (Calabrese et al., 2004) of quetiapine versus placebo in acute bipolar depression was more straightforwardly positive, with a large effect size for quetiapine alone, including core mood symptoms. This study is being followed up with another clinical trial for possible replication. Since the current DSM-IV criteria for depression likely include many individuals with mixed states (Akiskal and Benazzi, 2003) as discussed earlier, it is possible that some of the efficacy seen with atypical antipsychotics in depression trials may represent improvement in mixed states.

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LONG-TERM PREVENTION OF DEPRESSIVE RECURRENCES Many placebo-controlled studies examined the long-term prophylactic efficacy of lithium against bipolar depression recurrences. A pooled analysis of 10 studies conducted in 1970 and 1980 (Goodwin and Jamison, 1990) showed recurrence rates of 34% and 81% respectively for patients who were taking lithium or placebo. Manic recurrences took place in 56% of patients in the placebo group versus 23% of patients treated with lithium; as far as depressive recurrences were concerned, the respective percentages were 37% and 21%. These data suggested a prophylactic efficacy of lithium against depressive, but particularly against manic episodes. These conclusions are concordant with data drawn from the main controlled studies on large samples. Amongst them, two studies (Prien, Kupfer and Mansky, 1994; Bowden et al., 2003) compared lithium and placebo in the prevention of recurrences after the remission of a manic episode. In both of them, lithium was more efficacious than placebo in the prevention of manic episodes, but no differences emerged with respect to depressive recurrences. However, since episode polarity tends to stay consistent in many patients with bipolar disorder, this natural course factor may confound these results. Since these studies began with mania as the index episode, the ability to detect benefit for prevention of depressive episodes may have been lessened due to the decreased frequency of depressive episodes in follow up. To account for this issue, other studies (Prien, Klett and Caffey, 1974; Bowden et al., 1994; Yatham et al., 2002; Bowden et al., 2003) examined course after an index depressive episode. One (Prien, Klett and Caffey, 1974) states that lithium was efficacious in delaying manic recurrences, but no differences emerged between lithium and placebo as far as total recurrences were concerned (either manic or depressive). Two of three other recent studies (Yatham et al., 2002; Bowden et al., 2003) also found that lithium was more active than placebo for manic than for depressive recurrences, while the third found no benefit with lithium compared to placebo (Bowden et al., 1994). While this may be the case, it is important to point out that lithium was a comparator agent in all of these studies (designed to assess efficacy of lamotrigine or olanzapine). Thus, none of these studies were designed to assess lithium responders, unlike the other agents which were all preselected to include only responders (to lamotrigine or olanzapine) in the study. Thus, the fact that lithium was still as or more effective than those agents for mania prevention speaks to the robustness of lithium’s benefit for mania prophylaxis, while less benefit for depressive prophylaxis may reflect the selection of a sample more likely to respond to the other agents. It is worthwhile to note that four randomized studies prospectively assessed lithium’s efficacy for prevention of depressive episodes, compared to imipramine, in patients with index depressive episodes, and in all of those studies lithium was more effective than placebo, and in no case was imipramine more effective than

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lithium (Ghaemi et al., 2001). Thus, lithium likely has notable benefits in prevention of depressive episodes in bipolar disorder, with the possibility that it is even more effective in prevention of manic episodes. Few data are available on the prophylactic antidepressant efficacy of carbamazepine and valproate. In fact, although carbamazepine has been used for more than 20 years in the prophylactic treatment of bipolar disorder, only one placebocontrolled study has evaluated its long-term efficacy, showing a positive outcome in 60% of the patients who were taking carbamazepine versus 22% of the patients in the placebo group (Okuma et al., 1981). Several controlled studies (Placidi et al., 1986; Lusznat, Murphy and Nunn, 1988; Coxhead, Silverstone and Cookson, 1992; Simhandl, Denk and Than, 1993; Greil et al., 1997) compared carbamazepine with lithium, stressing the trend of a major efficacy of lithium in classical bipolar pictures and of carbamazepine in mixed and rapid cycling pictures. With respect to valproate, Bowden etal. (2000) reported data drawn from a lithium and placebo-controlled study on 372 bipolar patients, whose manic symptomatology had been remitted for at least 3 months. Valproate and placebo did not differ in the length of time before the first recurrence, which was the primary outcome of the study; however, valproate proved much more efficacious than placebo in reducing the total number of recurrences, especially depressive ones. Further, this study did not employ an “enriched” design, i.e. initially selecting patients to be valproate responders in open treatment. This enriched design has since become standard in studies of newer agents like lamotrigine and olanzapine. When these data were analyzed limited to those who had responded to valproate previously to entering the study, the benefit of valproate was notably greater than placebo. An earlier double-blind lithium-controlled study showed an overlapping activity of both the drugs in the prevention of depressive recurrences, but in the valproate group the dropout rate was smaller than in the lithium group (10% vs 25%) (Lambert and Venand, 1992). As far as new anticonvulsants are concerned, the most interesting data concern lamotrigine. Initially, Calabrese et al. (2000) reported results drawn from a placebo-controlled study on 182 rapid cycling bipolar I and II patients. No differences emerged between placebo and lamotrigine in the main outcome measure, i.e. the time length before the addition of another drug. However, the retention rate was higher in the lamotrigine than in the placebo group. Moreover, a higher number of patients taking lamotrigine (41%) than placebo (26%) remained stable during the entire duration of the study (6 months). Thus, in rapid-cycling bipolar disorder, lamotrigine was not effective overall, though it might have had modest benefit in some patients. Subsequently, lamotrigine was compared with lithium and placebo in bipolar I patients with a recent (hypo)manic episode (Bowden etal., 2003). Using an enriched design, an open observation lasted 8–16 weeks, during which previous drugs were withdrawn and lamotrigine treatment was initiated; patients who responded to lamotrigine were randomly assigned for a period of 18 months to

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three different double-blind treatment groups: lamotrigine (100–400mg/day), lithium (0.8–1.1 mEq/L) or placebo. Out of 349 baseline patients, 175 became stabilized and were thereafter randomized: 59 to lamotrigine, 46 to lithium and 70 to placebo. In the primary outcome measure both lamotrigine and lithium were more efficacious than placebo in preventing recurrences of both depression and mania and in lengthening the remission period. In secondary analyses, lamotrigine was more efficacious than lithium in lengthening remission before depressive recurrences, while lithium worked better against manic, hypomanic or mixed recurrences. A similar study was conducted on bipolar depressive patients in remission (Yatham et al., 2002). After patients were stabilized openly with lamotrigine, they were randomly given: 50, 200, 400 mg/day lamotrigine, lithium or placebo. Again, both lamotrigine and lithium were more efficacious than placebo in lengthening remission periods for both depressive and manic recurrences. One limitation of these data is the high dropout rate, nearing 80% at 12–18 months, which appears to be a major problem in randomized prevention trials in bipolar disorder. With the limitations of the enriched design, these data support the efficacy of lamotrigine in the prevention of bipolar depression. Recently, five randomized studies on olanzapine in the prophylaxis of bipolar disorder have been conducted. (Only one was placebo-controlled, the other four comparing olanzapine directly to valproate (two studies), lithium or as add-on to valproate or lithium respectively). In the valproate studies (Tohen et al., 2003; Zajecka et al., 2002), olanzapine appeared to be slightly more effective. However, without a placebo arm, one cannot be certain whether these data demonstrate equal efficacy or equal inefficacy, especially since 85% of patients dropped out before the one year follow-up was complete. In the unpublished lithium study (Eli Lilly and Co., data on file), olanzapine appeared similarly effective to lithium overall, with better efficacy in prevention of mania. While this study had a lower overall dropout rate (about 60%), though still a high one, the benefit over lithium should not be overstated. Again, all these patients in this study, as in the others mentioned, were initially selected to be olanzapine responders for acute mania; to establish benefit over lithium, a similar study would perhaps have to be conducted with only lithium responders included. In other words, the generalizability of this study is only limited to olanzapine responders. The same issue holds for the add-on study (Tohen et al., 2004), in which responders to olanzapine plus mood stabilizer (valproate or lithium) for acute mania were randomized to stay on the combination or discontinue olanzapine (mood stabilizer alone). In the primary outcome, which was time to a new mood episode in those who had acutely responded to olanzapine (response defined as >50% improvement in manic symptom ratings), there was no benefit to continuing olanzapine versus stopping it. In a secondary outcome, which was time to symptomatic worsening (not relapse into full mood episodes) in those who remitted with olanzapine acutely (remission defined as Young Mania Rating Scale, YMRS, less than 7), olanzapine continuation was better than placebo.

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However, this result is only generalizable to those who achieve full remission with olanzapine acutely, and further, it suggests possible symptomatic benefit but not necessarily prevention of relapse into mood episodes. Further, the addition of olanzapine proved more efficacious than monotherapy with mood stabilizers in preventing manic recurrences (35% vs 15%), but not in depressive recurrences. Finally, a single unpublished industry-sponsored study has directly compared olanzapine to placebo for prophylaxis of mood episodes in bipolar disorder (Eli Lilly and Co., data on file). Again, all patients were initially selected if they responded to olanzapine for acute mania. Those patients were then randomized to continue olanzapine or stop it (rapid taper to placebo). Olanzapine was better than placebo in prevention of mood episodes for up to 1 year, with these data leading to FDA indication for this agent in the prophylaxis of mood episodes in bipolar disorder. However, it is notable that 80% of placebo patients relapsed within 2 months of starting the study, with little further relapse in that group from that point onward. The olanzapine continuation group relapsed at a rate of less than 50% in contrast. In other words, the entire difference between the groups has to do with the first two months of follow-up, which represents the continuation phase of treatment after response for acute mania, not the maintenance phase (generally defined as 6 months or longer). The rapid placebo relapse could reflect a withdrawal phenomenon, which has been demonstrated with similarly designed early studies of lithium. Hence, one might conclude that this study suggests that if patients respond to olanzapine acutely, and then the medication is stopped, they will relapse within 2 months. But whether this report proves long-term efficacy at 6 months, one year or longer would seem to be uncertain. In summary, olanzapine may be similar to valproate or lithium in the prophylactic treatment of mood episodes in those who are olanzapine responders for acute mania. However, these data should be viewed with caution, especially as relates to lithium, since they represent very few studies, no replication with lithium in particular. The presence of unreported negative data cannot be excluded and the contrast with scores of studies by multiple investigators with lithium is notable. Further, olanzapine may enhance the prophylactic activity of mood stabilizers against manic episodes in those with complete remission with olanzapine for acute mania, although its efficacy against depressive recurrences will need further study. Likewise, maintenance phase prevention of recurrence of new mood episodes with olanzapine monotherapy will benefit from new investigations. It is often not sufficiently recognized that antidepressants have been proven ineffective in the prevention of depressive episodes in bipolar disorder. In a recent systematic review of the randomized literature, Ghaemi et al. (2001) identified only seven long-term double-blind randomized studies on the utilization of antidepressants in the treatment of bipolar disorder (especially type I): 5 with TCAs, 1 with bupropion and 1 with fluoxetine. All of them demonstrated that antidepressants were not more efficacious than lithium alone (Prien, Klett and Caffey 1979;

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Quitkin, Kane and Rifkin, 1981; Kane, Quitkin and Rifkin, 1982; Prien et al., 1994). Moreover, one study supplied evidence suggesting a worsening of the long-term course of the disorder with antidepressant use, especially by increasing the frequency of manic recurrences (Quitkin, Kane and Rifkin, 1981). With respect to the influence of antidepressants on the course of bipolar II disorder, Amsterdam et al. (1998) reported post hoc analyses of clinical studies on unipolar, pointing out that the percentage of manic switches with fluoxetine were low in frequency in patients with bipolar II disorder (5%). However, what was insufficiently emphasized in that report was that the switch rate with bipolar II disorder was still higher than in unipolar depression (0.5%). Thus, the authors concluded that SSRIs may be used in the treatment of bipolar depression with a limited (hypo)manic switch risk; the higher switch risk with bipolar II disorder is concerning to us. In the interpretation of these data, it must be taken into account that a comparison group treated with mood stabilizers was lacking; moreover, manic features were not investigated with adequate instruments. Finally, after one year of follow-up, the baseline sample was reduced from 80 to 10 subjects; therefore the ability to draw conclusions about one year outcome was very limited. With all these limitations, manic switches with fluoxetine were still more frequent in bipolar II disorder than in unipolar depression.

(HYPO)MANIC SWITCHES Antidepressants can worsen bipolar illness in two ways. Acutely, they can cause hypomanic or manic switch, defined as change in polarity from depression immediately to mania or hypomania within 2 months of starting an antidepressant. In long-term use, they can cause rapid-cycling or cycle acceleration, defined as two or more mood episodes during a period of chronic antidepressant treatment lasting 6 months or longer compared to a similar time frame without antidepressant use. In this section, we will initially focus on the risk of acute antidepressant-induced (hypo)manic switch. The rates of (hypo)manic switches among bipolar depressives treated with antidepressants reported in the literature ranges from 10% to 70% (Möller and Grunze, 2000; Thase and Sachs, 2000). The extreme variability of these estimates is due to the differences in sampling procedures, treatment setting and symptomatologic evaluation. Some data derive from randomized controlled trials, others from naturalistic studies; in some research, patients are treated with antidepressants in monotherapy, in others, these drugs are combined with mood stabilizers. A recent meta-analysis (Gijsman et al., 2004) limited to randomized placebocontrolled trials concluded, based on five included studies, that there was no evidence that antidepressants were associated with acute mania. However, only one of those studies utilized lithium in all patients (Nemeroff et al., 2001). In two early studies from the 1980s in which no mood stabilizer was used (Himmelhoch et al. 1982,

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Mendelwicz and Youdim, 1983), not a single patient developed mania during the study period (usually up to 2 months), which raises the possibility that manic symptoms were not carefully or systematically assessed (measurement bias). In another study (Cohn et al., 1989), no acute mania was observed with fluoxetine compared to a few cases with placebo and imipramine, but again lithium was used preferentially in the fluoxetine arm of that study, biasing the results. Another study (Tohen et al., 2003) included was the olanzapine fluoxetine combination study, in which similar switch rates were observed with olanzapine fluoxetine combination as with olanzapine plus placebo (about 5% each). All in all, three (Himmelhoch et al. 1982, Mendelwicz and Youdim, 1983, Cohn et al., 1989) of these five studies are so flawed they should not be included in an analysis using high quality data. The other two studies (Nemeroff et al., 2001, Tohen et al., 2003) suggest that switch rates with antidepressants may be low when combined with olanzapine or lithium, though one cannot rule out any antidepressant-induced switch due to the low statistical power to detect switch rates in these studies, even when combined in a meta-analysis. It is also notable that switch rates with the TCA arm in the lithium study were elevated, with low statistical power (thus making statistical significance less relevant). Although it would seem reasonable to limit one’s assessment of the risk of antidepressant-induced mania to randomized placebo-controlled trials, one limitation of this approach is that such trials are not primarily designed to assess this issue (they are mainly designed to assess efficacy). Thus, they are not powered to identify such serious though relatively infrequent (if present 20% of the time or less) side effects. Furthermore, side effects are frequently underestimated in clinical trials because of numerous exclusion criteria that screen out those with risk factors for serious side effects. In the case of antidepressant-induced mania, some potential risk factors, such as substance abuse (Goldberg and Whiteside, 2002), are common exclusion criteria, which could be leading to a serious underestimation of this risk in randomized studies. This is a common issue with side effects, as demonstrated in the past with the problem of sexual dysfunction with SSRIs and more recently with the controversial issue of suicidality and SSRIs. In both those situations, the randomized clinical trial data underestimated or explained away either common (sexual dysfunction) or serious (suicidality) side effects. This is why large-scale observational experience is a legitimate means of exploring such side effects, and one should not feel limited to randomized data in this context. With this background, some conclusions seem reasonable. For instance, TCAs seem to be associated with a higher rate of (hypo)manic switch in comparison with other classes of antidepressants. MAOIs have not been reported to induce fewer “switches” than tricyclics, although several studies reported a greater efficacy in patients with bipolar I depression (for the literature review see Goodwin and Jamison, 1990); interestingly, the hypomanic switches on MAOIs tend to be more euphoric compared with the greater dysphoria encountered with the TCAs. SSRIs

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may result in a lower number of “switches” than tricyclics; however, usually this conclusion derives from a pooled analysis (Peet, 1994), wherein a rate of 4% with SSRIs, versus 12% with tricyclics and 4% with placebo is reported. The data included in the pooled analysis were based on selected randomized trials of unipolar patients and, therefore, are limited to the few bipolar II patients included in these samples (before DSM-IV in 1994, since criteria for bipolar II disorder were not part of the nosology, such patients were not identified for exclusion from unipolar clinical trials). Moreover, the information on (hypo)manic switches was not explored with specific instruments, but was culled from an evaluation of the adverse events. We know from the experience with SSRI-related sexual dysfunction that this approach can seriously underestimate side effects due to measurement bias. It is likely that egosyntonic hypomania, very frequent with SSRIs in clinical practice, is recorded as full remission instead of adverse reaction. The results of other clinical studies in unipolar patients treated with fluoxetine and venlafaxine are subjected to the same biases (Amsterdam, 1998; Amsterdam and Garcia-Espana, 2000). In contrast with these findings, the contemporary literature is extremely rich in case reports and series reporting (hypo)manic switch with SSRI not only in patients with major depression but also in patients treated for dysthymia, anxiety, eating and impulse control disorders (for review see Perugi and Akiskal, 2002). Only a few studies have explored systematically the prevalence of antidepressantinduced “switches” and the influence of a concomitant treatment with mood stabilizers. Bottlender et al. (1998) reported a 25% rate in bipolar I patients; in the group who presented (hypo)manic switches, tricyclics were more frequently utilized (79.5%) than in the non-switching group of patients (51.3%); conversely, mood stabilizers were used less in switching patients (59% vs 82.4%). These findings seem to confirm previous observations indicating a higher rate of (hypo)manic switches with tricyclics than with SSRIs (Weissman, Leaf and Tischler, 1988; Anthony, Folstein and Ronamoski, 1985). Henry, Sorbara and Lacotte (2001) observed, in a 6-week prospective nonrandomized study, switch in 12 (27%) out of 44 patients, 7 (16%) with hypomania and 5 (11%) with mania. Switches were less frequent in patients treated with lithium than in the rest of the sample (15% vs 44%). Switch rates were as high with SSRIs as with TCAs (both above 20%). The number of previous episodes was not associated with an increased risk of switching, although it was positively correlated with the total score of the scales for hypomania. These well-conducted observational studies suggest that antidepressant-induced (hypo)mania is only partially prevented by concomitant treatments with mood stabilizers, and further that switch rates with SSRIs appear to be notably higher in real-world patients (about 20%) than suggested by randomized studies. Unfortunately, randomized studies on bipolar depression comparing SSRIs with other antidepressants are very few, as well as studies reporting a systematic

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evaluation of risk of switching with SSRIs (Cohn et al., 1989; Sachs, Lafer and Stoll, 1994; Young et al., 2000; Nemeroff et al., 2001). A trial reported somewhat less switching on fluoxetine in comparison with imipramine in bipolar depression (Cohn et al., 1989), but lithium was preferentially used in the fluoxetine group. The two studies comparing adjunctive paroxetine, imipramine and placebo in patients treated with lithium (Nemeroff et al., 2001) or with lithium and valproate (Young et al., 2000) have shown a low risk of switching with paroxetine. And finally, Sachs, Lafer and Stoll (1994) reported a low rate of switches with bupropion (1/9 trials) in comparison with nortriptyline (5/10 trials) in a randomized clinical trial, which was statistically significant even though the sample size was small. Recently, Post et al. (2001, 2003) reported data on hypomanic switches in patients with bipolar depression included in a double-blind randomized trial comparing adjunctive bupropion, sertraline and venlafaxine to mood stabilizers. Of the patients included in the acute phase of the treatment (10 weeks), 14% presented manic (6%) or hypomanic (8%) switch. Among the patients who entered in the long-term maintenance phase (1 year), the rate of switching increased to 33% (20% hypomanic, 13% manic). No statistical difference was reported among the three antidepressants utilized; however, because of the absence of placebo control, it was very difficult to reach (arrive at) a firm conclusion on the differences between the rate of spontaneous switches and those induced by antidepressant treatments. Although controlled trials are essential, naturalistic observation can provide some useful indications. In several studies on rapid-cycling bipolar patients, antidepressants were considered the cause of the increased frequency of cycles in a percentage of cases ranging from 25 to 35% (Koukopoulos et al., 1980; Wehr et al., 1988; Altshuler et al., 1995; Ghaemi, Boiman and Goodwin, 2000). Even for the induction of rapid-cycling, it is not clear whether the combination with mood stabilizers might provide some protection. On clinical grounds, this is a reasonable strategy.

ANTIDEPRESSANT-INDUCED CYCLE ACCELERATION OR RAPID-CYCLING As noted in the previous section, a long-term potential risk of antidepressants is induction of cycle acceleration or rapid-cycling. Cycle acceleration, we suggest, is not simply hypomanic switches that happen later in the course of treatment, but rather a worsening of the course of illness, often with longer and more frequent depressive episodes. Because of its long-term complex nature, it is difficult to assess cycle acceleration definitively in the randomized setting. In fact, perhaps there is only one study that has attempted to do so (Wehr et al., 1988): in that report, 51 patients were identified with rapid-cycling bipolar disorder. Of that group 17 were observed by history to appear to have tricyclic antidepressant-induced

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rapid cycling. Those 17 patients were then double-blind randomized to come off TCAs at some point in follow up and were switched to placebo for a random period of time. Out of 17 patients, 10 (or 20% of the original sample) appeared to have clear TCA-related cycle acceleration in this double-blind placebo-controlled on–off paradigm. No other study approaches a placebo-controlled paradigm. Unfortunately, this trial was part of a larger assessment of these patients, and the actual data underlying these results are sparsely presented in the original report. Nonetheless, with its limitations, this is the only placebo-controlled assessment of this topic, and it supports an association between antidepressant use and cycle acceleration. Observational evidence can be cited both for and against this association, as is the case with observational evidence for many topics. One reason observational data can provide conflicting results is due to the presence of confounding factors: other factors which may explain the results but are not recognized or controlled in the statistical analysis. In the absence of randomization (which automatically removes confounding factors), statistical methods like multivariate regression models can help reduce such confounding bias. Unfortunately, almost none of the observational studies on this topic have attempted any method to reduce relevant confounding factors. For instance, a frequently cited report by Coryell et al. (2003) suggested that antidepressants are not associated with rapid cycling because when the index polarity was included in a regression model, depressive index polarity was statistically associated with rapid cycling, the effect of antidepressants no longer being notable. However, the investigators did not include any of a number of other potential confounding factors in their regression model, such as age, gender, substance abuse, past psychosis, number of depressive or manic episodes in the past, or age of onset. These factors might be related to later rapid cycling, and thus the actual effect of antidepressants, independent of these factors, remains unclear. It is worth noting that in our clinical experience, as documented in repeated recent observational studies from our group and other centers (Ghaemi Boimann and Goodwin, 2000; Ghaemi et al., 2004; Yildiz and Sachs, 2003; Cicero et al., 2003), we estimate that about one-third of patients with bipolar disorder appear to experience antidepressant-associated rapid-cycling. Except for the data discussed above, we have not seen any other studies of any kind which have systematically assessed cycle acceleration comparing periods of antidepressant use and no antidepressant use which report no prevalence of antidepressant-induced cycle acceleration. Many frequently cited studies on this topic in fact do not assess long-term cycle acceleration with antidepressants (Moller et al., 2001, Altshuler etal., 2003). While this observation needs to be more carefully assessed statistically due to potential confounding factors, it seems clinically important that such a large number of patients appear to worsen in association with some of our treatments. Again, given that the only available randomized data support this association, caution would appear to be in order. It must finally be considered that the clinical

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substrate may have something to do with both switching and cycle acceleration (possibly greater in the depression–(hypo)mania-interval than in the reverse patterns; see Benazzi and Akiskal, 2005).

RECURRENCES AFTER THE INTERRUPTION OF ANTIDEPRESSANT MEDICATIONS Our review of the literature on antidepressant treatment of bipolar depression may be summarized as follows. Antidepressants may be acutely effective for the current major depressive episodes, but long-term continuation is ineffective at best and harmful at worst. If one accepts these conclusions, then use of antidepressants would be short term, with discontinuation after recovery from the acute major depressive episode (perhaps within 2–6 months). This indeed was the suggestion of the most recent revision of the American Psychiatric Association treatment guidelines for bipolar disorder (American Psychiatric Association, 2002), severely criticized by some in Europe (Moller et al., 2001). However, it could potentially be possible that using antidepressants could lead to cycle acceleration, while stopping them could lead to depressive relapse. The two possibilities are not contradictory. If depressive relapse frequently followed antidepressant discontinuation, though, clinicians would be in a major dilemma. A recent much-cited study claims just that result. Those authors (Altshuler et al., 2001) initially compared the risk of depressive recurrence in 25 bipolar patients, who stopped antidepressants they were using in combination with mood stabilizers, versus 19 patients who did not interrupt. The interruption of antidepressants was associated with a high risk of depressive recurrence, while the continuation of these drugs for the entire period of the study was not associated with a high risk of (hypo)manic switch. More recently, in a prospective 1-year follow-up study on 84 bipolar patients treated with sertraline, venlafaxine and bupropion (Altshuler et al., 2003), 71% of those who stopped antidepressant medications presented a recurrence in comparison to 41% of those who continued; 18% of the patients showed a manic relapse, but only 6% were using antidepressants at the time of the switch. This would suggest that antidepressants were not uniquely effective in their cohort, and when effective, was largely limited to a “bipolar-friendly” antidepressant such as bupropion (Haykal and Akiskal, 1990; Sachs, Lafer and Stoll, 1994). Further, and most importantly, these were all observational studies which made no attempt to statistically correct for confounding factors, such as varying prevalence of rapid-cycling in the two arms, reasons for discontinuation versus continuation of antidepressants by patients or clinicians, number of depressive or manic episodes, past antidepressant-induced mania, age of onset of illness, past substance abuse, and past psychosis. In correspondence, the investigators reported that no patients with rapid cycling were in the study,

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a point not mentioned in the paper, which would be quite unusual given the typical prevalence of rapid-cycling illness. Nonetheless, the other confounding factors were not assessed, making any direct assessments of the effect of antidepressants highly liable to confounding bias. There are two randomized studies of the same topic which find the opposite results to the above nonrandomized reports. In the first (Prien et al. 1984), patients initially stabilized on lithium plus imipramine openly for acute bipolar depression were double-blind randomized to continuation of the combination or discontinuation of imipramine. Both groups had almost identical relapse rates at 1-year follow-up. In the second study (Ghaemi et al., 2004), patients initially stabilized on mood stabilizers (mostly lithium) plus antidepressants (mostly SSRIs) for acute bipolar depression were openly randomized to continue both agents or discontinue antidepressant. Again, in an interim analysis of 33 patients, both groups had identical relapse rates and very similar overall mood morbidity at one year follow-up. In fact, the only difference was worsened mood morbidity (mostly depressive) in the nonrapid-cycling subgroup randomized to continue antidepressant. These latter data are preliminary and need to be reassessed when this ongoing study ends. Overall, however, the randomized data do not support increased risk of depressive relapse with antidepressant discontinuation in bipolar disorder. The clinical dilemma is how to identify patients who, with long-term use of antidepressants, develop an increasing frequency of episodes and rapid-cycling and those who, when antidepressant medications are discontinued, tend to produce depressive recurrences. Those patients with a history of past switching on antidepressants are likely to do it again, so it is a good idea to avoid antidepressants in such patients. In practice it is generally best to utilize mood stabilizers as the preferred choice of treatment and reserving antidepressants for nonresponders.

CONSIDERATIONS FOR CLINICAL SUBTYPES AND THEIR COMORBIDITY Clinical trials for the treatment of acute bipolar depression have failed to demonstrate better efficacy of antidepressants compared to lithium and other mood stabilizers. Moreover during antidepressant treatment, switches into mania or hypomania are frequently reported, in both bipolar I and II disorders (Goldberg, Rabin and Whiteside, 2001; Henry Sorbara and Lacotte, 2001). Therefore, antidepressants, and especially tricyclics, should not be considered as first treatment choice for bipolar depression, and mood stabilizers should be the preferred choice. In particular lithium and lamotrigine appear to have acute antidepressant properties in bipolar patients. Other mood stabilizers, like valproate, may also be acutely effective in some bipolar patients. Only in the most severe or resistant forms might antidepressants be added, and then always in combination with mood stabilizers; high dosages of antidepressants and their presumably synergistic combination should

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be avoided. Their long-term use, even with mood stabilizers, is justified in rare cases only. Even in those studies frequently cited to support long-term antidepressant use (Altshuler et al., 2003), only about 15% of patients with bipolar depression appear to benefit from long-term antidepressant use. In many patients it is advisable to combine two or even three mood stabilizers or mood-stabilizing adjuncts (lithium plus valproate, lithium plus olanzapine, lamotrigine plus quetiapine) before adding an antidepressant. With this approach, the acute depressive symptoms of most patients can be treated and one can then usually continue the mood-stabilizing combination for the long -term, as opposed to long-term risk of mood destabilization with antidepressants. When patients are not acutely suicidal, such approaches emphasizing mood stabilizers can be taken. Earlier use of antidepressants may be needed in very severely suicidal patients, or hospitalized patients, in whom more rapid recovery is desired; yet even then, care should be taken to plan to discontinue antidepressants in most patients after the acute major depressive episode resolves. Clinical experience suggests that some patients indeed may need long-term antidepressant treatment, but that group is a minority (15–20% of the bipolar population, Ghaemi and Goodwin, 2001), and even then, in our experience, many of those patients develop an oscillating course of mood swings that may be mild but is generally not consistently euthymic. Although the recent APA treatment guidelines agree on this approach, antidepressants remain the most frequently prescribed drugs in bipolar disorder in practice. In a sample of bipolar I depressed outpatients we followed up in the last 3 years (Perugi etal., unpublished data), 4 out of the 5 most frequently co-prescribed drugs for bipolar disorder had been antidepressants (citalopram, paroxetine, sertraline and venlafaxine), with valproate as the fifth drug. Their naturalistic use in bipolar depression in the practice setting is surprisingly under-evaluated. Some claim that this frequent use of antidepressants by practitioners may highlight important benefits that are not captured by the scientific literature. In fact, a recent meta-analysis (Gijsman etal., 2004) argues that the placebo-controlled randomized evidence supports the idea that antidepressants should be used almost without hesitation in bipolar depression. We have discussed the limitations of that meta-analysis on its own terms, but we would also add that that review was limited to studies of acute bipolar depression. Even if one grants short-term utility, long-term benefits have been disproven with these agents, and long-term risks are hard to ignore. It seems difficult for us to explain, based on standard models of scientific assessment, why clinicians and some researchers, not to mention many patients, are so infatuated with using these drugs in the long term. Psychotic symptoms are common in bipolar depression (Marneros, Deister and Rohde, 1990) and therefore, especially when symptoms are incongruous, antipsychotics may be helpful (Kaskey, Nasr and Meltzer, 1980). In the treatment of psychotic features, atypical antipsychotics are as efficacious as the typicals and are less likely to induce depression. Olanzapine has been studied most in

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antidepressant-resistant depression, with some efficacy especially if combined with fluoxetine; this latter combination seems to strengthen the efficacy of both of the drugs. At the moment the prophylactic activity of olanzapine against depressive recurrences has not been proven. One recent study also supports the efficacy of quetiapine in acute bipolar depression. In long-term treatment, olanzapine and other atypical antipsychotics should not be very likely to induce depressive recurrences. The treatment of bipolar II patients is often complicated by the presence of comorbidity. In many cases, the concomitant anxiety, impulse control or eating disorders represent the major complaints and require specific treatment. Most of the controlled trials on bipolar disorder exclude patients with comorbid drug abuse, anxiety and impulse control disorders and vice versa; as a consequence, the empirical basis for treating patients with complex comorbidity are almost exclusively derived from open clinical experience (Table 11.2). This is a deplorable situation because the most common patients treated in everyday clinical practice are bipolar II with complex comorbidity. The “pure” bipolar disorder is a platonic concept that is not even encountered in a trial population! Anxious bipolar patients (i.e. those with high anxiety ratings) are less likely to respond to lithium (Young et al., 1993). Controlled data suggest valproate may be more effective than lithium in mania associated with depressive features, even when the depressive features are mild (Swann et al., 1997). Since anxiety symptoms are often seen in mixed states and may even be related to depression in mania, future investigations should evaluate anxious features as possible predictors of response to valproate (and other antimanic agents) in mania. Actually, valproate has been used successfully in the treatment of panic disorder (Lum et al., 1990). In addition, in an open-label study, Calabrese and Delucchi (1990) reported that rapid-cycling bipolar disorder patients with comorbid panic attacks experienced reduction in their panic symptoms with valproate treatment. Benzodiazepines – such as clonazepam – are relatively safe and well tolerated when used in combination with mood stabilizers. However, long-term benzodiazepine use may be problematic due to the development of tolerance, physical dependence and withdrawal Table 11.2: Sequence of pharmacotherapy for bipolar comorbidity • • • •

Panic attacks – stabilize bipolar first1 OCD – (over) stabilize bipolar first2 Adult ADHD – (over) stabilize bipolar first3 Alcohol/Stimulant abuse – detoxify first4

Note: 1 VPA and/or GBT may suffice 2 Consider risperidone (augmentation of SRI) 3 Consider dexedrine if mood stabilizers inadequate 4 VPA, CBZ, GBT may treat both conditions

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phenomena. Gabapentin – which has been shown to be effective in panic disorder (Pande et al., 1997) and social phobia – seems to be helpful when anxiety disorders or alcohol abuse are comorbid (Perugi and Akiskal, 2002). Antidepressants, which are often used in the treatment of anxiety disorders, may worsen the course of the mood disorder by precipitating (hypo)mania, mixed states or rapid-cycling. Antidepressant-induced (hypo)manic symptoms have been reported to occur in the course of the treatment of virtually all anxiety disorders, including obsessive-compulsive, panic disorder/agoraphobia and social phobia (Sholomskas, 1990; Himmelloch et al., 1991; Steiner, 1991). In bipolar disorder, prophylactic treatment with mood stabilizers may prevent antidepressant-induced switching (Jann, Bitar and Rao, 1982; Kane, Quitkin and Rifkin, 1982), but effective management of depressive mixed states may require discontinuation of antidepressant drugs. However, discontinuation of antidepressants may create problems; these include recurrence of depressive or anxious symptoms and, although rarely, precipitation of (hypo)mania (Landry, 1997). When treating comorbid bipolar and anxiety disorders, it is imperative to begin treatment with a mood stabilizer first. In the treatment of comorbid bipolar disorder and panic disorder/agoraphobia, it appears reasonable to utilize as first choice mood stabilizers which have been shown to possess some anti-panic efficacy, such as valproate. In patients with persistent and disabling anxiety, combination with short-term (<2 months) clonazepam or small dosages of SSRI or tricyclics (i.e. paroxetine or trimipramine) can be considered. Paroxetine may be considered an optimal choice because it is effective in all anxiety disorders as well as major depression, and additionally has proven efficacious in bipolar II depression in combination with mood stabilizers (Young et al., 2000). Less information is available for comorbid bipolar disorder and social phobia. A small positive study (Pande et al., 1997) on gabapentin in social phobia suggests the possible efficacy of this drug for both mood and anxiety disorders. The combination of mood stabilizers – such as lithium, valproate and carbamazepine with SSRIs, RIMAs or MAOIs – might reduce the number of switches in these patients. However, there is virtually no information on long-term outcome of patients treated with drug combinations for comorbid bipolar disorder and social anxiety. Patients with bipolar and comorbid obsessive-compulsive disorder are among the most difficult to treat. While no mood stabilizer has been shown to exert any antiobsessive-compulsive activity, highly effective anti-obsessive pharmacological treatments (e.g. high doses of clomipramine or SSRIs) are likely to trigger (hypo)manic switches and to increase mixed states in bipolar spectrum patients. A combination of different mood stabilizers (e.g. lithium plus antiepileptics) is often necessary – preferably coupled with those antidepressants less likely to induce rapid-cycling (e.g. MAOIs). However, many of these patients present residual obsessive compulsive symptomatology and very severe manic or mixed

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episodes (aggressive, hostile mood) that may require hospitalization. In some cases, SSRI augmentation with low-dose atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) can be considered on an empirical basis. Indeed, even if in some cases, atypical antipsychotics have been reported to exacerbate obsessions and compulsions (Baker et al., 1992), in others, these drugs display a mood stabilizing, antiaggressive activity which permits an efficacious approach to obsessive-compulsive symptoms (McDougle et al., 2000). Since depressive mixed states [DMX] are not identified by formal diagnostic systems (Akiskal and Benazzi, 2003), international guidelines offer no suggestions for their treatment. Actually, many bipolar patients during the depressive phase show hypomanic features, especially motor agitation and thought acceleration. In these cases the depressive symptomatology tends to become chronic, resistant to antidepressants and less responsive to classic mood stabilizers. In some cases antidepressants might worsen symptomatology and their interruption may succeed in improving the mixed depressive symptomatology (Koukopoulos et al., 1995; Koukopoulos and Koukopoulos, 1999). In other cases, the association of two mood stabilizers (lithium plus anticonvulsants) or the combination with atypical antipsychotics – such as olanzapine – is necessary. Olanzapine or quetiapine might be particularly indicated in agitated depression with irritability and impulsivity, as well as in the case of psychotic features. This may be one reason why atypical antipsychotics work in bipolar depression – especially when antidepressant-resistant. When DMX persists or is particularly severe (psychomotor agitation or inhibition, psychotic features, catatonia, high suicide risk, etc.), electro-convulsive therapy should be considered.

CONCLUDING REMARKS Bipolar depression is frequently misdiagnosed and inappropriately treated. Mania and bipolar I depression continue to be underestimated, because either bipolar patients’ insight is poor or detection of manic symptoms is not always straightforward. Nonetheless, clinicians appear more inclined to diagnose bipolar I than II. Lack of consensus on the definition of bipolar spectrum and difficulty in the retrospective diagnosis of hypomania should be considered the major obstacles to the correct identification of bipolar II depression. Even when properly identified, there is no consensus on its treatment. Nearly every guideline on bipolar disorder is focused on bipolar I. The principles of bipolar I management are relatively straightforward: using 1 or 2 established mood stabilizers, avoiding antidepressant augmentation if at all possible and limiting them to relatively short courses, augmenting with an atypical antipsychotic when deemed necessary for psychotic exacerbations and/or for long-term fine-tuning the response; thyroid augmentation is seldom necessary today, unless a female patient on lithium develops subclinical hypothyroidism.

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Electroconvulsive therapy is the treatment of choice for depressive stupor and should be considered for severe suicidal mixed states. It is the clinical management of bipolar II which presents the greater challenge today. Table 11.3 summarizes general principles in its management. The remaining paragraphs of this chapter expand on specific commonly encountered situations with the group of patients. Antidepressant use may be problematic for a large number of patients suffering from bipolar depression. Therefore a thorough diagnostic evaluation must precede any therapeutic decision in patients presenting with depression. Mood stabilizers are the first choice in the treatment of bipolar depression, with the addition of antidepressants only in the most resistant cases. Atypical antipsychotics, in particular olanzapine and quetiapine, should be considered in nonresponders or when psychotic or mixed features are present. Unfortunately, the use of classical mood stabilizers, such as lithium, carbamazepine and valproate, is sometimes limited by side effects. The new anticonvulsants with reduced side effects might represent promising therapeutic tools. In particular, lamotrigine seems to be efficacious in the treatment of bipolar depression and in the prevention of rapid cycling and depressive recurrences. The frequent coexistence of bipolar disorder (mostly bipolar II) and anxiety, impulse control, eating and substance use disorders is a substantial clinical challenge pertaining to a large number of patients. Accurate diagnosis is a central concern. The

Table 11.3: Recommendations for bipolar II disorder 1. Begin with mood stabilizers. 2. Consider low dose standard mood stabilizers (lithium or valproate) initially to limit side effects. 3. Avoid most antidepressants in monotherapy. 4. Bupropion and paroxetine are perhaps least offensive. 5. Limit antidepressants as much as possible to short-term use, with long-term use reserved for those who relapse after antidepressant discontinuation. 6. Especially avoid antidepressants, short or long term, in those with a history of frequent switches on antidepressants and/or rapid cycling course. 7. Divalproex is best for bipolar II mixed states. 8. Mood stabilizer combinations may be helpful when response to monotherapy is suboptimal. 9. Consider novel anticonvulsants with few side effects (gabapentin, topiramate), as augmenting agents, especially with comorbidities (gabapentin for anxiety disorders, topiramate for eating disorders). 10. Lamotrigine is emerging as the treatment of choice when above procedures fail. It is particularly efficacious for cyclothymic and “borderline” cases. 11. Lithium, oxcarbazepine, quetiapine or loanzapine augmentation can help to smoothe the rough edges (irritability, anxiety, restless activation) not uncommonly observed in patients requiring high doses of lamotrigine.

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use of psychotropic combinations is rendered necessary because of the syndromic complexity and the contrasting effects of pharmacological treatments. The identification of differential patterns of comorbidity may provide important information in distinguishing more homogeneous clinical subtypes of affective disorders from the genetic, temperamental and therapeutic point of view. The pattern of complex relationships among these disorders requires better-designed prospective observations. This is also true for putative temperamental (e.g. cyclothymia, interpersonal sensitivity) and personality (e.g. histrionic and avoidant) factors, which might play a predisposing or pathoplastic role in several clinically comorbid syndromes. Finally, the unresolved question of mixed depressive states (major depressive episode plus intra-episode hypomanic symptoms) haunts clinicians in their daily practice. The latter are very common in bipolar inpatients, but they are scarcely studied and seldom even recognized. Unfortunately, hypomanic symptoms during depressive episodes – such as racing thoughts, hypersexuality and psychomotor acceleration – are overshadowed and not considered as possible indicators of mixed state by the contemporary classificatory systems. This nosographic limbo represents a “true clinical tragedy” (Akiskal and Pinto, 1999) in outpatient practice, since it could negatively influence the treatment choices, privileging the use of antidepressants rather than mood stabilizers, atypical antipsychotics or electroconvulsive therapy. On clinical grounds, augmentation with mood stabilizer (especially anticonvulsant) and atypical antipsychotic (those with sedative properties) are valuable in excited, labile, impulsive–depressive mixed states (Akiskal and Benazzi, 2003).

ACKNOWLEDGMENT The authors thank Dr Cristina Toni for her clinical input.

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Sultzer DL, Cummings JL. Drug-induced mania causative agents, clinical characteristics and management. A retrospective analysis of the literature. Med Toxicol Adv Drug Exper 1989; 4: 127–143. Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, Dilsaver SC, Davis JM. Depression during mania: Treatment response to lithium or divalproex. Arch Gen Psychiatry 1997; 54: 37–42. Thase ME, Sachs GS. Bipolar Depression: Pharmacotherapy and related therapeutic strategies. Biol Psychiatry 2000; 48: 558–572. Tohen M, Chengappa KN, Suppes T, Zarate CA Jr., Calabrese JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD, Tollefson GD, Breier A. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002; 59: 62–9. Tohen M, Ketter TA, Zarate CA, Suppes T, Frye M, Altshuler L, Zajecka J, Schuh LM, Risser RC, Brown E, Baker RW. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: A 47-week study. Am J Psychiatry 2003; 160: 1263–71. Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003; 60: 1079–88. Tohen M, Chengappa KN, Suppes T, Baker RW, Zarate CA, Bowden CL, Sachs GS, Kupfer DJ, Ghaemi SN, Feldman PD, Risser RC, Evans AR, Calabrese JR. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabilizer vs. mood stabilizer alone. Br J Psychiatry 2004; 184: 337–45. Vieta E, Martinez-Aran A, Goikolea JM. A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood-stabilizers. J Clin Psychiatry 2002; 63: 508–512. Vieta E, Gastò C, Otero A, Nieto E, Vallejo J. Differential features between Bipolar I and Bipolar II Disorder. Compr Psychiatry 1997; 38: 98–101. Watanabe S, Ishino H, Otsuki S. Double-blind comparison of lithium carbonate and imipramine in treatment of depression. Arch Gen Psychiatry 1975; 32: 659–668. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 1987; 144: 1403–1411. Wehr TA. Sack DA, Rosenthal NE, Cowdry RW. Rapid cycling affective disorder: Contributing factors and treatment responses in 51 patients. Am J Psychiatry 1988; 145: 179–84. Weissman MM, Leaf PJ, Tischler GL. Affective disorders in five United States communities. Psychol Med 1988; 18: 141–53. Wicki W, Angst J. The Zurich Study. X. Hypomania in a 28- to 30-year-old cohort. Eur Arch Psychiatry Clin Neurosci 1991; 240: 339–48. Winokur G, Coryell W, Endicott J, Akiskal HS. Further distinctions between manicdepressive illness (bipolar) and primary depressive disorder (unipolar). Am J Psychiatry 1993; 150: 1176–1181. Winokur G, Turvey C, Akiskal H, Coryell W, Solomon D, Leon A, Mueller T, Endicott J, Maser J, Keller M. Alcoholism and drug abuse in three groups bipolar I, unipolars and their acquaintances. J Affect Disord 1998; 50: 81–89. Winsberg ME, DeGolia SG, Strong CM, Ketter TA. Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression. J Affect Disord 2001; 67(1–3): 207–12.

