Bipolar Disorder: Clinical and Neurobiological Foundations

Bipolar Disorder

Bipolar Disorder: Clinical and Neurobiological Foundations Edited by Lakshmi N. Yatham and Mario Maj © 2010 John Wiley & Sons, Ltd. ISBN: 978-0-470-72198-8

Bipolar Disorder: Clinical and Neurobiological Foundations Editors Lakshmi N. Yatham Department of Psychiatry, The University of British Columbia, Vancouver, Canada

Mario Maj Department of Psychiatry, University of Naples SUN, Naples, Italy

This edition first published 2010, Ó 2010 by John Wiley & Sons, Ltd Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific, Technical and Medical business with Blackwell Publishing. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Other Editorial Offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. 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 or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. 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. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Web site is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Web site may provide or recommendations it may make. Furthermore, readers should be aware that Internet Web sites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Bipolar disorder : clinical and neurobiological foundations / editors, Lakshmi N. Yatham and Mario Maj. p. cm. Includes bibliographical references and index. ISBN 978-0-470-72198-8 (cloth) 1. Manic-depressive illness. I. Yatham, Lakshmi N. II. Maj, Mario, 1953– [DNLM: 1. Bipolar Disorder. WM 207 B6161 2010] RC516.B5223 2010 616.89’5—dc22 2010005586 ISBN: 9780470721988 A catalogue record for this book is available from the British Library. Set in 9.25/12pt, Palatino by Thomson Digital, Noida, India Printed in Singapore by Markono Print Media Pte Ltd 1

2010

Contents

Preface

vii

List of Contributors

ix

12 Genetics of Bipolar Disorder

Falk W. Lohoff and Wade H. Berrettini 13 Structural Brain Imaging in Bipolar Disorder

1 From Mania to Bipolar Disorder

1

2 Clinical Features and Subtypes of Bipolar

8

Fred K. Goodwin and D.Z. Lieberman 17

Lewis L. Judd and Pamela J. Schettler 31

Mark A. Frye and Giulio Perugi 44

Jan Fawcett 6 Update on the Epidemiology of Bipolar Disorder

52

62

69

Ivan J. Torres and Gin S. Malhi 83

90

R. Sabes-Figuera, D. Razzouk and Paul E. McCrone

Robert M. Post and Marcia Kauer-Sant’Anna

17 Molecular Biology of Bipolar Disorder

210

228

18 Mitochondrial Dysfunction and Oxidative

244

Tadafumi Kato, Flavio Kapczinski and Michael Berk 19 Neuroendocrinology of Bipolar Illness

255

Timothy Dinan and Michael Bauer Disorder

21 Treatment Adherence in Bipolar Disorder

263

96

275

Jan Scott and Mary Jane Tacchi 22 Acute Mania

11 An Introduction to the Neurobiology of Bipolar

Illness Onset, Recurrence and Progression

16 Neurotransmitter Systems in Bipolar Disorder

Greg Murray and Allison Harvey

Hagop S. Akiskal and Kareen K. Akiskal 10 Economics of Bipolar Disorder

200

20 Circadian Rhythms and Sleep in Bipolar

9 The Genius-Insanity Debate: Focus on Bipolarity,

Temperament, Creativity and Leadership

Disorder: Focus on Cerebral Metabolism and Blood Flow

Stress

Zolt an Rihmer and Jan Fawcett 8 Neurocognition in Bipolar Disorder

In Kyoon Lyoo and Perry F. Renshaw

Ana Andreazza, Jun Feng Wang and Trevor Young

Kathleen R. Merikangas and Tracy L. Peters 7 Suicide and Bipolar Disorder

133

Marina Nakic, John H. Krystal and Zubin Bhagwagar

5 DSM-V Perspectives on Classification

of Bipolar Disorder

Diffusion Tensor Imaging, and Magnetic Resonance Spectroscopy in Bipolar Disorder