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Worrall EP, Moody JP, Peet M, Dick P, Smith A, Chambers C, Adams M, Naylor GJ. Controlled studies of the acute antidepressant effects of lithium. Br J Psychiatry 1979; 135: 255–62. Yatham LN, Bhnke K, Timotijevic I, Naukkarinnen H, Bowden C, Thavethiran I. A placebo controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar disorder. Int J Neuropsychopharmacol 2002; 5 (Suppl. 1) S58 Yatham LN, Calabrese JR, Kusumakar V. Bipolar depression: criteria for treatment selections, definition of refractoriness, and treatment options. Bipolar Disord 2003; 5: 85–97. Yildiz A, Sachs GS. Do antidepressants induce rapid cycling? A gender-specific association. J Clin Psychiatry 2003; 64: 814–18. Young, LT, Cooke RG, Robb JC, Levitt AJ, Joffe RT. Anxious and non-anxious bipolar disorder. J Affect Disord 1993; 29: 49–52. Young LT, Joffe, RT, Robb JC, MacQueen M, Marriott M, Patelis-Siotis I. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry 2000; 157: 124–126. Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry 2002; 63: 1148–55.

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12 Bipolarity in Women: Therapeutic Issues Susan L. McElroy1, Lesley M. Arnold2 and Lori L. Altshuler3 1

Psychopharmacology Research Program University of Cincinnati College of Medicine, Cincinnati, USA 2 Women’s Health Research Program University of Cincinnati College of Medicine, Cincinnati, USA 3 Mood Disorders Research Program, UCLA, USA

INTRODUCTION Although mania is equally prevalent in women and men, female bipolarity differs from male bipolarity in clinically and theoretically important ways. This chapter reviews gender differences in the epidemiology, phenomenology, course and comorbidity of the bipolar spectrum, discusses interactions between the female reproductive cycle and bipolar disorder and highlights special issues regarding the treatment of female bipolarity, particularly in pregnancy and the postpartum. It also addresses some theoretical implications of the differences between female and male bipolarity.

EPIDEMIOLOGY AND GENDER DISTRIBUTION OF THE BIPOLAR SPECTRUM Epidemiologic studies of mood episodes have consistently shown that major depressive episodes are more common in women than men, whereas manic episodes are equally distributed between the sexes (Kessler et al., 1993, 1994; Regier et al., 1988; Weissman et al., 1991; Szádóczky et al., 1998). The gender distribution of hypomania has been less thoroughly studied, but preliminary epidemiologic data suggests hypomania, defined by various criteria, may also be equally common in women and men (Angst, 1998; Angst et al., 2003; Judd and Akiskal, 2003; Szádóczky et al., 1998). Regarding the gender distribution of affective symptoms,

Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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epidemiologic data have consistently shown that depressive symptoms are more common in women than men (Weissman et al., 1991). However, epidemiologic data are inconsistent as to the gender distribution of manic symptoms, with two studies suggesting they are equally common in women and men (Angst, 1998; Judd and Akiskal, 2003), and another suggesting they are more common in adolescent girls than adolescent boys (Lewinsohn, Klein and Seeley, 1995). Consistent with findings of mood episodes, epidemiologic studies of mood disorders have shown that depressive disorders (both major depressive disorder and dysthymia) are more common in women, whereas bipolar I disorder is equally common in women and men (Kessler et al., 1993, 1994; Regier et al., 1988; Szádóczky et al., 1998; Weissman et al., 1991; Wittchen, Nelson and Lachner, 1998). Less is known, however, about the gender distribution of the soft bipolar spectrum disorders, which include bipolar II disorder, cyclothymia, bipolar III disorder and beyond (Akiskal et al., 2003; Angst et al., 2003; Cassano et al., 1992, 1999), and which are substantially more common than bipolar I disorder, occurring in 5.1% (Judd and Akiskal, 2003) to 23.7% (Angst et al., 2003) of the general population. Available community data regarding their gender distribution are mixed. The Epidemiologic Catchment Area (ECA) study, using DSM-III criteria, did not find a difference in the gender distribution of bipolar II disorder (lifetime prevalence 0.5% vs 0.4% in women vs men), but the overall rate of bipolar II disorder (0.5%) was lower than that of bipolar I disorder (0.8%) (Weissman et al., 1991). Thus, the low prevalence rate of bipolar II disorder, and hence the lack of a female preponderance, in these data could reflect the use of an overly narrow definition of hypomania (Judd and Akiskal, 2003). A national epidemiologic survey of bipolar disorders from Hungary, using methodology similar to the ECA study except for DSM-III-R criteria, also found no difference in the prevalence of bipolar II disorder between females (2%) and males (2%) (Szádóczky et al., 1998). Moreover, this study found that bipolar II disorder was more common than bipolar I disorder (2.0% vs 1.5%), and that manic episodes without depressive episodes were more common in males than females (2.2% vs 0.8%). In a study of the prevalence of DSM-IV mental disorders in a random sample of 3021 respondents aged 14–24 years from metropolitan Munich (which used the Composite International Diagnostic Interview), females and males showed similar rates of hypomania and bipolar I disorder (1.7% vs 1.4% and 1.7% vs 1.1%, respectively). Bipolar II disorder was significantly more common in females than males (0.7% vs 0.2%, respectively). However, bipolar II disorder was less common than bipolar I disorder (0.4% vs 1.4%), again raising the issue of how accurately hypomania was diagnosed. A 20-year prospective community cohort study of young adults from Zurich using broader definitions of both hypomania and bipolarity found that bipolar II disorder (defined as DSM-III-R major depressive episodes with hypomania or hypomanic symptoms) and minor bipolar disorder (defined as dysthymia, minor

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depression or recurrent brief depression with hypomania or hypomanic symptoms) were more common in women (58.4% and 59% females, respectively) whereas pure hypomania (hypomania or hypomanic symptoms without depression) was more common in men (33.7% females), but the differences were not statistically significant (42.5% females in the control group) (Angst et al., 2003). In the only epidemiologic study of bipolar spectrum disorders and manic symptoms in an adolescent population, Lewinsohn, Klein and Seeley (1995) found that there were significantly more females in the group with major depressive disorder (69.9%) than in a combined group with bipolar disorder (66.7%) and manic symptoms (56.7%), as well as a significantly greater proportion of females in the latter two groups than in the group without mental illness (47.9%). Moreover, in the group with bipolar disorder, only two persons had bipolar I disorder; the other 16 had bipolar II disorder (N = 11) or cyclothymia (N = 5). Clinical studies are also mixed as to whether there are gender differences in the distribution of bipolar I versus bipolar II disorder. Some studies have found that bipolar II disorder is more common than bipolar I disorder in women than in men (Angst, 1978; Benazzi, 1999, 2001). Consistent with these studies are reports of equally high rates of females between unipolar major depression and bipolar II depression in clinical populations (Benazzi and Akiskal, 2003; Hantouche et al., 1998). A number of other studies, however, have not found significant differences in the gender distribution between patients with bipolar I and bipolar II disorders (Cassano etal., 1992; Hendrick etal., 2000; Judd etal., 2003c; Kukopulos et al., 1980; Robb et al., 1998). Of note, no clinical studies, to our knowledge, have found bipolar II disorder to be more common in men than in women. In short, available evidence suggests that “hard” or “core” bipolarity, characterized by mania or prominent hypomania, may have an equal gender distribution, and possibly a male predominance when defined by minimal associated depression. By contrast, “soft” bipolarity, particularly when defined by mild hypomania or hypomanic symptoms and prominent associated depression, may have a female predominance. However, more accurate knowledge of the gender distribution of bipolarity must await further epidemiologic studies that use operationalized definitions of the bipolar spectrum that validly reflect clinical reality along with assessment methodologies that accurately assess all signs and symptoms of bipolarity (especially those of hypomania and various mixed states) (Cassano et al., 1999).

GENDER DIFFERENCES IN PHENOMENOLOGY IS FEMALE BIPOLARITY CHARACTERIZED BY A DEPRESSIVE DIATHESIS? Considerable evidence has shown that depressive symptoms are more common than manic and hypomanic symptoms in both females and males with bipolar

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I and II disorders (Angst, 1978; Judd et al., 2002, 2003c). However, several lines of evidence suggest female bipolar disorder is even more likely than male bipolar disorder to be characterized by depressive symptoms (Leibenluft, 1996, 1997, 1999). Kupfer et al. (2002) evaluated the mood ratings of 2839 participants in a Bipolar Disorder Registry and found the group as a whole was more likely to have symptoms of depression than mania (64% vs 33%). Women, though, were more likely than men to report depression (67% vs 57%, p = 0.001) and had a higher mean depression symptom score (0.68 vs 0.60, p = 0.03). Women were also more likely to report a depressive episode at illness onset (Chengappa et al., 2003; Kupfer et al., 2002). Further support for female bipolar disorder having a depressive diathesis comes from a number of studies reporting that bipolar women have more frequent episodes of depression than bipolar men (Angst, 1978; Angst and Sellaro, 2003; Robb et al., 1998; Roy-Byrne et al., 1985; Rybakowski et al., 1980; Taschev, 1973). Some of these studies, however, found no significant differences in the length of depressive episodes between women and men (Robb et al., 1998). In addition, other studies have not found differences in the frequency of depressive episodes between females and males with bipolar disorder (Hendrick et al., 2000; Winokur et al., 1994). By contrast, studies of temperament in mood disorder have found that women have high rates of antecedent depressive temperament (Perugi et al., 1990), whereas men have high rates of hyperthymic temperament (Akiskal et al., 1998). Another finding suggesting that female bipolarity is characterized by a predominance of depressive symptoms and/or episodes is its frequent misdiagnosis as unipolar depression. In their registry of 2839 persons with bipolar disorder, Kupfer et al. (2002) found that bipolar women were more likely than bipolar men to receive diagnoses of depression. Similarly, in a study of 345 patients with DSM-IV bipolar I or II disorder, time from illness onset to maintenance lithium treatment was significantly longer for women (9.14 years, SD = 8.77) than men (7.02 years, SD = 7.32) (Baldessarini, Tondo and Hennen, 1999). The authors’ concluded that this delay in treatment might reflect differences in clinical presentation. Yet another finding supporting a depressive diathesis for female bipolarity is its relationship with suicidality as compared to women in the general population and bipolar men. In the general population, women attempt suicide 2–3 times more often than men, but men account for 65% of completed suicides (Goodwin and Jamison, 1990; Kornstein and Wojcik, 2002). In both the ECA and National Comorbidity Studies, the lifetime rate of suicide attempts was higher in persons with bipolar disorder than in those with unipolar depression or any other Axis I disorder (Chen and Dilsaver, 1996; Kessler, Borges and Watters, 1999). Like women and men in the general population, bipolar women were more likely to attempt suicide than bipolar men (Chen and Dilsaver, 1996; Kessler, Borges and Watters, 1999). However, studies have not shown a clear predominance of males among persons with bipolar disorder who committed suicide (Goodwin and

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Jamison, 1990; Isometsä et al., 1994; Tsai et al., 2002). For example, in a study of all 31 suicide victims with DSM-IV bipolar I disorder in Finland within a 1-year period, 13 (42%) were female and 18 (58%) were male (Isometsä et al., 1994). Similarly, in a recent Chinese study of all 43 patients with DSM-IV bipolar I disorder who had committed suicide following admission after January 1, 1985 until December 31, 1996, 19 (44%) were female and 24 (56%) were male (Tsai etal., 2002). Indeed, two recent studies of mortality in patients with hospital diagnoses of bipolar disorder found that bipolar women had higher standardized mortality ratios for suicide than bipolar men (20.3 vs 18.1 and 22.4 vs 15.0, respectively) (Hoyer, Mortensen and Olesen, 2000; Ösby et al., 2001). Finally, additional support for female bipolarity having a depressive diathesis is its association with mixed mania and rapid cycling – two affective states characterized by prominent depressive symptoms (McElroy et al., 1992; Calabrese et al., 2001a) (see below).

IS FEMALE BIPOLARITY CHARACTERIZED BY MIXED STATES (MIXITY)? In general, studies have not found gender differences in the core phenomenological features of mania (Lewinsohn, Klein and Seeley, 1995). However, many clinical studies have found that bipolar women are more likely than bipolar men to experience mixed mania (Arnold, McElroy and Keck, 2000; Akiskal et al., 1998; Cassidy and Carrol, 2001; McElroy et al., 1992, 1995; Robb et al., 1998). In a review of 17 studies of mixed mania, of the 6 studies that provided information on gender distribution, 5 studies reported that mixed mania was more common in women, whereas 1 reported that mixed mania was more common in men (McElroy etal., 1992). A subsequent review evaluated 13 studies that reported on the gender distribution in mixed mania using broad, intermediate and narrow definitions of mixed mania according to the amount of required depression (Arnold, McElroy and Keck, 2000). Mixed mania was more common in women when defined narrowly (mania with syndromal major depression), but equally common in women and men when defined by lesser degrees of depression (mania with any depressive symptom or mania with several depressive symptoms). Akiskal et al. (1998) obtained a similar finding when they examined the gender distribution of 104 manic inpatients using a dimensional scheme to define pure versus dysphoric (mixed) mania. Specifically, they found significantly more women in the “definite” dysphoric mania category (presence of ≥3 depressive symptoms), but not the “probable” dysphoric mania category (presence of 2 depressive symptoms), compared with a combined group of patients with “pure” and “doubtful” dysphoric mania (absence of depressive symptoms and 1 depressive symptom, respectively) (91% vs 63% vs 58%). It is unclear whether the depressive mixed state (syndromal depression with hypomania or manic symptoms) is more common in females than males, in part

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because the gender distribution of this particular mixed state has yet to be assessed with a widely accepted operational definition (Benazzi, 2002). For example, Sato et al. (2003) compared 958 depressed inpatients (863 unipolar, 25 bipolar II and 70 bipolar I) regarding co-occurring manic symptoms. They found that depressive mixed states, defined as having two or more manic symptoms during a depressive episode, were numerically, but not significantly, more common in females than males with bipolar I depression (59% vs 41%), bipolar II depression (52% vs 48%) and unipolar depression (70% vs 30%). In short, epidemiologic studies on the full spectrum of bipolar mixed states are needed before their gender distribution can be accurately known. Nonetheless, taken together, available clinical data suggest female bipolarity is characterized by mixity, or the co-occurrence of manic and depressive symptoms.

IS FEMALE BIPOLARITY CHARACTERIZED BY RAPID CYCLING (CYCLICITY)? Rapid cycling, most commonly defined as four or more mood episodes in one year, has been reported to be more common in bipolar women than in bipolar men in numerous clinical studies (Bauer, Whybrow and Winokur, 1990a; Bowden et al., 2000; Calabrese and Delucchi, 1990; Coryell, Endicott and Keller, 1992; Coryell et al., 2003; Dunner and Fieve, 1974; Dunner, Patrick and Fiene, 1977; Kukopulos et al. 1980 and 1983; Maj et al., 1999; Nurnberger et al., 1988; Robb et al., 1998; Wehr et al., 1988). Although there are no epidemiologic studies of rapid cycling bipolar disorder, two meta-analyses have supported an association between female bipolarity and rapid cycling. In the first, Tondo and Baldessarini (1998) analyzed 10 studies of 2057 bipolar patients and found that rapid cycling occurred in significantly more women (29.6%) than men (16.6%). In the second, Kupka et al. (2003) analyzed 20 studies of 3709 bipolar patients and similarly found that significantly more rapid cyclers were women (66%) than were nonrapid cyclers (53%). Of importance is one study showing that gender distribution in rapid cycling varied depending on how it was defined, with higher rates of females seen in definitions that waived duration criteria for mood episodes and required circularity of course (i.e. were associated with more extreme mood instability or more frequent polarity shifts) (Maj et al., 1999). This observation also raises the issue that the rapid cycling construct of 4 mood episodes in 1 year does not completely overlap with that of cyclicity, or the alternation of manic or hypomanic and depressive symptoms or episodes. As a dimensional construct, cyclicity may more accurately reflect the phenomenology or course of bipolar disorder, and thus, the higher rates of rapid cycling in women with bipolar disorder may reflect an association between female bipolarity and greater cyclicity (Kupka, 2003).

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ASSOCIATION OF FEMALE BIPOLARITY WITH MIXITY AND CYCLICITY Several hypothesis have been proposed to explain the association of mixed states and rapid cycling with female bipolarity. These have included an interaction of bipolarity with the female reproductive cycle, the greater prevalence of thyroid dysfunction in females, the greater exposure of women to non-mood stabilizing psychotropics, and a greater vulnerability of females with bipolar disorder to develop mania or rapid cycling upon antidepressant exposure (Leibenluft, 1996, 1999; Parry, 1989). There is limited support for all four hypotheses. Thus, estrogen has numerous neurotransmitter and neuroprotective effects, some of which may be associated with mood-altering properties (Burt, Altshuler and Rasgon, 1998; Fink et al., 1996; Hendrick, Altshuler and Burt, 1996; Seeman, 1997). Indeed, as discussed below, exogenous estrogen administration has been reported to have antidepressant effects (Klaiber et al., 1979), and to induce mania and rapid cycling (Oppenheim, 1984; Zohar etal., 1985) in women with mood disorders. Also, bipolar mood symptoms may worsen during certain phases of the female reproductive cycle, particularly the postpartum, but also the premenstrual phase of the menstrual cycle and the perimenopause and menopause (Arnold, 2003; Kukopulos etal., 1985; Rasgon et al., 2003). Exacerbation of bipolarity coincident with female reproductive cycle function has been hypothesized to be due in part to the cyclic nature of estrogen secretion from puberty to menopause, and subsequently, its near complete withdrawal (Seeman, 1997). In addition to being more common in women than men, thyroid dysfunction is more common in patients with mood disorders than in the general population and may interfere with treatment responsiveness of depression (Hendrick, Altshuler and Whybrow, 1998). Both mixed mania and rapid cycling have both been associated with elevated rates of overt and subthreshold thyroid abnormalities in some studies (Bauer, Whybrow and Winokur, 1990a; Cowdry et al., 1983; Kupka, 2003; Leibenluft, 1996). Zarate, Tohen and Zarate (1997) reported that first-episode patients with mixed mania (n = 15) were more likely to have elevated TSH than patients with pure mania (n = 57) after controlling for age and gender. Chang et al. (1998) found that the mean TSH was higher and the mean T4 lower in 14 patients with mixed mania as compared to 23 patients with pure mania. Frye et al. (1999) showed an association between a low mean level of free T4 and greater number of mood episodes and greater severity of depression in lithium-treated patients with bipolar disorder. In their meta-analysis of 20 studies, Kupka et al. (2003) found a significant association between current rapid cycling and clinical or subclinical hypothyroidism, but not between lifetime rapid cycling and hypothyroidism. Other studies, however, have not found an association between thyroid impairment and either mixed mania (Cassidy, Ahearn and Carroll, 2002; Joffe et al., 1994) or

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rapid cycling (Joffe, Kutcher and MacDonald, 1988; Kupka et al., 2002; Wehr et al., 1988). Of note, studies examining thyroid function in mixed mania and rapid cycling have used varied methodologies, including different subject inclusion criteria and different definitions of thyroid impairment. Further studies of thyroid function in mixed and rapid cycling states and relationship with gender are needed. Epidemiologic studies have shown that women are in fact more likely than men to be prescribed antidepressants and anxiolytics, but not antipsychotics (Hohmann, 1989; Kisely et al., 2000; Middleton et al., 2001). Moreover, preliminary clinical data suggest that females may be more likely than males to develop rapid cycling when exposed to antidepressants. Yildiz and Sachs (2003a) evaluated the records of 129 patients with bipolar disorder (55% women), 45% of whom had experienced a rapid cycling course. For the entire group, there was no difference in the rates of rapid cycling between patients who were exposed to antidepressants prior to their first manic or hypomanic episode (56%) and those who were not (42%). Additional analysis, however, found that the rate of rapid cycling among the female bipolar patients exposed to antidepressants prior to their first manic or hypomanic episode (77%) was significantly higher than the rate of rapid cycling among the female bipolar patients who were not similarly exposed (41%). By contrast, the rate of rapid cycling among the male bipolar patients who were exposed to antidepressants prior to their first mania or hypomania (36%) did not differ from those who were not similarly exposed (43%). Further analyses showed that women and men did not differ regarding antidepressant exposure prior to first mania or hypomania, and that women and men with rapid cycling did not differ regarding first episode type. Moreover, logistic regression with rapid cycling as the dependent variable showed a significant interaction between antidepressant use prior to first mania or hypomania and gender.

IS FEMALE BIPOLARITY CHARACTERIZED BY ATYPICALITY? A number of studies examining possible gender differences in the phenomenology of unipolar major depression have found that women are more likely than men to report atypical or reverse vegetative symptoms, particularly increased appetite and weight gain (Kornstein and Wojcik, 2002). Studies comparing the phenomenology of bipolar and unipolar depression have similarly suggested that bipolar depression is more likely to be associated with atypical features (Benazzi and Akiskal, 2003; Goodwin and Jamison, 1990; Mitchell et al., 2001). No studies have assessed possible gender differences in the phenomenology of bipolar depression. However, associations between bipolar II disorder and atypical features in particular have been described (Angst etal., 2003; Perugi etal., 1998), and as discussed earlier, there may be an association between bipolar II disorder and female gender. More research is needed to understand the relationships among bipolarity, atypicality and gender.

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GENDER DIFFERENCES IN COURSE AND OUTCOME A number of gender differences beyond depressive episode frequency have been reported in the course and outcome of bipolar disorder. First, several studies have found that females have a later age of illness onset than males (Robb et al., 1998; Viguera, Baldessarini and Tondo, 2001; Yildiz and Sachs, 2003b). Several studies have also reported that onset during the fifth decade of life is more common in women (Leibenluft, 1996). Other studies, however, have not found gender differences in the age of onset of bipolar disorder (Bellivier et al., 2001; Goodwin and Jamison, 1990; Hendrick et al., 2000; Suppes et al., 2001; Winokur et al., 1994). Indeed, the one epidemiolgic study that reported age of onset for both genders found a nonsignificantly earlier onset of illness for females than males (17.9 vs 22.0 years) (Szádóczky et al., 1998). Nonetheless, reports of females having a later onset of illness are consistent with clinical findings that patients with prepubertal mania are more likely to be male (Geller et al., 2002). Second, several gender differences in episode pattern occurrence have been described in bipolar disorder. Thus, some studies (Kubacki, 1986; Szádóczky et al., 1998), though not all (Abrams and Taylor, 1974), have reported that unipolar mania is more common in males than females. Some studies (Viguera, Baldessarini and Tondo, 2001), though not all (Kukopulous et al., 1980), have reported that bipolar women are more likely than bipolar men to have an episode pattern of depression followed by mania (sometimes called the DMI pattern), whereas bipolar men are either equally likely or more likely to have the episode pattern of mania followed by depression (the MDI pattern). However, gender differences have not been found in rates of developing hypomanic or manic episodes following first hospitalization for major depression with psychotic features (DelBello et al., 2003). Another episode pattern difference is that a bimodal peak of psychiatric hospitalizations in the spring and fall has been observed in female patients with bipolar disorder as compared to a unimodal peak in the spring in bipolar male patients (D’Mello, NcNeil and Msibi, 1995). Further supporting a possible relationship between female bipolarity and seasonality are reported associations of seasonal affective disorder (Rosenthal et al., 1984) and DSM-III-R seasonal mood disorder (Faedda et al., 1993b) with both female gender and bipolar disorder. Finally, some studies have reported gender differences in the impact and longterm outcome of bipolar disorder. Thus, even when euthymic, female patients with bipolar disorder have been found to report their health and well-being to be poorer overall than male patients (Robb et al., 1998). In a large community survey, Mood Disorder Questionnaire (MDQ)-positive women reported significantly more disruption in social/leisure life (17.2% vs 10.8%, p = 0.002) and family life (23.62% vs 15.8%, p = 0.001) in the 12 months prior to study participation compared with MDQ-positive men (Hirschfeld etal., 2003). Specifically, MDQ-positive women

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reported significantly more symptom disruption as a result of irritability, increased confidence, talkativeness, distractibility and spending money compared with MDQ-positive men. Hendrick et al. (2000) compared the course of illness of 63 women and 68 men with DSM-IV bipolar disorder attending a mood disorders program over a 3-year period. Women and men displayed similar numbers of depressive episodes, manic episodes and hospitalizations for depressions. However, women were hospitalized significantly more often than men for mania. By contrast, other data suggest females may have better functional outcomes than males. Loyd, Simpson and Tsuang (1985) compared the outcome of women and men hospitalized for mania (diagnosed by Feighner etal. criteria), and found a trend (x2 = 9.21, df = 4, p < 0.06) for women to have more favorable outcomes, which he attributed to their having slightly better occupational and residential outcomes. In a prospective follow-up study of 73 manic patients 1.7 years after hospitalization, there was a minor trend for women to show more favorable overall functioning (p<0.20) and a significant finding for women to show better work functioning (p < 0.01) (Harrow et al., 1990). Similarly, in a prospective study of 75 inpatients with DSM-III bipolar disorder who had recovered from a manic episode, Tohen, Waternaux and Tsuang (1990) found that male gender predicted poorer residential status at 4-year follow-up. Moreover, bipolar men may be more likely than bipolar women to become involved with the forensic system. In the large community survey mentioned earlier, almost three times as many MDQ-positive men had been jailed, arrested or convicted of a crime compared with MDQ-positive women (36.5% vs 13.1%, p < 0.00001) (Calabrese et al., 2003). Taken together, these findings raise the issue of whether some of the gender differences in bipolarity reflect gender differences in help-seeking behavior or access to health care (Weissman and Olfson, 1995).

GENDER DIFFERENCES IN COMORBIDITY Bipolarity is highly comorbid with a number of other mental and general medical disorders (Angst, 1998; Angst et al., 2003; Boyd et al., 1984; Calabrese et al., 2003; Kessler et al., 1997), and these comorbid disorders may have adverse effects on the course, outcome and treatment response of bipolar disorder (Black etal., 1988a,b; Frank et al., 2002; McElroy et al., 2001). Common co-occurring mental disorders include anxiety, substance use and eating disorders (Angst, 1998; Boyd et al., 1984; Chen, Who and Dilsaver, 1995; Kessler et al., 1997). Some of these disorders (anxiety and eating disorders) are more common in women in general, and are likely to be more common in females with bipolar disorder than in males with bipolar disorder (Calabrese et al., 2003; Frank et al., 2002; Krüger, Shugar and Cooke, 1996; Lewinsohn, Striegel-Moore and Seeley, 2000; MacKinnon etal., 2002). Substance use disorders, though more common in bipolar men than in bipolar

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women, are nonetheless much more common in women with bipolar disorder than in women without bipolar disorder (Frye et al., 2003; Hendrick et al., 2000). Indeed, based on data for 267 bipolar patients enrolled in the Stanley Foundation Bipolar Network, the risk of alcoholism was greater for women with bipolar disorder (odds ratio = 7.35) than for men with bipolar disorder (odds ratio = 2.77) as compared to the general population (Frye et al., 2003). Also, in a study of 41 manic patients at first hospitalization, women had a higher rate of alcohol abuse or dependence than men (36.0% vs 6.3%) (Strakowski etal., 1992). Thus, substance abuse in a female should be considered a marker for bipolarity. General medical disorders that frequently co-occur with bipolar disorder include migraine (Breslau, Merikangas and Bowden, 1994), thyroid disease (Hendrick, Altshuler and Whybrow, 1998; Kupka, 2003; Kupka et al., 2002) and overweight and obesity (Elmslie et al., 2000; McElroy et al., 2001). Both migraine (Breslau, Merikangas and Bowden, 1994) and thyroid disease (Tunbridge etal., 1977; Vanderpump etal., 1995) are more common in women than men in general, and in bipolar women than bipolar men in particular (Blehar et al., 1998; Calabrese et al., 2003). As noted earlier, both overt and subclinical thyroid disease has been hypothesized to contribute to the higher rates and rapid cycling and mixed states in women with bipolar disorder. It might also contribute to the depressive diathesis of female bipolarity (Kleiner et al., 1999). Cole et al. (2002) found that lower pretreatment thyroid function (i.e., lower FTI and higher TSH values) was significantly associated with longer time to response in 65 patients with bipolar depression. Regarding obesity and bipolar disorder, one study of 644 patients from the United States and Europe found that women were more likely to be obese and extremely obese, whereas men were more likely to be overweight (McElroy et al., 2001). Another study of 89 euthymic outpatients from New Zealand found that women and men had similar rates of obesity, but that women had higher rates of overweight (Elmslie et al., 2000). Obesity has been associated with a higher rate of recurrence, particularly depressive recurrence, in lithium-treated bipolar patients (Fagiolini et al., 2003). Female patients with bipolar disorder are also more likely to report a history of sexual abuse, but not physical abuse, than male bipolar patients (Leverich etal., 2002). A history of childhood or adolescent abuse has been associated with a worse course of bipolar disorder, including earlier age of onset, greater comorbidity and a higher rate of suicide attempts (Leverich et al., 2002). Preliminary studies suggest comorbidity in general is either more common in mania at first hospitalization in women than men (Strakowski et al., 1992) or equally common in women and men with bipolar disorder (Black et al., 1988a,b; Vieta et al., 2001), but this issue needs more study. Possible gender differences in the effects of comorbidity on the presentation, course, outcome and treatment response of bipolar disorder have not been systematically evaluated (Black et al., 1988a,b).

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BIPOLAR DISORDER AND THE REPRODUCTIVE CYCLE MENSTRUAL CYCLE There is limited evidence that bipolar disorder may worsen during the premenstrual (late luteal) phase in some women (Blehar et al., 1998; Hendrick, Altshuler and Burt, 1996; Leibenluft, 1996, 1997). Ota, Mukai and Gotoda (1954) described female bipolar patients whose manic relapses occurred regularly during the premenstrual phases of their cycles. Diamond et al. (1976) reported an increased rate of hospitalizations among women attending a lithium clinic during their luteal phase. D’Mello, Pinheiro and Lalinec-Michaud (1993) described 2 women who experienced recurrent irritability, hyperactivity and decreased need for sleep in the 5 days before their menses but who were euthymic for the remainder of their menstrual cycles. Their mood symptoms responded to maintenance lithium treatment. Kukopulous et al. (1985) and Conrad and Hamilton (1986) each described women with bipolar disorder who experienced late luteal symptomatic exacerbations with lithium level decreases. In one case, increasing the lithium dose 1 week prior to menses successfully maintained lithium levels and prevented the premenstrual deterioration over a 2-year period (Conrad and Hamilton, 1986). More recently, Blehar et al. (1998) reported that 66% of 186 women with bipolar I disorder described regularly occurring premenstrual or menstrual (early follicular) mood changes. Similarly, in a prospective evaluation of 17 women with bipolar disorder who kept daily self-reported mood ratings, 11 (65 %) reported a significant change in mean mood between the first 7 days and the last 7 days during at least one menstrual cycle, with 6 of the 11 reporting a significant mood change in more than one menstrual cycle (Rasgon et al., 2003). However, there was no clear pattern to the mood changes across the menstrual cycle. No studies, to our knowledge, have evaluated DSM-IV premenstrual dysphoric disorder (PMDD) in females with bipolar disorder. Roy-Byrne et al. (1985b) found that 25% of 16 women with bipolar disorder met criteria for a premenstrual “depressive syndrome.” Endicott et al. (1985) reported that females with bipolar II disorder (N = 66; 71%) were more likely to suffer from “premenstrual dysphoria” as compared to females with bipolar I disorder (N = 122; 44%) or unipolar depressive disorder (N = 104; 42%). Price and DiMarzio (1986) found that 15 (60%) of 25 women with rapid-cycling bipolar disorder reported “severe premenstrual tension syndrome.” Interestingly, a consistent relationship between the menstrual cycle and rapid cycling has not been found (Diamond et al., 1976; Leibenluft et al., 1999; Price and DiMarzio, 1986; Wehr et al., 1988). Bipolar disorder may also affect menstrual function. Thus, Rasgon et al. (2000) reported that 18 (81.8 %) of 22 women taking lithium (N = 11), valproate (N = 10) or both (N = 2) had menstrual irregularities. In addition, in 14 (63.6%) women, the menstrual irregularities preceded the onset of the bipolar disorder. In another study, 59% of 17 prospectively evaluated bipolar women, including those taking

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oral contraceptives, displayed long menstrual cycles (Rasgon et al., 2003). In both studies, the authors hypothesized that menstrual abnormalities in bipolar disorder might be due in part to the hypothalamic pituitary adrenal axis dysfunction associated with the illness.

PREGNANCY Although early reports suggested pregnancy was protective against mood episodes, more recent data indicate that bipolar women who are pregnant experience mood episodes at rates similar to those who are not pregnant (Blehar et al., 1998; Nonacs, Viguera and Cohen, 2002). Viguera, Tondo and Baldessarini (2000) compared recurrence rates for 101 women with DSM-IV bipolar disorder (68 BP I, 33 BP II) during pregnancy and the postpartum (N = 42) or during equivalent periods for age-matched, nonpregnant controls (N = 59) after either rapid (1–14 days) or gradual (15–30 days) discontinuation of stable lithium maintenance treatment. Recurrence rates after lithium discontinuation were similar for pregnant (52%) and nonpregnant women (58%), but had been much lower than both in the year before treatment was discontinued (21%). In addition, recurrence risk was greater after rapid than after gradual discontinuation and for patients with a history of four or more mood episodes, but was similar for bipolar I and II disorders. The increased recurrence rate with rapid discontinuation of lithium is consistent with previous studies in broader groups of bipolar patients (Baldessarini et al., 1997; Faedda et al., 1993a) and further underscores pregnancy’s lack of protective or “mood stabilizing” effects in bipolar disorder.

POSTPARTUM PERIOD Extensive data show that the postpartum is a high risk period for mood and psychotic episodes for females in general (Miller, 1999). This is particularly true for females with bipolar disorder, who are at increased risk of experiencing first onset and recurrent depressive, manic, mixed and psychotic episodes (Kendell, Chalmers and Platz, 1987; Leibenluft, 1996). For example, one study found that 13 (36%) of 36 consecutively hospitalized bipolar mothers reported onset of the disorder in the postpartum compared with none of 8 bipolar fathers, with postpartum relapse rates of 25% to 40% after subsequent pregnancies (Hunt and Trevor, 1995). In another study, one-third of women with bipolar disorder developed manic episodes temporally related to childbirth (Kubacki, 1986). A retrospective review of the impact of reproductive events on the course of bipolar disorder in 30 outpatient mothers showed that 67% had experienced postpartum mood episodes, and that the rate of recurrent postpartum episodes after subsequent pregnancies was 64% (Freeman, Arnold and McElroy,

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2002a). In addition, the presence of mood symptoms during pregnancy was significantly associated with postpartum mood episodes. Similarly, in their study of 101 gravid and nongravid women with DSM-IV bipolar disorder who discontinued lithium maintenance treatment, Viguera, Tondo and Boldessarini (2000) found that, among the patients who remained stable over the first 40 weeks after lithium discontinuation and were subsequently followed from week 41 through week 64, postpartum recurrences were 2.9 times more frequent than recurrences in nonpregnant women (70% vs 24%, respectively). Although women with bipolar disorder often have postpartum mood episodes, it is unknown how often postpartum depression represents bipolar disorder. Several studies, however, have found that postpartum depression is often characterized by bipolar features, including emotional lability, psychosis, disorientation and elevated hypomania ratings (Dean and Kendell, 1981; Lane et al., 1997). By contrast, it is well documented that postpartum psychosis is more frequently associated with bipolar disorder than any other psychiatric disorder (Videbech and Goulinev, 1995; Chaudron and Pies, 2003). The rate of postpartum psychosis in women with bipolar disorder has been reported to be between 20% and 30% (Jones and Craddock, 2001). Women who have had one postpartum psychotic episode are at a high risk of recurrent mood episodes (Jones and Craddock, 2001). Moreover, women with bipolar disorder who have a family history of postpartum psychosis are at higher risk of puerperal episodes than other bipolar women (Jones and Craddock, 2001). Of note, preliminary genetic evidence indicates that variation at the serotonin transporter gene influences susceptibility to postpartum episodes in women with bipolar disorder (Coyle et al., 2000).

MENOPAUSE Although cross-sectional and longitudinal studies have suggested a positive association between the perimenopause and depressive symptoms (Burt, Altshuler and Rasgon, 1998), the relationship between menopause and bipolar disorder has received little empirical study (Leibenluft, 1996). Preliminary data, however, suggest some bipolar women who are perimenopausal or postmenopausal may experience an increase in mood symptoms (Freeman, Arnold and McElroy, 2002a). In one study, 19% of 56 postmenopausal bipolar women reported worsening of mood symptoms after menopause (Blehar et al., 1998). In a follow-up study of 68 women with rapid-cycling bipolar disorder, 28% were noted to begin rapid cycling during the perimenopausal age range (45–54 years) (Kukopulos etal., 2003). In another study, bipolar women who were not using hormone replacement therapy (HRT) during the perimenopause and menopause were significantly more likely to report worsening of mood symptoms, primarily depressive, than those not using HRT, suggesting HRT had a protective effect during this period (Freeman et al., 2002b).

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TREATMENT OF BIPOLAR DISORDER IN FEMALES GENDER AND RESPONSE TO MOOD STABILIZERS Very few studies have systematically assessed possible gender differences in response to mood stabilizers (Leibenluft, 1996; Viguera, Baldessarini and Tondo, 2001). Available data, however, suggest gender does not affect pharmacodynamic response of bipolarity to lithium. Viguera, Tondo and Baldessarini (2000) systematically reviewed 17 studies of 1043 lithium-treated subjects with major mood disorders that allowed determination of separate response rates for men and women. Response rates were similar for women and men for major mood disorder (63.5% vs 59.9%) and for bipolar disorder (63.5% vs 59.9%). Similarly, in a retrospective study of lithium prophylaxis in bipolar disorder, gender did not impact overall morbidity (Berghofer, Kossmann and Muller-Oerlinghausen, 1996). In a study of the effectiveness of restarting lithium treatment after its discontinuation in patients with bipolar I and II disorders, both the response to lithium discontinuation and its re-institution did not differ in women and men (Tondo et al., 1997). More recently, Viguera, Baldessarini and Tondo (2001) evaluated 360 men and women with DSM-IV bipolar disorder before and during lithium maintenance monotherapy. Although women started lithium maintenance treatment at an older age, women did not differ from men regarding treatment response when defined by episodes per year, hospitalizations per year or percent of time ill. Indeed, a survival analysis of time to first recurrence during lithium maintenance treatment showed significantly earlier recurrence in men than women. Of note, women required or tolerated slightly (but significantly) lower serum concentrations of lithium than men (mean serum lithium [mEq/L]: 0.60 ± 0.13 vs 0.64 ± 0.14) (Viguera, Baldessarini and Tondo, 2001). Possible gender differences in the pharmacodynamic response of bipolarity to valproate, carbamazepine and atypical antipsychotics have been less systematically evaluated. No data exist, however, to suggest clinically relevant gender differences in response to these agents. For example, a reanalysis of pooled data from two double-blind, placebo-controlled trials of olanzapine in acute bipolar mania showed that females and males responded equally well to the drug (Baldessarini et al., 2003). However, one retrospective study found that the mean dose of typical antipsychotic medication was higher in a group of bipolar women who were older than 40 years compared with a younger group. The finding was hypothesized to be due to the older women’s declining estrogen levels and subsequent loss of estrogen’s putative antidopaminergic effects (D’Mello and McNeil, 1990). There may be gender differences in side effects to mood stabilizers. Women may be more likely to develop lithium-associated hypothyroidism and weight gain, whereas men may be more likely to develop tremor (Henry, 2002; Johnston and Eagles, 1999). It is unknown if the increased rate of hypothyroidism in

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lithium-treated bipolar women represents the increased rate of thyroid disease in women than men in general, if women are more vulnerable than men to lithium’s thyrotoxic effects, or if a combination of these factors applies. In one study, the only factor predictive of hypothyroidism with lithium treatment (beyond female gender) was weight gain during the first year of treatment (Henry, 2002). In another study of 226 bipolar outpatients, thyroid autoimmunity, defined as the presence of thyroperoxidase antibodies, was found to be equally and highly prevalent in women and men with bipolar disorder; thyroid autoimmunity tended to be associated with hypothyroidism; lithium exposure was associated with hypothyroidism but not thyroid autoimmunity; and women were more likely than men to develop hypothyroidism (Kupka et al., 2002). Thus, thyroid autoimmunity and lithium exposure were independent, but cumulative, risk factors for hypothyroidism, especially in bipolar women. Typical antipsychotic medications and the novel antipsychotic risperidone are associated with hyperprolactinemia. Hyperprolactinemia may cause galactorrhea, amenorrhea and menstrual cycle irregularities, anovulation, infertility and sexual dysfunction, as well as anxiety, depression and hostility (Dickson and Glazer, 1999; Dickson, Seeman and Corenblum, 2000). Antipsychotic-associated hyperprolactinemia can be managed by (1) switching to a prolactin-sparing antipsychotic (i.e. olanzapine, quetiapine or clozapine); (2) lowering the dose of the typical antipsychotic or risperidone; or (3) adding a dopamine agonist, such as bromocriptine (Dickson, Seeman and Corenblum, 2000). Whether or not there is a relationship between polycystic ovarian morphology (PCO), hyperandrogenism (hyperandrogonemia and/or hirsutism) and polycystic ovarian syndrome (PCOS; ovulatory dysfunction, polymenorrhea, amenorrhea or oligomenorrhea with clinical evidence of hyperandrogenism but no other endocrinopathy) and valproate exposure in females with epilepsy (Bauer etal., 2000; Duncan, 2001; Isojärvi et al., 1993, 1996) or bipolar disorder (Akdeniz et al., 2003; O’Donovan et al., 2002; Rasgon et al., 2000) remains controversial. Some authorities have argued that the weight gain from the use of valproate, rather than the drug itself, may be responsible for the development of reproductive endocrine abnormalities in predisposed females (Duncan, 2001). Until more data are available, reproductive-aged females with bipolar disorder treated with valproate (and other mood stabilizers associated with weight gain) should be monitored for menstrual irregularities and hyperandrogenism.

GENDER AND RESPONSE TO ANTIDEPRESSANTS The treatment of bipolarity with antidepressants, in general, is controversial because of inadequate data regarding their short- and long-term efficacy in bipolar spectrum depression (Ghaemi etal., 2003; Keck etal., 2003; Thase and Sachs, 2000), and inconsistencies in available data regarding their ability to induce hypomania,

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mania, mixed states and rapid cycling (Akiskal et al., 2003; Altshuler et al., 1995; Calabrese et al., 1999; Coryell et al., 2003; DelBello et al., 2003). Nonetheless, clinical studies suggest that some patients with bipolar I and II disorder destabilize upon antidepressant exposure (Benazzi, 1997), whereas others require acute and even maintenance treatment with antidepressants (typically in combination with mood stabilizers) for optimal response (Altshuler et al., 2003b). Moreover, available data suggest that there are gender differences in the pharmacodynamic and pharmacokinetic response of major depressive disorder to antidepressants (Kornstein and Wojcik, 2002; Yonkers et al., 1992). These include findings that women with major depression may respond better to serotonin selective reuptake inhibitors (SSRIs) than to tricyclics (which does not appear to be true for men) (Kornstein et al., 2000), and that women may respond better than men to augmentation strategies with triiodothyonine (Coppen et al., 1972; Whybrow, 1995), lithium (Dallal et al., 1990) and stimulants (Askinazi, Weintraub and Karamouz, 1986). Possible gender differences in the response of bipolar depression to antidepressants have not been systematically evaluated, except for the observation that females may be more likely than males to develop rapid cycling upon antidepressant exposure (Yildiz and Sachs, 2003). Further research into possible gender differences in the response of bipolarity to antidepressants is greatly needed.

MANAGEMENT OF MIXED STATES AND RAPID CYCLING Although considerable clinical experience suggests that mixed states and rapid cycling are more difficult to treat than pure states and non-rapid cycling, respectively, extremely little is known about gender differences in the treatment response of these presentations (Arnold, McElroy and Keck, 2000). Among patients with mixed mania in one review, however, gender did not predict response to lithium, valproate or carbamazepine (Arnold, McElroy and Keck, 2000). Early studies suggested that the anticonvulsants carbamazepine and valproate might be superior to lithium in both mixed states (McElroy et al., 1992; Post etal., 1987) and rapid cycling (Calabrese and Delucchi, 1990; Calabrese etal., 2001b). Data from one placebo-controlled study have since suggested that the presence of depressive symptoms during bipolar mania may predict a better acute anti-manic response to valproate than to lithium (Swann et al., 1997). By contrast, subsequent clinical data have suggested carbamazepine and valproate are each frequently inadequately effective as monotherapy agents for mixed mania (Dilsaver et al., 1993) and rapid cycling (Calabrese et al., 2001a; Okuma, 1993). In addition, clinical data have indicated that although lithium fails to prevent recurrences in many cases of rapid cycling, it still often leads to considerable improvement (Baldessarini et al., 2000; Greil and Kleindienst 1999; Kupka, 2003; Kupka et al., 2003). Fortunately, increasing open-label and controlled reports have suggested that atypical antipsychotics may be effective as monotherapy or adjunctive therapy in

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the treatment of mixed states and rapid cycling, including in treatment-resistant females (Baldessarini et al., 2003; Calabrese, Meltzer and Markovitz, 1991; Keck et al., 2003a; Keck, Nelson and McElroy, 2003b; Parramon et al., 2002; Suppes et al., 1992; Vieta et al., 1998). Open reports and one controlled study suggest that the novel anticonvulsant lamotrigine may be effective for some patients with rapid cycling, particularly those with bipolar II disorder or prominent depressive symptoms (Bowden et al., 2000; Calabrese et al., 2000). Early reports that adjunctive levothyroxine improved mood stabilization in some patients with rapid cycling bipolar disorder (Bauer and Whybrow, 1990b), however, have not yet been supported by controlled trials.

TREATMENT OF COMORBID CONDITIONS Many of the mental conditions commonly comorbid with bipolar disorder in females respond to antidepressants. These are most anxiety disorders (Hudson et al., 2003), bulimia nervosa (Bacaltchuk, Hay and Mari, 2000), binge eating disorder (Carter et al., 2003) and premenstrual dysphoric disorder (Freeman, Arnold and McElroy, 1999). The use of antidepressants for the treatment of comorbid conditions is problematic in women with bipolar disorder because of the risk of precipitating hypomania, mania, mixed states and rapid cycling (Altshuler et al., 1995). Unfortunately, mood stabilizers have received very little systematic study in the treatment of these conditions – either with or without comorbid bipolarity. Nonetheless, preliminary controlled evidence suggests effectiveness of lithium for anorexia nervosa (Gross et al., 1981) and alcohol dependence (Fawcett et al., 1987); valproate for panic disorder (Lum et al., 1991) and alcohol dependence (Brady et al., 2002); carbamazepine for alcohol withdrawal (Malcolm et al., 1989); and adjunctive atypical antipsychotics for SSRI-resistant obsessive compulsive disorder (McDougle et al., 2000) and post-traumatic stress disorder (Stein, Kline and Matloff, 2002). Valproate, as divalproex, is approved by the FDA for migraine prevention (Jensen, Brinck and Olesen, 1994; Matthew et al., 1995; Silberstein, Saper and Matthew, 1993). Lithium (Singer, Cheng and Schou, 1974; Steiner et al., 1980) and valproate (Jacobsen, 1993) have been found to be ineffective in studies of premenstrual syndrome, but these studies had methodological limitations. Agents that may be effective in some of these comorbid conditions, but whose thymoleptic profiles have not been fully delineated, include gabapentin in social anxiety disorder (Pande et al., 1999); topiramate in alcohol dependence (Johnson et al., 2003), bulimia nervosa (Hoopes et al., 2003), binge eating disorder (McElroy et al., 2003), obesity (Bray et al., 2003) and migraine prevention (Storey et al., 2001); and zonisamide in obesity (Gadde et al., 2003).

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PHARMACOTHERAPY OF BIPOLARITY DURING PREGNANCY When deciding whether or not to use pharmacotherapy for women with bipolar disorder who wish to conceive or who already are pregnant, the risk that a psychotropic medication may harm the fetus must be balanced with the risk that untreated bipolar disorder may harm the pregnant woman and the fetus (Altshuler etal., 1996, 2003a; Arnold, 2003; Cohen and Rosenbaum, 1998; Freeman etal., 2002b; Viguera and Cohen, 1998; Yonkers et al., 2004). Specific risks to the offspring from prenatal exposure to psychotropic drugs include teratogenicity, perinatal syndromes and postnatal behavioral sequelae (see below). Although there are no systematic data on the effects of untreated manic, depressive, mixed and psychotic symptoms on fetal development, systematic studies have shown that other forms of psychopathology during pregnancy are associated with adverse effects on offspring. Thus, maternal depression during pregnancy has been associated with preterm delivery and low birth weight (Orr and Miller, 1995; Steer et al., 1992), and antenatal anxiety has been associated with an increased risk of both preterm delivery (Hedegaard et al., 1993) and behavioral problems in early childhood (Glover and O’Connor, 2002; O’Connor et al., 2002). In addition, rodent and primate research has shown a strong link between maternal antenatal stress and persistent impaired behavioral adjustment and emotional reactivity in offspring that is accompanied by changes in hypothalamus–pituitary–adrenal axis functioning (Glover and O’Connor, 2002; Weinstock, 2001). Thus, active bipolarity during pregnancy may have long-term deleterious effects on the infant. Indeed, obstetrical complications have been shown to be significantly worse in probands with bipolar disorder compared with their siblings without mood disorder, suggesting such complications could be etiologically significant in bipolar disorder (Kinney et al., 1998). As reviewed earlier, discontinuation of stable maintenance mood stabilizers increases the risk of relapse in nonpregnant and pregnant women with bipolar I and II disorder, and the risk of relapse is even higher in women who discontinue such medication abruptly (i.e. in less than two weeks) and in women with more recurrent illness (i.e. four or more prior depressive or manic episodes) (Viguera, Tondo and Baldessarini, 2000). Finally, repeated mood episodes, including those associated with discontinuation of stable maintenance mood stabilizer regimens, may lead to chronicity, treatment resistance and suicide in the mother (Post et al., 1992; Maj, 2000). The commonly used mood stabilizers lithium, valproate and carbamazepine all have evidence of teratogenicity. The risk estimate for cardiovascular malformations, including Epstein’s anomaly, after first trimester exposure to lithium is between 0.05% and 0.1% or 10–20 times the risk in the general population (Cohen and Rosenbaum, 1998). However, the absolute risk with lithium exposure remains low (1 in 1000 births) (Altshuler et al., 1996; Cohen et al., 1994). The risk of spina bifida

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after first trimester exposure to valproate or carbamazepine is 15 times the risk in the general population (Altshuler et al., 1996). After first trimester exposure to valproate, the risk estimate of spina bifida is 1% to 5% (Lammer, Sener and Oakley, 1987; Lindhout et al., 1992; Omtzigt et al., 1992); after first trimester exposure to carbamazepine, it is 0.5%–1.0% (Rosa, 1991). The risk of neural tube defects is further increased with the use of high doses of anticonvulsants and with multiple anticonvulsants (Battino etal., 1992; Koch etal., 1992; Nakane etal., 1980). Fetal exposure to carbamazepine and valproate, even late in the pregnancy, is associated with craniofacial abnormalities and cognitive dysfunction (Cohen and Rosenbaum, 1998; Koch et al., 1982; Omtzight et al., 1992; Rosa, 1991), as well as minor malformations that resolve with time, such as rotated ears, depressed nasal bridge, short nose, elongated upper lip and fingernail hypoplasia (Delgado-Escueta and Janz, 1992; Gaily and Granstrom, 1992; Jager-Roman et al., 1986; Jones et al., 1989; Koch et al., 1982). The most recognized perinatal syndrome associated with in utero lithium exposure is “floppy baby” syndrome, characterized by hypotonicity, cyanosis and lethargy (Schou and Amdisen, 1975; Woody, London and Wilbanks, 1971). Neonatal hypothyroidism, nontoxic goiter, nephrogenic diabetes insipidus, cardiac murmurs, arrhythmias and respiratory distress have also been reported (Arnold, 2003). The frequency of these syndromes are unknown, but all are presumed rare. Neither lithium nor carbamazepine have yet been associated with any reports of significant postnatal behavioral sequelae. In one study, 60 infants who were exposed to lithium in utero and born without malformations “had gone through a normal development, both physically and mentally” at a rate comparable to that 57 unexposed siblings (Schou, 1976). In another study, children who had a history of prenatal exposure to carbamazepine showed no neurodevelopmental problems compared with controls (Scolnik et al., 1994). Data for other putative mood stabilizers are limited. A case registry of 96 prospectively reported cases of exposure to olanzapine during pregnancy found that the rate of major malformations (1%), spontaneous abortions (12.5%), premature deliveries (2.1%) and stillbirths (3.1%) were within the range of normal historical controls (Ernst and Goldberg, 2002). A lamotrigine pregnancy registry reported a risk of major congenital defects of 1.8% with lamotrigine monotherapy during the first trimester (Ernst and Goldberg, 2002). Clozapine has been associated with perinatal syndromes (e.g. floppy infant syndrome and neonatal seizures) (DiMichele, Ramenghi and Sabatino, 1996; Stoner et al., 1997). However, several case reports found no association between clozapine and congenital anomalies (Barnes et al., 1994; Dickson and Hogg, 1998; Waldman and Safferman, 1993). Human data are currently inadequate to determine the teratogenicity of risperidone, ziprasidone, aripiprazole, topiramate or gabapentin. Electroconvulsive therapy, which is highly effective for bipolar manic, depressive and mixed states, has not been associated with deleterious effects on pregnant

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women or neonates (Ferrill, Kehoe and Jacisin, 1992; Miller, 1994). Although more data are needed, ECT should presently be viewed as a safe and effective treatment for bipolarity during pregnancy, especially for severe or life-threatening mood and psychotic episodes. Regarding antidepressants, no significant teratogenic effects have been found to date for tricyclics or SSRIs (Altshuler etal., 1996, 2003a; Cohen etal., 2000). Case reports and controlled studies have found obstetrical complications and perinatal syndromes with third-trimester exposure to fluoxetine or citalopram in some (Chambers etal., 1996; Laine etal., 2003), but not all (Goldstein, 1995; Pastuszak etal., 1993), studies. Effects of SSRIs other than fluoxetine in the third trimester have not been assessed. Preliminary data show no adverse long-term neurobehavioral effects from in utero exposure to TCAs (Nulman etal., 1997) or SSRIs (Altshuler etal., 2001). Pregnancy and medication risks should be discussed with all females with bipolar disorder of childbearing potential regardless of their immediate plans for pregnancy. Based on the particular features of a woman’s bipolarity, an individualized treatment plan can be developed that promotes the woman’s health and minimizes fetal exposure to potential teratogens (Altshuler et al., 1996, 2003a; Arnold, 2003; Cohen and Rosenbaum, 1998; Freeman etal., 2002b; Viguera and Cohen, 1998). Thus, women with mild bipolarity (e.g. one past hypomanic or manic episode and long periods of affective stability) may elect to gradually taper and discontinue medication prior to conception because of their relatively low risk of relapse (Tohen, Waternaux and Tsuang, 1990). Women with moderate bipolarity (e.g. 2–3 episodes of hypomania, mania or depression and relative interepisode euthymia) may also choose to taper and discontinue medication(s) prior to conception. However, as the risk of relapse is greater in these women, they may elect to continue pharmacotherapy until early confirmation of pregnancy, prolonging the time of prophylaxis. Once a woman is pregnant, a medication can be tapered in the 2 weeks prior to the establishment of the placental–fetal circulation, before the fetus is vulnerable to teratogens (Arnold, 2003; Viguera and Cohen, 1998). Because this strategy requires a more rapid medication taper it increases the risk of relapse. However, pharmacotherapy can be instituted for any recurrence of clinically significant symptoms. Women with severe or unstable bipolarity (e.g. 4 or more mood episodes and/or clinically significant subsyndromal symptoms) have a high rate of relapse, and the risks to the mother and fetus from the disorder may exceed the risks of psychotropic exposure to the fetus. Many of these women may not be able to safely discontinue pharmacotherapy during pregnancy. If pharmacotherapy during pregnancy is to be pursued, several general steps may reduce risk to the fetus. Using the lowest effective dose of any medication and limiting the number of medications decreases fetal exposure. Folate supplementation before and during pregnancy has been shown to reduce the risk of neural tube defects (MRC Vitamin Study Research Group, 1991). Although folate has not been proven to prevent neural tube defects in women receiving anticonvulsants,

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it is recommended that women who elect to continue anticonvulsants during pregnancy take folate (5 mg/day) starting at least 4 weeks before conception (if they are not already doing so) and continuing through week 12 of pregnancy (Altshuler et al., 1996; Ernst and Goldberg, 2002; Yonkers et al., 2004). Women who have taken mood stabilizers during the first trimester have the option of receiving a high resolution ultrasound and fetal echocardiogram at 18–20 weeks gestation to detect cardiac abnormalities, and an ultrasound at 16–19 weeks gestation to detect neural tube defects, followed, if necessary, by amniocentesis for detection of spina bifida (Altshuler et al., 1996; Arnold, 2003; Cohen et al., 1994; Ernst and Goldberg, 2002; Viguera and Cohen, 1998).

PHARMACOTHERAPY OF BIPOLARITY DURING THE POSTPARTUM AND LACTATION Prophylactic treatment with lithium has been shown to substantially reduce the risk of recurrence of mood and psychotic episodes during the postpartum (Austin, 1992; Chaudron and Pies, 2003; Cohen et al., 1995). Because of the extremely high risk for relapse during the postpartum, prophylaxis with mood stabilizers thought to be effective for the individual patient is generally recommended for the postpartum woman with bipolar disorder. When weighing the risks and benefits of breast-feeding in women with bipolar disorder, the most important consideration is the health of the mother and infant (Arnold 2003; Yonkers et al., 2004 ). Maternal postpartum illness has an adverse effect on both mother and developing infant. Although breast-feeding has immunological benefits for the infant and is encouraged by the American Academy of Pediatrics (2001), no psychotropic drugs are known to be absolutely safe for the breast-feeding infant, and bottle-feeding with formula is an obvious alternative (Arnold, 2003; Llewellyn and Stowe, 1998; Suri et al., 1999). There are limited data about the use of mood stabilizers while breast-feeding. The concentration of lithium in the serum of nursing infants is approximately onetenth to one-half the mother’s serum concentration (Schou and Amdisen, 1973; Sykes, Quarrie and Alexander, 1976). The American Academy of Pediatrics Committee on Drugs (2001), which had once stated lithium was contraindicated during breast feeding, now recommends that it “should be given to nursing mothers with caution.” Valproate serum concentrations in nurslings have ranged from 0.9% to 40% of maternal serum concentrations (Wisner and Perel, 1998). Valproate has not yet been associated with adverse effects in nursing infants, but data are limited and hepatotoxicity is a theoretical risk (Suri et al., 1998). Carbamazepine serum concentrations in nursing infants have ranged from 15% to 65% of maternal serum concentrations (Wisner and Perel, 1998). Carbamazepine has been associated with cholestatic hepatitis (Frey, Schubiger and Musy, 1990), and elevated gamma-glutamyltransferase (GGT) and direct bilirubin levels in nursing infants

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(Merlob, Mor and Litwin, 1992). The American Academy of Pediatrics Committee on Drugs (2001) considers both valproate and carbamazepine as “usually compatible” with breast-feeding. Information is also limited about other mood stabilizers, antipsychotics and antidepressants during breast feeding. Of 20 reports of nurslings exposed to olanzapine, 4 described adverse events. These included jaundice, sedation, cardiomegaly and a heart murmur; shaking, poor suckling and lethargy; protruding tongue; and rash, diarrhea and a sleeping disorder (Ernst and Goldberg, 2002). Serum levels of lamotrigine in nurslings have ranged from 25% to 30% of maternal serum concentrations, and there have been no reports of adverse effects in lamotrigine-exposed infants (Ohman, Vitols and Tomson, 2000; Tomson, Ohman and Vitols, 1997). Regarding typical antipsychotics, one nursling exposed to chlorpromazine was drowsy and lethargic for an unspecified amount of time, whereas 9 others had no adverse effects (Suri et al., 1999). Adverse effects reported in nurslings exposed to antidepressants have included respiratory depression for doxepin (N = 1) and increased crying, decreased sleep time, vomiting and diarrhea for fluoxetine (Suri et al., 1999; Wisner, Perel and Findling, 1996). The American Academy of Pediatrics Committee on Drugs (2001) has classified antidepressants as “drugs whose effects on nursing infants is unknown but may be of concern.” Because of the limited information about the risks of exposure to psychotropics through breast milk, careful monitoring of the infant is required and nursing should be discontinued if adverse effects occur in the infant. The nursling’s drug exposure might be minimized by the mother limiting the number of medications, using the lowest effective dose, and by taking her medication just after she has breast-fed and before the infant has a lengthy sleep period (American Academy of Pediatrics Committee on Drugs, 2001). If adverse effects are suspected, an infant serum level of the drug should be obtained. Some clinicians recommend serum levels for all infants 10 weeks of age or younger regardless of any behavioral or physical change because younger infants are at greater risk of drug accumulation than older infants (American Academy of Pediatrics Committee on Drugs, 2001). However, the clinical significance of a drug level in the nursing infant without signs of toxicity is unknown.

USE OF HORMONAL AGENTS IN WOMEN WITH BIPOLAR DISORDER Controlled data regarding the use of hormonal treatments in women with bipolar disorder are not available. Estrogen augmentation of antidepressant medication has been reported effective in the treatment of major depression in women in some (Klaiber et al., 1979), but not all (Zohar et al., 1985), studies (reviewed in Burt, Altshuler and Rasgon, 1998). The induction of mania (Zohar et al., 1985) and rapid cycling (Oppenheim, 1984) have been reported with the use of exogenous

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estrogen, further supporting the possibility that estrogen may have an antidepressant effect in some women. Moreover, as mentioned earlier, one retrospective study suggested HRT in menopausal bipolar women might protect against depressive symptoms (Freeman, Arnold and McElroy, 2002). However, there are two case reports of mood stabilization with a combination of estrogen and progesterone in women with bipolar disorder (Chouinard, Steinberg and Steiner, 1987). Available data on oral contraceptives in female bipolarity are equivocal. In a retrospective review of 33 bipolar women who had used oral contraceptives, 22 (67%) reported either not having (N = 17) or not recalling mood changes (N = 5), 4 (12%) reported improved mood symptoms and 7 (21%) reported worsened mood symptoms associated with oral contraceptive use (Freeman, Arnold and McElroy, 2002). In a prospective study of menstrual cycle related mood changes in 17 bipolar women, women taking oral contraceptives (N = 6) did not have significant mood changes across the menstrual cycle while those not taking oral contraceptives (N = 11) did (Rasgon et al., 2003). Of note, progesterone was reported to be ineffective in the treatment of postpartum mania in one woman (Meakin and Brockington, 1990). Interactions of psychotropics with oral contraceptives are a major concern for the bipolar woman of childbearing age. Carbamazepine induces the metabolism of oral contraceptives via the CYP3A4 cytochrome, hence lowering the efficacy of this method of birth control (Spina, Pisani and Perucca, 1996). The putative mood stabilizer, topiramate, may lower levels of ethinyl estadiol in oral contraceptives, potentially interfering with efficacy (Rosenfeld et al., 1997). Lithium, valproate, atypical antipsychotics, lamotrigine and gabapentin do not interfere with the metabolism or efficacy of oral contraceptives (Eldon et al., 1998; Elwes, Binnie, 1996; Shenfield, 1993). Sabers et al. (2001), however, presented 7 women with epilepsy treated with lamotrigine in whom oral contraceptives reduced lamotrigine plasma levels by 41–64% (mean 49%). This phenomenon requires further study in women with bipolar disorder.

EVALUATION OF WOMEN FOR AND WITH BIPOLARITY A complete assessment of bipolarity in females includes a psychiatric and medical history, family and social history and mental status exam with a focus on mood, psychotic, anxiety, substance use and eating disorder signs and symptoms (Arnold, 2003). Because female bipolarity frequently presents as depression, comorbid Axis I disorders, Axis II personality disorders, behavioral dysregulation (including hypersexuality) or general medical disorders (e.g. migraine or other types of pain, overweight or obesity), it is important to carefully evaluate for a history of hypomania or mania, including subthreshold hypomanic symptoms, in females with these presentations (Benazzi, 2001; Benazzi and Akiskal, 2003). Because patients often have difficulty identifying or recognizing hypomania, the use of structured clinical interviews, such as the Structured Clinical Interview for DSM-IV

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(SCID) (First et al., 2001), and screening instruments, such as the Mood Disorder Questionnaire (MDQ) (Hirschfeld etal., 2000) or the Hypomania Symptom Checklist (Angst et al., 2003), in combination with consultation of a significant other (with the patient’s permission), will improve the identification of bipolarity, particularly “soft” or “occult” forms. When indicated, the medical evaluation of female bipolarity includes a physical examination, weight and vital signs, various laboratory tests (e.g. thyroid function tests, metabolic and lipid screening profiles) and toxicology screen. General medical disorders to be considered include endocrine disorders (e.g. thyroid disease, PCOS), neurological disorders (e.g. multiple sclerosis, stroke), immunological diseases (e.g. systemic lupus erythematosis), infectious diseases (e.g. HIV/AIDS) and metabolic disorders (e.g. porphyurias, vitamin deficiencies). Medications that may cause or worsen mood symptoms in females include antidepressants, stimulants, drugs of abuse, corticosteroids, oral contraceptives and other hormonal agents, antihypertensives and benzodiazepines. Menstrual and reproductive history should be reviewed, and a history of any menstrual, pregnancy, postpartum or menopausal-related psychiatric symptoms should be determined. History of hormonal treatments and their effects on mood should also be assessed. Finally, a discussion of plans about contraception and pregnancy is critical in reproductiveaged females. Careful family planning should be advised as planned pregnancies maximize treatment options.

SUMMARY Although mania is equally prevalent in women and men, female bipolarity differs from male bipolarity in several important ways. Available epidemiologic data indicate there may be gender differences in the distribution of the soft spectrum disorders, depending on how they are defined. Thus, although two community studies found narrowly defined bipolar II disorder to be equally common in women and men (Weissman et al., 1991; Szàdóczky et al., 1998), another found DSM-IV bipolar disorder to be more common in adolescent and young adult females (Wittchen, Nelson and Lachner, 1998), another found a nonsignificant predominance of broadly defined bipolar II and minor bipolar disorders in women compared with a nonsignificant predominance of pure hypomania in men (Angst et al., 2003), and yet another found a predominance of bipolar II disorder and cyclothymia in adolescent girls (Lewinsohn, Klein and Seeley, 1995). Clinical studies are similarly mixed, with some suggesting women are more likely than men to have bipolar II disorder and others suggesting bipolar II disorder is equally common in women and men. Considerable evidence suggests women with bipolar disorder experience depressive symptoms and episodes, suicide attempts, mixed mania and rapid cycling more often than men with bipolar disorder. Although less well studied,

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bipolar women may be more likely than bipolar men to have atypical depression and a seasonal pattern of mood disturbance. Comorbidity with certain psychiatric and general medical disorders, especially anxiety disorders, eating disorders, migraine and thyroid disease, may be more common in women than men, and this comorbidity may adversely affect the course of bipolar disorder in women. While substance use disorders are more common in bipolar men than bipolar women, women with bipolar disorder are at higher risk for alcohol use disorders than are men with bipolar disorder. Thus, in addition to a depressive diathesis, female bipolarity may be characterized by mixity, cyclicity, atypicality, seasonality and psychiatric and medical comorbidity. Although women may be susceptible to delayed diagnosis and treatment, there is no evidence that gender affects response to mood stabilizers. Gender differences in response of bipolar disorder to antidepressants have not been evaluated except for the observation that women may be more likely to develop rapid cycling. Pregnancy neither worsens nor exacerbates bipolar disorder, but the postpartum is a period of high risk for onset and recurrence of bipolar disorder in women. Bipolar mood symptoms may also worsen in relation to the menstrual cycle and the perimenopause and menopause in some women. Treatment of bipolarity in women during pregnancy and lactation is challenging because available mood stabilizers pose potential risks to the developing fetus and infant. Individualized risk/benefit assessments of pregnant and postpartum women with bipolar disorder are required to promote the health of the woman and fetus and limit exposure of the fetus or infant to potential adverse effects of medication.

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13 Pediatric Bipolar Disorder: The Promise of Psychopharmacotherapy Joseph Biederman Clinical and Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School, USA

INTRODUCTION Over the last two decades, the view that mania in children is extremely rare or non-existent has been increasingly challenged by many case reports and series. DeLong and Nieman (1983) described a series of children presenting with severe symptoms highly suggestive of mania and responsive to lithium carbonate. Carlson (1984) suggested that prepubertal mania may be characterized by severe irritability, absence of episodes and high levels of hyperactivity. Similarly, Akiskal et al. (1985) reported on the case histories of a large groups of adolescent relatives of “classic” adult bipolar patients. They found that despite frank symptoms of depression and mania, and frequent mental health contacts, none of these youth had been diagnosed with an affective disorder. Weller et al. (1986) then reviewed over 200 articles published between the years of 1809 and 1982 and identified 157 cases which would likely be considered manic by modern standards. However, 48% of those subjects retrospectively diagnosed as manic according to DSM-III criteria were not considered so at the time of referral. Taken together, these reports suggested that pediatric mania may not be rare, but difficult to diagnose.

THE ATYPICALITY OF PEDIATRIC MANIA The atypicality (by adult standards) of the clinical picture of childhood mania has long been recognized (Davis, 1979; Weinberg and Brumback, 1976). Notably, the literature consistently shows that mania in children is seldom characterized by Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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euphoric mood (Carlson, 1983, 1984). Rather, the most common mood disturbance in manic children is severe irritability, with “affective storms,” or prolonged and aggressive temper outbursts (Davis, 1979). The type of irritability observed in manic children is very severe, persistent and often violent (Wozniak, Biederman, Kiely et al., 1995a). The outbursts often include threatening or attacking behavior toward family members, other children, adults and teachers. In between outbursts, these children are described as persistently irritable or angry in mood (Carlson, 1983, 1984; Geller and Luby, 1997). Thus, it is not surprising that these children frequently receive the diagnosis of conduct disorder. Aggressive symptoms may be the primary reason for the high rate of psychiatric hospitalization noted in manic children (Wozniak, Biederman, Kiely et al., 1995a). In addition to the predominant abnormal mood in pediatric mania, its natural course is also atypical compared with the natural course of adult mania. The course of pediatric mania tends to be chronic and continuous rather than episodic and acute (Carlson, 1983, 1984; Feinstein and Wolpert, 1973; McGlashan, 1988). For example, in a recent review of the past 10 years of research on pediatric mania, Geller and Luby (1997) concluded that childhood-onset mania is a non-episodic, chronic, rapid-cycling, mixed manic state. Such findings have also been reported by Wozniak etal. (1995a) who found that the overwhelming majority of 43 children from an outpatient psychopharmacology clinic who met diagnostic criteria for mania on structured diagnostic interview, presented with chronic and mixed presentation. Carlson, Bromet and Sieners (2000) reported that early onset manics were more likely to have comorbid behavior disorders in childhood and to have fewer episodes of remission of a 2-year period than did adult onset cases of mania. Thus, pediatric mania appears to present with an atypical picture characterized by predominantly irritable mood, mania mixed with symptoms of major depression, and chronic as opposed to euphoric, biphasic and episodic course. Although the atypical features noted in children with manic-like symptoms raises the possibility of misdiagnosis, adolescents with bipolar disorder may provide a valuable touchstone for evaluating the validity of the diagnosis made in children, since mania in adolescence has been more readily accepted (Ballenger, Reus and Post, 1982; McGlashan, 1988). Faraone et al. (1997) compared the features of mania in children with the diagnosis in adolescents with child-onset mania, and in adolescents with adolescent-onset mania. With the exception of more euphoria among adolescents with adolescent-onset mania, the frequencies of other symptoms of mania were strikingly similar between child and adolescent youth with mania. As was the case for children, the clinical presentation of mania among adolescents with childhood-onset was rarely biphasic: it was usually chronic and mixed with a simultaneous onset of depression and mania (Faraone et al., 1997). These results suggested that despite atypicality, the profile of manic features associated with childhood mania may, in fact, represent a clinically meaningful manic syndrome.

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While the adult course of pediatric mania awaits data from longitudinal studies, the adult literature provides some interesting clues on the subject. A review by McElroy et al. (1992) described “mixed mania,” which affects 20–30% of adults with mania. Subjects with mixed mania tend to have a chronic course, absence of discrete episodes, onset of the disorder in childhood and adolescence, a high rate of suicide, poor response to treatment and an early history of neuropsychological deficits highly suggestive of ADHD. Thus, McElroy et al. (1992) identified a manic syndrome in adults that shows the atypical features of pediatric mania. These findings suggest that pediatric cases with mania may develop into adults with mixed mania and thereby provide further evidence that the atypical manic features of children constitute a valid disorder.

COMORBIDITY WITH ADHD A leading source of diagnostic confusion in childhood mania is its symptomatic overlap with attention deficit hyperactivity disorder (ADHD). Systematic studies of children and adolescents show that rates of ADHD range from 60% to 90% in pediatric patients with mania (Borchardt and Bernstein, 1995; Geller et al., 1995; West et al., 1995; Wozniak, Biederman, Kiely et al., 1995a). Although the rates of ADHD in samples of youth with mania is universally high, the age at onset modifies the risk for comorbid ADHD. For example, while Wozniak etal. (1995a) found that 90% of children with mania also had ADHD, West et al. (1995) reported that only 57% of adolescents with mania were comorbid with ADHD. Examining further developmental aspects of pediatric mania, Faraone etal. (1997) found that adolescents with childhood-onset mania had the same rates of comorbid ADHD as manic children (90%) and that both these groups had higher rates of ADHD than adolescents with adolescent-onset mania (60%). Most recently, Sachs et al. (2000) reported that, among adults with bipolar disorder, a history of comorbid ADHD was only evident in those subjects with onset of bipolar disorder before 19 years of age. The mean onset of bipolar disorder in those with a history of childhood ADHD was 12.1 years (Sachs et al., 2000). Similarly, Chang, Steiner and Ketter (2000) studied the offspring of patients with bipolar disorder and found that 80% of manic children had comorbid ADHD and that the onset of mania in adults with bipolar disorder and a history of ADHD was 11.3 years of age. These findings suggested that the age of onset of mania, rather than chronological age at presentation, may be the critical developmental variable that identifies a highly virulent form of the disorder that is heavily comorbid with ADHD. Although ADHD has a much earlier onset than pediatric mania, the symptomatic and syndromatic overlap between pediatric mania and ADHD raises a fundamental question: Do children presenting with a symptoms suggestive of mania and of ADHD have ADHD, mania or both? One method to address these uncertainties has been to examine the transmission of comorbid disorders in families

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(Faraone and Tsuang, 1995; Faraone, Tsuang and Tsuang, 1999). If ADHD and mania are associated due to shared familial etiologic factors, then family studies should find mania in families of ADHD patients and ADHD in families of manic patients. Studies that examined rates of ADHD (or ADD, hyperactivity) among the offspring of adults with bipolar disorder all found higher rates of ADHD among these children compared with controls (Faraone et al., 1998). Although the difference in rates attained statistical significance in only one study, Faraone et al.’s (1998) metaanalysis documented a statistical and bidirectional significant association between bipolar disorder in parents and ADHD in their offspring as well as between ADHD in a child proband and mania in relatives. Wozniak et al. (1995b) used familial risk analysis to examine the association between ADHD and mania within families of manic children. They found that relatives of children with mania were at high risk for ADHD that was indistinguishable from the risk in relatives of children with ADHD and no mania. However, mania and the comorbid condition of mania plus ADHD selectively aggregated among relatives of manic youth compared with those with ADHD and comparison children (Wozniak, Biederman, Mundy et al., 1995b). Almost identical findings were obtained in two independently defined family studies of ADHD probands with and without comorbid mania (Faraone et al., 1998). Taken together this pattern of transmission in families suggested that mania in children might be a familially distinct subtype of either bipolar disorder or ADHD. The existence of a familial, developmental subtype is consistent with the works of Strober (1992), with his associates (1988), and Todd et al. (1993) who proposed that pediatric mania might be a distinct subtype of bipolar disorder with a high familial loading. One problem facing studies of ADHD and mania is that these disorders share diagnostic criteria. Of the seven DSM-III-R criteria for a manic episode, three are shared with the DSM-III-R criteria for ADHD: distractibility, motoric hyperactivity and talkativeness. To avoid counting symptoms twice toward the diagnosis of both ADHD and mania, two different techniques of correcting for overlapping diagnostic criteria have been used to evaluate the association between ADHD and pediatric mania (Biederman et al., 1996). In the subtraction method, overlapping symptoms are simply not counted when making the diagnosis. In the proportion method, overlapping symptoms are not counted but the diagnostic threshold is lowered to require that the same proportion of symptoms from the reduced set is required for the original diagnosis (Milberger et al., 1995). Using these methods, Biederman et al. (1996) showed that 48% of children with mania continued to meet criteria by the subtraction method and 69% by the proportion method. Using the subtraction method, 89% of the children with mania maintained a full diagnosis of ADHD and by the proportion method, 93% maintained the ADHD diagnosis. Taken together these results suggest that the

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comorbidity between ADHD and pediatric mania is not a methodological artifact due to diagnostic criteria shared by the two disorders. The potential for different rates of comorbidity with mania in the combinedsubtype, inattentive-subtype and hyperactive impulsive-subtype of ADHD is in need of further research. Faraone et al. (1998) studied 301 ADHD children and adolescents consecutively referred to a pediatric psychopharmacology clinic. Among these, 185 (61%) were the combined type, 89 (30%) the inattentive type and 27 (9%) the hyperactive/impulsive type. Bipolar disorder was highest among combined-type youth (26.5%) but was also elevated among hyperactive-impulsive (14.3%) and inattentive (8.7%) youth.

COMORBIDITY WITH CONDUCT DISORDER (CD) Like ADHD, CD is also strongly associated with pediatric mania. This has been seen separately in studies of children with CD, ADHD and mania. Wozniak et al. (1995a) reported that preadolescent children satisfying structured interview criteria for mania often had comorbid CD. Kovacs and Pollock (1995) reported a 69% rate of CD in a referred sample of manic youth and found that the presence of comorbid CD heralded a more complicated course of mania. Similar findings were reported by Kutcher, Marton and Korenblum (1989) who found that 42% of hospitalized youths with mania had comorbid CD. The Zurich longitudinal study found that hypomanic cases had more disciplinary difficulties at school and more thefts during their juvenile years than other children (Wicki and Angst, 1991). These reports are consistent with the well-documented comorbidity between CD and major depression (Angold and Costello, 1993) considering that juvenile depression often presages mania (Geller, Fox and Clark, 1994; Strober and Carlson, 1982). Biederman et al. (1997a, 1999a) investigated the overlap between mania and CD in a consecutive sample of referred youth and in a sample of ADHD subjects to clarify its prevalence and correlates. They found a striking similarity in the features of mania regardless of comorbid CD. Additionally, the age of onset of mania was similar in subjects with or without comorbid CD. In both groups, mania presented with a predominantly irritable mood, a chronic course, and was mixed with symptoms of major depression. Only two manic symptoms differed between these groups: “physical restlessness” and “poor judgment” were more common in the mania with CD group compared with the mania only group. Similarly, there were few differences in the frequency of CD symptoms between CD youth with and without comorbid mania. Although children with CD and mania had a higher rate of “vandalizing” compared with CD only subjects, this difference was not statistically significant. Both the comorbid and non-comorbid subjects with mania had high rates of major depression, anxiety disorders, oppositional disorder and psychosis than CD and ADHD children (Biederman, Faraone, Hatch et al., 1997a; Biederman et al., 1999a;

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Faraone, Tsuang and Tsuang, 1999). In addition mania comorbid with CD was associated with poorer functioning and an increased risk for psychiatric hospitalization (Biederman, Faraone, Hatch et al., 1997a). Subjects with both CD and mania also had a higher familial and personal risk for mood disorders than other CD subjects who had a higher personal risk for antisocial personality disorder (Faraone et al., 1998). Wozniak et al. (2001a) compared relatives of four groups of clinically referred probands defined as having: (1) (2) (3) (4)

both CD and mania (N = 26 probands, 92 relatives); mania without CD (N = 19 probands, 53 relatives); CD without mania (N = 16 probands, 58 relatives); and controls without mania or CD (N = 102 probands, 338 relatives).

The risk for mania in relatives of non-manic, non-CD probands was 4% and their risk for antisocial disorders was 7%. In reference to the control relatives, relatives of both manic groups had increased risks for mania (14% in each group), relatives of both groups of CD probands had increased risks for antisocial disorder (34% and 19%). However, the risk of antisocial disorders was not elevated in relatives of manic only probands (8%) and the risk for mania was not increased in the relative of CD only probands (9%). Taken together, these studies suggest that subjects who receive diagnoses of both CD and mania may, in fact, have both disorders. While the resolution of this important issue awaits further research, the mere diagnosis of mania in some CD children offers important therapeutic possibilities since delinquency and mania require very different treatment strategies.

COMORBIDITY WITH ANXIETY DISORDERS Although anxiety is frequently overlooked in studies of mania, pediatric studies of youth with panic disorder and youth with mania document an important and bidirectional overlap between anxiety and mania. In an examination of the clinical correlates of panic disorder, Biederman et al. (1997b) found that subjects with panic disorder and agoraphobia had very high rates of mania (52% and 31% respectively) that were greater than observed among psychiatric controls (15%). Wozniak et al. (1995) reported significantly more panic and other anxiety disorders in children with mania. Similar findings have been reported by Bowen, South and Hawkes (1994). They found that of 108 patients in a panic disorder treatment program, 23% had bipolar or cyclothymic mood disorder. Young et al. (1993) reported that patients with mania and high anxiety scores were more likely to have suicidal behavior, alcohol abuse, cyclothymia, anxiety disorders and a trend toward lithium non-responsiveness. Chen and Dilsaver (1995) examined the relationship between panic and bipolar disorders using the Epidemiologic Catchment Area database.

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They reported that the lifetime prevalence of panic disorder was 21% among subjects with bipolar disorder compared with only 0.8% among subjects who had neither bipolar nor unipolar depression. These findings strongly indicate that mania – at any age – is frequently comorbid with severe anxiety that requires additional clinical and scientific attention.

CORRESPONDENCE BETWEEN CATEGORICAL AND DIMENSIONAL MEASURES Many comorbidity findings in studies of juvenile mania have relied on structured diagnostic methodology delivered by trained raters. Although this method is considered “state of the art” for clinical research, it could be vulnerable to an assessor bias. Thus, it is useful to consider studies using methods that are independent of assessor training or expertise. One such measure is the Child Behavior Checklist (CBCL), one of the best studied psychometric measures of psychopathology in children (Achenbach and Edelbrock, 1983; Achenbach, 1991). The CBCL records, in standardized format, the behavioral problems and competencies of children aged 4–18, as reported by their parents or parent-surrogates. It is scored on the recently revised social competence and behavior problem scales of the Child Behavior Profile. The scales were originally constructed from analyses of parent ratings of 2300 clinically referred children and normed on 1300 non-referred children. Four studies have used the CBCL to characterize children and adolescents with categorical clinical diagnoses of pediatric mania (Biederman et al., 1995; Carlson and Kelly, 1998; Geller et al., 1998; Hazell, Lewin and Carr, 1999). The results from these reports have been strikingly consistent; all found that children satisfying diagnostic criteria for mania have a highly abnormal profile, which is consistent with structured diagnostic interview findings (Biederman et al., 1995; Carlson and Kelly, 1998; Geller et al., 1998; Hazell, Lewin and Carr, 1999). Each study found significantly elevated t-scores on the Aggressive Behavior subscale. Biederman et al., Geller et al. and Hazell et al. found increased t-scores on the Delinquent Behavior Scale, and Biederman et al., Carlson et al. and Hazell et al. found increased t-scores for the Thought Problems Scale. Although Carlson and Kelly (1998) did not find significant differences in the CBCL delinquent behavior scale in comparisons between hospitalized manic and ADHD children, the mean t-score of this scale was clearly in the clinical range in both groups. Considering the empirical nature of the CBCL, the distinctly abnormal CBCL profiles in manic youth compared with those with ADHD strongly suggest that psychopathological correlates of pediatric mania are not a function of assessor bias. The correspondence between clinical diagnoses and content-congruent scales of the CBCL also suggests that it should be evaluated as a potential screening instrument for pediatric mania in referred children.

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COMORBIDITY WITH SUBSTANCE USE DISORDERS An emerging literature suggests an extensive and bidirectional overlap between pediatric mania and substance use disorders (SUD) in youth (West et al., 1996; Biederman et al., 1997c; Wilens et al., 1997a). This literature also suggests that juvenile-onset mania may be a risk factor for SUD. For example, a prospective study of children and adolescents with and without ADHD found that early-onset mania was a risk factor for SUD independently of ADHD (Biederman et al., 1997c). Similarly, controlled studies in adults show that mania is often an antecedent and is strongly associated with SUD (Wilens et al., 1997b). Mania has also been shown to be over-represented among youth with SUD. For example, Wilens et al. (1997a) reported that psychiatrically referred adolescent outpatients with SUD were more likely than those without SUD to have comorbid mania and West et al. (1996) reported that 40% of inpatient adolescents with mania suffered from SUD. Wilens et al. (1999) found that mania significantly increased the risk for SUD independently of conduct disorder. Furthermore, they reported that the risk for SUD was carried by those subjects with an adolescent-onset form of mania. While this may be consistent with the notion that, like adults, adolescents self-medicate manic symptoms with substances of abuse (Khantzian, 1997), it is also be consistent with hypothesis that child- and adolescent-onset mania are etiologically distinct forms of the disorder with different risk profiles and natural courses. Biederman et al. (2000) recently used the family study design to address the putative familial risk of SUD associated with bipolar and conduct disorder (in the same sample as Wozniak et al. (2001a) described earlier). After accounting for CD in probands, mania in probands remained a risk factor for SUD in relatives, including both drug and alcohol addictions. Rather than concluding that the effects of CD or mania accounted for the relationship of the other with SUD, they reported results consistent with the idea that the effects of CD and mania on the risk for SUD were additive. Given this emerging literature on mood, conduct and substance use disorders, more work is needed to characterize the developmental relationship between substance use and mood dysregulation in adolescents. This is especially important given that substance abuse is frequently treatment refractory. It may be that the early identification and treatment of youth with mania could prevent the onset or complications of SUDs.

PEDIATRIC MANIA AND TRAUMA Although it has been long suspected that mania in children may be the result of trauma and associations between trauma and mania have been reported in adults, there has been relatively limited systematic research of this issue. Kessler et al. (1995) found elevated lifetime rates of mania among adult and adolescent subjects with PTSD. Helzer, Robins and McEvoy (1987) reported a strong association

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between manic-depressive illness and PTSD in adult subjects but did not determine if mania was primary or secondary to the trauma. This report further suggested that behavior problems including “stealing, lying, truancy, vandalism, running away, fighting, misbehavior at school, early sexual experience, substance abuse, school expulsion or suspension, academic underachievement, and delinquency” prior to age 15 predicted later PTSD (Helzer, Robins and McEvoy, 1987). Not surprisingly, the authors concluded that “this association may mean that persons with such behavior in childhood had a greater likelihood of experiencing trauma later on.” Since juvenile mania is commonly associated with extreme violence and severe behavioral dysregulation (Wozniak, Biederman, Kiely et al., 1995a) as well as hypersexuality, mania in children could be either a reaction to or a risk factor for trauma exposure. Using data from a longitudinal sample of boys with and without ADHD, Wozniak et al. (1999) identified pediatric mania as an important antecedent for, rather than consequence of, traumatic life events. This temporal relationship between mania and traumatic events could have important clinical and therapeutic implications. When traumatized children present with severe irritability and mood lability, there may be a tendency by clinicians to attribute these symptoms to having experienced a trauma. To the contrary, longitudinal research suggests the opposite: mania may be an antecedent risk factor for later trauma and not represent a reaction to the trauma (Wozniak et al., 1999).