John O. Brooks III, Po W. Wang and Terence A. Ketter

4 Comorbidity in Bipolar Disorder: A Focus on

Addiction and Anxiety Disorders

Paolo Brambilla and Jair C. Soares

15 Functional Brain Imaging Studies in Bipolar

3 The Long-Term Course and Clinical Management

of Bipolar I and Bipolar II Disorders

124

14 Functional Magnetic Resonance Imaging,

David Healy Disorder

110

285

Paul E. Keck, Jr, Susan L. McElroy and John M. Hawkins

v

vi

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Contents

23 Pharmacological Treatment of Bipolar

Depression

31 Psychoeducation as a Core Element of

294

Allan H. Young and Charles B. Nemeroff

32 Cognitive-Behavioural Therapy for Bipolar

304

Alan C. Swann

342

353

367

36 Bipolar Disorder in Women

463

Benicio N. Frey, Karine A. Macritchie, Claudio N. Soares and Meir Steiner

Chris J. Bushe and Mauricio Tohen 29 Somatic Treatments for Bipolar Disorder:

384

37 Phenomenology and Treatment of Bipolar

I Disorder in Children: A Critical Review

Mark S. George

477

Gabrielle A. Carlson and Elizabeth B. Weller

30 Novel Therapeutic Strategies for Bipolar

Rodrigo Machado-Vieira, Husseini K. Manji and Carlos A. Zarate Jr

453

Amy M. Kilbourne, David E. Goodrich and Mark S. Bauer

28 Bipolar Disorder and Safety Monitoring

Disorder

443

David J. Miklowitz 35 Collaborative Care for Bipolar Disorder

Ihsan M. Salloum, Luca Pani and Tiffany Cooke

ECT, VNS and TMS

430

Holly A. Swartz, Ellen Frank, Laura E. Zajac and David J. Kupfer Disorder

27 Management of Comorbidity in Bipolar

for Clinicians: A Review of the Evidence and the Implications

Bipolar Disorder

34 Family Therapy Approaches to Bipolar

Gordon Parker and Terence A. Ketter Disorder

422

33 Interpersonal and Social Rhythm Therapy for

333

Joseph F. Goldberg and Michael Berk 26 Management of Bipolar II Disorder

Disorder Sagar V. Parikh and Jan Scott

25 Rapid Cycling Bipolar Disorder:

Phenomenology and Treatment

412

Francesc Colom and Lesley Berk

24 Practical Pharmacological Maintenance

Treatment of Bipolar Disorder

Psychological Approaches for Bipolar Disorders

395

38 Bipolar Disorder in the Elderly

488

Martha Sajatovic and Lars Vedel Kessing Index

499

Preface

Bipolar disorder is a relatively recent concept, which emerged in the middle of the 20th century. However, bipolar disorder is not a new disease. Indeed, Aretaeus of Cappadocia, in his descriptions, captured the essence of the nature and course of mood changes of mania and depression almost 2000 years ago. The objective of this book is to describe the clinical and neurobiological foundations of the modern concept of bipolar disorder as defined by the American Psychiatric Association’s Diagnostic Manual of Mental Disorders and the International Classification of Diseases. In order to capture both the American and the international perspectives, the editors deliberately chose authors from different continents for most chapters. The book is divided into four sections. The first section covers the descriptive aspects of the disorder. This section begins with an historical overview of the evolution of the concept of bipolar disorder. While Dr. Healy admits that bipolar disorder is a distinct clinical entity, he argues that the boundaries of the modern concept of bipolar disorder have been shaped primarily by the interests of the industry over the past 15 years. The next two chapters review clinical features, course and outcome in the context of new data and suggest that depressive symptoms dominate the course of bipolar disorder and that the disorder is chronic for a significant proportion of patients. Comorbidity is the rule rather than an exception for bipolar patients and this chapter illustrates some of the common comorbidities patients with bipolar disorder experience. Dr. Fawcett then outlines the DSM-V process and some of the issues that the DSM-V will address with regard to classification of bipolar disorder in the next chapter. The remaining chapters in this section emphasize that bipolar disorder is common, associated with cognitive impairment in a significant proportion of patients, that suicide risk is high, and that the disorder is