TREATMENT CONSIDERATIONS Although it has been recognized since Kraepelinian times that bipolar disorder can have an onset in childhood (Kraepelin, 1921), studies of bipolar children are scarce (Weller, Weller and Fristad, 1995). As a result, little research is available to guide our therapeutic approach to the management of these difficult children. A few case reports and case series (Delong, 1978; DeLong and Nieman, 1983; DeLong and Aldershof, 1987; Alessi et al., 1994; Kafantaris, 1995; Wozniak and Biederman, 1996) reported on the effectiveness of lithium treatment in a heterogeneous sample of children. These reports found that lithium was most effective for childhood bipolar disorder and for children of lithium-responsive parents (DeLong and Aldershof, 1987). Although clinical record reviews have been very useful for generating therapeutic hypotheses, prior applications of this methodology have been limited. One major problem is that most chart review studies are based on the treatment being studied. For example, to address the effectiveness of mood stabilizers, all patients receiving these agents would be selected for review. Although providing useful information about effectiveness in a naturalistic setting, such work makes it difficult to address questions about diagnosis, because patients with the disorder of interest – who did not receive the treatment – are not selected for study. To overcome some of these difficulties, we designed a method that incorporates structured diagnostic interviews,

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no selection biases and systematic chart review ratings over multiple and variable review points. Using this approach, we reviewed clinical records of all pediatrically referred patients who, at initial intake, satisfied structured interview diagnostic criteria for mania and were subsequently treated at our center. This research method allowed us to test the following hypotheses: (1) mood stabilizers would be effective in treating manic-like symptoms; and (2) other medications would not lead to an improvement in manic symptomatology. The sample consisted of 49 (83%) boys and 10 (17%) girls who ranged in age from 3.5 to 17 years (10.8 ± 3.7 years), where 23 (39%) were adolescents (≥12 years) and 36 (61%) were children. The mean duration of mania identified by the structured diagnostic interview prior to treatment at our center was 3.0±3.0 years, the mean age of onset of manic-like symptoms was 6.3 ± 4.6 years, and the mean number of manic-like symptoms was 5.2 ± 1.2. In that 43 (73%) of the manic subjects presented with mixed mania, 9 (15%) presented with biphasic cycles of mania and depression and 7 (12%) exhibited only manic psychopathology. The mean number of days of follow-up available for analysis was 616.6 ± 391.5 days (range: 43–1605 days). Prescriptions for mood stabilizers were more frequently given to subjects with evidence of manic symptoms than to those without such symptoms (59% vs 7%, p < 0.01). Subjects who were prescribed mood stabilizers were more likely to have had manic symptoms at their first clinic visit (80% vs 33%, p = 0.001) and at subsequent follow-up visits (65% vs 25% of visits, p < 0.001). In addition, subjects who were prescribed mood stabilizers had a significantly higher percentage of visits with severe manic symptomatology (22% vs 3% of visits, p < 0.001). Using a time-varying Cox regression model, we found that the presence of manic symptoms from visit to visit significantly predicted the administration of mood stabilizers [rate ratio = 2.9, 95% confidence interval = (1.6, 5.5), p < 0.001]. This result was mainly accounted for by lithium carbonate and valproic acid, as they were the most prevalent medications prescribed at evaluation and during treatment in our center. Neither the number nor the type of concurrent medications of other classes differed between those with and without manic symptoms. To define improvement of manic symptoms, we required subjects to attain a severity score on the Mania Clinical Global Impression scale (CGI) of ≤2 (not ill, or borderline) and an improvement score of ≤2 (much or very much improved). We employed multivariate Cox regression analysis with time-varying covariates controlling for the effects of concomitant medications and severity of illness to estimate the effectiveness of mood stabilizers in improving manic-like symptoms. This analysis indicated that mood stabilizers significantly predicted improvement of manic symptoms independently of other medications prescribed at each visit [rate ratio = 4.9, 95% confidence interval=(1.2, 20.8), p = 0.031]. In contrast, treatment with TCAs, SSRIs, stimulants or typical antipsychotics was not associated with the improvement of manic symptoms when adjusted for treatment with mood stabilizers.

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Furthermore, interaction terms between mood stabilizers and other medications did not significantly improve the predictive ability of the model, indicating that the positive effect of mood stabilizers was not dependent upon the concurrent prescription of other medications. Total daily doses of lithium carbonate, carbamazepine and valproic acid were modeled separately controlling for the dosages of other medications and the severity of manic symptoms. While total daily doses of lithium carbonate ( p = 0.006) and carbamazepine (p = 0.01) significantly predicted improvement of manic-like symptoms, the dose of valproic acid did not (p = 0.9). Using the median dose of lithium carbonate and carbamazepine as the cut-off point, we were able to show that higher daily doses of lithium carbonate and carbamazepine led to increased rates of improvement. Despite the obvious limitations of a chart review, the methodology used in this study provides some assurance that the decrease in manic symptoms was due to mood stabilizers. If we had simply shown that patients treated with mood stabilizers eventually got better, that result could have been attributed to the normal waxing and waning of manic-like symptoms. Instead, the Cox model showed that mood stabilizers – but not other medications – predicted decreases in manic symptoms from one visit to the next. Moreover, by collecting data from all clinic visits we used all the information recorded in the medical records. This allowed us to model the effect of medication changes over time rather than conducting simple “before versus after” treatment comparisons. If decreases in manic symptoms were simply due to spontaneous remissions, then our evidence for effectiveness should not have been limited to time periods when mood stabilizers were used. Moreover a spontaneous remission hypothesis would not predict a differential effectiveness of mood stabilizers and other drugs and we should not have found any dose response effects as we did for lithium carbonate and for carbamazepine. Also unlikely is the hypothesis that the benefits observed were due to improvement of ADHD symptoms since evidence supporting the usefulness of mood stabilizers in ADHD is weak (Greenhill et al., 1973). Although treatment with mood stabilizers in this naturalistic chart review was associated with a statistically significant decrease in manic symptoms, this improvement was slow to develop and was associated with frequent relapses; only 17% of subjects improved by 6 months, 30% by one year and 65% by two years, indicating a slow rate of improvement. Using a definition of relapse as a score of much or very much worse on the CGI Mania Improvement scale, 40% of previously improved subjects relapsed within 2 months whereas the remaining subjects did not relapse for one year. This definition of relapse indicated unequivocal clinical evidence for worsening of manic-like symptoms. Although somewhat discouraging, these findings are consistent with outcome data from other naturalistic follow-up studies of bipolar children and adults (Strober et al., 1990; Strober et al., 1995). For example, the survival analysis from our study indicates that 65% of the children would improve if treated with lithium

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carbonate for 2 years. This finding is remarkably consistent with results from Delong and Aldershof (1987) who reported a 66% response rate for bipolar children treated with lithium carbonate over a 10–70-month treatment period and with findings reported by Strober et al. (1995) showing that multiple relapses were most often seen in subjects with mixed mania. Similarly, much research shows that adult bipolar disorder is marked by a slow response to treatment, multiple relapses and significant interepisode psychopathology, despite adequate pharmacotherapy (Goodwin and Jamison, 1990). For example, Gitlin et al. (1995) and Goldberg, Harrow and Grossman (1995) reported the naturalistic outcome of bipolar adults in the context of long-term maintenance pharmacotherapy. The bipolar adults had a high (73%) rate of relapse and considerable morbidity, irrespective of adequate pharmacotherapy. Goldberg, Harrow and Grossman (1995) reported that bipolar disorder in adults was associated with a very gradual improvement of symptoms over several years. In a 5-year follow-up study of bipolar adults, Keller et al. (1993) reported that mixed bipolarity had the lowest probability of recovery and a substantially faster time to relapse following recovery compared with non-dysphoric mania. In a review article, Solomon et al. (1995) reported that bipolar adults who failed lithium prophylaxis were characterized by many prior episodes, mixed (dysphoric) mania, comorbid psychopathology and rapid cycling. Because these clinical characteristics are commonly observed in juvenile mania (Wozniak, Biederman, Kiely et al., 1995a), it is not surprising to find that our juveniles with manic psychopathology had a chronic course, high level of relapse and limited response to pharmacotherapy. Results from a series of controlled clinical trials by Campbell et al. (1995, 1984) and Cueva et al. (1996) also documented the efficacy of mood stabilizers (lithium carbonate and carbamazepine) in the treatment of aggressive conduct disorder children. Although bipolar disorder was excluded, these psychiatrically hospitalized conduct disorder youth were treated for severe, uncontrollable and disorganized aggression and not necessarily for delinquency. Thus, it is possible that the therapeutic benefits observed in these children with antimanic treatments could have been due to their antimanic effects in treating aggressive manic children satisfying criteria for conduct disorder. In one of the few efforts of its kind, Geller et al. (1998) conducted a double-blind, placebo-controlled randomized clinical trial examining the safety and efficacy of lithium carbonate in the treatment of adolescents with bipolar disorder and comorbid SUDs. These investigators documented that treatment with lithium carbonate was associated with improved functioning and higher level of abstinence from drugs and alcohol. Kowatch et al. (2000) using an eight-week open study design compared the effectiveness and tolerability of lithium carbonate, divalproex sodium and carbamazepine in children with bipolar disorder. They found a 53% rate of improvement for divalproex sodium and much lower rates for lithium carbonate

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and carbamazepine. Likewise, Wagner et al. (2002) reported similarly modest effects in another trial of divalproex sodium in pediatric bipolar disorder. Recently, somewhat optimistic findings have resulted from investigations of atypical neuroleptics in the treatment of juveniles with bipolar disorder. In a retrospective chart review study of 28 youths with bipolar disorder, 82% of subjects showed improvement in both manic and aggressive symptoms with risperidone treatment (Frazier et al., 1999b). In contrast to the duration of treatment required for improvement with mood stabilizers, the average time to optimal response was 1.9 ± 1.0 months of therapy. Moreover, no serious adverse effects were observed. Similarly encouraging results were reported by Frazier, Biederman, Wilens and Spencer (1999a) in an open trial of olanzapine monotherapy. They found that treatment with olanzapine was associated with significant improvements in both the Children’s Depression Inventory and the Young Mania Rating scale in 23 manic children after 8 weeks of monotherapy on doses ranging from 2.5 to 20 mg/ day. Equally promising results have been recently reported by Biederman et al. (unpublished manuscript) using the same prospective 8-week open study design using risperidone monotherapy in the treatment of both manic and depressive symptoms in youth with bipolar I, bipolar II or bipolar spectrum disorder. Recently, DelBello et al. (2002) reported results from a randomized clinical trial that documented that the combination of divalproex sodium and quetiapine was superior to divalproex sodium alone in the treatment of an inpatient sample of adolescents with bipolar disorder. Findling et al. (2000) recently reported that risperidone was effective in treating aggression in children with conduct disorder and Aman et al. (2002) reported results from a double-blind study that documented that risperidone was superior to placebo in the treatment of youth with conduct disorder and sub-average intelligence. Although affective disorders were reported to have been excluded in both studies, it is unclear if this refers to the very rare ‘classic’ episodes of mania or the atypical cases of pediatric mania that are more commonly comorbid with conduct disorder. In fact, a secondary analysis of Aman et al. study results documented the efficacy of risperidone in improving both manic and depressive symptoms in this population. Taken together, these initial encouraging results support the need for additional short- and long-term controlled trials of atypical neuroleptics in the treatment of juvenile bipolar disorder, either as monotherapy or in combination with mood stabilizers. Because pediatric bipolar disorder is frequently mixed and comorbid with ADHD, its pharmacological management can be complicated since treatments for bipolar disorder do not treat ADHD and vice versa and antidepressants can precipitate mania. We used a novel chart review methodology to systematically evaluate the clinical records of pediatrically referred patients with a diagnosis of bipolar disorder and comorbid ADHD. Our results show that (1) the presence of mania interfered with the improvement of ADHD symptomatology during

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anti-ADHD pharmacotherapy and (2) ADHD symptoms were much more likely to improve after mood stabilization. These results suggest that the successful management of children with both mania and ADHD requires the deployment of disorder-specific treatments. However, they also document that treatment of ADHD symptomatology is only possible after mood stabilization (Biederman, Mick et al., 1999b). This finding supports the clinical recommendation (Wozniak, Biederman and Richards, 2001b) that in youth with bipolar disorder and comorbid ADHD, the sequence of treatments is critical; bipolar symptoms should be first and ADHD second. It is noteworthy that despite statistical significance, the rate of improvement of ADHD symptomatology observed after mood stabilization in our sample was only modest. This finding stresses the therapeutic difficulties associated with the treatment of children with manic symptoms and ADHD. Also, because of the severe disruption in functioning associated with exacerbation of manic symptoms, caution is needed in prescribing anti-ADHD treatments to ADHD children with mania. Clearly more work is needed to search for safe and effective treatments of ADHD symptomatology in the context of mania. Such work should evaluate whether aggressive anti-manic treatments may help prevent exacerbation of mania in children requiring anti-ADHD treatment for their comorbid ADHD. Similar therapeutic dilemmas and challenges are associated with the management of bipolar depression in youth. As documented in a report (Biederman et al., 2000), although SSRIs are selectively effective in the management of bipolar depression, they are also selectively likely to exacerbate mania in bipolar children. Clearly, more work is needed to evaluate the short- and long-term safety and efficacy of various treatment modalities in the management of bipolar youth and their common comorbidities.

SUMMARY Despite ongoing controversy, the view that pediatric mania is rare or non-existent has been increasingly challenged by not only case reports but also systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhoodonset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include: (1) its pattern of comorbidity may be unique by adult standards, especially its overlap with ADHD, aggression and conduct disorder; (2) its overlap with substance use disorders; and (3) its association with trauma and adversity.

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The explosive developments in neurosciences, neurobiology, genetics and neuroimaging will undoubtedly help advance the understanding of this complex and crippling disorder (Hyman, 2000), particularly its relationship to ADHD, CD and other psychotic and non-psychotic neuropsychiatric disorders. It is hoped that such advances can shed light on the etiology and underlying pathophysiology, including the identification of dysfunctional brain circuits that may underlie pediatric mania. For example, an emerging literature on the subjects has identified genetic markers associated with bipolar features in children with velo-cardio-facial syndrome (Papolos et al., 1996). More imaging research is needed to document the neuroanatomical underpinnings associated with pediatric mania. The symptomatic overlap and co-occurrence of mania with ADHD has produced debate as to whether these children have ADHD, mania or both. Despite this debate, many clinicians recognize that a substantial minority of children suffer from an extraordinarily severe form of psychopathology associated with extreme irritability, violence and incapacitation that is highly suggestive of mania. Clarifying the diagnoses of these very ill children would have substantial clinical implications. The emerging literature indicates that mania can be identified in a substantial number of referred children using systematic assessment methodology. Thus, this disorder may not be as rare as previously considered. Children with mania frequently demonstrate an atypical picture by adult standards with a chronic course, severely irritable mood and a mixed picture with depressive and manic symptoms co-occurring. Most children with childhood-onset mania may also have ADHD which requires additional treatment. Initial clinical evidence suggests that atypical neuroleptics may play a unique therapeutic role in the management of such youth. The high levels of comorbidity with other disorders is common, further requiring the cautious use of a combined pharmacotherapy approach. More research is needed to build a scientific foundation for the notion that pediatric mania is a unique developmental subtype of bipolar disorder.

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Wozniak, J., Biederman, J., Faraone, S. V., Blier, H., and Monuteaux, M. C. (2001a). Heterogeneity of childhood conduct disorder: further evidence of a subtype of conduct disorder linked to bipolar disorder. Journal of Affective Disorders, 64, 121–131. Wozniak, J., Biederman, J., and Richards, J. A. (2001b). Diagnostic and therapeutic dilemmas in the management of pediatric-onset bipolar disorder. Journal of Clinical Psychiatry, 62, 10–15. Young, L., Cooke, R., Robb, J., Levitt, A., and Joffe, R. (1993). Anxious and non-anxious bipolar disorder. Journal of Affective Disorders, 29, 49–52.

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14 Treatment for Bipolar Disorder in Older Adults Kenneth I. Shulman Department of Psychiatry, Sunnybrook & Women’s College Health Sciences Centre, Faculty of Medicine, University of Toronto, Canada

Although the focus of this chapter is on pharmacotherapy, the clinical issues unique to old age will be reviewed first. To treat effectively, clinicians require a clear understanding of classification, nosology and subtypes of bipolarity in late life in order to make informed clinical decisions.

CLASSIFICATION ISSUES AND SUBTYPES While the available evidence suggests that the primary form of bipolar disorder is strongly influenced by genetic factors (Goodwin and Jamison, 1990), the very high levels of medical and neurologic comorbidity within the elderly population tend to cloud the diagnostic picture (Shulman, 1997). Are we dealing with a “mood disorder due to a general medical condition” as defined by DSM IV? This diagnostic category suggests that “the disturbance is the direct physiologic consequence of a general medical condition”. However, given the high prevalence of comorbidity, the issue of “direct physiologic consequence” is a difficult one to interpret. Relevant to this discussion is the concept of secondary mania (Krauthammer and Klerman, 1978) that implies that cerebral organic factors are responsible for the manic syndrome. This is a common scenario in old age (Shulman et al., 1992). In a parallel literature, the neurologists use the term “disinhibition syndrome” that describes a condition that is essentially identical to the concept of secondary mania with a similar clinical spectrum. Clearly, diagnostic subtypes may have a strong influence on treatment approach. By and large, bipolar disorder in old age is associated with a late age of onset. In a retrospective study in which the mean age of index elderly bipolar patients Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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was 70, their mean age of first psychiatric hospitalization was age 55 (Shulman et al., 1992). In a more recent study, Wylie et al. (1999) used a cut-off of 49 years to define a late onset group of elderly bipolar patients who demonstrated an increase in cerebrovascular risk factors. While the community prevalence of bipolar disorder decreases from a high of 1.4% in young adults (Weissman et al., 1991) to a negligible prevalence of <0.1%, the opposite trend applies to the incidence of hospital admissions for bipolar disorder. Almost 20% of first admissions of patients with bipolar disorders in Finland occurred after the age of 60 (Rasanan, Tiihonen and Hakko, 1998). These elderly bipolars are very different than the very early age of onset found in most community surveys such as the Epidemiologic Catchment Area (ECA) study (Weissman et al., 1991) and the US National Comorbidity (Kessler et al., 1997) who reported a mean age of onset of bipolar disorder at 21 years. This late onset disorder is understandably associated with a high level of neurologic comorbidity characterized by a heterogeneous group of right hemisphere lesions (Starkstein et al., 1990; Strakowski et al., 1994; Steffens and Krishnan, 1998). Even when compared to age and sex-matched unipolar depressives, elderly bipolars had a significantly higher rate of coarse neurologic disorders (36% vs 8%) (Shulman et al., 1992). A subgroup whose first affective episode was mania in old age were even more likely to present with coarse neurological abnormalities (71%) than elderly patients with multiple previous episodes of bipolar disease (28%). Cerebrovascular disease featured as the predominant type of disorder in groups of elderly manic patients as well as those considered to be suffering from secondary mania (Tohen, Shulman and Satlin, 1994). Steffens and Krishnan (1998) went so far as to propose a vascular subtype of mania similar to the vascular depression subtype proposed by Alexopoulos et al. (1997). To further complicate the clinical picture in old age, significant cognitive dysfunction has been a consistent finding in most studies of mania (Broadhead and Jacoby, 1990; Berrios and Bakshi, 1991; Dhingra and Rabins, 1991). Originally, Spicer, Hare and Slater (1973) had hypothesized that the increase in first admission rates for mania was a reflection of an increased prevalence of dementia in this sub-population. However, the early studies of late life bipolar disorder were unable to confirm the increased incidence of dementia. The findings by Alexopoulos et al. (1993) with respect to pseudodementia and major depression raise concerns as to whether bipolar disorder is also a potential risk factor for the development of an irreversible dementia. Neuroimaging research has generally found increased hyperintensities on MRI scan. These hyperintensities are associated with risk factors such as hypertension, atherosclerotic heart disease and diabetes mellitus and strengthen the relationship of mania to cerebrovascular pathology. Other studies have shown an increased prevalence of silent cerebral infarctions on neuroimaging in late onset mania when compared to depression and earlier ages of onset for mood disorder

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(Kobayashi, Okada and Yamashita, 1991; Fujikawa, Yamawaki and Touhouda, 1995). The proportion of elderly manic patients whose onset was over the age of 60 with silent cerebral infarctions was more than 65% in these samples. Neuroimaging and other studies provide additional support for the proposal that there is indeed a vascular subtype of mania which may affect treatment choice and outcome. Clinical course and outcome shows that elderly bipolars even when compared to age and sex-matched unipolars have a very high rate of mortality. In one study, half of the elderly manic patients had died at a mean six-year follow-up compared to only 20% of age and sex-matched elderly depressives.

DETERMINANTS OF BIPOLARITY IN OLD AGE Three factors appear most relevant to the manifestation of manic syndromes and bipolarity in old age. (1) Genetic loading is not as prominent as in early onset disorders yet elderly manic bipolar patients still have a very significant familial prevalence of mood disorder (50–85%) in first degree relatives (Shulman and Herrmann, 2002a). An “affective predisposition” is common and this may include psychological rather than genetic vulnerability. (2) The long latency seen between first onset depression and later manifestation of mania in old age may reflect degenerative changes associated with normal aging in affectively vulnerable individuals. (3) Heterogeneous brain lesions associated with mania in late life affecting the right orbital frontal cortex may be specific factors in the manifestation of mania late in life.

GENERAL PRINCIPLES OF PHARMACOLOGIC MANAGEMENT IN OLD AGE Because there are no randomized controlled trials of pharmacological treatment in an elderly bipolar population, clinicians have had to rely on guidelines designed for mixed age populations (Shulman and Herrmann, 2002a). However, caution must be applied to this extrapolation as pharmacokinetic and pharmacodynamic changes associated with old age are relevant. Specifically, pharmacokinetic changes include effects on absorption, volume of distribution, hepatic metabolism as well as renal clearance. The pharmacodynamic changes include increased receptor sensitivity, decreased cholinergic function and an increase in monoamine oxidase levels. These factors combined with the high level of medical and neurologic comorbidity dramatically increase the risk of adverse events as well as drug interactions (Naranjo et al., 1995). Despite the well-known dictum “start low – go slow”, elderly patients remain extremely susceptible to

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drug toxicity which is one of the leading causes of delirium in old age (Inouye, 1998). The management of elderly bipolar patients must begin with a thorough medical assessment in order to rule out underlying medical and neurologic conditions and assessment of the potential for drug toxicity and drug interactions. Because of the background factors associated with late life mania, a thorough search for localizing neurological signs and symptoms must be part of the initial assessment. This should include a careful search for history of head injury, cerebrovascular disease and routine laboratory investigations assessing renal, hepatic and hematological functions as well as thyroid indices are necessary. Because of the high levels of comorbid neurologic disease, neuroimaging has been described as “essential” for elderly manics (Van Gerpen, Johnson and Winstead, 1999). Finally, despite the fact that no systematic studies of psychotherapeutic approaches or psychoeducation with elderly bipolars is available, these interventions should be considered in order to improve compliance with medication and potentially to improve social functioning by a better understanding of the illness for the patient and especially for their families (Bauer and McBride, 1996). Geriatric psychiatrists tend to involve families on a more routine basis than general psychiatrists. This is especially important in bipolar disorders and in elderly bipolar patients where the caregiver stress on elderly spouses and older family members is an important consideration.

MOOD STABILIZERS IN ELDERLY BIPOLARS LITHIUM CARBONATE Since the 1970s, lithium has been the mainstay treatment for bipolar disorder including the acute and maintenance phases. Over the last decade, a dramatic change in prescription patterns for lithium and divalproex in old age has been occurring (Shulman et al., 2003). In part related to marketing factors, recent data suggest that divalproex is widely used as an alternative to lithium for bipolar disorder. Clinicians are abandoning the new use of lithium carbonate in old age in favor of divalproex despite a lack of data to support this shift in clinical practice. The number of new lithium users in Ontario, Canada, fell from 653 older adults in 1993 to only 281 in 2001 (Shulman et al., 2003). The opposite trend applied to new users of divalproex which increased from 183 in 1993 to 1090 in 2001. This trend was the same when patients who had a diagnosis of dementia were eliminated. Despite the changing trends in new prescriptions, the longstanding use of lithium still makes it a commonly prescribed mood stabilizer in old age (Head and Dening, 1998). Pharmacokinetic factors must be taken into account as lithium clearance in old age is approximately half that of younger patients including a

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significant inter-individual variation (Hardy, Shulman and Zucchero, 1997). Lithium is eliminated more slowly from a smaller volume of distribution compared to younger individuals and elderly patients may require one-half less lithium carbonate than mixed age patients. Pharmacokinetic data show that lithium can be administered safely as a single dose in an elderly population (Hardy et al., 1987). In a similar study, elderly patients required 36% less lithium to reach the same lithium level compared to younger patients (Greil et al., 1985). In terms of efficacy, there are no randomized controlled trials of lithium carbonate in acute mania in the elderly. Evidence is derived primarily from uncontrolled naturalistic and retrospective case series that have suggested response rates similar to younger populations (Shulman and Herrmann, 1999). There is also a suggestion that the prevalence of lithium use is proportionately higher in elderly populations compared to mixed age samples (Head and Dening, 1998). Lithium is eliminated almost exclusively by the kidneys and age associated declines in creatinine and hence lithium clearance as well as glomerular filtration rates influence the serum levels of lithium attained. Pharmacodynamic factors suggest an increased sensitivity in old age resulting in an increase in adverse reactions and toxicity at serum levels that are generally considered to be normal in a mixed age population (Shulman and Herrmann, 1999). Indeed, the pharmacodynamic relationship between plasma lithium concentrations and acute anti-manic response is not well defined in elderly patients (Young et al., in press). A variety of case series and case reports have suggested that elderly patients may respond to serum lithium levels in the lower range of 0.5–0.8 mmol/L compared to the higher levels considered optimal in mixed age patients (0.8–1.2 mmol/L). Older adults are more vulnerable to delirium (Himmelhoch et al., 1980) and can develop neurotoxicity which lasts for prolonged periods of time after discontinuation and undetectable serum levels (Nambudiri, Meyers and Young, 1991). Similarly, an increased susceptibility to lithium-induced hypothyroidism has been well established in elderly women in particular. In one community study, 32% of 148 elderly people taking lithium were on thyroid replacement or had an elevated TSH (Head and Dening, 1998). Lithium and other drug interactions are particularly relevant in an elderly population receiving large numbers of medical drugs (Shulman and Herrmann, 1999). Thiazide diuretics can decrease lithium clearance by 25% and thereby increasing serum lithium levels. Furthermore, ACE inhibitors and loop diuretics as well as non-steroidal inflammatory drugs all serve to potentially increase lithium levels and must be monitored with great caution. Despite the potential difficulties with neurotoxicity and other adverse events, the dramatic change in prescription patterns for lithium carbonate in old age must be reconsidered in light of their longstanding use as a mainstay treatment for bipolar disorder. Before abandoning lithium carbonate in favor of newer drugs, the evidence in old age must be more firmly established. In the meantime, very

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careful monitoring and cautious management is particularly important in an elderly population.

DIVALPROEX Divalproex is quickly replacing lithium carbonate as the mood stabilizer of choice for late onset elderly manic patients (Shulman et al., 2003). In Ontario, Canada, the incidence of new prescriptions for divalproex surpassed that of lithium by 1997. Yet there is a distinct lack of data to support this shift in clinical practice. Only individual case reports and some case series are currently available to inform the use of divalproex in elderly bipolars (Shulman and Herrmann, 2002b). Most of these case reports indicate that divalproex is a well-tolerated mood stabilizer in old age. In a descriptive study, 21 elderly manic patients were rated as much improved with divalproex (Noaghiul, Narayan and Nelson, 1998). The mean dose of divalproex was 1400 mg/day with an average serum of 72 mmol/L. Chen et al. (1999) using retrospective data found lithium to be more effective for classic manic but similar to divalproex for mixed mania in late life. Divalproex has been reported to be well tolerated in elderly dementia patients treated for agitation (Porsteinsson, Tariot and Erb, 1997; Herrmann, 1998). Extrapolating from these patients to the bipolar population, it is likely that the main side-effects will continue to be sedation and gastrointestinal disturbances which can generally be modulated by dose reduction (Shulman and Herrmann, 1999). Because divalproex is highly protein-bound and a weak inhibitor of the cytochrome P4502D6, the potential for adverse reactions due to drug interactions remains a significant concern. It could inhibit the metabolism of tricyclic antidepressants, for example (Janicak, 1993). Despite its reports of being well tolerated, efficacy and effectiveness data are significantly deficient including its value in prophylaxis and bipolar depression. Some limited data are available regarding the use of divalproex in combination with lithium carbonate in older bipolar patients. This is a potentially beneficial approach in older patients who have difficulty tolerating ‘therapeutic’ levels for monotherapy. It is possible that by reducing both medications, one may be able to provide efficacy without reaching limiting side-effects. This approach was reported to be useful in two case series of elderly patients who were only partially responsive to lithium carbonate (Goldberg, Sachs and Kocsis, 2000; Schneider and Wilcox, 1998).

CARBAMAZEPINE Similar to the other pharmacological agents, there are no controlled trials of carbamazepine in an elderly population. Only a few case reports suggest its benefit

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in acute mania (Schneier and Kahn, 1990; Kellner and Neher, 1991). In a mixed age sample comparing the efficacy of carbamazepine and lithium in a double-blind study, a small proportion of elderly patients were included in both the carbamazepine and lithium arms (Okuma et al., 1990). Both drugs were considered efficacious but clearly an insufficient number of elderly patients were included to draw conclusions for the older population. Because carbamazepine is a potent inducer of the cytochrome P4502D6, it also has the potential for significant drug interactions (Janicak, 1993). Because clinical experience has reported carbamazepine to be potentially neurotoxic in an elderly sample, serum levels have been recommended to be below 9 μg/ml (Young, 1996).

NEW MOOD STABILIZERS Lamotrigine and oxcarbazepine show promising results in mixed age bipolars but have not been studied in any systematic manner in old age (Young et al., in press). Readers are referred to the relevant chapters on mixed age samples to assess the current evidence for the use of these and other newer agents.

ANTIPSYCHOTIC AGENTS Like mixed age samples, atypical antipsychotics are central to the acute management of mania in old age and may prove to be effective prophylactic agents. However, no systematic data are available on the efficacy or tolerability of atypical antipsychotic agents in elderly bipolar patients. It is known that typical antipsychotics like haloperidol and phenothiazines, commonly used as adjunct treatments for bipolar disorder, can cause significant side-effects including anticholinergic effects, orthostatic hypotension and extrapyramidal symptoms (Naranjo et al., 1995). Jeste et al. (1999) have suggested that atypical antipsychotics including risperidone, olanzapine and quetiapine may be better tolerated and produce less extrapyramidal symptoms including tardive dyskinesia. Two reports have suggested that clozapine may be useful in refractory or rapid cycling bipolars (Shulman, 1997; Frye, Altshuler and Bitran, 1996). Given the widespread use of atypical antipsychotics, one anticipates that more data will become available in elderly patients that may help to inform pharmacological management.

THE FUTURE The future directions in the pharmacological management of bipolar disorder in old age need to build on the existing knowledge base and clinical experience in

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spite of the limited systematic data that are currently available. The following issues will likely help advance our understanding in managing bipolar disorder in late life: 1. The elucidation of the pathogenesis of bipolarity in old age should lead to heuristically valuable subtypes that can be targeted for specific treatments and outcome studies. Shulman and Herrmann (2002a) have proposed four subtypes for consideration. These include: (a) Primary bipolar disorder. These are individuals with early onset of mood disorder continuing into old age. These patients are largely treated as outpatients and generally do not require hospitalization. (b) Latent bipolar disorder; this includes those individuals with an onset of depression in mid-life and a ‘conversion’ to mania late in life often after a long latency and multiple depressive episodes. This conversion may be due to ‘cerebral organic’ factors that may be due to normal degenerative changes with aging. (c) Secondary mania (disinhibition syndromes). This group of generally late onset manic syndromes occurs with a decreased history of familial predisposition or prior history of mood disorder. They tend to be associated with clear-cut neurologic disorders or other systemic medical disorders. (d) A less common group of unipolar manics; these have their onset early in life and continue to persist into old age with manic-only episodes. Each of these subtypes may require a different pharmacological approach on the assumption that they each have a different underlying pathogenesis. 2. The completion of a multi-center randomized controlled trial (RCT) in elderly bipolars will provide efficacy data for the most commonly used pharmacological agents. 3. Until the completion of such an RCT, the use of pharmaco-epidemiologic data and Consensus Conferences can help to guide treatment decisions. It seems likely that combination therapies will be more common, especially for refractory and rapid-cycling cases (Mondimore, Fuller and DePaulo, 2003). 4. Ultimately, a better understanding of bipolar disorder in old age may help to inform our understanding and management of bipolar disorders in the larger mixed age population. Specifically, the elucidation of brain areas that are most relevant to the manifestation of mania in old age may be a clue to the pathogenesis and physiologic pathways that are relevant to the manifestation of bipolar disorders in younger adults. This could result in targeted pharmacotherapy and might very well make the greatest impact on studying older bipolar patients.

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REFERENCES Alexopoulos GS, Meyers BS, Young RC, Mattis S and Kakuma T (1993) The course of geriatric depression with “reversible dementia”: A controlled study. American Journal of Psychiatry, 150, 1693–1699. Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Silbersweig D and Charlson M (1997) Clinically defined vascular depression. American Journal of Psychiatry, 154, 562–565. Bauer M and McBride L (1996) Psychosocial treatments for bipolar disorder. In Structured Group Psychotherapy for Bipolar Disorder: The Life Goals Program, Bauer M and McBride L (eds), Springer, New York, pp. 69–83. Berrios GE and Bakshi N (1991) Manic and depressive symptoms in the elderly: Their relationships to treatment outcome, cognition and motor symptoms. Psychopathology, 24, 31–38. Broadhead J and Jacoby R (1990) Mania in old age: A first prospective study. International Journal of Geriatric Psychiatry, 5, 215–222. Chen ST, Altshuler LL, Melnyk KA, Erhart SM, Miller E and Mintz J (1999) Efficacy of lithium vs valproate in the treatment of mania in the elderly: A retrospective study. Journal of Clinical Psychiatry, 60, 181–186. Dhingra U and Rabins PV (1991) Mania in the elderly: A five-to-seven year follow-up. Journal of the American Geriatrics Society, 39, 582–583. Frye MA, Altshuler LL and Bitran JA (1996) Clozapine in rapid cycling bipolar disorder (letter). Clinical Psychopharmacology, 16, 87–90. Fujikawa T, Yamawaki S and Touhouda Y (1995) Silent cerebral infarctions in patients with late-onset mania. Stroke, 26, 946–949. Goldberg JF, Sachs MH and Kocsis JH (2000) Low-dose lithium augmentation of divalproex in geriatric mania. Journal of Clinical Psychiatry, 61, 304. Goodwin FK and Jamison KR (1990) Manic-depressive illness, Oxford University Press, New York, pp. xxi–938. Greil W, Stolzenburg MC, Mairhofer ML and Haag M (1985) Lithium dosage in the elderly. A study with matched age groups. Journal of Affective Disorders, 9, 1–4. Hardy BG, Shulman KI and Zucchero C (1997) Gradual discontinuation of lithium augmentation in elderly patients with unipolar depression. Journal of Clinical Psychopharmacology, 17, 22–26. Head L and Dening T (1998) Lithium in the over-65s: Who is taking it and who is monitoring it? International Journal of Psychiatry, 13, 164–171. Herrmann N (1998) Valproic acid treatment of agitation in dementia. Canadian Journal of Psychiatry, 43, 69–72. Himmelhoch JM, Neil JF, Mayr SJ, Fuchs CZ and Licata SM (1980) Age, dementia, dyskinesis, and lithium response. American Journal of Psychiatry, 137, 941–945. Inouye, SK (1998) Delirium in hospitalized older patients: Recognition and risk factors. Journal of Geriatric Psychiatry and Neurology, 11, 118–125. Janicak PG (1993) The relevance of clinical pharmacokinetics and therapeutic drug monitoring: Anitconvulsants, mood stabilizers and antipsychotics. Journal of Clinical Psychiatry, 54, 35–41. Jeste DV, Lacro JP, Bailey A, Rockwell E, Harris MJ and Caligiuri MP (1999) Lower incidence of tardive dyskinesia in risperidone compared with haloperidol in older patients. Journal of the American Geriatrics Society, 47, 716–719. Kellner MB and Neher F (1991) A first episode of mania after age 80. Canadian Journal of Psychiatry, 36, 607–608.

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Kessler RC, Rubinow DR, Holmes C, Abelson JM and Zhao S (1997). The epidemiology of DSM-III-R bipolar I disorder in a general population survey. Biological Medicine, 27, 1079–1089. Kobayashi S, Okada K and Yamashita K (1991) Incidence of silent lacunar lesions in normal adults and its relation to cerebral blood flow and risk factors. Stroke, 22, 1379–1383. Krauthammer C and Klerman GL (1978) Secondary mania: Manic syndromes associated with antecedent physical illness or drugs. Archives of General Psychiatry, 35, 1333–1339. Mondimore FM, Fuller GA and DePaulo JR Jr (2003) Drug combinations for mania. Journal of Clinical Psychiatry, 64, 25–31. Nambudiri DE, Meyers BS and Young RC (1991) Delayed recovery from lithium neurotoxicity. Journal of Geriatric Psychiatry and Neurology, 4, 40–43. Naranjo CA, Herrmann N, Mittmann N and Bremner KE (1995) Recent advances in geriatric psychopharmacology. Drugs and Aging, 7, 184–202. Noaghiul S, Narayan M and Nelson JC (1998) Divalproex treatment of mania in elderly patients. American Journal of Geriatric Psychiatry, 6, 257–262. Okuma T, Yamashita I, Takahashi R, Itoh H, Otsuki S, Watanabe S, Sarai K, Hazama H and Inanaga K (1990) Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. Pharmacopsychiatry, 23, 143–150. Porsteinsson AP, Tariot PN and Erb R (1997) An open trial of valproate for agitation in geriatric neuropsychiatric disorders. American Journal of Geriatric Psychiatry, 5, 344–351. Rasanan P, Tiihonen J and Hakko H (1998) The incidence and onset-age of hospitalised bipolar affective disorder in Finland. Journal of Affective Disorders, 48, 63–68. Schneider AL and Wilcox CS (1998) Divalproex augmentation in lithium-resistant rapid cycling mania in four geriatric patients. Journal of Affective Disorders, 47, 201–205. Schneier HA and Kahn D (1990) Selective response to carbamazepine in a case of organic mood disorder. Journal of Clinical Psychiatry, 51, 485. Shulman KI (1997) Neurologic co-morbidity and mania in old age. Clinical Neuroscience, 4, 37–40. Shulman KI and Herrmann (1999) The nature and management of mania in old age. Psychiatric Clinics of North America, 22, 649–665. Shulman KI and Herrmann N (2002a) Bipolar disorder in old age. In Bipolar Disorders: 100 Years after Manic-Depressive Insanity, Marneros A and Angst J (eds), Kluwer Academic Publishers, Great Britain, pp. 153–174. Shulman KI and Herrmann N (2002b) Manic syndromes in old age. In Psychiatry in the Elderly, Jacoby R and Oppenheimer (eds), Oxford University Press, UK, pp. 683–695. Shulman KI, Tohen M, Satlin A, Mallya G and Kalunian D (1992) Mania compared with unipolar depression in old age. American Journal of Psychiatry, 142, 341–345. Shulman KI, Rochon P, Sykora K, Anderson G, Mamdani M, Bronskill S and Tran CTT (2003) Changing prescription patterns for lithium and valproic acid in old age: Shifting practice without evidence. British Medical Journal, 326, 960–961. Spicer CC, Hare EH and Slater E (1973) Neurotic and psychotic forms of depressive illness: Evidence from age-incidence in a national sample. British Journal of Psychiatry, 123, 535–541.

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Starkstein SE, Mayberg HS, Berthier ML, Fedoroff P, Price TR and Robinson RG (1990) Mania after brain injury: Neuroradiological and metabolic findings. Annals of Neurology, 27, 652–659. Steffens DC and Krishnan KRR (1998) Structural neuroimaging and mood disorders. Recent findings, implications for classification, and future directions. Biological Psychiatry, 43, 705–712. Strakowski SM, McElroy S, Keck P. and West S (1994) The co-occurrence of mania with medical and other psychiatric disorders. International Journal of Psychiatry in Medicine, 24, 305–328. Tohen M, Shulman KI and Satlin A (1994) First-episode mania in late life. American Journal of Psychiatry, 151, 130–132. Van Gerpen MW, Johnson JE and Winstead DK (1999) Mania in the geriatric patient population: A review of the literature. American Journal of Geriatric Psychiatry, 7, 188–202. Weissman MM, Bruce ML, Leak PJ, Florio LP and Holzer C III (1991) Affective disorders. In Psychiatric Disorders in America: The Epidemiologic Catchment Area Study, Robins LN and Regier DA (eds), Free Press, New York, pp. 53–80. Wylie ME, Mulsant BH, Pollock BG, Sweet RA, Zubenko GS, Begley AE, Gregor M, Frank E, Reynolds CF and Kupfer DJ (1999) Age at onset in geriatric bipolar disorder. American Journal of Geriatric Psychiatry, 7, 77–83. Young RC (1996) Treatment of geriatric mania. In Mood Disorders Across the Life Span, Shulman KI, Tohen M and Kutcher SP (eds), Wiley-Liss, New York, pp. 411–425. Young RC, Gyulai L, Mulsant B, Flint A, Beyer J, Shulman K and Reynolds CF III (in press) Pharmacotherapy of bipolar disorder in old age: Review and recommendations. American Journal of Geriatric Psychiatry.

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CHAPTER

15 Psychosocial Interventions in Bipolar Disorders: Rationale and Effectiveness David J. Miklowitz University of Colorado, Boulder, USA

INTRODUCTORY OVERVIEW The introduction of mood stabilizers for ameliorating the course of bipolar disorder – beginning with lithium carbonate in the late 1940s – is one of psychiatry’s greatest success stories. Mood stabilizers go far in hastening stabilization from episodes and reducing the frequency and severity of recurrences. However, most bipolar patients continue to have recurrences and a high degree of functional impairment even when maintained on optimal pharmacotherapy. The thesis of this chapter is that adjunctive psychosocial interventions can enhance the efficacy of drug treatment in stabilizing the course of the illness. This chapter will review the empirical literature on “disorder-specific psychotherapies” (DSPs) delivered in conjunction with pharmacotherapy for bipolar patients. It has several take-home messages. First, there are various forms of individual, family and group therapy which have been validated in randomized clinical trials. Most of these trials indicate that the combination of DSPs and medication elongates periods of wellness and reduces symptom severity when compared with treatment-as-usual interventions (or in some cases, less specialized psychotherapies). Second, most DSPs can be characterized as “psychoeducational” and share the common objectives of improving medication adherence, teaching illness and stress management skills, and modifying the impact of environmental triggers for recurrences. Third, the mechanisms of action of these psychosocial approaches are being elucidated. Fourth, the clinical practitioner can adapt these treatment models to the structure of his or her setting. Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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RATIONALE FOR COMBINING MEDICATION AND PSYCHOTHERAPY Although the literature on psychotherapy for bipolar disorder has a long history (e.g. Cohen et al., 1954), the approaches used prior to 1980 were relatively unfocused and not based on empirical findings about the nature, course or onset of bipolar disorder. Recent psychosocial approaches recognize three facts about the illness. First, the disorder is highly recurrent and disabling. Second, the effectiveness of mood stabilizers and atypical antipsychotic agents is limited by high rates of drug nonadherence. Third, psychosocial stress agents play an important role in provoking recurrences of the disorder. The findings of several longitudinal studies will illustrate these points. Among bipolar patients undergoing pharmacological treatment in outpatient settings, about 40% relapse within one year, 60% within two years and 73% within five years (Gitlin et al., 1995; Gelenberg et al., 1989). At least 50% of patients show significant mood symptoms in the intervals between major episodes (Gitlin et al., 1995; Harrow et al., 1990; Kalbag, Miklowitz and Richards, 1999). As many as 60% have social and occupational impairment in the 4–5 years after an acute illness episode (Coryell et al., 1993; Goldberg, Harrow and Grossman, 1995). The year following an acute episode of illness appears to be a particularly difficult time for patients, with only 26% achieving full symptomatic recovery and only 24% achieving full functional recovery (Keck et al., 1998). Psychosocial interventions that succeed in improving inter-episode functioning, especially during the high-risk postepisode period, may augment the prophylactic effects of drug treatment. Most longitudinal studies identify a substantial subgroup of patients who take their medications inconsistently or not at all. Between one-half and two-thirds of patients are fully or partially nonadherent with medications in the year following an acute episode, with the modal length of compliance with lithium averaging two months (Johnson and McFarland, 1996; Keck et al., 1997, 1998). Only about 21% of patients who take lithium are continuously adherent with it (Weiss et al., 1998). The reasons for nonadherence often include unpleasant side effects (e.g. weight gain, fatigue, cognitive dysfunction), complaints that mood stabilizers often reduce feelings of elation or exuberance yet do not adequately alleviate depressed mood, comorbid substance abuse or dependence disorders, lack of family or social supports and lack of information about the disorder (Aagaard and Vestergaard, 1990; Jamison and Akiskal, 1983; Goodwin and Jamison, 1990). Nonadherence is a poor prognostic indicator: abrupt discontinuation of lithium is one of the strongest predictors of rapid recurrence (Suppes et al., 1993). Thus, a secondary goal of psychosocial interventions is to enhance compliance with drug treatments through identifying and challenging misunderstandings about the illness, improving insight, educating significant others and decreasing denial about the disorder.

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Finally, the course of bipolar disorder is strongly affected by life events, especially events that disrupt sleep/wake rhythms (e.g. taking a transatlantic flight; Malkoff-Schwartz et al., 1998) or that accelerate goal attainment (e.g. getting a job promotion; Johnson et al., 2000). It is also influenced by high levels of criticism, hostility, emotional overinvolvement or lack of warmth in family or marital relationships (Miklowitz et al., 1988, 2000; O’Connell et al., 1991; Priebe, Wildgrube and Muller-Oerlinghausen, 1989; Geller et al., 2002). At least one prospective study suggests that physical and sexual abuse during childhood or adolescence negatively affects the later course of the illness and the likelihood of suicide attempts (Leverich et al., 2002). Modern psychotherapies have grown in response to studies showing associations between psychosocial stressors and recurrences of the disorder. The rationale is that buffering the patient against the negative impact of life stressors and increasing the protective effects of the social/ familial environment may help increase the duration of wellness periods. In summary, findings from longitudinal studies raise the possibility that psychotherapy can add to the efficacy of pharmacotherapy in staving off recurrences, improving inter-episode functioning and enhancing drug adherence. To achieve these objectives, psychosocial interventions proceed with certain targets of change in mind. The common assumptions of modern DSPs are addressed in the next section.

COMMON OBJECTIVES OF DISORDER-SPECIFIC PSYCHOTHERAPIES Modern approaches to psychotherapy have certain objectives in common, as described in Table 15.1. First, they assume that patients will come to accept the illness if they understand basic facts about its nature, prognosis, biological and genetic causes, psychosocial provoking agents and treatment. Thus, all of the models include a degree of psychoeducation, the provision of information to patients (and, depending on the model, to relatives) about the disorder. Psychoeducation, Table 15.1: Common objectives of psychosocial treatments for bipolar disorder • • • • • • • • •

Educate the patient about bipolar disorder Decrease denial and foster acceptance of the illness Challenge mistaken assumptions about the disorder’s causes, course or treatments Encourage medication adherence and collaboration with the physician Teach patients to monitor mood symptoms daily Enhance the capacity to manage environmental/family factors that provoke symptoms Learn to spot early warning signs of new episodes Develop and implement relapse prevention plans Enhance social and occupational functioning

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unlike standard education, also addresses the patients’ emotional reactions to this information. For example, therapists address the patient’s emotional distress when coming to terms with having a recurrent, debilitating psychiatric disorder. Rejection of the illness notion and drug nonadherence may be related to mistaken assumptions about the course of the illness (“I will always be in and out of hospitals and dealing with psychiatrists”), disagreements between the patient and relatives about the necessity of medications or fears that one’s creativity will be squelched (“I will never achieve my goals;” “My creativity is ruined by medication”). Psychoeducation provides a realistic but optimistic view of the future. Second, DSPs encourage the patient to adhere to a medication regimen. The reasoning behind prescriptions for different medications are provided and the patient is encouraged to communicate openly with his or her physician about side effects or lack of clinical progress. Patients are encouraged to track their mood states so that they can determine whether medications are having a beneficial impact and whether one pole of the illness is changing more rapidly than the other. Treatment is seen as a collaborative process between the patient, the physician and, often, one or more family members. Third, each method includes a form of relapse prevention, which involves identifying early warning signs of relapses and developing steps for derailing episodes before they worsen. For example, a patient (and often, family members) can be coached to recognize preoccupations with money, increases in activity or mild decreases in sleep as signs heralding full-blown manic episodes. Under these conditions, they can be taught to call the physician for an emergency medical appointment, or make arrangements beforehand for a prescription of atypical antipsychotic medication. Depending on the method, patients may learn to recognize environmental conditions that provoke mood symptoms or contribute to developing episodes. For example, some patients report that hypomania is worsened by hostile interchanges with family members or coworkers; others report that overstimulation in social settings is associated with prodromal symptoms of mania such as racing thoughts or agitation. Fourth, virtually all of the methods involve some form of skill training. The target skill differs from model to model. For example, interpersonal and social rhythm therapy involves training patients to monitor and regulate their sleep/wake cycles. Family-focused therapy trains patients and caregivers to communicate and solve interpersonal problems more effectively. Cognitive-behavior therapy involves learning to identify and challenge automatic negative thoughts. Finally, all of the models entail strategies for enhancing social and occupational functioning in the aftermath of episodes. They assume that patients will make an attempt to reenter the working world, regain lost or damaged relationships or function as a spouse or parent. Methods for achieving these goals differ for each method. For example, group psychoeducation capitalizes on the advice given by others with the disorder for post-episode functioning; family therapy involves

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teaming up with family members to solve problems related to the work or relational environment. Interpersonal therapy involves gaining insight into one’s role in causing relationship problems and strategies to establish more effective interpersonal relationships.

EMPIRICAL STUDIES OF PSYCHOSOCIAL INTERVENTION Disorder specific psychotherapies for bipolar disorder can be roughly divided into three groups: individual modalities, family therapies and group psychoeducational interventions. The empirical studies of these modalities are reviewed here. All of the studies have examined psychotherapy as an adjunct to medication; none of them view psychosocial interventions as monotherapy.

INDIVIDUAL COGNITIVE-BEHAVIORAL TREATMENT Cognitive-behavioral treatment (CBT) was originally developed for depressive disorders and later for anxiety disorders (Beck et al., 1979; Clark, Beck and Alford, 1999). Traditional CBT for depression consisted of behavioral activation exercises (e.g. scheduling pleasant daily events to alleviate depressed mood), anxiety reduction techniques (e.g. graded exposure to feared stimuli) and teaching patients to recognize and challenge dysfunctional thoughts and replace them with more balanced interpretations of events. The cognitive-behavioral model seems well suited to bipolar disorder: bipolar patients show distinct cognitive distortions and attributional styles during manic, hypomanic and depressive episodes, although it is not clear that thinking is distorted during periods of remission (Reilly-Harrington et al., 1999; Lyon, Startup and Bentall, 1999). Cochran (1984) conducted the first randomized trial of CBT using a six-session treatment that was focused on restructuring the patient’s attitudes toward lithium and enhancing medical adherence. The comparison group received lithium and standard medication management. Over 6 months of follow-up, the CBT group had better drug compliance and fewer hospitalizations related to noncompliance than the comparison patients. The strength of the CBT seemed to lie in its identification and restructuring of negative cognitions related to medication-taking (e.g. “taking lithium means I’m very sick”). The Cochran study focused on one aspect of disease management – medical adherence. Another approach – although not strictly cognitive-behavioral – focused on skill training related to relapse prevention. Perry et al. (1999) educated patients about their early warning signs of mania and depression and taught them to seek early intervention when these symptoms first appeared. In an 18-month study, 69 patients were randomly assigned to drug treatment, supportive care and 7–12 sessions of psychoeducation or drug treatment and supportive care only. The

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investigators observed a 30% reduction in manic relapses, longer survival time prior to manic relapse and enhanced social functioning in the experimental treatment condition. The intervention did not affect time to depressive relapse, possibly because depressive prodromes are less distinctive and unfold more gradually than manic prodromes. A broad-based cognitive-behavioral approach was described by Lam et al. (2000, 2003) at the Institute of Psychiatry in London. This treatment, which has a strong psychoeducational bent, acquaints patients with features of the disorder such as understanding the interactive roles of biological vulnerability and stress, the importance of keeping regular sleep/wake cycles and recognizing and seeking early intervention for prodromal symptoms. Additionally, therapists taught patients to restructure their cognitive distortions, including “dysfunctional high goal attainment beliefs” (e.g. “there is no risk to this business investment I’m about to undertake”) and the resulting behaviors (e.g. frantic attempts to make up for lost time). The treatment lasted 6 months and averaged 14 sessions (range 12–18), with two booster sessions offered during a 6-month follow-up phase. A total of 103 bipolar I patients were assigned to CBT and routine pharmacotherapy (mood stabilizers plus adjunctive agents) or routine pharmacotherapy alone. The patients were in remission but were deemed to be at high risk for relapse based on histories of repeated episodes. Over one year, the relapse rate for the CBT group was 44% and for the comparison group, 75%. Patients in the CBT group also required fewer days of hospitalization (particularly for depression) and were better able to cope with the prodromal symptoms of mania than the routine pharmacotherapy group. Notably, patients in CBT had better drug compliance over the year of treatment and follow-up, but still showed longer periods of stability when the effects of compliance were statistically controlled. A study in Glasgow, UK by Scott, Garland and Moorhead (2001) assigned 42 bipolar patients to CBT (20 sessions over 26 weeks) and pharmacotherapy or a routine care wait-list condition. Similar to the models previously described, CBT consisted of education about bipolar disorder, encouragement of drug compliance, cognitive restructuring, stabilization of sleep/wake cycles and relapse prevention. The sample consisted of 42 patients who began the study in a variety of clinical states. At 6 months, patients in CBT had greater improvements in depression symptoms, global functioning and self-ratings of internal activation than patients in the wait-list condition. It appears that adding individual CBT to mood stabilizers is effective in elongating periods of wellness, improving symptom status and, in some cases, enhancing medication adherence and social functioning. Nonetheless, there are unanswered questions about CBT, such as whether its effects are superior to the effects of other forms of psychotherapy matched in amount of therapist contact. All of the studies compared CBT to a non-psychotherapy comparison group. Future research should also examine the avenues through which the treatment achieves

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its clinical effects, including whether it leads to reductions in the cognitive distortions and attributions believed central to disturbed mood states.

INTERPERSONAL AND SOCIAL RHYTHM THERAPY Several investigators have described a social rhythm stability hypothesis of bipolar episodes (Wehr, Sack and Rosenthal, 1987; Ehlers, Frank and Kupfer, 1988; Ehlers et al., 1993; Frank et al., 1997). In this model, disruption of sleep is a “final common pathway” to symptoms of mood disorder when considered in the context of genetic vulnerability, neurophysiological abnormalities and life stress (Goodwin and Jamison, 1990). Sleep/wake cycles are directly affected by social rhythms, such as, when a person goes to work, how much social stimulation he or she receives during the day, exercise routines and other personal habits. Life stressors that disrupt social rhythms and sleep/wake cycles are hypothesized to be the most potent in precipitating manic episodes. Indeed, Malkoff-Schwartz et al. (1998) found that in a sample of bipolar I patients, patients who developed manic episodes were more likely to have had social-rhythm disruptive events (e.g. illness in a child that requires a mother to lose sleep; staying up to study for an exam) in the 8 weeks prior to episode onset when compared to an 8-week control period that did not precede an episode. Patients who developed depressive episodes were comparatively less likely to have social-rhythm disruptive events in the 8 weeks before their episodes. Frank and associates (1999, 2000) developed their individual “interpersonal and social rhythm therapy” (IPSRT) based on the social rhythm stability model. It is derived from the interpersonal therapy for depression, which has been found in several randomized trials to be effective in the stabilization of major depressive symptoms (Elkin et al., 1995; Klerman et al., 1984; Weissman, Markowitz and Klerman, 2000). The beginning phases of IPSRT are initiated shortly after episode onset and focus on taking a history of the illness and identifying social-rhythm disruptive events that precipitated prior episodes. Patients become acquainted with the “Social Rhythm Metric,” a self-report form for tracking daily routines, sleep/wake cycles and mood (Monk, 1991). Clinicians assist patients in identifying a problem area that may have contributed to the most recent illness episode, and clarify how the patient’s styles, habits or mood states contributed to the development of this problem. Interpersonal problems usually fall into the broad categories of grief over loss, role transitions, interpersonal disputes and interpersonal deficits. Another problem category – grieving over the lost healthy self – is also recognized in IPSRT as characteristic of recurrent bipolar patients, especially those with good premorbid adjustment. The intermediate phases of IPSRT involves teaching patients to regularize their daily routines and sleep/wake cycles and identify events (e.g. upcoming travel; visits from relatives) that are likely to provoke changes in these routines. Solving

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interpersonal problems usually requires insight by the patient into his or her habitual patterns of dealing with others (e.g. the tendency to withdraw from immediate conflict but to become angry and vengeful later) and exposure to new approaches to interpersonal problem-solving. In the final phase of IPSRT, the focus is on relapse prevention, including ongoing stabilization of social and sleep routines, and implementing new strategies for resolving interpersonal conflicts. Interpersonal and social rythm therapy has been examined in two studies. In the ongoing University of Pittsburgh Maintenance Therapies study, patients were assigned randomly during an acute treatment phase to weekly IPSRT with mood stabilizers or to an active clinical management and medication condition. This latter treatment was also administered weekly but focused on symptom management and medical adherence rather than interpersonal relationships. Once patients were stabilized, they were randomized again to IPSRT or active clinical management for a 2-year maintenance phase. Sessions were tapered to biweekly and then monthly during this phase. The results of the Maintenance Therapies study are still being observed, but two conclusions can be drawn. First, during acute treatment and stabilization, IPSRT was more successful than active clinical management in getting patients to stabilize their social rhythms. Second, stability of the treatments across phases of the study appeared important. Patients who were randomly assigned to the same treatment modality in both study phases (i.e. IPSRT in both the acute and preventative phase, or active clinical management in both phases) had fewer recurrences and less severe symptoms in the preventative maintenance phase than patients who switched from one modality to the other. The investigators interpreted their findings to suggest that keeping treatment regimens constant helped patients to remain stable, whereas changing treatment parameters contributed to destabilization. In a non-randomized open trial, Miklowitz et al. (2003b) examined the effects of a treatment that combined individual IPSRT sessions with family-focused psychoeducational sessions (see the next section), which they referred to as integrated family and individual therapy (IFIT). Sessions of individual IPSRT alternated biweekly with sessions of family therapy for up to one year. Patients also received standard medication management. Part of the rationale for involving family members was that patients would have an easier time stabilizing social rhythms if spouses or parents assisted them in the process. Integrated family and individual therapy was given to 30 bipolar I and bipolar II patients whose outcomes were compared with 70 historical comparison patients who received medication, a limited amount of family education and crisis management. Over the study year, patients in IFIT had longer survival intervals and greater improvement in depressive symptoms than patients in the comparison condition, even after medication regimens were statistically controlled. No effects of IFIT on manic symptoms were observed.

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Thus, IPSRT is a promising treatment. The Pittsburgh Maintenance Therapies trial will determine whether the effects of IPSRT on mood symptoms are superior to the effects of active clinical management in the 2-year maintenance phase of the study. Future studies should examine the effects of IFIT against its components – IPSRT and family educational therapy – to determine whether a synergy develops between the two modalities in stabilizing patients after an illness episode.

FAMILY-FOCUSED THERAPY Involving family members in the outpatient treatment of recurrent psychiatric disorders has a long and somewhat checkered history. Early approaches viewed family caregivers as pathogens who contributed to the onset of psychosis or mood disorder through their disturbed transaction patterns (e.g. Bateson et al., 1956; Fromm-Reichmann, 1948). Later approaches viewed families coping with schizophrenia or bipolar disorder as highly distressed, and their negatively expressed emotional attitudes as reflecting styles of coping with the burden of illness in a relative (Imber-Mintz et al., 1987). This shift in thinking led more recent writers to focus on family members as allies in the treatment process (Anderson, Reiss and Hogarty, 1986; Falloon, Boyd and McGill, 1984; Liberman et al., 1981). Family intervention for bipolar disorder is a more recent development. The first approach was proposed by Clarkin et al. (1990; Glick et al., 1990) at the Cornell University Medical Center. Their model involved 9 sessions of inpatient family intervention for a mixed group of psychotic, unipolar affective and bipolar affective patients. The model focused on enhancing post-hospital adjustment and maximizing drug adherence. Inpatients (N = 186) randomized to inpatient family intervention had better symptomatic and global functioning 6–18 months after hospital discharge than patients who were assigned to standard care alone. A post hoc analysis by Clarkin et al. (1990) revealed benefits in their small sample of bipolar patients (N = 21), although only among the female subjects. More recently, Clarkin et al. (1998) reported results from a randomized trial involving married, recently ill bipolar patients (N = 33) who were assigned to a 25-session psychoeducational couple therapy plus mood stabilizers or mood stabilizers only. The couple’s intervention involved an educational focus on bipolar disorder, methods to enhance spousal communication and drug compliance. No differential effects of the marital intervention were observed over 11 months on recurrence or symptoms. However, patients in the couple intervention did show greater enhancement of functional outcomes (as indexed by Global Assessment of Functioning scores) and higher medication compliance scores than the comparison patients. More consistent results have been reported in studies of family-focused therapy (FFT; Miklowitz and Goldstein, 1997). This psychoeducational model is administered in 21 sessions (weekly, biweekly, then monthly) over 9 months once the patient

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has begun to recover from an acute manic or depressive episode. In the first segment, psychoeducation (usually 7 or more sessions), patients and their caregiving relatives (typically parents or spouses) learn about the nature, symptoms, course and treatment of bipolar disorder; the notion that episodes come about as an interaction between genetic, biological and stress factors; the importance of continued adherence to medications to stave off recurrences; and the role of stress management in reducing the likelihood of future episodes. Families are taken through a “relapse drill” (Marlatt, 1985) in which they learn to identify incipient signs of relapse and develop a plan for how they will act as a family should those signs appear (e.g. who will call the physician; good and bad ways to communicate with the symptomatic family member; how to keep the environment low in stress). The intermediate and later phases of FFT focus on enhancing the emotional atmosphere of the family through skill training. These techniques are directed at reducing levels of negative expressed emotion. In communication enhancement training (7–10 sessions), patients and relatives learn through role-playing and behavioral rehearsal to listen actively, deliver positive feedback and constructive criticisms, and to diplomatically ask for changes in other family members’ behaviors. Inter-session homework assignments help these skills to generalize to other settings. In the late phases of FFT, the focus shifts to problem-solving. Specific illness, family or work-related problems are defined, and the family is taught a series of steps to “brainstorm” solutions, evaluate the pros and cons of each solution, choose one or a set of solutions and develop an implementation plan. Once the family or couple has learned the problem-solving method, families are encouraged to practice these techniques on their own. Two randomized trials have been conducted with FFT. In the first (Miklowitz et al., 2003a) conducted at the University of Colorado, Boulder, 101 bipolar I patients who began in a manic, mixed or depressive phase were assigned to 9 months of FFT and standard medication maintenance or a comparison condition known as crisis management (CM) and medication maintenance. CM was delivered over 9 months and consisted of two sessions of family education, crisis intervention sessions as needed, and face-to-face research follow-ups. Patients were included only if they had family members active in their care. Over a two-year follow-up, patients in FFT had a 35% reduction in relapse likelihood, longer survival intervals without relapsing (73.5 vs 53.2 weeks) and a greater likelihood of completing the study without relapsing (52% vs 17%). They also showed greater stabilization of depressive symptoms and, to a lesser extent, manic symptoms. Family-focused therapy led to modifications over the first year in positive affect and positive communication skills, as expressed within family interactions. Improvements in the degree with which patients were able to engage with their family members during directed interaction exercises (conducted before and after treatment) predicted clinical improvement, particularly of depression symptoms (Simoneau et al., 1999). FFT was also associated with better medication adherence

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than CM over the course of the 2-year study. Adherence predicted improvements in mania symptoms, but not depression symptoms. Thus, FFT may operate through two avenues: improving family relationships, which may help alleviate depression symptoms, and improvements in drug compliance, which mediates improvement in mania symptoms. These findings need to be replicated in larger samples that examine more systematically the timing of changes in adherence, family communication and mood symptoms. The Colorado study compared FFT to a treatment-as-usual comparison condition. How would it have performed against an individual therapy of comparable intensity and duration? This question was examined in a second randomized study conducted at the University of California, Los Angeles (Rea et al., 2003). These investigators randomly assigned 53 hospitalized, bipolar I manic patients to FFT and medications or a comparison individual therapy called individually focused patient management (IFPT), also with medications. IFPT had many of the same elements as FFT – support, psychoeducation, encouragement of drug adherence and managing symptoms and life stressors – but did not involve family members. IFPT consisted of half-hour individual sessions delivered on the same time schedule as FFT (21 sessions over 9 months). Patients in FFT had fewer relapses and fewer hospitalizations over the 2-year study than patients in IFPT. FFT assisted participants in avoiding rehospitalizations through teaching them to recognize relapses early and obtain medical treatment. When patients in FFT did relapse, they were less likely (55%) to be hospitalized than patients in IFPT who relapsed (88%). However, the effects of FFT were not seen until the 1-year post-treatment interval, during which rehospitalizations were observed in 12% of the FFT group and 60% of the IFPT group. No differences in hospitalization or relapse rates were seen during the first year of treatment. Possibly, patients and relatives did not fully absorb the relapse prevention, communication skills or problem-solving skills until the treatments had been largely completed. A similar pattern was observed in the Colorado study, wherein differential reductions in mood disorder symptoms were only observed for the FFT group after the 6-month follow-up point. Thus, the combination of family psychoeducation and drug treatment appears to improve symptom functioning, enhance family functioning and help patients and caregivers to avoid hospitalization through early intervention. The positive effects of FFT and other family approaches on drug compliance deserve further investigation. Possibly, involving family members in the psychoeducational process increases the likelihood that patients will learn skills to manage their disorder.

GROUP PSYCHOEDUCATION Several investigators have demonstrated the benefits of group treatment. Groups are potentially a cost-effective alternative to individual or family therapy when therapist

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contact hours must be kept to a minimum. Theoretically, patients begin to accept the disorder and feel less stigmatized when in the company of others dealing with the illness. They may also learn self-care skills from each other (e.g. strategies for counteracting suicidal thoughts). Bauer et al. (1998) examined a two-phase group psychoeducation approach known as the Life Goals program, consisting of 5 weekly group psychoeducation sessions focused on relapse prevention followed by an open-ended phase focused on problem-solving on social and occupational goals. In an open treatment trial (N = 29), patients showed increases in their knowledge about the disorder, and 70% reached their first self-identified life goal. Thus, the treatment is promising as a means of enhancing community functioning. There are no data from this open trial on clinical improvement among patients. A randomized trial by Colom et al. (2003) at the University of Barcelona, Spain, systematically addressed whether group psychoeducation and support is effective as an adjunct to standard pharmacotherapy for adult bipolar I and II patients. They examined 120 patients who had been in remission for at least 6 months. One group received mood-stabilizing medications and 21 weekly sessions of group psychoeducation, with a focus on illness awareness, early detection of prodromal symptoms and medication compliance. The groups also had the secondary objectives of educating patients about the importance of lifestyle and sleep regularity, avoiding alcohol and street drugs, and coping with the interpersonal consequences of past and future episodes. Groups were held for 90 minutes and contained between 8 and 12 patients. The comparison patients also received group sessions, but the groups were unstructured and did not involve psychoeducation. Thus, the design provided a control for the amount of patient/therapist contact and the supportive impact of the group structure. The group psychoeducation was superior to the unstructured group in a number of ways. At the end of two years, 92% of the control patients and 67% of the psychoeducation patients had recurrences. Time to recurrence was longer in the psychoeducation group, and the number of hospitalizations was lower. Patients in the psychoeducation group also required fewer hospital days. The groups did not appear to differ on medication adherence. Interestingly, the proportion of patients relapsing from depression was consistently lower in the psychoeducation groups across the active treatment phase and the 2-year follow-up, whereas the proportion of patients with manic/hypomanic or mixed recurrences was only lower at the 2-year follow-up. Thus, the treatment had more rapid effects on depressive recurrences than on manic recurrences. Clearly, group psychoeducation is a promising intervention. It is interesting to note that in the Colom et al. (2003) study, patients were more likely (27%) to drop out of the more effective group psychoeducation than the unstructured groups (12%). The most frequent reason for dropout was manic recurrences. This finding raises the broader question of how best to retain patients in psychosocial interventions

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once they have had a recurrence. Most treatment models encourage patients to continue after their acute episode has resolved, and to use the relapse as a learning experience to clarify the nature of early warning signs, hidden psychosocial triggers and productive vs. unproductive ways to interact with the mental health system. However, it may be difficult for some patients to return to a group after a manic episode, especially if they are ashamed of behaviors they performed while manic.

IMPLEMENTING PSYCHOSOCIAL INTERVENTIONS IN COMMUNITY PRACTICE The foregoing review finds that structured psychosocial treatments are powerful adjuncts to pharmacotherapy in laboratory-based randomized trials. There is an increasing recognition, however, that treatments developed in laboratory settings have lower effect sizes when they are transported into the community – what has been called the “efficacy/effectiveness gap” (Hollon et al., 2002). None of the treatments described in this chapter have been examined within community mental health facilities, using the clinicians that work in them, focusing on the populations they serve and limited by the financial constraints under which they work. There are also no data on whether any of these treatments reduce treatment costs, which would make them more attractive in managed care settings. Several of the treatments had beneficial effects on rehospitalization rates or number of hospital days, suggesting that some forms of therapy, even if more costly in the short run, diminish costs in the long run. To make the transition into regular use in community settings, DSPs need to be distilled down to their most effective (and cost-effective) ingredients. If a clinician only has 6 sessions in which to treat a bipolar patient, how should he or she proceed? Some of the DSPs have detachable modules or free-standing self-care exercises. For example, a clinician may choose to conduct only the psychoeducational module of FFT (7 sessions) or the social-rhythm stabilization exercises associated with IPSRT. He or she may decide to spend 3–4 sessions with a client teaching the cognitive restructuring techniques of CBT (e.g. the use of thought records). Patients or relatives, especially if already knowledgeable, may be able to rapidly draw up relapse prevention plans. Buttressing these brief treatments with monthly maintenance sessions may keep treatments economical while increasing the longevity of their effects. Indeed, one maintenance study for recurrent depression showed that monthly sessions of interpersonal therapy – even in the absence of medication – lengthened the time between episodes among patients who had been previously stabilized on the combination of imipramine hydrochloride and interpersonal therapy (Frank et al., 1990). Accomplishing these objectives depends on the availability of brief, efficient therapist-training materials specific to each treatment modality. Clinical manuals

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supplemented by training videotapes can go far in influencing clinicians’ routine practice. Weekend continuing education seminars may serve a similar purpose. Some clinical materials can be made directly available to patients via the world wide web. Examples include the mood chart used routinely in the STEP program (www.stepbd.org). Patients can download a blank mood chart and receive instructions on how to complete it. Self-assessment measures, such as the Mood Disorder Questionnaire (Hirschfeld et al., 2000) are also available (www.ndmda.org). Parents of bipolar children can download age-appropriate mood charts or devise individualized educational plans with help from the Child and Adolescent Bipolar Foundation (www.bpkids.org). Self-help manuals serve a similar purpose if they include guided exercises addressing topics such as early recognition of mood states, cognitive restructuring, handling medication side effects, social rhythm tracking or educating significant others about the disorder (e.g. Miklowitz, 2002; Fawcett, Golden and Rosenfeld, 2000; Greenberger and Padesky, 1995). Clinicians should be aware, however, that education is not the same as psychoeducation: patients will still need to meet with a clinician to discuss problems related to accepting the diagnosis, the stigma of the illness, feelings about taking medications or loss of creativity, or conflicts with significant others. Finally, educationally oriented support groups can serve an important function as supplements to psychotherapy and medication management. The groups run by the National Alliance for the Mentally Ill (e.g. “Family to Family;” www.nami.org) or the Depression and Bipolar Support Alliance (www.ndmda.org) are good examples. There are currently no data on the effectiveness of these programs in improving the course of bipolar disorder or alleviating distress and burden among relatives, but they serve an important support function. If alcohol or drug abuse is present, dual-diagnosis alcoholics/narcotics anonymous groups can be recommended if they contain members who recognize the validity of comorbid psychiatric conditions and the separate treatments required for each.

CONCLUSIONS AND FUTURE DIRECTIONS Disorder-specific psychosocial interventions help address the limited efficacy of medications alone in long-term prophylaxis. Randomized trials of psychosocial intervention indicate that family-focused psychoeducation, IPSRT, cognitive therapy and group psychoeducation augment the stabilizing effects of drug treatment. Several of the studies found favorable effects for DSPs even when compared with “nonspecific” treatments (e.g. supportive individual or group therapy) that were matched in duration and amount of therapist/patient contact. At this point, little is known about the mechanisms of action (avenues of change) of the various approaches. FFT and individual CBT both have positive effects on medication adherence, but their prophylaxis against relapse does not appear to be solely a function of compliance. FFT has also been found to enhance the interactions

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of patients with their spouses or parents, whereas CBT has positive effects on social functioning and monitoring of prodromal symptoms. IPSRT is successful in its objective of improving daily routines and sleep cycles, although it is unclear whether these improvements predicting greater stabilization of mood symptoms. Future studies need to identify therapeutic mechanisms, which may lead to the development of more efficient models with more enduring effects. There are currently no data on whether one of the DSPs works better than the others. Studies that examine this question are likely to yield complex results that go well beyond “A is better than B” conclusions. For example, family psychoeducational approaches may have a stronger impact on depression than mania symptoms. Certain of the cognitive-behavioral models (Perry et al., 1999) had stronger effects on mania than depression symptoms, whereas other models (Lam et al., 2003) had somewhat stronger effect sizes for depression. The group psychoeducational intervention (Colom et al., 2003) had more rapid effects in preventing depressive than manic recurrences. It is intriguing to consider the meaning of these seemingly disparate results: Is family or group support more critical to the alleviation of depressive than manic symptoms? Are treatments oriented toward relapse prevention more likely to be effective in derailing manic symptoms, especially because depressive prodromes are more difficult to detect (Lam and Wong, 1997)? These differential effects on the two poles of the illness may also reflect differences in study designs. The majority of the patients in the two randomized studies of family therapy were recruited in an acute manic or mixed episode, whereas several of the CBT studies, and the single group pychoeducation study, recruited patients in recovered states. Future studies will need to consider the polarity of symptoms at follow-up after controlling for the clinical state of patients at study entry. The ongoing Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD; Sachs etal., 2003; Miklowitz and Otto in press) may partially address these issues. In STEP-BD, the efficacy of various pharmacologic and psychosocial interventions is examined in 16 treatment centers across the US. In the randomized portion of STEP, acutely depressed bipolar patients are assigned to medication and FFT, IPSRT, CBT or an education-based psychosocial control. Because all patients begin in an acutely depressed state, it may be possible to assess the relative impact of treatments on the reemergence of manic, mixed and depressive symptoms. This review also raises the question of the relative benefits of individual versus group formats for psychosocial care. Theoretically, group support is more costeffective than individual therapy, because as many as 12 patients can be seen in a single session by one therapist. The same question could be raised about multifamily psychoeducation formats. McFarlane et al. (1995) found that multifamily formats were more cost-effective than single family formats for families of schizophrenic patients, but no similar comparison has been conducted in bipolar

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disorder. Multi-family groups have been associated with high drop-out rates in some studies (Leff et al., 1990). When considering the relative benefits of group versus individual formats, the clinician should consider whether the patient is able to handle the interpersonal stress associated with group formats, and whether family members are comfortable in such a setting. Finally, the applicability of DSPs to early-onset patients deserves more consideration. Pediatric-onset bipolar illness is an especially pernicious and debilitating subtype of the disorder, often associated with high rates of comorbidity and a difficult course of illness (see Biederman, Chapter 13 of this book). Pediatric patients are affected by environmental stressors such as the absence of a parent or low parental warmth (Geller et al., 2002). The development of psychoeducational interventions for this population is in its infancy, but positive results for family-based approaches have already emerged (Fristad, Gavazzi and Mackinaw-Koons, 2003; Miklowitz et al., 2004a; Pavuluri et al., 2003). Early intervention at the first signs of onset may go far in preventing the rapid recurrences and suicide attempts that characterize adults with onset in childhood or adolescence (Coryell et al., 2003; Geller and Luby, 1997).

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Pavuluri MN, Graczyk PA, Henry DB, Carbray JA, Heidenreich J, and Miklowitz DJ (2004) Child and family-focused cognitive behavioral therapy for pediatric bipolar disorder: Development and preliminary results. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 528–529. Perry A, Tarrier N, Morriss R, McCarthy E, and Limb K (1999) Randomised controlled trial of efficacy of teaching patients with bipolar disorder to identify early symptoms of relapse and obtain treatment. British Medical Journal, 16, 149–153. Priebe S, Wildgrube C, and Muller-Oerlinghausen B (1989) Lithium prophylaxis and expressed emotion. British Journal of Psychiatry, 154, 396–399. Rea MM, Tompson M, Miklowitz DJ, Goldstein MJ, Hwang S, and Mintz J (2003) Family focused treatment vs. individual treatment for bipolar disorder: Results of a randomized clinical trial. Journal of Consulting and Clinical Psychology, 71, 482–492. Reilly-Harrington NA, Alloy LB, Fresco DM, and Whitehouse WG (1999) Cognitive styles and life events interact to predict bipolar and unipolar symptomatology. Journal of Abnormal Psychology, 108, 567–578. Sachs GS, Thase ME, Otto MW, Bauer M, Miklowitz D, Wisniewski SR, Lavori P, Lebowitz B, Rudorfer M, Frank E, Nierenberg AA, Fava M, Bowden C, Ketter T, Marangell L, Calabrese J, Kupfer D, and Rosenbaum JF (2003) Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biological Psychiatry, 53, 1028–1042. Scott J, Garland A, and Moorhead S (2001) A pilot study of cognitive therapy in bipolar disorders. Psychological Medicine, 31, 459–467. Simoneau TL, Miklowitz DJ, Richards JA, Saleem R, and George EL (1999) Bipolar disorder and family communication: Effects of a psychoeducational treatment program. Journal of Abnormal Psychology, 108, 588–597. Suppes T, Baldessarini RJ, Faedda GL, Tondo L, and Tohen M (1993) Discontinuation of maintenance treatment in bipolar disorder: Risks and implications. Harvard Review of Psychiatry, Sep–Oct 1, 131–144. Wehr TA, Sack DA, and Rosenthal NE (1987) Sleep reduction as a final common pathway in the genesis of mania. American Journal of Psychiatry, 144, 210–214. Weiss RD, Greenfield SF, Najavits LM, Soto JA, Wyner D, Tohen M, and Griffin ML (1998) Medication compliance among patients with bipolar disorder and substance use disorder. Journal of Clinical Psychiatry, 59, 172–174. Weissman MM, Markowitz J, and Klerman GL (2000) Comprehensive Guide to Interpersonal Psychotherapy. Basic Books, New York, NY.

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CHAPTER

16 The Pivotal Role of Psychoeducation in the Long-Term Treatment of Bipolar Disorder Francesc Colom and Eduard Vieta Stanley Research Center, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Spain

INTRODUCTION All severe medical illnesses may improve their outcome by including in their regular treatment some aspects concerning healthy habits, behavioral changes that may benefit the course of the illness, symptoms management and adherence issues. This “good integrative practice” model has shown its efficacy in several medical conditions such as cardiac illness (Linden, 2000), diabetes (Olmsted et al., 2002) and asthma (Durna and Ozcan, 2003). Psychiatric disorders are, due to its intimate nature where behavior and decisions-taking are often altered, the field that may benefit more from this approach. Moreover, bipolar disorders – maybe because it is the only serious illness that is considered quite often as a “gift” by some of the people who suffer from it – are, amongst all psychiatric disorders, one of the illnesses in which psychoeducation may play a more crucial role (Table 16.1). Unfortunately, this therapeutic need did not receive research support until a few years ago, despite the fact that most bipolar-focused clinics were using some sort of “common-sense-based” psychoeducation and related approaches based on clinical experience since at least the early 1970s (Jamison and Akiskal, 1983). Early trials of psychological interventions in bipolar disorders were classically affected by major methodological pitfalls. Most of them were published without appropriate control groups and, without blind evaluation of results, used outcome measures that had little clinical relevance or were small sample sized. However, the sudden Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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Table 16.1: Why is psychoeducation so crucial in bipolar patients? • Bipolar patients have, frequently, a lack of illness insight. • Healthy habits are often dismissed in bipolar patients. • Up to 90% of bipolar patients have considered to withdraw medication without any medical advice. • Up to 40% of bipolar euthymic patients have some adherence problem. • Non-adherence is the first cause of relapse. • The difference between a good and a poor outcome is, probably, the most dramatic amongst all psychiatric disorders, as it is the only severe mental disorder in which remission “ad integrum” exists. • Outcome may be clearly improved by an adequate pharmacological treatment. • A poor clinical outcome often turns into an irreversible psychosocial and work-functioning impairment. • A poor clinical outcome is associated to later neuropsychological impairment.

rise of interest in bipolar disorders coming from biological psychiatry and psychopharmacology has been followed by an important effort on performing well-designed controlled studies that have offered some significant results in the last few years. In the last five years, psychoeducation has crossed the border between common sense and evidence, and nowadays its implementation in daily therapeutic routines is not a mere purpose of excellence but a good clinical practice concern. On the other hand, the introduction of newer drugs that provide similar or better efficacy than previous ones with an outstanding tolerability profile, together with crucial findings on the impact of bipolar disorders in the quality of life and social, cognitive and occupational functioning, has subtly driven professionals to a remarkable change of paradigm in which our therapy targets are broadening from symptom improvement to full recovery (which involves both symptomatic and functional recovery). Following this new paradigm, there is a lot we can do from an integrative treatment approach that includes pharmacotherapy and psychological issues. Table 16.2 shows the different goals covered by pharmacotherapy, psychological interventions and the combination of both. The amount of psychological treatments proposed in the last few years is quite important and there is a considerable variability of approaches and paradigms – going from psychoanalysis to behavioral therapy – but, as reviewed elsewhere (Colom et al., 1998; Swartz and Frank, 2001), just a few have proven efficacy. From a seminal phase where every paradigm essayed to fit in the bipolar patient therapeutic needs, we have moved to a phase of consolidation of well-tested approaches. Most studies seem to indicate a high efficacy of psychoeducationbased programs in the prevention of relapses. The efficacy-data of psychological techniques, namely cognitive behavioral therapy and interpersonal therapy, is promising at the present but needs further evidence.

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Table 16.2: Goals in the treatment of bipolar disorders Therapeutic Goal Treatment of acute episodes Treatment of psychotic symptoms Prophylaxis of recurrences Treatment of anxiety and insomnia Prevention of suicide Avoiding drug abuse Treatment adherence Coping with impairment Information and adjustment to chronic illness Improve inter-episodic functioning Emotional support Family support Early identification of prodromal symptoms Coping with psychosocial consequences of past and future episodes

Medication

Psychological Intervention

+ + + + + + + + − − − − −

− − + + + + + + + + + + +

−

+

INTERVENTION IN AN ACUTE EPISODE To date, no psychological intervention has shown any efficacy in treating manic and hypomanic phases of the disease. The truth is that, to the best of our knowledge, there are no published trials – negative or positive – testing the efficacy of any psychotherapy in alleviating manic or hypomanic symptoms. On the other hand, we would say that – fortunately – this is not an urgent clinical need, as the efficacy, effectiveness and rapidity of old and newer antimanic drugs leave little room for other meaningful approaches. The role of psychological interventions as an add-on to mood stabilizers in bipolar depression is far more exciting than its role in the unipolar field due to the restrictions in the use of antidepressants because of the risk of switching. Combination of psychotherapy and antidepressants would be the first choice in the treatment of bipolar depression according to a survey performed with Canadian psychiatrists (Sharma etal., 1997); only 15% would start treating a bipolar depression with medication alone. To date, two psychological interventions have shown some efficacy in the treatment of bipolar depression, namely cognitive-behavioral therapy and social rhythm therapy. Both might be considered as a choice for the treatment of non-psychotic bipolar depression, following the advice of several international treatment guidelines (Frances et al., 1998). Expert-consensus US guidelines claim psychotherapy as the second step – following the optimization of mood stabilizer – in the treatment of bipolar depression, at the same level as electroconvulsive therapy (ECT) or antidepressants. We are not so optimistic regarding this privileged role of psychotherapy. On the other hand, we have to consider the high suicide rates associated with bipolar

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depression, which would justify a more ambitious intervention. Psychotherapy would be a useful add-on for most depressed bipolar patients, but not at the same level as ECT or antidepressants, specially because the markers of response would be very different for each treatment. Psychological intervention might be the first choice for non-severe bipolar depression, and specially for depressed rapid-cyclers and bipolar III, due to the switch risk. On the other hand, we should not exclude cognitive-behavioral therapy (CBT) or interpersonal social-rhythm therapy (IPSRT) from the treatment of severe bipolar depression, as it has an important role as add-on in the prevention of suicide.

COGNITIVE-BEHAVIORAL THERAPY (CBT) In unipolar depression, CBT has shown its efficacy, both in combination or in monotherapy (Ward et al., 2000; Keller et al., 2000, Scott et al., 2000). However, these results cannot be generalized to bipolar depression, as unipolar and bipolar depression have some subtle but relevant clinical differences. Bipolar depression is often characterized by inhibition, lethargy and apathy – mainly “behavioral symptoms” – and, on the contrary, unipolar depression would rather be defined by desperation, pessimistic thoughts and other cognitive signs (Goodwin and Jamison, 1990). Although it is true that cognitive symptoms are not absent in bipolar depression, they may be more typical of unipolar depression. Thus, bipolar depression would better deserve a behavior-focused therapy, more than a classical cognitive therapy. This difference has been largely misconsidered by cognitive experts, who have unsuccessfully tried to treat bipolar depression following Beck’s model (Leahy and Beck, 1988). However, newer formulations of CBT which include educative elements and emphasize the importance of sleep and habits have been successfully tested, showing the efficacy of this modern CBT in preventing depressive episodes (Lam et al., 2003). Other studies show the feasibility of CBT in bipolar depression and suggest its implementation in treatment routines, though these reports suffer generally from small sample size (Palmer and Williams, 1995; Patelis-Siotis et al., 2001). The same pitfall is seriously hindering the conclusions from other studies trying to assess the efficacy of CBT in improving depressive symptoms (Zaretsky, Segal and Gemar, 1999). A well-designed study (Scott, Garland and Moorhead, 2001) showed improvements in depressive symptoms and functioning for CBT patients compared to the waiting-list control group. The same study clearly suggested the efficacy of CBT in improving subthreshold symptoms. Amongst the behavioral interventions that have traditionally been used to approach depression, sleep deprivation showed some nice efficacy rates – between 40% and 75% of patients improved – (Schilgen and Tolle, 1980), but most of the patients (50–80%) relapsed after sleep regulation (Giedke and Schwarzler, 2002). To the best of our knowledge, the only existing study on sleep deprivation including

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bipolar spectrum patients is Heim’s study (1988), which compared 50 bipolar and cyclothymic patients receiving bright-light treatment to 50 patients receiving partial sleep deprivation, the results being slightly superior for the bright-light treatment group. Unfortunately, the study did not include a placebo (sham-light) arm, so it is difficult to conclude anything about the therapeutic outcome from such methodology. Sleep deprivation may not be an appropriate intervention for bipolar depression but behavioral strategies for reducing the number of sleeping hours in depressed, hypersomnic patients are largely advised.

INTERPERSONAL SOCIAL RHYTHM THERAPY (IPSRT) One of the major advantages of interpersonal therapy – as developed by the late Gerald Klerman and his team (1984) – is that it allows a simple and reliable assessment of its results and is time-limited. These characteristics have turned IPSRT, specially adapted to the needs of bipolar patients by the Pittsburgh group, into a desirable standard for psychological interventions in bipolar disorders. Interpersonal therapy was designed initially for the treatment of unipolar depression but its use has rapidly been extended to other disorders, including panic and bipolar disorders. The classic study by Frank et al. (1990) was the first in proving higher efficacy of a psychological intervention, as opposed to placebo on recurrent unipolar depressed patients. The same group (Frank et al., 1990) developed interpersonal maintenance therapy and interpersonal social rhythm therapy, two updated interventions that fit very well in the day-by-day treatment algorithms of bipolar patients. As commented, its efficacy on unipolar depression has already been proven (Elkin et al., 1989, 1995; Frank et al., 1991), and data on bipolar depression are very promising: patients on IPSRT experienced less depressive relapses, earlier recovery from depression and less subthreshold depressive symptomatology than patients assigned to other treatment conditions (Frank etal., 1999; Frank, 1999). On the other hand, IPSRT has the almost unique advantage of being both an acute treatment and a maintenance treatment. This allows the therapist to maintain the same treatment paradigm all along. This kind of approach has been associated with a better outcome (Frank et al., 1999). IPSRT has also shown to be efficacious for preventing bipolar suicide, in a well-structured study (Rucci et al., 2002). All these facts make IPSRT both a reality and a promise in the treatment of bipolar depression, but larger studies are needed – and fortunately they are already ongoing.