associated with significant economic burden. This section also contains a fascinating review of the genius–insanity debate. The biological aspects section begins with an overview of the neurobiology of bipolar disorder by Robert Post. Subsequent chapters address in greater detail some of the following questions: what is the current status with regard to the search for bipolar susceptibility genes? What brain regions and brain chemicals are altered in bipolar patients? Are changes in neurotransmitters and neurohormones still relevant or are changes in post-receptor signalling pathways more critical to the neurobiology of bipolar disorder? Is bipolar disorder associated with oxidative stress, mitochondrial dysfunction or alterations in biological rhythms? Treatment adherence is a major challenge in the management of bipolar disorder. Thus, the section on management begins with an overview of reasons for non-adherence and strategies to improve adherence. This is followed by a series of chapters that describe the current status of the pharmacological management of various phases and subtypes of bipolar disorder. This section also contains chapters that review the role of novel treatments, somatic treatments, and safety monitoring, as well as the role of psychological treatments as adjuncts to pharmacotherapy. The final section on special populations provides clinicians with the latest information and guidance on the management of bipolar disorders in women, children and the elderly. We hope that this book will become a useful resource for psychiatrists and other health care professionals to improve their understanding and management of bipolar disorder. Lakshmi N. Yatham Mario Maj

vii

List of Contributors

Hagop S. Akiskal University of California at San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161-9116, USA Kareen K. Akiskal International Mood Center, La Jolla, CA 92093-0603, USA

John O. Brooks III Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, B8-233b NPI, Los Angeles, CA 90024-1759, USA

Ana Andreazza Department of Psychiatry, University of British Columbia, 2255 Westbrook Mall, Vancouver, BC V6T 2A1, Canada

Chris J. Bushe Lilly UK, Lilly House, Priestley Road, Basingstoke, RG24 9NL, UK

Mark S. Bauer Center for Organization, Leadership, and Management Research (152M), Boston VA Healthcare System, 150 South Huntington Avenue, Boston, MA 02130, USA

Gabrielle A. Carlson Department of Child and Adolescent Psychiatry, Stony Brook University School of Medicine, Putnam Hall-South Campus, Stony Brook, NY 11794-8790, USA

Michael Bauer Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universita¨t Dresden, Fetscherstraße 74, D-01307 Dresden, Germany Lesley Berk ORYGEN Research Centre and Department Clinical & Biomedical Sciences, University of Melbourne, Victoria, Australia Michael Berk Barwon Health and the Geelong Clinic, University of Melbourne, Kitchener House, Ryrie Street, Geelong, Victoria 3220, Australia Wade H. Berrettini University of Pennsylvania School of Medicine, Room 2206, 125 South 31st Street, Philadelphia, PA 19104, USA Zubin Bhagwagar Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA; Bristol Myers Squibb, USA Paolo Brambilla Inter-University Center for Behavioural Neurosciences, Department of Pathology and Experimental & Clinical Medicine, Section of Psychiatry, University of Udine, Udine, Italy

Francesc Colom Bipolar Disorders Program, Clinical Institute of Neuroscience, IDIBAPS-CIBERSAM, Hospital Clinic Barcelona, University of Barcelona, Barcelona, Catalonia, Spain Tiffany Cooke Emory University, Rollins School of Public Health, 1518 Clifton Road Northeast Atlanta, GA 30329, USA Timothy Dinan Department of Psychiatry, Cork University Hospital, Wilton, Cork, Ireland Jan Fawcett Department of Psychiatry, University of New Mexico School of Medicine, National Institute of Albuquerque, Albuquerque, NM 87131, USA Ellen Frank Department of Psychiatry and Department of Psychology, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA ix

x

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List of Contributors

Benicio N. Frey Department of Psychiatry and Behavioural Neurosciences, McMaster University and Women’s Health Concerns Clinic, St. Joseph’s Healthcare, Hamilton, ON, Canada

Marcia Kauer-Sant’Anna Molecular Psychiatry Laboratory, Department of Psychiatry, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil

Mark A. Frye Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street, Rochester, MN 55905, USA

Paul E. Keck, Jr. Lindner Center of HOPE and Department of Psychiatry, University of Cincinnati College of Medicine, 4075 Old Western Row Road, Mason, OH 45040, USA