INTERVENTION IN MAINTENANCE PSYCHOEDUCATION Improving maintenance treatment is, no doubt, the field where psychological interventions have shown to be more efficacious. Including a psychological

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intervention in the acute treatment of a bipolar depression is an option, depending in part of the patient’s profile and preference, switch risk, personality issues and risk of suicide. Including a psychological intervention, at least for some months, in the maintenance treatment is almost a must, as the benefits in terms of less relapses and hospitalizations are very clear and the cost very low. On the other hand, most of the targets of psychological treatment that may lead our patients to a good social, interpersonal and occupational functioning may be only reached once the patient is euthymic. Moreover, cognitive dysfunction existing in both mania and depression may be a serious problem for the engagement of the patient in the psychological treatment and for obtaining a good outcome (Martínez-Arán et al., 2000; Vieta, Colom and Martínez-Arán, 2002). Unfortunately, nowadays most bipolar treatment algorithms do not pay attention to the fact that psychological interventions are able to enhance both medication compliance and clinical outcome, and many guidelines do not include any sort of psychological intervention in any phase of the treatment of bipolar disorder. Catching the opinion of most bipolar experts, we are sure that this failure will be corrected in a very short time. Psychoeducation – as every working psychological intervention – is essentially based on common sense but goes beyond a mere delivery of information. Psychoeducation is aimed at providing the bipolar patients with a theoretical and practical approach toward understanding and coping with the consequences of illness – in the context of a medical model – and allows them to actively collaborate with the physician in some aspects of the treatment. Briefly, the main goals of psychoeducation are the enhancement of adherence, the improvement of illness management skills such as early recognition of episode recurrence and development of strategies for effective coping with symptoms, and the improvement of social and occupational function and quality of life. Pioneering studies by Peet and Harvey (Harvey and Peet, 1991; Peet and Harvey, 1991) showed some changes in patients’ attitudes toward lithium, but gave no clinical outcome measures. In Europe, the studies of Eduard van Gent (2000) should be also pointed out, as they showed a significant decrease of non-compliant behavior and hospitalizations amongst psychoeducated patients. In a recent paper (Colom et al., 2003a), our group has shown the efficacy of group psychoeducation in preventing all sort of bipolar episodes and increasing time to relapse at two-year follow-up. The number of hospitalizations per patient was lower for the psychoeducation group. This study had a reasonably large sample size (N = 120) and a random allocation of subjects to either a treatment condition (psychoeducation plus standard pharmacological treatment) or nonintervention (non-structured intervention plus standard pharmacological treatment). Our study has one of the biggest effect-size of all studies published until now regarding psychological interventions. On the other hand, it is interesting to see how psychoeducation may be useful even in those complex patients fulfilling criteria for a comorbid personality disorder (Colom et al., in press). This might be

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particularly interesting if we consider on the one hand the poor outcome of comorbid bipolar patients (Dunayevich et al., 2000; Vieta et al., 2001; Bieling et al., 2003; Leverich et al., 2003) and on the other hand the complexity of their treatment (Black et al., 1988; Colom et al., 2000). The first part of our program consists of destigmatization and improvement of illness awareness, trying to state that the patient is not guilty from his/her illness, but – at the same time – is responsible for the good care. This issue usually merges great debate amongst our patients and is very useful to warm-up group functioning and, on the other hand, it is a necessary first part of our program. Table 16.3 shows the sessions of our psychoeducation program. One of the main targets of psychoeducation concerns the enhancement of treatment adherence, usually very poor in bipolar patients even when euthymic (Colom et al., 2000) which consumes up to the 40% of all the sessions. This may be seen as excessive by some professionals coming from other psychological approaches but our experience – and our results – tell us that patients’ problems with adherence have often a lot to do with misinformation or ignorance, so it is worth making an extra effort to improve this crucial issue. In fact, reasons linked to psychological fears, ignorance and other related preoccupations (Morselli, Elgie and GAMIAN-Europe, 2003) appear to explain, together with axis-II Table 16.3: Sessions of the psychoeducation program (Colom et al., 2003a,b) Contents of the Barcelona Psychoeducative Program 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Introduction What is bipolar illness? Causal and triggering factors Symptoms (I): Mania and hypomania Symptoms (II): Depression and mixed episodes Course and outcome Treatment (I): Mood stabilizers Treatment (II): Antimanic agents Treatment (III): Antidepressants Serum levels: Lithium, carabamazepine and valproate Pregnancy and genetic counselling Pychopharmacology vs. Alternative therapies Risks associated with treatment withdrawal Alcohol and street drugs: Risks in bipolar illness Early detection of manic and hypomanic episodes Early detection of depressive and mixed episodes What to do when a new phase is detected? Life-style regularity Stress management techniques Problem-solving techniques Final session

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comorbidity (Colom et al., 2000), the vast majority of adherence problems, as stated in Figure 16.1. The early detection of prodromal symptoms is another main issue approached by our psychoeducation program. Early detection of prodromal signs has shown its efficacy in preventing mania but not depression and increasing time to relapse, in the study by Perry and colleagues (1999), where the patients that were included in a program of individual teaching of prodromal signs had a significantly better outcome than control patients. Patients frequently do not notice new relapses until it is too late, specially when we are dealing with mild – but long-term impairing – hypomanic episodes. Patients enrolled in the psychoeducation program learn to easily identify common signs of manic relapses, which constitutes the first step of early detection. In a second step, the patients who may be helped by their relatives, friends or partner choose which signs are more relevant for them, keeping in mind their own personality and temperament, the intimate characteristics of their relapses and which signs are easier to identify. A third step is based on the detection of pre-prodromal signs; for some patients, a small change in behavior (that includes changing preferred readings, music or dress), subtle body sensations or newer interests (most of the times related with esoteric hobbies or hobbies from early ages) that tend to repeat on every episode is completely informative of the onset of a new episode. Our program also pays attention to sleep habits regularity, with a general advice to sleep between 7 and 9 hours a day, and to the risks derived from drug (ab)use, with a singular concern about caffeine misuse, which is common in bipolar individuals and may have an impact in the quality of sleep.

Feel ashamed Feel dependent It is slavery I am a little afraid It is unhealthy Fear of long-term side effects Medication not really needed Side effects My physical condition Treatment is useless Got pregnant 0

5

10 15 Patients (%)

20

25

Morselli et al., 2002

Figure 16.1: BEAM survey: Reasons why patients are concerned about taking medication (% patients)

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It is meaningful to wonder if all these educational blocks are indispensable, or in other words, how does psychoeducation work. It is quite clear that psychoeducation is surely working through adherence enhancement but, from the results of our trial, the question may arise whether the other issues are also efficacious or not. To solve this question, we performed a study on the efficacy of our psychoeducation program in a fully compliant bipolar population, with similar results on prophylaxis (Colom et al., 2003b). Thus, the weight of psychoeducation seems to go beyond compliance enhancement and may lay on a tripod model composed of (1) lifestyle regularity and healthy habits, (2) prodromal signs detection and early intervention and (3) treatment adherence.

OTHER INTERVENTIONS IN MAINTENANCE TREATMENT Recent studies (Lam et al., 2003) have shown the efficacy of cognitive-behavioral therapy in the prevention of all types of bipolar episodes at one-year follow-up. However, we shall argue that this would be a “psychoeducation flavored” CBT, quite far from traditional Beckian CBT. CBT has also shown some promising results in the treatment of comorbid substance abuse in bipolar patients, showing good efficacy in preventing manic but not depressive phases (Weiss, Griffin and Greenfield, 2000). Adherence-focused CBT (Cochran, 1984) has been shown to be efficacious in its main goal, but also in lowering the number of relapses. A further development of this approach offers remarkable results as well (Scott and Tacchi, 2002). The IPSRT has also shown promising results in increasing time to relapse, diminishing interpersonal problems and improving medical adherence (Frank, Swartz and Kupfer, 2000). Its combination with family therapy offers a strong prevention of depression and a longer time to relapse (Miklowitz et al., 1988, 2003). Family intervention is one of the most successfully tested psychological approaches in bipolar disorders, thanks to the great effort of the Colorado group. Again, the results are specially relevant in the prophylaxis of depression, but also on increasing time to relapse and improving adherence (Miklowitz et al., 2000). When compared to individual intervention, family therapy also shows good results: the patients receiving family-focused treatment were less likely to be rehospitalized during the two-year follow-up and experienced less relapses (Rea et al., 2003). Whether relatives and patients would deserve different approaches is still a matter of debate (Reinares et al., 2002). Our group has shown that family psychoeducation has a positive impact on the understanding of the disease by the patient’s relatives, on decreasing the subjective burden of the disease and on reducing the patient’s blame from the relatives (Reinares et al., in press).

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WHERE DO WE GO NOW? Psychoeducation is no longer just a matter of common sense; if we care about evidence-based therapeutic routines, we should implement psychoeducation as a standard treatment for bipolar patients. The evidence is large and there is no controversy in the literature about what can be done. Interestingly, several groups from all over the world reported similar positive results and arrived to very similar conclusions; almost every intervention tested contains an important part of psychoeducative elements concerning both compliance enhancement and early identification of prodromal signs, stresses the importance of life-style regularity and explores patients’ health beliefs and illness awareness. The only difference amongst all the approaches reviewed concerns the proportion in which every element is present in a certain intervention (Table 16.4). In any case, the usefulness of psychotherapy for improving the outcome of bipolar patients is nowadays unquestionable, and future treatment guidelines should promote its regular use amongst clinicians. Group psychoeducation (Colom et al., 2003) and CBT (Lam et al., 2003) would be the only interventions guarantying class “A” and “B” effect as coadjunctivant mood stabilizers, according to the nomenclature of Ketter and Calabrese (2002) – a very interesting profile. Their only flaw is that they may not work in monotherapy (without drug treatment). As clinicians, it is our major duty to offer the best treatment available to our patients. Psychoeducation is efficacious, and the only logical consequence of this evidence-based assertion is to go to a universal implementation of this relatively user-friendly technique in routine clinical practice.

Table 16.4: Therapeutic targets approached by psychoeducation* Therapeutic Target Prophylaxis of depression Prophylaxis of mania Time to relapse adherence Enhancement

Early Family IPSRT + Family Psychoeducation Detection CBT IPSRT Therapy Therapy ++

?

++

+

++

++

++

++

++

?

?

?

++

++

++

++

++

++

++

?

++

+

++

?

++ – Strong Evidence; + – Some Evidence; ? – No data available. * (Colom et al., 2003), Early Detection of Prodromal Signs (Perry et al., 1999), CBT (Lam et al., 2003; Scott et al., 2001), IPSRT (Frank et al., 1999; Miklowitz et al., 2000), Family Therapy (Miklowitz et al., 2000) and combination of IPSRT and Family Therapy (Miklowitz et al., 2003) in maintenance treatment of bipolar disorders.

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Goodwin FK, Jamison KR (1990) Manic-Depressive Illness, Oxford University Press, New York. Harvey NS, Peet M (1991) Lithium maintenance: Effects of personality and attitude on health information acquisition and compliance. Br J Psychiatry, 158, 200–204. Heim M (1988) Effectiveness of bright light therapy in cyclothymic axis syndromes – a cross-over study in comparison with partial sleep deprivation. Psychiatr Neurol Med Psychol (Leipz), 40, 269–277. Jamison KR, Akiskal HS (1983) Medication compliance in patients with bipolar disorders. Psychiatr Clin North Am, 6, 175–192. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J (2000). A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med, 342, 1462–1470. Ketter TA, Calabrese JR (2002) Stabilization of mood from below versus above baseline in bipolar disorder: A new nomenclature. J Clin Psychiatry, 63, 146–151. Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES (1984) Interpersonal psychotherapy of depression. Basic Books, New York. Lam DH, Watkins ER, Hayward P, Bright JA, Wright K, Kerr N, Parr-Davis G, Sham P (2003). A Randomized Controlled Study of Cognitive Therapy for Relapse Prevention for Bipolar Affective Disorder. Outcome of the first year. Arch Gen Psychiatry, 60, 145–152. Leahy RL, Beck AT (1988) Cognitive therapy of depression and mania. In Depression and mania, Gorgotas A, Cancro R (eds), Elsevier, New York. Leverich GS, Altshuler LL, Frye MA, Suppes T, Keck PE Jr, McElroy SL, Denicoff KD, Obrocea G, Nolen WA, Kupka R, Walden J, Grunze H, Perez S, Luckenbaugh DA, Post RM (2003) Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. J Clin Psychiatry, 64, 506–515. Linden W (2000) Psychological treatments in cardiac rehabilitation: Review of rationales and outcomes. J Psychosom Res, 48, 443–454. Martínez-Arán A, Vieta E, Colom F, Benabarre A, Reinares M, Gastó C, Salamero M (2000). Cognitive dysfunctions in bipolar disorder: Evidence of neuropsychological disturbances. Psychother Psychosom, 69, 2–18. Miklowitz DJ, Goldstein MJ, Nuechterlein KH, Snyder KS, Mintz J (1988) Family factors and the course of bipolar affective disorder. Arch Gen Psychiatry, 45, 225–231. Miklowitz DJ, Simoneau TL, George EL, Richards JA, Kalbag A, Sachs-Ericsson N, Suddath R (2000). Family-focused treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy. Biol Psychiatry, 48, 582–592. Miklowitz DJ, Richards JA, George EL, Frank E, Suddath RL, Powell KB, Sacher JA (2003) Integrated family and individual therapy for bipolar disorder: Results of a treatment development study. J Clin Psychiatry, 64, 182–191. Morselli PL, Elgie R, GAMIAN-Europe (2003) GAMIAN-Europe/BEAM survey I – global analysis of a patient questionnaire circulated to 3450 members of 12 European advocacy groups operating in the field of mood disorders. Bipolar Disord, 5, 265–278. Olmsted MP, Daneman D, Rydall AC, Lawson ML, Rodin G (2002) The effects of psychoeducation on disturbed eating attitudes and behavior in young women with type 1 diabetes mellitus. Int J Eat Disord, 32, 230–239. Palmer A, Williams H (1995). CBT in a group format for bipolar affective disorder. Beh Cogn Psychother, 23, 153–168.

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Patelis-Siotis I, Young LT, Robb JC, Marriott M, Bieling PJ, Cox LC, Joffe RT (2001) Group cognitive behavioral therapy for bipolar disorder: A feasibility and effectiveness study. J Affect Disord, 65, 145–153. Peet M, Harvey NS (1991) Lithium maintenance: I. A standard education program for patients. Br J Psychiatry, 158, 197–200. Perry A, Tarrier N, Morris R, McCarthy E, Limb K (1999) Randomised controlled trial of efficacy of teaching patients with bipolar disorder to identify early symptoms of relapse and obtain treatment. BMJ, 318, 149–153. Rea MM, Tompson MC, Miklowitz DJ, Goldstein MJ, Hwang S, Mintz J (2003). Familyfocused treatment versus individual treatment for bipolar disorder: Results of a randomized clinical trial. J Consult Clin Psychol, 71, 482–492. Reinares M, Colom F, Martínez-Arán A, Benabarre A, Vieta E (2002) Therapeutic interventions focused on the family of bipolar patients. Psychother Psychosom, 71, 2–10. Reinares M, Vieta E, Colom F, Martínez-Arán A, Torrent C, Comes M, Goikolea JM, Benabarre A, Sánchez-Moreno (2004). Impact of a psychoeducational family intervention on caregivers of stabilized bipolar patients. Psychother Psychosom. 73, 312–319. Rucci P, Frank E, Kostelnik B, Fagiolini A, Mallinger AG, Swartz HA, Thase ME, Siegel L, Wilson D, Kupfer DJ (2002) Suicide attempts in patients with bipolar I disorder during acute and maintenance phases of intensive treatment with pharmacotherapy and adjunctive psychotherapy. Am J Psychiatry, 159, 1160–1164. Schilgen B, Tolle R (1980). Partial sleep deprivation as therapy for depression. Arch Gen Psychiatry, 37, 267–71. Scott J, Tacchi MJ (2002) A pilot study of concordance therapy for individuals with bipolar disorders who are non-adherent with lithium prophylaxis. Bipolar Disord, 4, 386–392. Scott J, Teasdale JD, Paykel ES, Johnson AL, Abbott R, Hayhurst H, Moore R, Garland A (2000) Effects of cognitive therapy on psychological symptoms and social functioning in residual depression. Br J Psychiatry, 177, 440–446. Scott J, Garland A, Moorhead S (2001) A pilot study of cognitive therapy in bipolar disorders. Psychol Med, 31, 459–467. Sharma V, Mazmanian DS, Persad E, Kueneman KM (1997) Treatment of Bipolar Depression: A Survey of Canadian Psychiatrists. Can J Psychiatry, 42, 298–302. Swartz HA, Frank E (2001) Psychotherapy for bipolar depression: A phase-specific treatment strategy? Bipolar Disord, 3, 11–22. Van Gent EM (2000) Follow-up study of 3 years group therapy with lithium treatment. Encephale, 26, 76–79. Vieta E, Colom F, Corbella B, Martinez-Aran A, Reinares M, Benabarre A, Gasto C (2001) Clinical correlates of psychiatric comorbidity in bipolar I patients. Bipolar Disord, 3, 253–258. Vieta E, Colom F, Martínez-Arán A (2002) Chronicity, milder forms, and cognitive impairment in bipolar disorder. In Bipolar Disorder WPA Series, Maj M, Akiskal HS, López-Ibor JJ, Sartorius N (eds), Evidence and experience in Psychiatry, volume 5. Wiley, Chichester, pp. 182–184. Ward E, King M, Lloyd M, Bower P, Sibbald B, Farrelly S, Gabbay M, Tarrier N, Addington-Hall J (2000) Randomised controlled trial of non-directive counselling, cognitive-behaviour therapy, and usual general practitioner care for patients with depression. I: Clinical effectiveness. BMJ, 321, 1383–1388. Weiss R, Griffin M, Greenfield S (2000) Group therapy for patients with bipolar disorder and substance dependence: Results of a pilot study. J Clin Psychiatry, 61, 361–367. Zaretsky AE, Segal ZV, Gemar M (1999) Cognitive therapy for bipolar depression: A pilot study. Can J Psychiatry, 44, 491–494.

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17 The Role of Treatment Setting in the Pharmacotherapy of Bipolar Disorder Jean-Michel Azorin Department of Psychiatry, Ste Marguerite Hospital, France

Due to the increasing evidence that the costs of psychiatric hospitalization constitute the major component of treatment costs for bipolar patients (Keck et al., 2000), it seems that nowadays third-party payers for psychiatric services have taken over from the civil rights upholders in challenging the justification for hospital treatment for such patients. As hospitalization appears to be inevitable in a vast majority of cases, just as pharmacotherapy certainly is, one is regrettably witnessing an increased tendency to reduce the hospital length of stay of those patients during their manic and depressive phases, which goes together with a dramatic reduction in hospital beds. The same trend toward managed care utilization as it was implemented in the US is now “threatening” European countries, one of the most refractory so far being France due to its public health maintenance organization system which provides inpatient as well as outpatient care, in accordance with its humanitarian tradition (since Pinel liberated the mentally ill from their chains). As French clinicians are, in this regard, at a crossroad between tradition and modernism, it may be interesting to try to look at what they are about to lose but also acquire in changing their utilization of treatment settings for bipolar patients. These issues are in some ways generic to other countries as well.

IMPLEMENTATION OF DRUG TREATMENT ACCORDING TO PHASE AND SEVERITY OF ILLNESS During manic and depressive phases of illness, hospitalization is often required for drug treatment. This is especially the case for severe, psychotic and suicidal patients. For those refusing hospitalization, involuntary commitment may be necessary. Limited insight into illness, danger to self or others, significant impairment of daily activities or uncontrollable behavior have to be considered for admission to “closed” units in the hospital. During the manic phase there is a need for a quiet Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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and structured environment in so far as a high level of stimulation may drive and perpetuate the episode and lead to increased use of medication and dosage. This may be the reason why seclusion rooms are sometimes used. In any case, such an environment has to be provided during the hospitalization; mild and moderate patients too may benefit from it, when their home environment is a source of marked stress and high expressed emotion. Open day hospital or outpatient treatment are alternating in milder or moderately severe cases. When choosing to treat manic and depressive patients in these settings, clinicians need to carefully assess the quality and availability of family and social support which may take on some of the responsibility of the hospital staff, keeping in mind that mild and moderate episodes may progress to more severe forms unexpectedly. The treatment setting can also influence the choice of drugs. The urge for rapid control of symptoms may have priority, especially in emergency rooms, leading to preferential use of intramuscular preparations, whereas in mood centers mood stabilizers tend to be preferentially prescribed as first line medications, even for acute episodes. Availability of drugs with mood stabilizing properties as intramuscular preparations may thereby facilitate and extend clinicians’ compliance with current guidelines (Goodwin and Jamison, 1990; Menninger, 1995; American Psychiatric Association, 2002).

PRETREATMENT EVALUATION AND MONITORING OF PHARMACOTHERAPY Prescribing a drug treatment, especially a mood stabilizer, in patients suffering from bipolar disorder, necessitates a careful pretreatment evaluation and further close monitoring. This is mainly due to the number of medical conditions contraindicating the use of mood stabilizers – above all lithium – likely to interfere with their use. Moreover the high frequency of side effects which can impinge on almost all body functions with this type of medication warrants a thorough assessment of baseline medical status. This is all the more true as non-adherence largely depends on the occurrence of side effects which has to be regularly monitored and which patients have to be informed of. Furthermore many of the available mood stabilizers necessitate blood levels monitoring. All the foregoing reasons explain why the pharmacotherapy of bipolar patients has to be conducted in a skilled medical environment. This is not the case for all settings, especially in some European countries where the therapeutic milieu, in either hospital or ambulatory centers, remains largely under the influence of psychodynamic practitioners. Such a milieu is typically associated with the tendency of bipolar disorder to be under-recognized and often misdiagnosed. It has been shown to be the case in France for both manic (Akiskal et al., 1998) and depressive (Hantouche et al., 1998) bipolar patients, however, the same

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phenomenon has been observed in the US too (Hirschfeld, Lewis and Vornik, 2003). These patients are frequently receiving neuroleptics or antidepressants that may exacerbate their illness course and contribute to render it chronic. In France one may find a host of such patients in psychiatric hospitals or day care centers with a diagnosis of “chronic psychotic” and a treatment based on neuroleptic depot preparations. This emphasizes the need for mood centers, especially in European countries, as well as the usefulness of information and continuing medical education for clinicians on bipolar disorder. In addition to pharmacotherapy and medical expertise, these centers provide education of patient and significant others and psychotherapy (especially group psychotherapy) as adjunctive treatments (Colom et al., 2003).

DRUG RESPONSE AND TREATMENT SETTING Can the treatment setting influence the response to pharmacotherapy? It has been long known that hospitalization was likely to affect a patient’s response to drugs. Inpatients were sometimes found to respond to drugs they have not responded to as outpatients (Kotin, Post and Goodwin, 1973). Enhanced treatment-adherence and influence of the therapeutic milieu have been evoked as explanations of this phenomenon. Controlled trials have demonstrated that monotherapy with a mood stabilizer could be effective in the short term; however, it seems that maintenance treatment may often require more “aggressive” pharmacotherapy with a combination of drugs. In one study conducted in acute mania (Pope, Mc Elroy and Keck, 1991), of the 20 patients randomly assigned to divalproex, 9 responded with at least 50% improvement at the end of the 21-day study period; however, after completion of the study when the investigators continued to follow the responders, they found that one patient discontinued divalproex due to side effects, 6 required the addition of antipsychotics or other mood stabilizers and only 2 continued with monotherapy. In fact, combination treatment has been shown to be far more common than monotherapy among ambulatory bipolar patients (Solomon etal., 1997). Nearly 50% were found to receive three or more psychotropic agents, whereas only 18% received monotherapy, according to a recent survey (Levine et al., 2000). One reason which could explain those prescription patterns is the fact that bipolar patients are prematurely discharged, before they achieve full remission. Some studies (Cooke et al., 1996; Keitner et al., 1996) have found residual mania in about 70% of cases and residual depression in about 60%, which represent high rates of clinical symptomatology that have been demonstrated to increase the risk of relapse and recurrence (Keller et al., 1992). In an NIMH study, both bipolar I and II patients spent nearly 50% of weeks – during an average of 13 years of naturalistic prospective follow-up – with some level of affective symptoms, mostly depressive in nature (Judd et al., 2002, 2003).

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This gap between drug response and illness recovery may represent a serious challenge to our conception of modern pharmacotherapy. Short hospital stays thereby compromise patient welfare.

FROM EFFICACY TO EFFICIENCY OF PHARMACOTHERAPY IN BIPOLAR ILLNESS One way to bridge this gap has been to emphasize the difference existing between the efficacy of a drug and its efficiency. The first concept refers to the pharmacological and symptomatic effect, whereas the second stresses its consequences for the healing and easing of illness (Azorin, Naudin and Kaladjian, 2002). It is the first we are assessing when we measure a drug response with a rating scale, but we are referring to the second when we are speaking of quality of life and recovery. This difference is not without consequences on how we are taking care of our patients, even when we are prescribing a drug. If we are restricting ourselves to the concept of efficacy, we just expect from a medication a mere and direct physiological change, whereas referring to that of efficiency allows us to expect from the patient that he will be able to use the changes induced by the drug as a means to achieve recovery, that is an indirect effect. One could speak thereby of the antimanic or antidepressant effect of a drug which sets free the coping strategies the patient can use to recover. Mania or depression is certainly an illness, but from a psychodynamic and/or arthropological viewpoint it has been also considered as a crisis in identity, that is temporary dissolution of a rigid, sclerotic identity, acquired through over-identification to social roles and value-fixation (Kraus, 1977). That means a particular way of being in relationship with oneself, the others and the world: in this context, depression, but also to some extent mania, conveys the meaning of a threat to identity, and giving the patient a sick role has been deemed giving him a substitutive and protective identity, especially during the hospitalization phase. In certain cases premature discharge could thereby mean anew a loss of identity and precipitate relapses. Offering patients a therapeutic milieu may be not just passively awaiting changes in rating scales using “magical” drugs, but trying, on the basis of these changes, to help them reconstitute a more flexible identity in an appropriate setting. Traditional representations of the role of hospitalization in the treatment of mental disorders which still prevail in some European countries have been changing during the last decade. Progresses in pharmacotherapy and technical interventions may partly explain those changes, but economic pressure and the necessity of cost savings are certainly the main determinants. Nevertheless, clinical experience suggests that bipolar patients characterized by their instability of mood may benefit from the highly structured setting offered by the psychiatric hospital. A mood episode is not only a phase in illness but also an identity crisis which necessitates a person-centered approach. The hospital

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represents a protected setting where the conflicts keeping this crisis going can be expressed and sometimes resolved (Goodwin and Jamison, 1990). We still do not know what the consequences of losing benefit from such settings could be in the long run, in spite of the progress in modern treatments. Some of these consequencies are, however, perceptible such as the “trans-institutionalization” phenomenon which has appeared in many countries, with an increasing number of bipolar patients found in prison populations (Goodwin and Jamison, 1990; London and Taylor, 1982). This is a grave problem facing Western psychiatry which, in its attempt to shorten acute psychiatric hospitalization for bipolar patients, is creating homelessness, with its resultant lack of family supervision, and the development of social marginalization of the mentally ill – and at worst leading to a criminal incarceration – instead of the more benign and humane psychiatric hospitalization when needed.

REFERENCES Akiskal HS, Hantouche EG, Bourgeois ML, Azorin JM, Sechter D, Allilaire JF, Lancrenon S, Fraud JP, Châtenet-Duchêne L. Gender, temperament, and the clinical picture in dysphoric mixed mania: Findings from a French national study (EPIMAN). J Affect Disord 1998, 50, 175–186. American Psychiatric Association. Guidelines for bipolar disorder. Practice guidelines. American Psychiatric Press. Washington DC. 2002. Azorin JM, Naudin J, Kaladjian A. Efficacité et efficience des psychotropes. Evol Psychiatr 2002, 67, 170–183. Colom F, Vieta E, Martinez-Aran A, Reinares M, Goikolea JM, Benabarre A, Torrent C, Comes M, Corbella B, Parramon G, Corominas J. A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry 2003, 60, 402–407. Cooke RG, Robb JC, Young LT, Joffe RT. Well-being and functioning in patients with bipolar disorder assessed using the MOS 20-item short form (SF-20). J Affect Disord 1996, 39, 93–97. Goodwin FK, Jamison KR, Manic-depressive illness. Oxford University Press, Oxford. 1990. Hantouche EG, Akiskal HS, Lancrenon S, Allilaire JF, Sechter D, Azorin JM, Bourgeois ML, Fraud JP, Châtenet-Duchêne L. Systematic clinical methodology for validating bipolar – II disorder: Data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord 1998, 50, 163–173. Hirschfeld RMA, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: How far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 Survey of individuals with bipolar disorder. J Clin Psychiatry 2003, 64, 161–174. Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, Solomon DA, Leon AC, Keller MB. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003, 60, 261–69. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, Keller MB. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002, 59, 530–37.

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Keck PE, Mc Elroy SL, Arnold LM, Dewan NA, Bennett JA. The costs of treatment of bipolar disorder. In: A. Marneros, J Angst (eds). Bipolar Disorders: 100 years after manic-depressive insanity. Kluwer Academic Publishers, Dordrecht. 2000, pp. 437–448. Keitner GI, Solomon DA, Ryan CE, Miller IW, Mallinger A, Kupfer DJ, Frank E. Prodromal and residual symptoms in bipolar I disorder. Compr Psychiatry 1996, 37, 362–367. Keller MB, Lavori PW, Kane JM, Gelenberg AJ, Rosenbaum JF, Walzer EA, Baker LA. Subsyndromal symptoms in bipolar patients. A comparison of standard and low serum levels of lithium. Arch Gen Psychiatry 1992, 49, 371–376. Kotin J, Post RM, Goodwin FK. Drug treatment of depressed patients referred for hospitalization. Am J Psychiatry 1973, 130, 1139–1141. Kraus A. Sozialverhalten und Psychose Manisch-Depressiver. Enke, Stuttgart. 1977. Levine J, Chengappa KNR, Brar JS, Gershon S, Yablonsky E, Stapf D, Kupfer DJ. Psychotropic drug prescription patterns among patients with bipolar I disorder. Bipolar Disord 2000, 2, 120–130. London WP, Taylor BM. Bipolar disorders in a forensic setting. Compr Psychiatry 1982, 23, 33–37. Menninger WW. Role of the psychiatric hospital in the treatment of mental illness. In: Kaplan HI, Sadock BJ (eds): Comprehensive textbook of psychiatry/VI, vol 2, Williams and Wilkins, Baltimore. 1995, pp. 2690–2696. Pope HG Jr, Mc Elroy SL, Keck PE Jr. Valproate in the treatment of acute mania: A placebo-controlled study. Arch Gen Psychiatry 1991, 48, 62–68. Solomon DA, Ryan CE, Keitner GI, Miller IW, Shea MT, Kazim A, Keller MA. A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder. J Clin Psychiatry 1997, 58, 95–99.

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18 Suicide Prevention Zoltán Rihmer National Institute for Psychiatry and Neurology, Budapest, Hungary

Suicide behavior and particularly committed suicide, which is the most serious complication of untreated major psychiatric illness, is one of the most tragic events in human life. Although suicide is very complex, multi-causal behavior, history of major mood disorders (particularly in the presence of previous suicide attempt) constitutes the most important risk factor. However, other familial-genetic, clinical and psychosocial factors can also play a relevant role in the development of suicidal process.

MOOD DISORDERS AND SUICIDE Psychological autopsy studies from several countries of the world consistently show that over 90% of consecutive suicide victims have one or more Axis I (mostly untreated) major psychiatric disorders at the time of their deaths, and major mood disorders (59–87%), schizophrenia/schizoaffective disorder (10–12%) and substanceuse disorders (10–15%) are the most common principal diagnoses. Dysthymic disorder, anxiety disorders, personality disorders or serious medical illness itself as the only diagnoses in suicide victims are quite rare, but they are commonly present as additional diagnoses (Cheng et al., 2000; Goodwin and Jamison, 1990; Hawton and van Heeringen, 2000; Rihmer, Belsö and Kiss, 2002). Reviewing 17 follow-up studies on committed suicide in patients with primary affective disorders, Guze and Robins (1970) found that about 15% of formerly hospitalized depressed patients would die by suicide. Goodwin and Jamison (1990) also concluded that 19% of depressed patients (mainly inpatients) died by suicide. In their metaanalysis of studies on suicide risk in psychiatric disorders, Harris and Barraclough (1997) analyzed separately the risk of suicide in unipolar major depression and in bipolar disorder. They found that the risk of suicide was about 20-fold for patients with index diagnosis of unipolar major depression, and the same figure for bipolar disorder was 15. However, these three studies (Goodwin and Jamison, 1990; Guze and Robins 1970; Harris and Barraclough, 1997) cannot provide a precise Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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estimation of separate suicide risk in unipolar and bipolar disorder, that is they overestimate the risk for unipolar depression and underestimate it for bipolar disorders. The main sources of these are that the index diagnosis frequently changes during the follow-up from unipolar depression to bipolar disorder (Akiskal et al., 1995; Goldberg, Harrow and Whiteside, 2001), and in the studies reviewed by the mentioned authors the diagnostic category of bipolar II depression (depression with hypomania but not with mania) which is the most common form of bipolar disorders has not been considered separately. It is very likely that the majority of bipolar II patients in these studies were included in the unipolar major depressive subgroup. In addition, recent results showed that about 50% of unipolar depressions were found to be bipolar depressions after careful and skillful probing for past hypomania or mania as well as focusing on not only mood but also overactivity (Benazzi and Akiskal, 2003a; Ghaemi, Boima and Goodwin, 2000).

SUICIDE RISK IN BIPOLAR DISORDERS Since specific diagnostic subtypes of major mood disorders (unipolar, bipolar I and bipolar II) show several differences from both the clinical and research perspective (Akiskal, 2002; Akiskal et al., 1995; Goodwin and Jamison, 1990; Tondo et al., 1999), it is logical to assume that each subgroups might have its own different suicide risk. Considering only the six studies, in which unipolar, bipolar I and bipolar II patients were analyzed separately, and summarizing the data (Rihmer and Kiss, 2002; Table 18.1), it can be seen that the rate of previous suicide attempts is the lowest in unipolar major depression (12%) and the rate of prior suicidal behavior in bipolar patients (types I and II combined) is significantly higher (19%) than that of unipolars. The lifetime rates of suicide attempts in bipolar I and in bipolar II patients (17 and 24% respectively) are also significantly higher than the same figure for unipolar patients. Contrasting only bipolar I and bipolar II Table 18.1: Lifetime prevalence of suicide attempt(s) in unipolar major depression, bipolar I and bipolar II disorder according to six independent studies, reviewed by Rihmer and Kiss (2002) Lifetime prevalence of suicide attempts (%)

Diagnostic subtype Unipolar major depression (n = 1214) Bipolar I disorder (n = 606) Bipolar II disorder (n = 253) Bipolar I + II vs unipolar Bipolar I vs unipolar Bipolar II vs unipolar Bipolar II vs bipolar I

chi-square = 21.32 chi-square = 9.41 chi-square = 26.59 chi-square = 5,85

12 17 24 df = 1 df = 1 df = 1 df = 1

p < 0.001 p < 0.01 p < 0.001 p < 0.02

Range (%) 9–19 10–18 18–56

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subgroups, the history of suicide attempts is significantly higher in bipolar II than in bipolar I patients. Analyzing the ECA database, Judd and Akiskal (2003) recently also reported that the rate of prior suicide attempt(s) was substantially higher in bipolar II (34%) than in bipolar I (24%) patients, while the same figure for unipolar major depression was 16% (Chen and Dilsaver, 1996). Analyzing the clinical characteristics of 230 inpatients with recurrent major depression, Bulik et al. (1990) found that bipolar II diagnosis was significantly more frequent among the 67 patients who attempted suicide (19%) than in the 163 patients who did not attempt suicide (9%). Dunner, Gershon and Goodwin (1976) reported that 3% of the 73 unipolar, 6% of the 68 bipolar I and 18% of the 22 bipolar II patients died by suicide during their 1–9-year follow-up study. In contrast to the above-mentioned studies, Angst et al. (2002) found that during the 34–38-year follow-up study of hospitalized patients with major mood disorders (unipolar, n = 186, bipolar I and II combined, n = 220), a higher proportion of unipolar patients died by suicide than that of bipolar patients (14% vs 8%). Considering all the above, the findings strongly suggest that bipolar II patients might be overrepresented among suicide victims. The two published reports where the prevalence of bipolar II, bipolar I and unipolar depression have been analyzed separately among the suicide victims shows that among the 125 consecutive suicide victims with primary major depression at the time of suicide, 44% had bipolar II depression, 2% had bipolar I depression and 54% had first episode or recurrent unipolar depression (Rihmer et al., 1990; Rihmer, Rutz and Pihlgren, 1995; Table 18.2). Because the lifetime prevalence rates of DSM-III/IV bipolar II illness in the population are relatively low compared with unipolar major depression (2–5% and 15–17% respectively) (Angst, 1998; Szádóczky et al., 1998), these results suggest that bipolar II disorder imparts a particularly high risk of committed suicide among the three different subgroups of major mood disorders. Analyzing the specific diagnostic subtypes of 69 consecutive (nonviolent) suicide attempters with current DSM-IV major depression in Budapest, Hungary, it has been found that 45 (65%) had unipolar major depression, 19 (28%) had bipolar II depression and 5 (7%) had bipolar I depression (Balázs et al., 2003). Considering the fact that the lifetime prevalence rates of DSM-III-R unipolar major depression, Table 18.2: Diagnostic distribution of bipolar II, bipolar I and unipolar major depression among consecutive suicide victims with major depressive episode at the time of suicide Bipolar II

Bipolar I

Unipolar

Source

Rate

%

Rate

%

Rihmer et al. 1990 Rihmer, Rutz and Pihlgren, 1995 Total

46/100 9/25 55/125

46 36 44

1/100 2/25 3/125

1 8 2

Rate

%

53/100 14/25 67/125

53 56 54

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bipolar II and bipolar I disorder in the general population of Hungary are 15.1%, 2.0% and 1.5% respectively (Szádóczky etal., 1998), this study suggests that bipolar II patients are relatively overrepresented not only among depressed suicide victims (Rihmer et al., 1990; Rihmer, Rutz and Pihlgren, 1995) but also among depressed suicide attempters. Bipolar patients with comorbid anxiety, personality and substance-use disorders are also at an increased risk of attempted or completed suicide (Chen and Dilsaver, 1996; Balázs etal., 2003; Isometsä etal., 1994; Tondo etal., 1999; Vieta etal., 1997). One of the major sources of the highest suicide risk in bipolar II patients may be the very high rate of comorbid anxiety disorders (Akiskal, 1981; Rihmer etal., 2001), substance-use disorders (Akiskal, 1981; Vieta et al., 1997; Brieger, 2000) and depressive mixed states, frequently called “agitated depression” (Benazzi and Akiskal, 2003b; Koukopoulos and Koukopoulos, 1999). The importance of depressive mixed states in predicting suicide is supported by the recent study of Maser et al. (2002). In a long-term naturalistic follow-up study of moderately to severely ill affective disorder patients (80% of them were in-patients at the index episode) they found that 39% of those who later committed suicide (n = 36) as well as 20% of the nonsuicidal comparison subjects (n = 373) were in mixed or cycling depressive episode at intake. Among bipolar patients, however, it is not the depressive episode that is the only risk period for suicide. In contrast to classical (i.e. euphoric) mania, where suicidal tendency is extremely rare, suicidal thoughts and attempts are relatively common in dysphoric (mixed) mania or hypomania (Isometsä etal., 1994; Strakowski et al., 1996; Tondo et al., 1999). Family history of suicide is a significant risk factor for suicide behavior, particularly in persons with bipolar disorder. Bipolar patients with positive family history of suicide in first-degree relatives were found to be significantly more likely to attempt suicide (38%) than those without (14%) (Roy, 1983), and it has been reported that 0.9% of unipolar depressives, 1.8% of bipolar I and 2.9% of bipolar II patients had a family history of committed suicide (Dunner, Gershon and Goodwin, 1976). Another study has found a 6.5-fold higher rate of suicide committed among the first-degree relatives of 129 bipolar II (3.9%) than that of the 188 bipolar I (0.6%) patients (Tondo et al., 1998). Recent adverse life events, as well as permanent psychosocial stressors, have been shown to be also a risk factor for attempted or completed suicide, particularly in the frame of major depressive, mixed depressive or dysphoric manic episodes (Cheng et al., 2000; Hawton and van Heeringen 2000). However, it should be noted that these adverse life events are frequently the results of the patient’s own (socially disinhibited) behavior during their manic or hypomanic episodes. In spite of the fact that the lifetime prevalence of major mood disorders (unipolar and bipolar forms combined) in the population is about 20% (Angst, 1998; Szádóczky et al., 1998), they remain highly under-referred, underdiagnosed and

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Table 18.3: Clinically significant major suicide risk factors in bipolar disorders Diagnostic subtype Bipolar II > bipolar I Previous suicide attempt Violent > nonviolent High lethality > low lethality Clinical features Severe depression, hopelessness, insomnia,guilt Mixed depressive episode (e.g. agitation) Comorbid anxiety, substance-use and personality disorder Dysphoric (mixed) mania or hypomania Family history of suicide in first-degree relatives Psychosocial stressors Lacking adequate acute and long-term treatment Noncompliance with the treatment

undertreated, and it is particularly true for bipolar II patients (Balázs et al., 2003; Isometsä et al., 1994; Goldberg, Harrow and Whiteside, 2001; Rihmer et al., 1990; Rihmer, Belsö and Kiss, 2002). On the other hand, despite the fact that up to 66% of suicide victims contact different levels of health care 4 weeks before suicide (Hawton and van Heeringen 2000; Rihmer, Belsö and Kiss, 2002), the rate of adequate pharmacotherapy among depressed suicide victims is disturbingly low (Hawton and van Heeringen 2000; Isacsson, 2000; Rihmer et al., 1990; Rihmer, Belsö and Kiss, 2002). Since successful acute and long-term pharmacotherapy of mood disorders relieves not only the clinical symptoms but parallel with this also decreases or vanishes suicidality, appropriate acute and long-term treatment of mood disorders can be declared as a key issue in suicide prevention (Isacsson, 2000; Rihmer, Belsö and Kiss, 2002; Tondo and Baldessarini 2000; Baldessarini, Tondo and Hennen, 2003). Therefore, lacking treatment in patients with major mood (particularly bipolar) disorder as well as noncompliance with the treatment can also be considered as major suicide risk factors. Table 18.3 shows the clinically most important suicide risk factors in bipolar disorders.

SUICIDE PREVENTION IN BIPOLAR DISORDERS Since suicide is a multicausal human behavior with many biological, psychological and cultural components, its prevention should also be complex, even in the case of bipolar disorder which is the “most biological” illness in the field of psychiatry and which requires long-term pharmacotherapy in the majority of the cases. Since bipolar disorders usually show a peak onset between 15 and 25 years of age, but there is 8–10 years of delay in correct diagnosis (Akiskal, 2002; Ghaemi, Boima

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Table 18.4: Suicide prevention strategies in bipolar disorders: the role of health care I.

Elimination of acute suicide danger (emergency hospitalization, sedation, anxiolysis, crisis-intervention) II. Improving the diagnosis and treatment of bipolar disorder with particular regard to the soft clinical manifestations 1. Education of health care workers, patients and relatives 2. Adequate acute and long-term treatment/aftercare (pharmacotherapy, non-pharmacological interventions such as psychoeducation, psychotherapy, cognitive therapy, family counselling/family therapy, etc.) III. Improving the patients’ compliance (psychoeducation, psychotherapy, cognitive therapy, etc.) IV. Reducing the stigma against bipolar disorders via media

and Goodwin, 2000; Goodwin and Jamison, 1990; Szádóczky et al., 1998), early detection of bipolarity, the nature of the disorder, including the soft manifestations as well, is the first step in suicide prevention. Misdiagnosis of bipolar depression as unipolar depression results in treatment with antidepressants alone, and this can have negative effects on the course of the illness, because of inducing mixed depressive episodes, hypomanic or manic switches, rapid cycling and therefore increasing the chance of suicidal behavior (Benazzi, 2003; Benazzi and Akiskal, 2003b; Ghaemi, Boima and Goodwin, 2000; Henry et al., 2001; Koukopoulos et al., 1983). The role of health care in the suicide prevention of bipolar patients is summarized in Table 18.4. As suicide behavior in bipolar patients occur mostly during pure or mixed depressive episodes and less frequently in the frame of dysphoric (mixed) mania, but practically never during euthymia (i.e. suicide in bipolar disorders is state-dependent) (Isometsä et al., 1994; Simpson and Jamison, 1999; Tondo et al., 1999), it is logical to assume that effective acute and long-term treatment has a strong protection against suicide and probably against other complications (secondary substance-abuse disorders, marital instability, loss of job, cardiovascular mortality, etc.).

THE ROLE OF PSYCHOPHARMACONS IN SUICIDE PREVENTION OF BIPOLAR PATIENTS While successful acute pharmacotherapy of depressive or mixed episodes can only prevent the risk of suicide connected with a given episode, it is adequate prophylactic therapy that can provide long-term results in patients with bipolar illness.

LITHIUM The efficacy of lithium in the treatment of manic states and in prevention of recurrences of bipolar patients is well documented (Goodwin and Jamison, 1990;

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Goodwin, 1999; Maj, Tortorella and Bartoli, 2000; Bowden, 2002), and recent data indicate that combination of lithium (and other mood-stabilizers) with antidepressants reduces the chance of hypomanic or manic switching when bipolar depression is treated with antidepressants (Henry et al., 2001). However, about 50% of bipolar patients do not show satisfactory prophylactic response to lithium; positive family history of bipolar illness, early onset, mania–depression-interval type of course predicts a good prophylactic response, while higher frequency of episodes, depression– mania-interval type of course and comorbid substance-use disorders indicate poor response (Bowden, 2002; Goodwin and Jamison, 1990; Goodwin, 1999; Maj, Tortorella and Bartoli, 2000). In a 34–38-year-long naturalistic follow-up study including 220 formerly hospitalized bipolar I and bipolar II patients, Angst et al. (2002) found that patients who received long-term pharmacotherapy (lithium, neuroleptics, antidepressants) tended to live longer and to have significantly (2.5-fold) lower suicide rate (13.1% vs 5.2%) than untreated bipolars. Interestingly, they also found significantly lower rates from all natural deaths among treated vs untreated bipolars. In a large-scale, retrospective, “real world” observational study on more than 20 000 bipolar I or bipolar II patients (where milder or nonsuicidal cases were probably overrepresented among patients who had never been treated with any mood stabilizer), Goodwin et al. (2003) have found a 42% reduction in suicide deaths among patients taking lithium compared to those who were not treated with any mood stabilizers. In a recent, comprehensive review of 34 studies (involving 42 groups with lithium maintenance and 25 groups without lithium) including more than 16 000 unipolar and bipolar patients, Baldessarini, Tondo and Hennen (2003) reported a 21-fold risk reduction for attempted and completed suicides either in unipolar or in bipolar patients with long-term lithium treatment. In the total sample, the risk reduction was somewhat higher for suicide attempts than for completed suicides (93% vs 82%). For all suicide acts, risk reduction for bipolar I, bipolar II and unipolar depressive patients ranked 67%, 82% and 100%, respectively. The authors also concluded that the robust reduction of suicidal behavior with lithium maintenance in bipolar and unipolar patients to overall levels was close to general population rates. This marked anti-suicidal potential of lithium seems to be more than the simple result of its prophylactic effect, as it has been demonstrated that during the long-term lithium prophylaxis of 167 recurrent affective disorder patients with at least one prior suicide attempt, a significant reduction in the number of suicide attempts was found not only in the excellent responders (93%), but also in moderate responders (83%) and in poor responders (49%) (Ahrens and Müller-Oerlinghausen, 2001). The clinical importance of this finding is that in the case of lithium nonresponse, when the patient has one or more suicide risk factor, instead of switching lithium to another mood stabilizer, the clinician should retain lithium (even on a lower dose) and combine it with another mood stabilizer.

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ANTIEPILEPTICS The place of antiepileptics (valproate, carbamazepine, lamotrigine) in the acute and long-term treatment of bipolar disorders are well established. Predictors of better response to anticonvulsants than to lithium are mixed episodes, rapid cycling, comorbid substance-use disorders and previous lithium nonresponse (Bowden, 2002; Goodwin and Jamison, 1990; Goodwin, 1999; Maj, Tortorella and Bartoli, 2000). Unfortunately, very few data are available on the antisuicide effects of anticonvulsants in bipolar disorder. In a randomized, open-label, perspective, 2.5-year follow-up study Thies-Flechtner et al. (1996) investigated the number of suicide events in 175 bipolar, 110 schizoaffective and 93 recurrent depressive patients. The patients were randomly assigned to lithium, carbamazepine or amitriptyline. There were 14 serious suicide events (9 completed suicides and 5 serious attempts) during the study and 7 out of the 14 events (6 suicides and 1 attempt) were among the bipolar patients. Most of the 14 suicide acts happened in the carbamazepine group (4 suicides and 5 attempts), and none of the 14 suicidal patients were taking lithium. These results also indicate that lithium has a strong antisuicidal effect which markedly exceeds its prophylactic efficacy. This effect may be related to the well-known antiaggressive and serotonin-agonistic activity of lithium (Ahrens and Müller-Oerlinghausen, 2001; Goodwin and Jamison, 1990). In a population-based retrospective cohort study on more than 20 000 patients with bipolar I or bipolar II disorder, Goodwin et al. (2003) compared the risk of suicide and suicide attempts during lithium treatment with that during divalproex or carbamazepine treatment. There was no exposure to lithium, divalproex or carbamazepine during 45% of all person-years of the follow-up (mean: 2.9 years). After adjustment for age, sex, comorbid disorders and concommittant use of other psychotropics, the authors found that the risk of suicide deaths and suicide attempts resulting in hospitalization were 2.7 times and 1.8 times higher during treatment with divalproex and 1.5 times and 2.9 times higher during treatment with carbamazepine than during treatment with lithium. These results are in good agreement with the findings of Thies-Fletchner et al. (1996), who reported that among patients treated for bipolar disorders the risk of suicidal behavior was lower during lithium treatment than during treatment with carbamazepine. On the other hand, however, in a retrospective chart review study of 140 outpatients with bipolar disorders treated continuously for a minimum of 6 months during a 23-year period of private practice, Yerevanian, Koek and Mintz (2003) found a more than two-fold reduction in nonlethal suicidal behavior, compared with no treatment with mood stabilizers (lithium, valproate or carbamazepine). The frequency of nonlethal suicidal behavior was not different during treatment with lithium, compared with valproate or carbamazepine. It is also important to note that only one completed suicide (during a period off of lithium) occurred in this sample.

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OTHER PSYCHOPHARMACONS The role of typical and atypical antipsychotics in the treatment of mania, mixed states and psychotic depression is well considered (Bowden, 2002; Goodwin and Jamison, 1990; Maj, Tortorella and Bartoli, 2000). Preliminary results suggest that some atypical antipsychotics (olanzapine, risperidone, clozapine) might have a mood-stabilizing effect (Keck and McElroy, 2003), but their putative specific anti-suicidal effects need further studies. Antidepressants have very limited value in the long-term treatment of bipolar disorders because of their mood-destabilizing effects (Benazzi, 2003; Bowden 2002; Maj, Tortorella and Bartoli, 2000). However, rates of hypomanic or manic switches during treatment with SSRIs are much lower than with TCAs, and mood stabilizers further reduce the risk of the mood switch (Bowden, 2002; Henry et al., 2001).

THE ROLE OF PSYCHOSOCIAL INTERVENTIONS IN SUICIDE PREVENTION OF BIPOLAR PATIENTS In the last decade more and more effective psychosocial interventions in the field of bipolar disorders were developed primarily for patients who show insufficient response to acute and long-term pharmacotherapy, who cannot tolerate drugs or who are noncompliant with the treatment (Bauer, 2002). The main targets of these interventions are: preventing medication noncompliance with psychoeducation or with cognitive-behavioral therapy, lifestyle modification, teaching patients and relatives to identify early symptoms of relapse and obtain treatment as early as possible, and modification of family and other interpersonal conflicts (Bauer, 2002; Colom and Vieta, 2002; Lam et al., 2003; Fava et al., 2001). These psychosocial techniques specifically designed for relapse/recurrence prevention in bipolar patients are effective either alone, or mostly in conjunction with mood stabilizers, and they are discussed in detail elsewhere (Bauer, 2002; Colom and Vieta, 2002; Miklowitz, Chapter 15 in this book). These psychosocial interventions, while reducing relapse/recurrence may indirectly reduce the risk of suicide. However, there is only one published study concerning the effect on suicidality of intensive psychosocial treatment that specifically targeted suicidality in bipolar disorder. Rucci et al. (2002) investigated the lifetime rates of suicide attempts among 175 bipolar I patients during a 2-year period of intensive pharmacotherapy (lithium, valproate, carmabazepine), and one of two adjunctive psychosocial interventions (psychotherapy specific to bipolar disorder or nonspecific intensive clinical management). They found that the patients experienced threefold reduction in the rate of suicide attempts during the acute treatment phase and a 18-fold reduction during maintenance. There was no significant difference regarding suicide attempts between the two subgroups with different psychosocial interventions.

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However, the interaction between pharmacotherapy and psychosocial interventions is quite complex. It has been reported that successful episode-preventive medication with mood stabilizers in bipolar patients counteracted dysfunctional cognitions (including lowered self-esteem), and adjunctive cognitive therapy could help to optimize the long-term course of bipolar illness (Wolf and MüllerOerlinghausen, 2002). We are, of course, unable to prevent all suicides. However, our present pharmacological and psychosocial intentions are effective enough to minimize the chance of suicide in patients with bipolar disorder that represents the highest risk of self-inflicted death.

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Bowden CL (2002) Pharmacological treatment of bipolar disorder: A review. In Bipolar disorder, Maj M, Akiskal HS, Lopez-Ibor JJ, Sartorius N (eds), John Wiley & Sons, Chichester, pp. 191–221. Bulik CM, Carpenter L, Kupfer SJ, Frank E (1990) Features associated with suicide attempts in recurrent major depression. Journal of Affective Disorders, 18, 29–37. Chen YW, Dilsaver SC (1996) Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorders relative to subjects with other axis I disorders. Biological Psychiatry, 3, 896–899. Cheng ATA, Chen THH, Chen CC, Jenkies R (2000) Psychological and psychiatric risk factors for suicide. Case-control psychological autopsy study. British Journal of Psychiatry, 177, 360–365. Colom F, Vieta E (2002) Treatment adherence in bipolar patients. Clinical Approaches in Bipolar Disorders, 1, 49–56. Dunner DL, Gershon ES, Goodwin FK (1976) Heritable factors in the severity of affective illness. Biological Psychiatry, 11, 31–42. Fava GA, Bartolucci G, Rafanelli C, Mangelli L (2001) Cognitive-behavioral management of patients with bipolar disorder who relapsed while on lithium prophylaxis. Journal of Clinical Psychiatry, 62, 556–559. Ghaemi SN, Boima EE, Goodwin FK (2000) Diagnosing bipolar disorder and the effect of antidepressants: A naturalistic study. Journal of Clinical Psychiatry, 61, 804–808. Goldberg JF, Harrow M, Whiteside JE (2001) Risk for bipolar illness in patients initially hospitalized for unipolar depression. American Journal of Psychiatry, 158, 1265–1270. Goodwin FK (1999) Anticonvulsant therapy and suicide risk in affective disorders. Journal of Clinical Psychiatry, 60 (Suppl. 2), 89–93. Goodwin FK, Jamison KR (1990) Manic-Depressive Illness. Oxford University Press, New York. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee Y, Revicki D (2003) Suicide risk in bipolar disorder during treatment with lithium and divalproex. Journal of American Medical Association, 290, 1467–1473. Guze SB, Robins E. (1970). Sucide and primary affective disorders. British Journal of Psychiatry, 117, 437–438. Harris EC, Barraclough B (1997) Suicide as an outcome for mental disorders. British Journal of Psychiatry, 170, 205–228. Hawton H, van Heeringen C (eds) (2000). International Handbook of Sucide and Attempted Suicide. John Wiley & Sons, Chichester. Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M (2001) Antidepressant-induced mania in bipolar patients: Identification of risk factors. Journal of Clinical Psychiatry, 62, 249–255. Isacsson G (2000) Suicide prevention — a medical breakthrough? Acta Psychiatrica Scandinavica, 102, 113–117. Isometsä ET, Henriksson MM, Aro HM, Lönnqvist JK (1994) Suicide in bipolar disorder in Finland. American Journal of Psychiatry, 151, 1020–1024. Judd LL, Akiskal HS (2003) The prevalence and disability of bipolar spectrum disorders in the US population: Re-analysis of the ECA database taking into account subtreshold cases. Journal of Affective Disorders, 73, 123–131. Keck PE Jr, McElroy S (2003) Redefining mood stabilization. Journal of Affective Disorders, 73, 163–169. Koukopoulos A, Koukopoulos A (1999) Agitated depressions as a mixed state and the problem of melancholia. Psychiatric Clinics of North America, 22, 547–563.

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Koukopoulos A, Caliari B, Tundo A, Floris G, Reginaldi D, Tondo L (1983) Rapid cyclers, temperament and antidepressants. Comprehensive Psychiatry, 24, 249–258. Lam DH, Watkins ER, Hayward P, Bright J, Wright K, Kerr N, Parr-Davis G, Sham P (2003) A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder. Archives of General Psychiatry, 60, 145–152. Maj M, Tortorella A, Bartoli L (2000) Mood stabilizers in bipolar disorder. In Bipolar disorders. 100 years after manic depressive insanity, Marneros A, Angst J (eds), Kluwer Academic Publishers, Dordrecht, pp. 351–372. Maser JD, Akiskal HS, Schettler P, Scheftner W, Mueller T, Andicott J, Solomon D, Clayton P (2002) Can temperament idedentify affectively ill patients who engage in lethal or nonlethal suicidal behavior? A 14-year prospective study. Suicide and Life-Threatening Behavior, 32, 10–32. Rihmer Z, Kiss K (2002) Bipolar disorders and suicide risk. Clinical Approaches in Bipolar Disorders, 1, 15–21. Rihmer Z, Rutz W, Pihlgren H (1995) Depression and suicide on Gotland. An intensive study of all suicides before and after a depression-training programme for general practitioners. Journal of Affective Disorders, 35, 147–152. Rihmer Z, Belsö N, Kiss K (2002) Strategies for suicide prevention. Current Opinion in Psychiatry, 15, 83–87. Rihmer Z, Barsi J, Arató M, Demeter E (1990) Suicide in subtypes of primary major depression. Journal of Affective Disorders, 18, 221–225. Rihmer Z, Szádóczky E, Füredi J, Kiss K, Papp Zs (2001) Anxiety disorders comorbidity in bipolar I, bipolar II and unipolar major depression: Results from a population-based study in Hungary. Journal of Affective Disorders, 67, 175–179. Roy A (1983) Family history of suicide. Archives of General Psychiatry, 40, 971–974. Rucci P, Frank E, Kostelnik B, Fagiolini A, Mallinger AG, Swartz HA, Thase ME, Siegel L, Wilson D, Kupfer DJ (2002) Suicide attempts in patients with bipolar I disorder during acute and maintenance phases of intensive treatment with pharmacotherapy and adjunctive psychotherapy. American Journal of Psychiatry, 159, 1160–1164. Simpson SG, Jamison KR (1999) The risk of suicide in patients with bipolar disorders. Journal of Clinical Psychiatry, 60 (Suppl. 2), 53–56. Strakowski SM, McElroy SL, Keck PE Jr, West SA (1996) Suicidality among patients with mixed and manic bipolar disorder. American Journal of Psychiatry, 153, 674–676. Szádóczky E, Papp Zs, Vitrai J, Rihmer Z, Füredi J (1998) The prevalence of major depressive and bipolar disorders in Hungary. Journal of Affective Disorders, 50, 153–162. Thies-Flechtner K, Müller-Oerlinghausen B, Seibert W, Walther A, Greil W (1996) Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Pharmacopsychiatry, 29, 103–107. Tondo L, Baldessarini, RJ. (2000) Reduced suicide risk during lithium maintenance treatment. Journal of clinical Psychiatry, 61 (Suppl. 9), 97–104. Tondo L, Baldessarini RJ, Hennen J, Floris G (1998) Lithium maintenance treatment of depression and mania in bipolar I and bipolar II disorders. American Journal of Psychiatry, 155, 638–645. Tondo L, Baldessarini RJ, Hennen J, Minnai GP, Salis P, Scamonatti L, Masisa M, Ghiani C, Mannu P (1999) Suicide attempts in major affective disorder patients with comorbid substance use disorders. Journal of Clinical Psychiatry, 60 (Suppl. 2), 63–69.

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Vieta E, Benabarre A, Colom F, Gastó C, Nieto E, Otero A (1997) Suicidal behavior in bipolar I and bipolar II disorder. Journal of Nervous and Mental Diseases, 185, 407–409. Yerevanian BI, Koek RJ, Mintz J (2003) Lithium, anticonvulsants and suicidal behavior in bipolar disorder. Journal of Affective Disorders, 73, 223–228. Wolf T, Müller-Oerlinghausen B (2002) The influence of successful prophylactic drug treatment on cognitive dysfunction in bipolar disorders. Bipolar Disorders, 4, 263–270.

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CHAPTER

19 Principles of Caring for Bipolar Patients Hagop S. Akiskal 1 and Kareen K. Akiskal 2 International Mood Center, University of California at San Diego, USA 2 International Mood Center, San Diego, USA and French Depressive and Manic-Depressive Association, Rennes, France

Il faut aimer les alienés pour être digne et capable de les server. (The psychiatrist must have special love for the severely mentally ill, in order to deserve and be capable of serving them.) Esquirol (1845)

INTRODUCTION This final chapter of the book considers aspects of bipolar illness that have to do with its practical long-term clinical management on a day-to-day basis. In other words, we will cover what is generally considered the art of how to care for these patients. This art which obviously has to take into consideration the existing clinical science on bipolar disorder (Bauer et al., 2001; Otto, Reilly-Harrington and Sachs, 2003; Colom et al., 2003; Lam et al., 2003), nonetheless derives largely from the authors’ intimate hands-on experience with patients and their families. It is based on the clinical experience of the first author (HSA), who has directed mood and/or bipolar clinics since 1973, as well as the patient advocacy experience of the second author (KKA), who responded to various crisis telephone inquiries from families and patients – more often the former. This dual experience of both authors spans more than the illness itself in that it involves, among others, familial, social, educational, financial and legal aspects. The principles we enunciate herein are not meant to be an exhaustive discussion of these issues but instead focus on the main areas that need to be taken into consideration for optimal outcome. Although formal “manualized” therapeutic programs for bipolar disorder exist, they derive from specific theoretical perspectives such as cognitive-behavior therapy and circadian rhythms, or their application in psycho-education. These are

Bipolar Psychopharmacotherapy: Caring for the Patient Edited by Hagop S. Akiskal and Mauricio Tohen # 2006 John Wiley & Sons, Ltd ISBN: 0-470-85607-6

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valuable contributions summarized in Chapters 15 and 16 in this book, but are limited to specific areas of dysfunction in bipolar illness. In this chapter, instead of applying particular theoretical perspectives in the treatment of bipolar disorder, we integrate therapeutic principles that we have learned from caring for bipolar patients and their families.

THE MAJOR PLAYERS IN BIPOLAR DISORDER THE PATIENT The patient is not always aware of the illness. Although the depressive phase causes a great deal of suffering, both patient and family may initially ascribe it to misfortune, trauma or love loss. Later they may invoke moral explanations such as “laziness.” But ultimately when depression fully declares itself, recurring on a cyclical basis, especially in the face of observable dysfunction and disability and suicidal preoccupation or attempts, it becomes inescapable that both patient and significant others will understand that these manifestations constitute signs of a veritable illness. Patients and families are more likely to accept help for the depressive phase. The manic phase with its poor judgment and lack of insight robs the patient of the capacity to understand the pathological nature of excited behavior. Significant others, too, may initially misunderstand manic signs and symptoms as indicative of misbehavior due to youthfulness, hardheadedness or erotic excesses. Ultimately parents recognize the excited phases to be the real illness leading to grave dysfunction, but not so with the patients who continue to insist that they are feeling fit and well and that there is nothing wrong with their behavior, and they wish to behave as they please. One of the tragedies of bipolar illness is that considerable destruction of the social fabric of the patient’s life does occur as a result of numerous manic episodes (Krober, 1993) before they can be brought to accept treatment; some never do so. Overall, the foregoing considerations suggest that if and when patients accept treatment it is likely to be for the depressive phase, that is, with anti-depressants which, in monotherapy, have the distinct disadvantage of switching the patient into the excited phase – or at least not to protect against it – thereby leading to increased cycling (Kukopulos et al., 1980) or mixed states (Akiskal and Mallya, 1987). Patients’ motivation to continue with mood stabilizers, often given during crises against their will, is rarely adhered to beyond a short period. Because they do not feel ill in their excited phase, they can find a myriad of banal reasons to stop their mood stabilizing medication. Unfortunately there is a litany of side effects that they can invoke to stop their medication. The main conclusion to be drawn from the above statement is that the cognitive dysfunction of bipolar illness (Martinez-Aran et al., 2004) – which unfortunately

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is not even in the criteria of DSM IV for bipolar disorder – represents the most handicapping aspect of the illness. Such “illness agnosia” is the basis for the failure to understand the need for treatment, and is often associated with personal and social “deficits” (Akiskal et al., 2003b).

THE FAMILY The cyclical recurrence of depressive and excited episodes is highly disruptive to family life. In addition, patients may use highly abusive language toward their loved ones. Relationships with peers, especially of a romantic nature, are often strained, tempestuous and on a disaster path. Academic and professional promises are not fulfilled. The family is extremely frustrated and confused. Although they wish the best treatment for their bipolar member of the family, in the beginning years of the illness they may deny its presence because it is traumatic for the family to accept that yet another member of the family has come down with the illness. They hope and wish it will go away. Even if hospitalization is required, they may in the beginning opt against it to avert the stigma implied in psychiatric hospitalization for the affected member, as well as for the family at large. Eventually the consequences of bipolar disorder become unbearable for the family – and dire for the patient. But the patient is typically unwilling to accept treatments in which they see unacceptable and artificial “restraints.” Such attitudes inaugurate the long phase of battles with family and significant others regarding the need for hospitalization and/or regular outpatient visits. These may eventually translate into legal conflicts between patients and the family. Not infrequently, these conflicts involve financial battles over inheritance, trust funds and social security benefits. Under the worst scenario, adolescent and even older bipolar patients may accuse parents of inflicting trauma and emotional abuse – even sexual abuse (Akiskal, 2004). This is not to say that the latter never takes place. What is regrettable is that inexperienced or earnest mental health clinicians all too often take reports of “abuse” at their face value, instead of considering them as a reflection of the extreme emotional climate at home – the high EE (expressed emotion) family (Akiskal, 1996). With chronically relapsing illness, it is often the mother who carries the brunt of the illness’ burden. We are not aware of specific programs anywhere in the world addressing psychological support for the mother. Such mothers themselves often go through periods of despair, hope and denial about their adult bipolar children. This is often a lonely despair, about which kin not living with the family are ignorant of or indifferent to; at worst, such kin may even display critical and angry attitudes towards the caregiving mother (i.e. “You are a bad mother – you are not taking care of your sick child”), or even worse (“Your child’s illness is due to you having abandoned her”). Such criticism toward the mother is also routinely verbalized by the bipolar offspring, but unlike that of kin, may cycle into effusive expression of love and gratitude in a state-dependent fashion.

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The case of illness declaring itself in a marriage, separation or divorce is a common complication. Such individuals may return to their family of origin, where again the mother carries the burden of caring for an “adult child” – otherwise the patient may end up becoming periodically institutionalized or homeless.

THE PSYCHIATRIST AND OTHER CLINICIANS Non-psychiatric physicians usually shun away from bipolar illness as a specialized area. Also many clinical psychologists consider bipolarity to represent the domain of psychiatry. This is fortunately gradually changing. Psychologists are increasingly assuming an important role on the therapeutic team in the long-term care of bipolar patients. The same is equally true for social workers, nurses and doctors of pharmacy. Although psychiatrists during their training do gain experience in diagnosing and treating this illness, most university medical centers do not offer specialized training in bipolar disorder. As a consequence, unless a psychiatric trainee has a special interest in this area, his or her experiential base in this disorder is likely to be less than optimal; in particular, they gain little hands-on experience in the long-term care of bipolar patients. Patients and their families are always seeking information to understand this illness and its frustratingly complex course. One of the most difficult problems for the patient and the family is to find the “right psychiatrist” who can manage bipolar disorder. That the number of such psychiatrists is relatively small is not the fault of the clinician, but rather the lack of vision in graduate medical education. Much of what most psychiatrists do in their clinical practice involves affective disorders in the broad sense, yet their formal educational curriculum does not reflect this. Neurotic and depressive disorders are relatively easy to comprehend and manage, and illnesses like schizophrenia and dementia have the veneer of organic disease, whereas bipolarity has such a complex interplay of social and occupational behavior that is less fathomable for the average psychiatric trainee. Their lack of exposure to phenomenology, psychology, pharmacology and long-term course of bipolar disorder creates a major public health problem. The so-called “classic bipolar” disorder is a platonic myth – from which most patients deviate in significant ways. An inexperienced clinician then will often misattribute bipolar disorder to other mental disorders, such as schizophrenia, anxiety and unipolar disorders, or personality and substance use disorders (Akiskal and Puzantian, 1979; Hirschfeld et al., 2003). Sadly, the cross-sectional erratic behavior of bipolar patients is often labeled “borderline” – if not frankly “psychopathic.” Such labels alone will militate against any meaningful long-term alliance of patients with clinicians. There are reasons to believe that continuing medical education programs focusing on bipolar disorder are beginning to positively impact the recognition and treatment of

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bipolarity in its broad expressions. There now exist pockets of clinical excellence in bipolar disorder and, refreshingly, most are in practice settings outside academia.

THE MOOD CLINIC In part because of the reasons just discussed, there exist very few mood and/or bipolar clinics in the world. Of the few existing ones, most are located in the United States. They used to be called “lithium” clinics (Fieve, 1975), because rigorous use of lithium with due attention to medical aspects and blood levels was mandatory. This helped in the medicalization of bipolar disorders at a time when psychiatry was basking in psychodynamics. However, positive results with lithium were largely limited to bipolar patients who were willing to adhere to the relatively tight regimes required. These clinics were crucial for adherence to the prophylactic use of this agent (Akiskal, 1999) and suicide prevention (Muller-Oerlinghausen, Grof and Schou, 1999). Mood clinics had a broader agenda and emphasized integration of different therapeutic modalities. Although this was more congruent with the emergence of an “eclectic psychiatry,” mood clinics did not become popular perhaps because they competed for the clientele of psychiatrists in both academia and general practice. What psychiatry missed in the process was the opportunity for mood clinics to train residents and fellows to become specialists of mood disorders. In such clinics, routine prospective follow-up revealed high rates of transformation of depression into bipolar disorder (Akiskal et al., 1983), particularly bipolar II subtype (Akiskal et al., 1978; Akiskal, 2005). This would have liberated psychiatrists from the rigidity in our formal diagnostic system for mood disorders where patients fall into the unipolar and bipolar molds. In clinical reality, most affectively ill patients fall in a spectrum between these extremes (see Chapter 1). But to properly appreciate this perspective, the clinician must experience over the prospective follow-up, the gradual – though at times subtle – transformation of unipolar patients into soft bipolarity. Family history, especially when buttressed with family interviews, will further inform the psychiatrist where DSM-IV and ICD-10 fail abominably – as the proper diagnosis of bipolar disorder needs to be continuously revised by the evolving nature of affective and related disorders in family members. It is also important to appreciate that mood patients over prospective observation develop what otherwise might be regarded as “unusual” – namely, the common development, among others, of psychotic, panic, phobic, obsessivecompulsive, dysmorphic, bulimic, addictive and impulse-control disorders (Perugi, Toni and Akiskal, 1999). Such complexity is the rule, rather than the exception. Short of such an exposure to the familial and longitudinally evolving nature of affective illness, the psychiatrist in training could not gain optimal experience of the most common types of bipolar disorder. Furthermore, in such a setting a team of mental health professionals could bring their knowledge and

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experience to bear upon the treatment of these patients. Thereby, a therapeutic link would be forged between the patients, their families and the clinic at large, including the trainees. This is a good scenario for treatment adherence – and makes caring possible. The situation is different with the current bipolar programs in many academic centers which are focused primarily on industry-supported pharmaceutical research and secondarily on research related to the psychobiology of the illness supported by National Health Institutes or Councils. Most of these programs are at the mercy of the vagaries of funding, which means that neither the staff nor the patients have long-term continuity. This is a sad scenario, which does not take the lifelong nature of the illness into consideration. This is not to say that bipolar programs as they exist today do not advance knowledge. On the contrary, a great deal has been learned about the illness itself and its treatment – witness the large number of new treatments introduced in the last decade, which is the theme of this book. The problem is that much of the advance is not in the long-term care of the patient. Even collaborative or cooperative programs from funding institutes – which have the luxury of longer follow-up – do not primarily focus on the long-term care of the patient, and sadly spend little funding to train specialists in bipolar disorder. Most research scientists who, by the very nature of their funding, train interviewers or raters of psychopathology rather than clinical practitioners. As a result, they produce research administrators who know more about methodology, institutional review boards and the art of “grantsmanship” than caring for bipolar patients. A pessimist might conclude that the gap between those who actually care for bipolar patients and those who do research on how to care for such patients is widening. An optimist might point to a large volume of an increasingly sophisticated literature on caring for bipolar patients and their families (Reinares and Vieta, 2004). The real question though is why our field has not developed a sufficient number of mood or bipolar clinics to accommodate the somatic and psychosocial needs of these patients in an integrated fashion. That patients and families with bipolar illness have long been frustrated in this respect is perhaps the main driving force for the development of bipolar advocacy organizations.

MENTAL HEALTH ADVOCACY ORGANIZATIONS The foregoing challenges, as well as the need for a long-term perspective, led to the development of such organizations – several of which are devoted to depressive and bipolar disorders. They promised self-help support, education, destigmatization, advocacy for better services, advocacy for relevant research and the administration of research awards that are advancing knowledge about the needs of patients rather than mere theoretical or basic science developments. These lofty goals are obviously helpful for patients as well as for their families, and could impact public health (Lish et al., 1994).

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The major downside of these organizations is that their main advisors are highlevel researchers rather than clinicians; with few exceptions they tend to maintain the status quo of research rather than caring for patients in their academic institutions. Furthermore, advocacy organizations are vulnerable to the tensions and conflicts inherent to large organizations, including the inevitable clash of temperaments of its executive members.

SOCIETY AND THE MEDIA Bipolar patients are poorly understood by the public at large. This is generally true for all serious mental illness, but there are two aspects rather unique to bipolar disorder, and which often find resonance in the media. The first is that bipolar individuals are over-represented in the corporate world and in politics: scandals in the sexual and financial arena, so alluring to the media and to the public at large, tend to give a “bad name” to the illness. The other aspect is the tendency of some researchers and media to glamorize bipolarity as a “genius disease,” especially in the artistic domain and theoretical science. This is problematic because such benefits characterize a minority of patients, usually at the soft end of the spectrum (Akiskal and Akiskal, 1988) or among the “unaffected” relatives of bipolar patients (Coryell et al., 1989). Many patients are disappointed that their doctors are unable to help them reap the “benefits” of their bipolarity. If not properly handled, this may create mistrust between the doctor and the patient. This could also generate conflict between bipolar patients, their employer and institutions in which they work. Patients may feel entitled to advantages and even tolerance for their outrageous behavior on the grounds that manic-depression confers creative spurts upon them. While greater understanding of bipolar disorder has occurred recently, this does not necessarily translate into greater tolerance of the irregular work habits of bipolar patients!

CARING FOR BIPOLAR PATIENTS 1. Bipolar illness is a disease with strong genetic determinants which is exacerbated and complicated by psychosocial factors. Competent pharmacotherapy must be matched with sophisticated yet practical psychosocial interventions. There is no longer such a philosophical divide between the two (Mundt, 2003; Fuchs, 2004). “Medication visits” are necessary but insufficient: quality time is needed to explore and address psychotherapeutic issues (Table 19.1). However, such lofty goals are more easily articulated than carried out. In current practice, especially in public mental health settings, pharmacotherapy and psychotherapy are disassociated, thereby making their integration difficult. Combining them in one person, obligatorily a physician, has the disadvantage

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Bipolar Psychopharmacotherapy Table 19.1: Psychotherapeutic issues in bipolar disorder • • • • • • • • • • • • •

Denial of the illness Developmental delays and emotional immaturity Uneven careers, talent and creativity Financial extravagance Burden on the family Risky sexual behavior Marriage, pregnancy, genetics Tempestuous relationships, lovelife, divorce Stigma about chronic illness Effects of bipolar medications on temperament Fears of return of illness episodes Grieving over years lost due to bipolarity and its complications Self-regulation and regulation of self-esteem

that psychiatrists may not have all the requisite skills for the newly developed unwieldy list of psychosocial interventions and, even if they did, it may be impractical for one person to administer them all. The so-called “team approach” is an optimal compromise, but has the danger of becoming administrative rhetoric rather than a genuine forum for integration. To make things worse, patients and families may disrupt the precarious balance of integrated treatments. That is why treatments for bipolar patients must be administered by visionaries committed to practical tasks – a rare blend of talents. 2. Availability of family members or significant others who are willing to participate in the therapeutic process, who can monitor adherence to treatment, provide information about the course of illness under treatment and could be trusted during times of crisis is crucial. Such support and participation is crucial in bipolar disorder with its proverbially unpredictable exacerbations. Patients’ denial of illness and reticence to seek help represent major factors in relapse, and the pivotal role of a caring family cannot be underestimated in this regard. Adherence to treatment is a complex subject (Table 19.2); also see Jamison and Akiskal (1983). In the authors’ experience, love and respect for or dependency Table 19.2: Factors in treatment non-adherence Cultural: Stigma, anti-medication attitudes Illness: No insight, mania, initial episodes Comorbidity: Alcohol/drug abuse Medication: Unacceptable side effects Patient: Young, low socio-economic status male, missing highs Family: Lack of supervision Physician: Inexperience, inconsistency, or hiding behind authoritarian attitudes Health climate: Undermining continuity of care

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upon a significant other or an authority figure in the family is crucial for treatment adherence. 3. The attitude of significant others which is of the greatest help is one of concern and emotional warmth while maintaining objectivity. This is an important corollary of the first principle because, given the tempestuous interactions that occur in this illness, individuals close to the patient cannot avoid being – or coming across as – critical. While it is true that critical attitudes may lead to further exacerbation of the illness – particularly depression – it would be unrealistic to think that they would not occur. It is warmth that counterbalances critical attitudes whether in bipolar disorder or schizophrenia (Okasha et al., 1994), representing an important vehicle in facilitating caring. 4. Feedback by peers – meaning by other bipolar patients and other bipolar families – is often more effective than that given by professionals and the patient’s immediate family. This means that exposure to peers in a format such as group therapy (Table 19.3) can play a fundamental role in combating denial (Graves, 1993). 5. Mood charting of life events and prevalent mood on a daily basis can help the patient understand the connection of such moods to life events, for example hypomania to sexual unfaithfulness, irritable mood to loss of job. Unwieldy methods of charting deriving from research protocols are not of much use in practice. Mood charting should be individualized to make sure that it is patient-friendly. 6. Limit setting can be achieved through the group therapeutic process. However, in some instances, only a close family member can be trusted to place such limits. We are specifically referring to delegating financial control at critical junctures to a spouse, parent or sibling. This pertains, among others, to checks, credit cards and inheritance. As for the latter, lawyers may be necessary to protect the patient’s and family’s rights. In this endeavor, one must rely upon lawyers whose loyalty has been tested beforehand. Tragically, impulsive spending often leads to financial ruin before such measures are instituted.

Table 19.3: Group therapy for bipolar patients • • • • • • •

To involve others (e.g. spouses) in the therapeutic process To educate about the nature of the illness and its treatment To challenge denial To enhance compliance to prophylactic medication To identify the impending signs of relapse To impose external control over risk-taking To explore new homeostatic strategies for the “stabilized” self

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Bipolar Psychopharmacotherapy Mental health professionals regrettably have little or no training in such matters. The authors are familiar with cases where lawyers, instead of being patient advocates, further depleted the patients’ financial means.

7. Functioning is more important than mood stabilization. While rapid control of mania in the acute phase is desirable, over-stabilizing patients with “aggressive” pharmacotherapy is unlikely to lead to treatment adherence in the long run. It is best if the psychiatrist “goes halfway” in meeting reasonable requests by the patient about dosage and the optimum mix of medications. Implicitly, the psychiatrist will still have the upper hand from a medical point of view, while permitting the patient some participation in the therapeutic choices. Once recovered from major episodes, permitting some degree of self-management is a valuable but difficult goal to attain. Vigilance is necessary to make sure that the patient does not take this as a mandate to do as he or she pleases, while at the same time reassuring that the psychiatrist is aware of the difficulty the patient has in entirely surrendering the control of the self to some “ideal” of stabilization that is in a textbook’s or guidelines’ doses or blood levels. For instance, while it is true that better control of bipolar episodes is achieved with high blood lithium levels, most patients cannot tolerate such levels, hence they stop it (Gelenberg et al., 1989). In summary, the goal of treatment is not to aggressively overmedicate the patient to mediocrity, the psychiatrist should endeavor to help patients attain their best functioning without risking relapse. This is a more delicate art than helping patients maintain optimum blood pressure or blood glucose. But the “battles” over chemistry and health between patients and doctors as to who controls or is in charge of the patient’s temperament, life and soul are analogous in principle in both internal medicine and psychiatry. The art of managing such matters, while fundamental in our teaching efforts, is difficult to transmit – yet they must be practiced. This is what makes being a doctor fundamentally different from being a scientist. It is amazing how the current craze for scientific medicine continues to obscure this difference. Our point is that the issues involved are not unique to psychiatry, and to express our reservation concerning the complacency of many in our field who feel that “evidence-based” guidelines represent a sufficient measure for practice. 8. It follows then that for the patient to trust a psychiatrist, he or she must respect the patient’s temperament and individuality, that indeed his or her aim is to bring out the optimum of what is positive and desirable in patient’s temperament in terms of interpersonal charm and professional achievement (Akiskal and Akiskal, 2005). Nonetheless, as alluded to earlier, it is generally best to downplay literature about bipolarity as a “genius disease.” First of all, “genius” is multi-factorial and if it is associated with bipolarity, it is generally at the soft end of the bipolar spectrum and not at the psychotic end (Akiskal

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and Akiskal, 1988). While it is understandable that some literature advocates the idea that bipolar individuals are very successful individuals in the arts and other domains (Jamison, 1996; Arnold, 1995), the intent of this literature is best understood as an attempt to de-stigmatize the illness. The unfortunate fact is that despite many positive attributes, the majority of ill bipolar patients cannot be expected to be creative or eminent unless they are independently gifted – and the course of the illness is permitting. In our report from a large urban mood clinic (Akiskal and Akiskal, 1988), “creativity” (which was liberally defined) was limited to basically 8% of bipolar II. Should too much be made of the prospects of eminence in bipolar disorder in a given patient, the patient may feel cheated that the psychiatrist and the team of mental health workers somehow failed in bringing out the best in him or her. 9. Comorbid personality disorder – particularly the “B label” – is best handled by not diagnosing it, as more often than not, it is a reflection or complication of the illness (Akiskal, 2004). The emphasis must be on rigorous treatment of the bipolar illness itself. We have elsewhere shown that the use of temperament constructs is much more germane to understanding bipolar disorder, as they identify traits which make individuals vulnerable to the illness, while at the same time fostering adaptive function (Akiskal, 1992; Akiskal et al., 2005). Family members, like psychiatrists and psychologists, in their frustration often invoke characterologic factors to explain the unproductive or “bad” behavior of their bipolar kin. It is best to conceive of such behavior as “faulty habits” that maintain the illness or are developed to deal with it. Addressing such habits with behavioral interventions is more likely to lead to change in the desired direction than characterologic labels that fault the patient and exculpate the clinician. Social workers can play a vital role in this process as they are more likely to be Meyerian in philosophy. 10. Because psychiatric tragedies, including social scandals, often occur in the lives of bipolar patients, the psychiatrist must be available at times of crisis. A non-judgmental attitude by the psychiatrist when all others are attacking the patient would assure enlisting the patient’s cooperation in solving the crisis with minimal consequences (Akiskal, 2000). Being non-judgmental, however, does not mean that the psychiatrist is condoning the behavior that led to the crisis. Because such crises often stem from poor judgment due to (hypo)mania or depression (more often the former than the latter), the psychiatrist must attempt to steer the patient out of the crisis rather than wait for the patient to find his or her way out. 11. Related to the above, and given the fact that depression is more painful subjectively and less likely to impair insight than hypomania, outcome of prophylactic treatment is, in our experience, more likely to be associated with

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Bipolar Psychopharmacotherapy better adherence when initiated during the former. Despite one study favoring such a conclusion (Lenzi et al., 1989), there is surprisingly little systematic data on this very critical subject. Thus, more attention needs to be paid to phase-specific pharmacologic treatments, such as Koukopoulos’ notion (Chapter 10), that “mania-depression-free interval” patients do better on lithium than those with “depression-mania-free intervals”.

12. The most serious crisis in bipolar disorder is suicidality. The clinician should err on the safe side and consider admitting the patient to the hospital. Electroconvulsive therapy is an option which often proves to be life-saving. Faced with a suicidal bipolar patient, half-baked theoretical or existential discussions must be avoided. Although lithium is touted to be unique in its antisuicidal properties (Goodwin et al., 2003), probably most, if not all, approved agents for bipolar disorder are as effective (Angst etal., 2002; Yerevanian etal., 2003). 13. The psychiatrist should avoid taking a Calvinistic approach to alcohol and substance use. Thus, one must not be unreasonable in prohibiting alcohol and/or marijuana which based on occasional use has not shown to have destabilized the patient. However, abstinence from stimulant agents, including caffeine, is mandatory. Opiate-dependent patients can be stabilized on methadone (Maremmani et al., 2003). 14. Many bipolar patients, even in their trait condition are “activity junkies” (Akiskal, 2005). Unfortunately, most types of excessive activation – whether it is spending money, frequent travel, excessive risk-taking in sex, drugs of abuse, gambling, working 2–3 shifts – can destabilize them. The destabilizing effect of activation is also pertinent to therapeutic agents for depression – and we are specifically referring to antidepressants. They should be used sparingly, for rigorous indications (i.e. severe or suicidal depression), and only for as long as needed. Thus, antidepressants should almost always be administered along with mood-stabilizing or anti-manic medications. “Bipolar-friendly” antidepressants (e.g. bupropion) might be preferred, but even these are not entirely safe – from a switching standpoint – in monotherapy. Lamotrigine may prove to be a viable “antidepressant” for many acute bipolar depressions, and this may be particularly true for bipolar II. 15. Sleep hygiene is an important ingredient in the overall management of bipolar disorder. However, because yearning for freedom from time constraints (rhythmopathy) is part of the core pathology of the illness, it often remains an elusive goal. Pragmatic approaches are preferred over unwieldy protocols developed in chronobiology labs. Nonetheless, understanding of chronobiologic principles can help to develop individualized circadian approaches in situations of shift work and jet lag. Useful approaches to the rhythmopathy include total darkness which should enhance sedating pharmacotherapy to prevent sleep

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deprivation and maintain restorative sleep. Thus, given the anxious arousal and insomnia or decrease need for sleep in bipolar disorder, rather than solely depending on behavioral management, it is often desirable to use sedating properties of existing anti-bipolar agents to treat anxious arousal at night. By the same token, although it is best to treat bipolar patients combining approved medication for the bipolar indication – or those with evidence from controlled studies – the exception can be made for agents such as gabapentin or clonazepam, as augmentation agents for anxiolysis, or sleep restoration. 16. The same remarks apply to topiramate as an agent for weight reduction. Weight management and associated metabolic issues represent a relatively new challenge, and must be rigorously addressed. When weight is a major concern, although one must preferably use weight-neutral approved medications for bipolar disorder, this should not be at the expense of effectiveness. That is, if a bipolar patient responds best or exclusively to medication which leads to weight gain, it may sometimes be disastrous to substitute it with weight-neutral medication. Thus, rather than risking destabilization, the psychiatrist must consider concurrent weight management. This is obviously an art in which the field of medicine at large has yet to prove its worth in terms of long-term effectiveness. But one can learn something by trying different approaches which may fail in some, but work in others. In our experience, “diet” is a term that elicits frustration. Lifestyle changes, such as incorporating walking in one’s daily routine, are more likely to be rewarding and effective. 17. Bipolar disorder is multidimensional and requires rational polypharmacy working on different substrates, which means that anti-psychotics, anti-convulsants and mood stabilizers are often to be combined (Chapter 9). Because abrupt withdrawal of an agent from the medication regimen is likely to lead to premature or early relapse, it is generally best to augment rather than substitute agents in the medication regimen. 18. It is generally futile to meddle with the patient’s love life, for this is hardwired! Nonetheless when the erotic life is tempestuous to such a degree it is causing extreme pain and suffering or it is hopelessly or delusionally fixated on unavailable love objects (erotomania), an open discussion can prepare the ground for exploratory psychotherapy. Regrettably, antipsychotics which reduce sexual desire may have to be used in some instances. 19. A great deal of research, covered in Chapter 16 of this book, supports the use of psycho-educational practices in treatment adherence and in reducing denial. What this literature does not sufficiently emphasize is that psychoeducation is a two-way street. The doctor himself or herself must learn about the patient and his or her disease, not from textbooks, but from direct daily interactions with the patient and his or her family.