Mark George Brain Stimulation Laboratory, MUSC IOP, Radiology and Neurosciences Medical University of South Carolina, 67 President Street, Room 502 North, PO Box 250861, Charleston, SC 29425, USA

Lars Vedel Kessing Department of Psychiatry, Rigshospitalet, University Hospital of Copenhagen, 2100 Copenhagen, Denmark

Joseph F. Goldberg Mount Sinai School of Medicine, New York, NY, USA David E. Goodrich VA Ann Arbor National Serious Mental Illness Treatment Research and Evaluation Center, 2215 Fuller Road, Ann Arbor, MI 48105, USA Fred K. Goodwin Department of Psychiatry and Behavioral Sciences, Center on Neuroscience, Medical Progress, and Society, George Washington University Medical Center, Washington, DC 20037, USA

Terence A. Ketter Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 2124, Stanford CA 94305, USA Amy M. Kilbourne VA Ann Arbor Serious Mental Illness Treatment Research and Evaluation Center, 2215 Fuller Road, Ann Arbor, MI 48105, USA John H. Krystal Department of Psychiatry, Yale University School of Medicine, Yale-New Haven Hospital, 300 George Street, Suite 901, New Haven, CT, 06511, USA

Allison Harvey Psychology Department, Sleep and Psychological Disorders Lab, University of California, 3210 Tolman Hall, Berkeley, CA 94720-1650, USA

David J. Kupfer Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA

John M. Hawkins Lindner Center of HOPE; Associate Professor, Department of Psychiatry, University of Cincinnati College of Medicine, 4075 Old Western Row Road, Mason, OH 45040, USA

D.Z. Lieberman George Washington University Medical Center, 2150 Pennsylvania Avn., NW, Department of Psychiatry and Behavioral Sciences, 8th Floor, Washington, DC 20037, USA

David Healy Hargest Unit, North Wales Department of Psychological Medicine, Cardiff University, Ysbyty Gwynedd, Bangor, LL57 2PW, UK

Falk W. Lohoff University of Pennsylvania School of Medicine, Department of Psychiatry Center for Neurobiology and Behavior Translation Research Laboratories., 125 South 31st Street, Room 2213, Philadelphia, PA 19104, USA

Lewis L. Judd Department of Psychiatry, University of California at San Diego (UCSD), 9500 Gilman Drive, MC: 0603, La Jolla, CA 92093-0603, USA

In Kyoon Lyoo Seoul National University, Seoul, South Korea

 vio Kapczinski Fla ISBD Hospital de Clinicas, UFRGS Brizil Porto Alegre, RS, Brazil

Rodrigo Machado-Vieira Experimental Therapeutics, Mood and Anxiety Disorders Research Program, NIMH-NIH, Bldg 15K, 15 North Drive, MSC 2670, Bethesda, MD 20892, USA

Tadafumi Kato Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Hirosawa 2-1, Wako, Saitama, 350-0198, Japan

Karine A. Macritchie Institute of Mental Health, Department of Psychiatry, University of British Columbia, Suite 403 - 5950 University Blvd., Vancouver, BC V6T 1Z3, Canada

List of Contributors

Gin S. Malhi Department of Psychiatry, University of Sydney, CADE (Clinical Assessment Diagnostic Evaluation) Clinic, Royal North Shore Hospital, Sydney, Australia Husseini K. Manji Johnson & Johnson Pharmaceuticals Group, 1125 Trenton-Harbourton Road, E32000, Titusville, NJ 08560, USA Paul E. McCrone Centre for the Economics of Mental Health, Section of Community Mental Health Service and Population Research, Department PO24, Institute of Psychiatry, King’s College, De Crespigny Park, London SE5 8AF, UK Susan L. McElroy Lindner Center of HOPE and Department of Psychiatry, University of Cincinnati College of Medicine, 4075 Old Western Row Road Mason, OH 45040, USA Kathleen R. Merikangas Genetic Epidemiology Research Branch, Porter Neuroscience Research Centre, National Institute of Mental Health, Building 35, Room 1A-201, 35 Convent Drive, MSC 3720, Bethesda, MD 20892-3720, USA David J. Miklowitz UCLA Semel Institute for Neuroscience and Human Behavor Division of Child and Adolescent Psychiatry, 760 Westwood Plaza, Rm 58-217 David Geffen School of Medicine at UCLA, Los Angeles, CA 90024-1759, USA Greg Murray Faculty of Life and Social Sciences, Swinburne University of Technology, PO Box 218 John Street, Hawthorn 3122, Australia Marina Nakic Department of Psychiatry, Yale University School of Medicine, Yale-New Haven Hospital, 300 George Street, Suite 901, New Haven, CT, 06511, USA Charles B. Nemeroff Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami FL, USA Luca Pani Istituto Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Sede di Cagliari-Pula and PharmaNess Scarl, Edificio 5 - Parco Scientifico e Tecnologico della Sardegna - 09010 Pula (Cagliari), Italy Sagar V. Parikh Department of Psychiatry, University Health Network, University of Toronto, Room 9M-329, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada