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20. Side effects of medications are sometimes intolerable and may necessitate adjustment of dosage or even substitution with a better tolerated medication. However, in a patient whose illness has been brought under reasonable remission, it is best not to make major adjustments in the medication regimen. The risk of relapse is a more serious concern in this instance than the nuisance of certain side effects. This is a situation when the therapeutic relationship with the physician is extremely important for the patient to trust his or her judgment on this matter, namely that it is not always possible to eliminate all side effects, and once “good enough functioning” has been achieved, it is best not to risk destabilization. Nonetheless, all reasonable efforts must be made such that all adjustments are made to assure that side effects are tolerable enough to not compromise adherence. The principle here is meeting the patient half way. 21. However, periodic minor adjustment of medication can be considered at times of expected major stress, including circadian stress such as transmeridian travel, or when past course has revealed seasonal exacerbation, or for specific psychosocial situations leading to relapse; proper upward medication adjustment should be prescribed prior the expected time of the occurrence of these stressful events. 22. Supporting the family, the spouse or other carers – and particularly the mother – of bipolar patients is a cardinal principle that is often neglected in contemporary psychiatry. Not only is this necessary to make sure that the patient has an effective support in the family, but to prevent the family from breaking down. Family members of the patient often carry the same bipolar genes in dilute form, compared to that of the patient, and it is the stress of being exposed to an extremely ill offspring that for the first time brings about depression in the mother. Illness of one’s offspring, from an evolutionary standpoint, represents an extreme stress for a woman. It is such stress operating on a modest genetic vulnerability that brings about a depressive outcome for the mother. Support to the family often requires individual or group therapy. Patient advocacy organizations can also play a vital role in this respect. 23. The value of genetic counseling is limited because patients in our experience typically present after the fact (i.e. when pregnant). The risks of bipolar medication for the fetus, especially that of lithium, in our experience are exaggerated. Since such anticonvulsants as divalproate are not approved for long term prophylaxis in bipolar disorder, the risk of spinal tube malformations can be avoided by not using this agent in the first trimester of pregnancy. Nonetheless, pregnant bipolar patients may require careful assessment in consultation with gynecologists or specialized women’s bipolar clinics which have experience in such matters. Prospectively identified patients, which can be accomplished in a mood clinic, can be provided with risk estimates for offspring, especially when family history is loaded with affective illness or has pedigrees with psychotic bipolar illness and/or suicide.

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24. Bipolar patients are preferably treated in group practice. Such a setting will provide the opportunity for consultation from colleagues, or time-limited appointments with other members of the team when the primary physician is on vacation or ill. This could help in diluting negative transference reactions, while at the same time giving the patient the benefit of a second or third opinion. Ideally however, and especially in the public domain where most bipolar patients are treated, a mood or bipolar clinic provides many advantages (Table 19.4). Such clinics provide an experienced, sophisticated multidisciplinary team including psychiatrists, psychologists, social workers, nurses and doctors of pharmacy. Not only does the team provide greater variety of treatments tailored to the different needs of the patient, but it is better able to assure adherence, longitudinal care and prevention. It also provides a resource for other mental health professionals in the community. Thus a patient can have pharmacotherapy, psycho-education, individual psychotherapy, group therapy, behavioral therapy and social interventions. Of all the psychosocial treatments, psycho-education has the best data-based status, and has been covered in Chapters 15 and 16. In the mood clinic setting it is also possible to provide support for the family caregivers, making sure that they become acquainted with the psychological and social skills to monitor the patient’s progress. Finally and most importantly, the setting of a mood clinic provides the opportunity to observe and diagnose illnesses in family members before they fully declare themselves. This could include spouses, siblings or children (Akiskal et al., 1985a). This is of immense public health importance, yet it has been insufficiently capitalized in psychiatry. This is regrettable given the inexorable course of the illness once it develops into full steam. Finally, secondary prevention can be achieved by family members identifying early signs of impending relapse. Patients can also be taught to monitor their own behavior and mental state in achieving this goal. A combination of the two sources of information is needed because in general caregivers might be oversensitive in identifying signs of a relapse, while patients often are less inclined to do so.

Table 19.4: The role of a mood or bipolar clinic • • • • • • • •

Combines service, training and research Experienced multi-disciplinary staff Focus on the family or couple Sophisticated treatment Better treatment adherence Longitudinal care Prevention A resource for other mental health professionals

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25. Maximize Treatment Adherence. All the principles we have discussed will be defeated if good-enough treatment adherence is not achieved. Indeed, these principles should contribute significantly to such adherence. The following can help further maximize adherence: educating both patient and family about early signs of relapse, monitoring adherence to medication, making sure appointments in the clinic are kept, minimize dosing frequency, tailoring medication side effects to those which are least likely to interfere with a patient’s functioning, medication support group therapy, and of course, psychoeducation.

SPECIAL CONSIDERATIONS FOR HYPOMANIC AND CYCLOTHYMIC PATIENTS Much of the literature in the treatment of bipolar disorder is focused on bipolar I. In this section, we discuss adherence issues particularly relevant to hypomania, as well as special psychological problems posed by cyclothymic patients. Bipolar patients are notoriously nonadherent with maintenance oral medication (Jamison and Akiskal, 1983). Many patients whose mood swings are attenuated by medication may complain of feeling “flat” (especially with lithium) because of a relative depression; others may describe memory problems, which are not easy to document. In such cases, it is necessary to rule out atypical relapses without vegetative signs or lithium-induced hypothyroidism (especially in women). The latter is best accomplished with the TRH stimulation test. Other patients complain that the loss of hypomanic drive and indefatigability adversely affects their work and relationships. Couples therapy may be indicated when treatment results in decreased assertiveness in a patient who previously took an aggressive, active role in sexual and social activities. Other patients may complain of decreased productivity and creativity. However, a systematic survey conducted by Schou (1979) among artists showed actual decreases in creativity to be uncommon; this is so because lithium generally offers the opportunity for more “even” periods devoted to interpersonal, scholastic, professional, and artistic pursuits. Adherence can often be enhanced by using the lowest possible dose that is compatible with freedom from major episodes, without necessarily preventing all mood oscillations. Another strategy is to combine two medications with different mechanisms of action and side effect profiles, but administering each at “subtherapeutic doses,” which would be synergistic and therapeutic in combination. A trial-and-error period, during which the patient’s mental status is closely followed, is necessary to establish such a balance. This approach is especially welcome by those bipolar patients who experience euphoric hypomanic moods. Many bipolar patients have considerable psychological assets, such as personal charm, affective warmth, creative bent and a high drive to fight for or advance various causes. These assets can often be capitalized in attempts to reconstruct lives that have been shattered because of impulsiveness and poor social judgment.

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In general, depth interpretations are unlikely to change these impulsive excesses, and voluntary control of such behavior is desirable, for example, turning over the checkbook to the spouse (Akiskal, Khani and Scott-Strauss, 1979). The foregoing issues are particularly relevant in the treatment of the cyclothymic-bipolar II spectrum. Because these conditions begin at an early age and pursue a periodic lifelong course, they may be mistaken for primary characterological disorders. These soft bipolar conditions are distinguished from the classical (or so-called major) mood disorders in that their baseline manifestations are subsyndromal, intermittent, and typically lifelong. That is, in the patient’s habitual condition, the affective psychopathology does not typically crystallize into discrete episodes. However, clear-cut and unmistakable syndromal episodes are not uncommonly superimposed on the lifelong course of these temperaments. It is this very intermittence that creates their resemblance to personality disorders. This is further reinforced by lifelong maladjustment in scholastic, occupational, and conjugal areas, secondary to chronically unstable and unpredictable moods. Finally, the mood change is often quite subtle, with behavioral and personal disturbances dominating the clinical presentation. For instance, in the University of Tennessee study of cyclothymic patients (Akiskal et al., 1977), affective manifestations were masked by interpersonal crises. Repeated marital failure or romantic breakups, episodic promiscuous behavior, alcohol and drug abuse, uneven work and school record, geographic instability and dilettantism were the cardinal reasons for which these patients had come to clinical attention. Unpredictability of moods is a major source of distress for cyclothymic individuals, who cannot predict from one day to the next how they will feel. This undermines their sense of self and gives rise to apprehension, even during euthymic periods (Akiskal, Khani and Scott-Strauss 1979). Indeed, this temperamental propensity to change from one affective state to another with very little ego control over the change is one of the principal reasons why psychodynamically oriented clinicians may consider cyclothymic and bipolar II disorders as an expression of “borderline” characterological psychopathology. Old and current data (Akiskal et al., 1985b; Deltito et al., 2001; Akiskal et al., 2003a; Akiskal, 2004) suggest that in many cases the direction of causality is in the opposite direction, that is, borderline features arise from the affective instability. Mixed states of short duration with extreme irritability occur in all subtypes of cyclothymia and are often associated with sedative hypnotic and alcohol abuse. Borderline characterological psychopathology is usually most severe in cases in which such irritable periods predominate. These irritable cyclothymics (Akiskal and Mallya 1987; Akiskal et al., 2003) are habitually moody-irritable and choleric with infrequent euthymia; they tend to brood; are hypercritical, complaining and obtrusive; and typically evidence dysphoric restlessness and impulsivity. In view of their high propensity to affective recurrences, cyclothymia and bipolar disorder NOS are at high risk for having stormy object relations, which often give

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rise to serious interpersonal disturbances. While these disturbances warrant considerable psychotherapeutic attention, such attention may prove futile in the absence of competent pharmacotherapy of the affective instability.

CONCLUSION There has been a revolution in the epidemiology, clinical phenomenology, classification, pharmacological, psychotherapeutic and public health aspects of bipolar disorder. The advances are so enormous that bipolar disorder should be considered a major subspecialty in psychiatry. This is particularly true given the lifelong nature of the illness, the unpredictable exacerbations, the disruption in social, occupational and conjugal life, substance and medical comorbidity, and the high risk of suicide. Such an illness requires a coordination of services involving psychiatrists, nurses, social workers, psychologists and pharmacists. It is no longer possible to think of solo practice in the management of this illness. The spectrum aspects require attention to diagnostic sophistication, not only in the patient, but also in the family. This would achieve early case detection. This would be a model of practice that is necessary to teach training psychiatrists and other mental health professionals. The substantial advances in science are unlikely to make any impact on prevention and public health without such clinical units. It is regrettable that the number of such units has not substantially increased since the 1970s. Most programs deliver research rather than care. It is the latter aspect that now needs to be instituted. For this to happen, there needs to be “political” change in the climate of academic psychiatry and public mental health. What we need is the proper structure of caring for the affectively ill, mood or bipolar clinics – just as there exist diabetes clinics, glaucoma clinics, pain clinics – and multidisciplinary clinics that conduct research, train specialists, while providing high quality care. The worst scenario for bipolar patients is that the lack of structures for caring for them in the current shortage of psychiatric beds is creating a new asylum on the streets of “civilized nations” in the form of homelessness – and what is worse, turning the mentally ill into prison inmates. This is contrary to the spirit of Pinel’s humanitarian reforms which unchained the mentally ill and liberated them. Such liberation envisaged the right for hospital treatment when needed. It was not a blanket endorsement for keeping patients out of the hospital under any circumstances. Today the severely mentally ill are roaming in the streets and are liable to all the hazards and abuses of such an existence. Civilized nations must not tolerate such outcome for those unfortunate members of its society who are bipolar, psychotically ill and poor. There was a time when medical schools cared for the disadvantaged. Today, they erect proud institutes of molecular biology, cancer and cardiovascular health. Modern psychiatry began two centuries ago with a humanitarian revolution, followed by one of understanding the mind, culminating

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in the psychopharmacological revolution. A major theme of this book is an eloquent example of the success of the latter paradigm as it pertains to bipolar disorder. Bipolar disease is a spectrum of genetically based illnesses and, without competent modern pharmacotherapy, it is hopelessly impossible in most cases to attenuate its cyclic course and provide a life relatively free from major episodic eruptions, despair and suicide. What we now need is a culture of caring within a broader social psychiatry. For psychiatry which does not safeguard the basic dignity of every man or woman with serious mental illness is not psychiatry at all. Today, many young psychiatrists and psychologists, aspiring to emulate their academic seniors in universities and research hospitals, measure prestige and success in multimillion dollar grants and/or the limelight in national and international congresses. Ultimately, what we lecture about (“teach”), write and do, must be measured against a less “prestigious” but more humane goal of caring for patients on a daily basis. The names of such dedicated mental health professionals are typically absent from the list of lecturers in national and international symposia on bipolar disorder – and their names do not adorn the pages of this book. We dedicate this chapter to them.

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Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003; 290: 1467–73. Graves JS. Living with mania: A study of outpatient group psychotherapy for bipolar patients. Am J Psychother. 1993; 47: 113–26. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003; 64: 161–74. Jamison KR, Touched with Fire: Manic Depressive Illness and the Artistic Temperament. New York, Free Press, 1996. Jamison KR, Akiskal HS: Medication compliance in patients with bipolar disorders. Psychiatr Clin North Am. 1983; 6: 175–192. Krober HL: [Illness perception and coping with illness of bipolar manic-depressive patients]. Fortschr Neurol Psychiatr. 1993; Aug. 61(8): 267–73. Kukopulos A, Reginaldi D, Laddomada P, Floris G, Serra G, Tondo L. Course of the manic-depressive cycle and changes caused by treatment. Pharmakopsychiatr Neuropsychopharmakol. 1980; 13: 156–67. Lam DH, Watkins ER, Hayward P, Bright J, Wright K, Kerr N, Parr-Davis G, Sham P. A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the first year. Arch Gen Psychiatry. 2003; 60: 145–52. Lenzi A, Lazzerini F, Placidi GF, Cassano GB, Akiskal HS. Predictors of compliance with lithium and carbamazepine regimens in the long-term treatment of recurrent mood and related psychotic disorders. Pharmacopsychiatry. 1989; 22: 34–7. Lish JD, Dime-Meenan S, Whybrow PC, Price RA, Hirschfeld RM. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord. 1994; 31: 281–94. Maremmani I, Pacini M, Lubrano S, Lovrecic M, Perugi G. Dual diagnosis heroin addicts. The clinical and therapeutic aspects. Heroin Add & Rel Clin Probl. 2003; 5: 7–98. Martinez-Aran A, Vieta E, Reinares M, Colom F, Torrent C, Sanchez-Moreno J, Benebarre A, Goikolea JM, Comes M, Salamero M. Cognitive function across manic or hypomanic, depressed,and euthymic states in bipolar disorder. Am J Psychiatry. 2004; 161: 262–70. Muller-Oerlinghausen B, Grof P, Schou M. Lithium and suicide prevention. Br J Psychiatry. 1999; 175: 90–1. Mundt C: Psychotherapy and the novel biological paradigms–how do they relate? Seishin Shinkeigaku Zasshi. 2003; 105: 171–184. Okasha A, el Akabawi AS, Snyder KS, Wilson AK, Youssef I, el Dawla AS. Expressed emotion, perceived criticism, and relapse in depression: A replication in an Egyptian community. Am J Psychiatry. 1994; 151: 1001–1005. Otto MW, Reilly-Harrington N, Sachs GS. Psychoeducational and cognitive-behavioral strategies in the management of bipolar disorder. J Affect Disord. 2003; 73: 171–81. Perugi G, Toni C, Akiskal HS. Anxious-bipolar comorbidity: Diagnostic and treatment challenges. Psychiatr Clin North Am. 1999; 22: 565–583. Reinares M, Vieta E: The burden on the family of bipolar patients. Clin Approach Bipolar Disord. 2004; 3: 17–23. Schou M: Artistic productivity and lithium prophylaxis in manic-depressive illness. Br J Psychiatry. 1979; 135: 97–103. Yerevanian BI, Koek RJ, Mintz J. Lithium, anticonvulsants and suicidal behaviour in bipolar disorder. J Affect Disord. 2003; 73: 223–8.

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Index ABS, see Agitated Behavior Scale (ABS) ACES, see Agitation-Calmness Evaluation Scale (ACES) Acute depression clinical subtypes 218–22 lamotrigine 46–8, 54–6 pharmacotherapy 202–3 second generation antipsychotics 125 Acute mania anticonvulsants 63 haloperidol 106–8 lamotrigine 46, 56 olanzapine 87–91, 97 second generation antipsychotics 127–30 tranquillization 105–6 treatment setting 347–8 Add-on therapy benzodiazepines 67–8 lamotrigine 46, 55 ADHD, see Attention-deficit hyperactivity disorder (ADHD) Adolescent-onset mania 280 Advocacy organizations 372–3 Aggression 280 Agitated Behavior Scale (ABS) 91 Agitated depression 170, 356 Agitation 90–1 Agitation-Calmness Evaluation Scale (ACES) 91 Akiskal, H. S. 172 Alcohol alcohol-induced mood disorders 198 care principles 378 gender distribution 243 polypharmacy 154 psychosocial interventions 325

Amitriptyline 360 Anticonvulsants 18–19, 63–70 bipolar disorder 205–7 mechanisms of action 158 see also individual drugs Antidepressants 4 acute bipolar depression 203–5, 218–20 anxiety 221 augmenting agents 70–3 care principles 378 chronic psychotic condition 349 cycle acceleration 215–17 depressive recurrences 211–12 discontinuation 72–3, 176, 180, 217–18 historical overview 169–73 hypomania/mania 196 (hypo)manic switches 212–15 lamotrigine combination therapy 46–7, 55–6 lithium therapy 20 misdiagnosis 194–5 mixed states 199 olanzapine combination therapy 92–5 pediatric bipolar disorder 286–7, 290–1 polytherapy 140, 148 psychosocial interventions 335 suicidality 361 women’s health 242, 249–52, 255, 256 Antiepileptics antidepressant effects 177 lithium therapy 20 mania 177–8 suicidality 361

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390 Antipsychotics chronic psychotic condition 349 combination therapy 28, 56 geriatric bipolar disorder 307 hormonal changes 108–9 lithium therapy 20 mania 178 mood stabilization 109 polytherapy 136 psychotic symptoms 219 sedation 106 sexual desire 379 suicidality 361 tranquillization 106–7 women’s health 242, 250, 258 see also Atypical antipsychotics; individual drugs Anxiety bipolar comorbidity 221 pediatric bipolar disorder 283–4 polytherapy 152–3 Anxiety-associated depression 186 Aripiprizole 126, 128, 130 Attention-deficit hyperactivity disorder (ADHD) 4 pediatric bipolar disorder 281–3, 286, 290–2 polytherapy 142 Atypical antipsychotics aripiprizole 126, 128, 130 clinical trials 127–31 clozapine 85–6, 125–8, 131, 254, 307 gender distribution 249 lamotrigine combination therapy 56 lithium therapy 20 long-term treatment 130–1 mania 178 mixed states 222 polytherapy 135, 147, 154 psychotic symptoms 219 second generation 125–32 suicidality 361 thymoleptic activity 126–7 ziprasidone 127, 129 see also Olanzapine; Quetiapine; Risperidone Atypicality gender distribution 243 pediatric mania 279–81

Index B-cell lymphoma/leukemia-2 gene (bcl-2) 37 Benzodiazepines add-on therapy 67–8 anxiety 220–1 lorazepam 67–8, 90–1, 106, 112 polytherapy 152 Bipolar disorder not otherwise specified 2, 65, 141, 383 Bipolar I anticonvulsants 65, 70–1, 73 gender distribution 235–6, 239, 243–4 lamotrigine 43–4, 47, 48–50, 55–8 mania 176, 177, 186 mixed states 199–200 olanzapine 85 polytherapy 140, 147–8 public health 1–3 quetiapine 128 suicidality 354–7, 359 thyroid hormones 222–3 Bipolar II anticonvulsants 65–6 diagnostics 193, 194–9, 202, 222–4 gender distribution 235–7, 239, 240, 243–4, 257 lamotrigine 43–4, 48–50, 55–8 mania 183 mixed states 199–200 polytherapy 140, 148 public health 1–2 quetiapine 128 suicidality 354–7, 361 Bipolar III 3, 336 Bipolar IV 185 Bipolar NOS 2, 65, 141, 383 Blood level monitoring 348 Breastfeeding 17, 256–7 Brief Psychiatric Rating Scale 107 Bupropion depressive recurrences 208–9, 217 polytherapy 147, 154 switches 72 CABF, see Child and Adolescent Bipolar Foundation (CABF) Cade, J. F. J. 10 Calcium antagonists 74

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Index Carbamazepine 18, 35, 63–5 bipolar disorder 201 depressive recurrences 208 drug interactions 45–6 efficacy 63–4 geriatric bipolar disorder 303 haloperidol combination therapy 116–19 mania 177 pediatric bipolar disorder 140–1, 289–91 polytherapy 140, 147, 153, 156–7 risperidone combination therapy 116–19 suicidality 360 women’s health 249, 251, 256 Care principles 367–85 comorbid personality disorder 377 cyclothymia 383–5 family considerations 369–70 family/significant others 374–5 functioning 376 genetic counseling 380 hypomania 328–4 limit setting 375–6 media 373 mental health advocacy organizations 372–3 mood charting 375 mood clinics 371–2, 381 patient considerations 368–9 polypharmacy 379 psychiatrists 370–1, 376 psychoeducation 379 psychosocial interventions 373–4 sleep hygiene 378–9 societal views 373 treatment adherence 382 weight management 379 CBCL, see Child Behavior Checklist (CBCL) CCT (complex combination therapy), see Polytherapy CGI Scale, see Clinical Global Impressions (CGI) Scale Child and Adolescent Bipolar Foundation (CABF) 140, 326 Child Behavior Checklist (CBCL) 285 Children’s Depression Inventory 291

391 Chlorpromazine 1, 10, 105–7, 171 Cholesterol 35 Chromium picolinate 74 Chronic psychotic condition 349 Clinical Global Impressions (CGI) Scale 47, 288 Clonazepam 67–8 Clozapine 85–6, 125–6 acute bipolar mania 127–8 geriatric bipolar disorder 307 long-term treatment 131 women’s health 254 Cognitive-behavioral treatment (CBT) 317–19, 325, 327, 336–7, 341–2 Combination therapy haloperidol 108, 116–19 lithium-resistance 135–60 lithium therapy 20 olanzapine 85, 87–8, 90–3, 96–8 polytherapy 135–60 risperidone 116–19 second generation antipsychotics 128 valproate 28–9 see also Polytherapy Community practice 325–6 Comorbidities anxiety 220–1 diagnostics 198–9 gender distribution 244–5, 252 geriatric bipolar disorder 301 pediatric bipolar disorder 279–93 personality disorder 377 Complex combination therapy (CCT), see Polytherapy Conduct disorder (CD) 283–4 Corticotropin-releasing factor (CRF) 38 Cortisol 108 CRF, see Corticotropin-releasing factor (CRF) Criminality 351, 384 Cross-sectional diagnoses 13 Cycle acceleration 215–17 Cycle sequence 174–5 Cyclothymia 2–3, 180, 198–9, 382–4 Cytochrome P450 64, 65 Delirium 304 Dependency 68

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392 Depression benzodiazepines 68 care principles 368 diagnostics 194–5 evolutionary theory 186 gender distribution 235–7 historical overview 169 lamotrigine 43–4, 46–8, 50–1, 54–6 lithium therapy 173 nervous exhaustion 185–6 olanzapine 92–5 oxcarbazepine 66 patient conception 172 polytherapy 142–5, 152–3 primacy in bipolar cycles 184–6 psychosocial interventions 335 recurrences 9–13, 19–20, 208–12, 217–18, 220, 223 risperidone 109 second generation antipsychotics 125, 128 suicidality 353 treatment-refractory 152–3 treatment setting 347 valproate 30 Depression and Bipolar Support Alliance 326 Diagnostic and Statistical Manual of Mental Disorders (DSM) 2–3, 170 diagnostics 193–5 gender distribution 235, 243–4 pediatric bipolar disorder 279 suicidality 355 Diagnostics 1–3, 4, 193–202 bipolar II 193, 195–9, 218–22 bipolar depression 193–5 comorbidities 198–9 hypomania 195–8 mixed states 199–202 Discontinuation antidepressants 72–3, 176, 217–18 antipsychotics 85 lithium therapy 176 olanzapine 97 polytherapy 159–60 psychosocial interventions 313 valproate 32–3, 38 Disinhibition syndromes 308

Index Disorder-specific psychotherapies (DSPs) 313–28 Divalproex, see Valproate DMI pattern 243 Dopamine (D2) receptors 86 Dopamine (DA-2) receptors 108–9 Drug A/drug B fallacy 18 Drug interactions 45–6 Drug response 349–50 DSM, see Diagnostic and Statistical Manual of Mental Disorders (DSM) DSPs, see Disorder-specific psychotherapies (DSPs) Duloxetine 152 Dysphoric mania 32–3, 356–7 ECA, see Epidemiological Catchment Area (ECA) database Ecstasy 179 ECT, see Electroconvulsive therapy (ECT) Efficiency of pharmacotherapy 350–1 Electroconvulsive therapy (ECT) mania 174, 180 psychosocial interventions 335–6 women’s health 255 Emotional warmth 375 Epidemiological Catchment Area (ECA) database 236, 302 Epilepsy historical overview 170 lamotrigine 53–4 levetiracetam 69 manic-depressive cycle 183 EPS, see Extrapyramidal symptoms (EPS) ERC-CBZ, see Carbamazepine ERK, see Extracellular signal-regulated kinase (ERK) pathway Esquirol, E. 184–5 Ethyl-EPA 73–4 Euphoric mania 32–3 Euthymia 87 Evolutionary theory 186 Exhaustion/depression 186 Extracellular signal-regulated kinase (ERK) pathway 37 Extrapyramidal symptoms (EPS) 85 antipsychotics 85 geriatric bipolar disorder 307 olanzapine 88, 98 risperidone 109–10

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Index Family-focused therapy (FFT) 316–17, 321–3, 325, 326–7 Family history 356, 371 Female, see Women’s health FFT, see Family-focused therapy (FFT) Floppy baby syndrome 254 Fluoxetine 47–8, 71, 73 acute bipolar depression 203 depressive recurrences 208–12 (hypo)manic switches 212 olanzapine combination therapy 92–5 Folate 153 Fosphenytoin 67 Functioning 376 Gabapentin bipolar disorder 206 mania 70 polytherapy 151–2 social phobia 221 GAP-43 protein 37–8 Gender distribution 235–7 antidepressants 242, 250–2, 255 atypicality 242 comorbidities 244–5, 252 course and outcome 243–4 epidemiology 235–7 mixed states 239–41, 245, 251 mood stabilizers 249–50 phenomenology 237–9 rapid cycling 240–2, 245, 246, 248 thyroid dysfunction 241–2, 245, 249–50 treatment of bipolar disorder 249–58 see also Women’s health Genetic counseling 380 Geriatric bipolar disorder 301–8 classification and subtypes 301–3, 308 comorbidities 301 determinants 303 management principles 303–4 mood stabilizers 304–7 Glomerular function 6 Glycogen synthase kinase 3 (GSK-3) 36 Griesinger, Wilhelm 169–70 Group psychoeducation 323–5 GSK-3, see Glycogen synthase kinase 3 (GSK-3)

393 Haloperidol 28, 66 acute mania 105–6 chlorpromazine comparison 106 combination therapy 108, 116–19 geriatric bipolar disorder 307 hormonal changes 108–9 lithium combination therapy 108 mania 105–8 mood stabilization 109, 116–19 olanzapine comparison 85–6, 98 risperidone comparison 112–16 side effects 116, 119–20 Hamilton Rating Scale for Depression (HAM-D) 47–8, 64, 86–8, 94–5 Heinroth, J. C. A. 169 Hepatic function, valproate 35 Homelessness 351, 384 Hormonal treatments 257–8 Hormone replacement therapy (HRT) 248, 258 Hospitalization 347–51 HRT, see Hormone replacement therapy (HRT) Hyperprolactinemia 250 Hyperthymia 181, 186 Hypomania antidepressant-associated 196, 212–15 care principles 382–4 depression 183 diagnostics 193–5 evolutionary theory 186 gender distribution 235–7 lamotrigine 50 mixed states 199–200 patient conception 172 polytherapy 146 psychosocial interventions 316 risperidone 110–19 suicidality 356 therapeutics 180 Hypomanic switches 213–15 Hypothyroidism 241, 249–50, 305 IFIT, see Integrated family and individual therapy (IFIT) IFPT, see Individually focused patient management (IFPT) Imipramine 71, 203–4, 208, 213, 215, 218 Individually focused patient management (IFPT) 323

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394 Integrated family and individual therapy (IFIT) 320–1 Interactions 45, 156, 157 Interactions, see Drug interactions Interpersonal and social rhythm therapy (IPSRT) 319–21, 325, 326–75, 337 Intoxication 16 IPSRT, see Interpersonal and social rhythm therapy (IPSRT) Irritability 29, 279 Janssen, Paul 105 Johnson, N. F. 173, 174 Kaplan-Meier survival rates 33–4 Kidney, see Renal function Kraepelin, E. 170, 182 183, 199–200 Lactation 16–17, 256–7 Lamotrigine 18–19, 43–59 acute bipolar depression 218–20 acute mood disturbances 46–8, 54–6 add-on therapy 46, 55 anti-excitatory effects 177–8 bipolar disorder 205–6 depression 43–4, 46–8, 50–1, 54–6 depressive recurrences 208–10, 217, 223 drug interactions 45–6 efficacy 43–4 geriatric bipolar disorder 307 maintenance therapy 49–51, 57 mania 48, 50, 56 mixed states 48, 56 pharmacodynamics 44–5 pharmacokinetics 45 polytherapy 151, 154 pregnancy 45, 57–8 rashes 51–3, 55 side effects 53–4 tolerability 53–4 women’s health 254, 257 Latent bipolar disorder 308 Levetiracetam 69 Levothyroxin (T4) 75 Lifestyle 172 Limit setting 375–6 Lithium carbonate 1, 10, 288, 289–91, 304–6

Index Lithium therapy 5 acute bipolar depression 203–4, 218–19 add-on therapy 68 alternative treatments 17–19 anxiety 220 benefits 21–2 Cade, J. F. J. 10 carbamazepine comparison 64–5 clinical trials 10–13, 17, 18 combination therapy 20, 55–6, 89–90, 96–8, 108, 116–19, 129 cycle sequence 174–5 depression 173 discontinuation 176 drug interactions 45–6 efficacy 12–14, 18 haloperidol comparison 108 historical overview 169 (hypo)manic switches 212–13 intoxication 16 laboratory considerations 5–6 lamotrigine comparison 50, 54 long-term prophylaxis 9–22 mania 169–73 methodology 13–14 olanzapine comparison 96–7 pediatric bipolar disorder 140–1, 286 polytherapy 138–41, 142, 154, 160 pregnancy and lactation 16–17 pretreatment evaluation 348 recurrent depressions 9, 10–13, 19–20, 207 relapse 95–7 renal function 15–16 resistance 135–60 serum concentration effects 15 side effects 15–17, 18 suicidality 20–1, 354–5 valproate comparison 28–38 women’s health 246–7, 249–50, 253, 256–7, 258 Lithium urate 10 Liver, see Hepatic function, valproate Lorazepam 67–8, 90–1, 106, 107 MADRS, see Montgomery-Asberg Depression Rating Scale (MADRS) Maintenance Therapies study 320

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Index Maintenance therapy lamotrigine 49–51, 57 olanzapine 95–7 psychosocial interventions 337–41 second generation antipsychotics 132 treatment setting 349 valproate 30–4 Major depressive disorder (MDD) 171 Mania anecdotal reports 179 antidepressant-associated 196, 202–15 antiepileptics 177–8 atypical antipsychotics 178 benzodiazepines 68 care principles 367 diagnostics 193 evolutionary theory 186 geriatric bipolar disorder 308 haloperidol 106–8 historical overview 169–73, 186 lamotrigine 48, 50, 56 lithium therapy 173–5 neuronal excitation 183–4 olanzapine 87–91, 97 oxcarbazepine 66 pediatric 279–81, 286–7, 291 pharmacological action 182 pharmacotherapeutic observations 173–9 primacy in bipolar cycles 169–87 psychosocial interventions 335 recreational stimulants 179 risperidone 119–19 second generation antipsychotics 126–30 secondary 308 suicidality 357–8 therapeutic implications 180–1 treatment setting 349–50 valproate 27–8, 29 Mania Rating Scale (MRS) 48 Mania with depressive features 29 Manic-depressive illness 171–3, 183–4 Manic switches 212–15 MAOIs, see Monoamine oxidase inhibitors (MAOIs) MARCKS protein 37–8 MDD, see Major depressive disorder (MDD) MDI pattern 243

395 MDMA 179 MDQ, see Mood Disorder Questionnaire (MDQ) Media 373 Menopause 248 Menstrual cycle 246–7 Mental health advocacy organizations 372–3 Migraine 151, 245 Minor bipolar disorder 236–7 Mixed states bipolar I 200–1 bipolar II 201–2 clinical management 223 diagnostics 199–202 gender distribution 239–40, 243, 250–1 historical overview 169 lamotrigine 48, 56 suicidality 357 Moncrieff, J. 12–13 Monitoring regimes 348–9 Monoamine oxidase inhibitors (MAOIs) 72 acute bipolar depression 203 (hypo)manic switches 212–15 polytherapy 135, 146 Montgomery-Asberg Depression Rating Scale (MADRS) haloperidol 116 lamotrigine 47–8 olanzapine 92–5 risperidone 115 Mood charting 375 Mood clinics 371–2, 381 Mood Disorder Questionnaire (MDQ) 243–4, 326 Mood stabilizers, see individual drugs MRS, see Mania Rating Scale (MRS) Multiple relapses 95–7 National Alliance for the Mentally Ill 326 National Institute of Mental Health (NIMH) 135–8, 142 Naturalistic trials 17 Nervous exhaustion 185 Neuroimaging techniques 302–3 Neuroleptics, see Antipsychotics; Atypical antipsychotics Neuronal excitation 183–4

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396 NIMH, see National Institute of Mental Health (NIMH) Nimodipine 74 Number needed to treat (NNT) 112–19 Obesity 245 Observer bias 12 Obsessive-compulsive disorder (OCD) 221–2 OFC, see Olanzapine-fluoxetine combination (OFC) Olanzapine 28, 35, 85–100 acute mania 87–91, 97 bipolar disorder 207, 222 clinical trials 86–7 combination therapy 87, 89–90, 92–5, 98–9 depression 92–5 depressive recurrences 208–9, 218, 223 efficacy 87–100 maintenance therapy 95–7 mania 75 mixed states 222 pediatric bipolar disorder 291 relapse 95–7 side effects 85, 97–100 tolerability 97–9 Olanzapine-fluoxetine combination (OFC) 207, 213 Olanzapine, mania 178 Old age, see Geriatric bipolar disorder Omega 3 fatty acids 73–4 Oral contraceptives 57, 246–7, 258 Oxcarbazepine 45, 66–7, 141, 307 Panic attacks 186, 220–1 PANSS-EC, see Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) Paroxetine 30, 47, 72, 203–4, 219 PCOS, see Polycystic ovarian syndrome (PCOS) Pediatric bipolar disorder 277–93 anxiety disorders 284–5 attention deficit hyperactivity disorder 281–3, 289, 291–2 atypicality of childhood mania 279–81 categorical and dimensional measures 285 comorbidities 281–6

Index conduct disorder 283–4 mania 279–81, 286–7, 289 polytherapy 140–1 substance use disorders 286 trauma 286–7 treatment 287–92 Personal relationships 316–17 Phenobarbital 45–6 Phenothiazines 307 Phenytoin 45–6, 67 Physical abuse 245 Physiological approaches 136, 148 Pinel, P. 169 PKC, see Protein kinase C (PKC) Placebo-controlled design 112 PMDD, see Premenstrual dysphoric disorder (PMDD) Polycystic ovarian syndrome (PCOS) 35, 250 Polytherapy atypical antipsychotics 135, 147, 154 care principles 380 case studies 145–7 chronic medical conditions 154–5 depression 142–5, 152–3 discontinuation 159–60 early intervention 158 inpatients 135–8 lithium-resistance 135–60 long-term prophylaxis 158–60 mechanistic rationales 155 outpatients 138–9 pediatric bipolar disorder 140–1 pharmacodynamics 157 pharmacokinetics 156–7 rapid cycling 141–3, 147–53 side effects 148, 155 targeted psychotherapy 157–8 treatment principles 147–54 Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) 91 Post-traumatic stress disorder (PTSD) 147, 286–7 Postpartum period 247–8, 256–7 Pregnancy bipolar disorder 245, 253–6 lamotrigine 45, 57–8 lithium therapy 16–17 valproate 38

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Index Premenstrual dysphoric disorder (PMDD) 246 Pretreatment evaluation 348–9 Primary bipolar disorder 308 Prolactin 108–9 Protein kinase C (PKC) 37 Psychiatrists 370–1, 376–9 Psychoanalysis 170 Psychoeducation 315–17, 323–6, 333–42, 379 Psychological aspects 3–5 Psychosis 5, 216, 321–3 Psychosocial interventions 313–28 acute episodes 335–7 care principles 373–82 cognitive-behavioral treatment 317–19, 325, 327, 336–7, community practice 325–6 discontinuation 314 empirical studies 317–25 family-focused therapy 316–18, 320, 321–2, 341 group psychoeducation 323–5 interpersonal and social rhythm therapy 319–21, 325, 326–7, 337 long-term treatment 333–42 maintenance therapy 337–41 objectives 315–17 psychoeducation 315–17, 323–6, 333–42, 379 rationale 314–15 recurrences 314, 316, 324–5 skill training 316 suicidality 361–2 Psychotherapy 157–8 PTSD, see Post-traumatic stress disorder (PTSD) Public health 1–3 Public opinion 373 Quality-adjusted life-years (QALY) 119 Quetiapine 116, 126–7, 128–9 bipolar disorder 205, 221 mixed states 220 pediatric bipolar disorder 140 Rapid cycling antidepressant-induced 215–16 bipolar disorder 49–50, 56

397 gender distribution 240–2, 244, 249–51 lithium therapy 173 polytherapy 141–2, 147–54 risperidone 119 second generation antipsychotics 132 Rashes 51–3, 55 Recreational stimulants 179 Recurrences antidepressant discontinuation 217–18 depression 9–13, 19–20, 208–9, 217, 220, 223 lithium discontinuation 176 long-term prevention 208–12 psychosocial interventions 313, 317, 325 Recurrent major depressive disorder 171 Refractory epilepsies 69 Refractory patients 135–160 Relationships 316–17 Renal function 15–16 Reproductive cycle 246–8 Risperidone 29, 35, 105, 109–20 clinical trials 112–19 combination therapy 116–19 economics 119 efficacy 112 gender distribution 250 haloperidol comparison 111–15 hypomania 111–19 long acting injection 110–11 mania 111–19 mood stabilization 116–19 pharmacokinetics 110 pharmacology 110 rapid cycling 119 side effects 111, 117, 119–20 SAD, see Seasonal affective disorder (SAD) Schizophrenia 1 antipsychotics 85–6 historical overview 169–70 risperidone 110, 111 suicidality 353 Seasonal affective disorder (SAD) 243 Second generation antipsychotics (SGAs) 125–32 Secondary mania 308 Sedation 106

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398 Selective serotonin reuptake inhibitors (SSRIs) 71–2 acute bipolar depression 203–5 anxiety 220 (hypo)manic switches 212–15 side effects 213 Serotonin-norepinephrine reuptake inhibitors (SNRIs) 151–2 Serotonin receptors 44 Sertraline 72 Sexual abuse 245 Sexual desire 379 SFBN, see Stanley Foundation Bipolar Network (SFBN) SGAs, see Second generation antipsychotics (SGAs) SJS, see Stevens-Johnson syndrome (SJS) Skill training 316 Sleep hygiene 378–9 SNRIs, see Serotonin-norepinephrine reuptake inhibitors (SNRIs) Social aspects 3–5 Social phobia 221 Societal views 373 Soft bipolar spectrum 1–3, 4 Spina bifida 253–4 SSRIs, see Selective serotonin reuptake inhibitors (SSRIs) Stanley Foundation Bipolar Network (SFBN) 72, 74, 138–9, 142 STEP, see Systematic Treatment Enhancement Program (STEP) Stevens-Johnson syndrome (SJS) 52–3 Substance-induced mood disorders 198 Substance use care principles 380 gender distribution 244–5 pediatric bipolar disorder 286 psychosocial interventions 325, 341 suicidality 357 Suicidality bipolar disorders 353–62 care principles 380 gender distribution 238–9 lithium therapy 20–1 mixed states 199 mood disorders 353–4 polytherapy 148, 151

Index preventative measures 357–62 psychopharmacotherapy 358–61 psychosocial interventions 361–2 selective serotonin reuptake inhibitors 251 therapeutic implications 180 treatment setting 347–8 valproate 35–6 Systematic Treatment Enhancement Program (STEP) 326 T3, see Tri-iodothyronin (T3) T4, see Levothyroxin (T4) Tardive dyskinesia 85–6, 111, 307 Targeted psychotherapy 157–8 TCAs, see Tricyclic antidepressants (TCAs) TEN, see Toxic epidermal necrolysis (TEN) Teratogenicity 16, 253–4 Thymoleptic activity 125–6 Thyroid dysfunction 241–2, 245, 249–50 Thyroid hormones 74–5 bipolar I 218–19 polytherapy 136, 142–5, 152–3 Thyroxin 153 Tiagabine 70 Tianeptine 71–2 Tolerability antipsychotics 85–6 lamotrigine 53–4 olanzapine 97–8 oxcarbazepine 67 valproate 34–5 Topiramate 69–70, 147, 151, 206–7 Toxic epidermal necrolysis (TEN) 52 Tranquillization 105–6 Trans-institutionalization 35 Tranylcypromine 72, 203 Trauma 286–7 Treatment-refractory patients 135–62 Treatment setting 347–51 Tri-iodothyronin (T3) 74–5 Tricyclic antidepressants (TCAs) 71–2 anxiety 220 cycle acceleration 215–16 depressive recurrences 208–9 (hypo)manic switches 212–13

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Index Valproate 18, 22, 27–38 acute bipolar depression 218–19 acute response 29–30 acute treatment 31–2 anxiety 220 bipolar disorder 205 carbamazepine comparison 64 combination therapy 28–9, 38, 58, 87–8, 96–8, 116–19 depression 30 depressive recurrences 208 discontinuation 32–3, 38 drug interactions 46 efficacy 28, 30 geriatric bipolar disorder 306 maintenance treatment 30–4 mania 27–8, 29, 177 mechanisms of action 36–8 olanzapine comparison 86–7, 96 pediatric bipolar disorder 140–1, 288–9, 290–1 polytherapy 140–1, 146, 150–1, 153, 156–7 pregnancy 38 serum concentration effects 33–4 side effects 34–5, 38 suicidal behavior 35–6 tolerability 34–5 women’s health 246, 249–50, 251, 253–4, 256–8 Valpromide 177 Venlafaxine 72, 152–3 Wehr, T. A. 172, 179 Weight management care principles 379 olanzapine 86, 98–100

399 polytherapy 147, 157 risperidone 111, 117 Women’s health 235–60 antidepressants 241, 250–6, atypicality 242 comorbidities 244–5, 252 course and outcome 243–4 depression 236–40 epidemiology 235–7 evaluation for bipolarity 258–9 hormonal treatments 257–8 lactation 16–17, 256–7 menopause 248 menstrual cycle 246–7 mixed states 239–42, 245, 251–2 phenomenology 237–9 postpartum period 247–8, 256–7 pregnancy 16–17, 38, 45, 57–8, 247, 253–6 rapid cycling 240–2, 245, 246, 248, 251 reproductive cycle 246–50 thyroid dysfunction 241–2, 245, 249–50 treatment of bipolar disorder 249–58 Young Mania Rating Scale (YMRS) haloperidol 115 olanzapine 87–90, 96–7 pediatric bipolar disorder 291 risperidone 115 Ziprasidone 125, 129 Zonisamide 69, 147