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xi

Gordon Parker School of Psychiatry, University of New South Wales (UNSW), New South Wales, Australia 2031; Black Dog Institute, Hospital Road, Prince of Wales Hospital, Ranwick, NSW 2031, Australia Giulio Perugi Department of Psychiatry, University of Pisa; Institute of Behavioural Sciences “G. De lisio”, Viale Monzone 3, 54031 Carrara, Italy Tracy L. Peters Genetic Epidemiology Research Branch, Mood and Anxiety Program, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Porter Neuroscience Research Center, Building 35, Room 1A-201, 35 Convent Drive, Bethesda, MD 20892-3720, USA Robert M. Post George Washington University Medical School, Bipolar Collaborative Network, 5415 W. Cedar Kabem Suite 201B, Bethesda, MD 20814, USA D. Razzouk Department of Psychiatry, Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil Perry F. Renshaw University of Utah, Salt Lake City, UT USA  n Rihmer Zolta Department of Clinical and Theoretical Mental Health, and Department of Psychiatry and Psychotherapy, Semmelweis Medical University, Ku´tvo¨lgyi Clinical Centre, Budapest, Hungary R. Sabes-Figuera Centre for the Economics of Mental Health, Health Service and Population Research Department PO24, Institute of Psychiatry, King’s College, De Crespigny Park, London SE5 8AF, UK Martha Sajatovic University Hospitals Case Medical Center, 10524 Euclid Avenue, Cleveland, OH 44106, USA Ihsan M. Salloum Department of Psychiatry, University of Miami Miller School of Medicine, 1120 NW 14th Street, Rm 1450, Miami, FL 33136, USA Pamela J. Schettler Mood Disorders Research Group, Department of Psychiatry, University of California at San Diego (UCSD), 9500 Gilman Drive, La Jolla, CA 92093-0603, USA

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List of Contributors

Jan Scott University Department of Psychiatry, Newcastle University, Institute of Psychiatry, Institute of Neuroscience, Newcastle-upon-Tyne NE1 4RU, UK Claudio N. Soares Department of Psychiatry and Behavioural Neurosciences, McMaster University and Women’s Health Concerns Clinic, St. Joseph’s Healthcare, Hamilton, ON, Canada Jair C. Soares Department of Psychiatry and Behavioral Sciences, UT Houston Medical School, Houston, TX, USA Meir Steiner Department of Psychiatry and Behavioural Neurosciences, McMaster University and Women’s Health Concerns Clinic, St. Joseph’s Healthcare, Hamilton, ON, Canada Alan C. Swann Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, 1300 Moursund Street, Houston, TX 77037, USA Holly A. Swartz Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA Mary Jane Tacchi Institute of Psychiatry, Institute of Neuroscience, Newcastle University, Newcastle-upon-Tyne, NE1 7RU, UK Mauricio Tohen University of Texas Health Science Center at San Antonio, 7730 Floyd Curl Drive, San Antonio, TX 78229, USA



Sadly, Elizabeth B. Weller died during preparation of the manuscript

Ivan J. Torres Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; Riverview Hospital, British Columbia Mental Health and Addictions Services, 2601 Lougheed Highway, Coquitlam, BC V3C 4J2, Canada Jun Feng Wang Department of Psychiatry, University of British Columbia, 2255 Westbrook Mall, Vancouver, BC V6T 2A1, Canada Po W. Wang Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA Elizabeth B. Weller Deceased Allan H. Young Institute of Mental Health, Department of Psychiatry, University of British Columbia, Suite 430, 5950 University Blvd., Vancouver, BC V6T 1Z3, Canada Trevor Young, MD Department of Psychiatry, University of British Columbia, 2255 Westbrook Mall, Vancouver, BC V6T 2A1, Canada Laura E. Zajac Department of Psychology, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA Carlos A. Zarate, Jr. Experimental Therapeutics, Mood and Anxiety Disorders Research Program, National Institute of Mental Health (NIMH-NIH), Bldg 15K, 15 North Drive, Bethesda, MD 20892-2670, USA

Plate 1 Sample magnetic resonance spectroscopy spectra from P31 MRS at 2T (A) and from H1 MRS at 3T (B). Abbreviations: ATP, adenosine tri-phosphate; MRS, Magnetic Resonance Spectroscopy; PCr, Phosphocreatine; PDE, Phosphodiesters; Pi, Inorganic Phosphate; PME, Phosphomonoesters; T, Tesla. (a) A sample P31 spectra is shown. Reprinted from [3]. Association between cortical metabolite levels and clinical manifestations of migrainous aura: An MR-spectroscopy study. Brain;130:3102–3110, by permission of Oxford University Press. (b) A sample H1 spectra is shown. Reprinted from [4]. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol. Psych.; 64:718–726, by permission of Elsevier.

Plate 2 Schematic presentation of the findings from cross-sectional H1 MRS and P31 MRS studies that show differences in brain metabolite levels between adult patients with bipolar disorder and comparison subjects. Abbreviations: Cho, Choline; Cr, Creatine; Glx, Glutamate, Glutamine and g-amino butyric acid; MRS, Magnetic Resonance Spectroscopy; NAA, N-acetylaspartate; PCr, Phosphocreatine; PME, Phosphomonoesters. Regular triangles represent higher brain metabolite levels or metabolite/Cr þ PCr ratios in patients with bipolar disorder relative to comparison subjects. Inverted triangles represent lower metabolite levels or metabolite/Cr þ PCr ratios in patients with bipolar disorder relative to comparison subjects. Rectangles represent no differences in metabolite levels or metabolite/Cr þ PCr ratios between patients with bipolar disorder and comparison subjects. Bipolar Disorder: Clinical and Neurobiological Foundations Edited by Lakshmi N. Yatham and Mario Maj © 2010 John Wiley & Sons, Ltd. ISBN: 978-0-470-72198-8

Plate 3 Schematic presentation of the findings from longitudinal H1 MRS studies that examine medication effects on brain metabolite levels in adult patients with bipolar disorder. Abbreviations: Cho, Choline; Cr, Creatine; Glx, Glutamate, Glutamine and g-amino butyric acid; HDRS, 17-item Hamilton Depression Rating Scale; MRS, Magnetic Resonance Spectroscopy; NAA, N-acetylaspartate. (a) Lithium effects on brain metabolite levels in patients with bipolar disorder. Regular triangles represent increase in brain metabolite levels or metabolite/Cr þ PCr ratios in patients with bipolar disorder after lithium treatment compared to those in their baseline. Inverted triangles represent decrease in brain metabolite levels or metabolite/Cr þ PCr ratios in patients with bipolar disorder after lithium treatment compared to those in their baseline. Rectangles represent no changes in metabolite levels or metabolite/Cr þ PCr ratios in patients with bipolar disorder after lithium treatment. (b) Cytidine effect on brain metabolite levels and depressive symptoms in depressed patients with bipolar disorder. Bars represent estimated glutamate/glutamine changes from baseline in cytidine and placebo add-on patients with bipolar depression. P values above the bars indicate significant difference between treatment groups in rates of decreasing glutamate/glutamine levels throughout the treatment period with mixed-effect regression model. Squares and trend lines represent the estimated HDRS score in cytidine and placebo add-on patients with bipolar depression. Asterisks represent p < 0.01 significant difference between treatment groups in rates of improvement in HDRS scores from Week 1 through Week 4 with mixed-effect regression model. (Copied from Yoon et al. [Yoon, S.J., Lyoo, I.K., Haws, C., Kim, T.S., Cohen, B.M., Renshaw, P.F., in press. Decreased glutamate/glutamine levels may mediate cytidine’s efficacy in treating bipolar depression: A longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology.]. Courtesy should be sought).

Plate 4 Regions of increased and decreased FA in patients with bipolar disorder relative to comparison subjects. Abbreviations: Ant, Anterior; Post, Posterior; Sup, Superior. Red circles represent higher FA in patients with bipolar disorder relative to comparison subjects, blue circles represent lower FA in patients with bipolar disorder relative to comparison subjects. Parcellated white matter mask is adapted from stereotaxic white matter atlas [122].

Plate 5 Regions of increased and decreased activation under emotional processing tasks in patients with bipolar disorder. Abbreviations: Sup, Superior; Mid, Middle; Inf, Inferior. Regions of increased (red circle) and decreased (blue circle) activation under emotional processing tasks in patients with bipolar disorder from the Table .8. Regions were marked based on the Talairach coordinates, Brodmann areas or anatomical description in the literature. In patients with bipolar disorder, there were abnormal cortical and subcortical activations in the brain regions including prefrontal and temporal cortex, striatum, thalamus and amygdala when taking emotional processing tasks such as the facial affect recognition and emotional Go-NoGo tasks relative to comparison subjects.

Plate 6 A model of corticolimbic dysregulation in bipolar disorder. Areas generally associated with increased activation in bipolar disorder are in red and those with decreased activation are in blue. Note that colour-coding of regions is intended to represent the consensus findings for the region, because all findings have not been uniform. Numbers for BAs are provided where appropriate. ACC ¼ anterior cingulate cortex; AMYG ¼ amygdala; ATC ¼ anterior temporal cortex; CV ¼ cerebellar vermis; DLPFC ¼ dorsolateral prefrontal cortex; HYPTH ¼ hypothalamus; MOFC ¼ medial orbital prefrontal cortex; PHG ¼ parahippocampal gyrus; SGPFC ¼ subgenual prefrontal cortex; THAL ¼ thalamus; VLPFC ¼ ventrolateral prefrontal cortex. From Brooks et al. [6].

Plate 7 Metabolic changes associated with bipolar depression relative to healthy controls. Decreased absolute metabolism is in blue. From Brooks et al. [6].

Plate 8 Metabolic changes associated with bipolar mania relative to healthy controls. Regions with decreased metabolism are in blue, and increased metabolism in red. From Brooks et al. (2010).

Plate 9 Resting state cerebral metabolic differences in older, euthymic patients with bipolar disorder compared to healthy controls. Regions with increased metabolism in bipolar disorder patients are in red and those with decreased metabolism are in blue. From Brooks et al. [6].

CHAPTER

1

From Mania to Bipolar Disorder David Healy Hargest Unit, North Wales Department of Psychological Medicine, Cardiff University, Ysbyty Gwynedd, Bangor, UK

From Pinel to Kraepelin When the first asylums opened, around 1800, mania was a generic term for insanity. Philippe Pinel’s Treatise on Insanity that appeared in 1800 was accordingly named Trait
e sur la Manie. For 2000 years before Pinel, the chief determinant of diagnosis in medicine lay in the visible presentation of the patient. These visible presentations could lead to reliable diagnoses of tumours, diabetes, catatonia, epilepsy and insanity. The visible presentations of insanity involved flushing, overactivity and maniacal behaviour. Mania was diagnosed in patients who were overactive and who might now be seen as having schizophrenia, depression, delirium, senility, imbecility and other conditions. Pinel took a stand on the importance of science in medicine, and was the first to call for an Evidence Based Medicine. Faced with patients hospitalized for years, he was the first to incorporate the course of a patients’ disorders into his diagnostic considerations. He recorded outcomes where patients were treated or left untreated, and noting responses followed by relapses, argued that some disorders were periodic or recurrent and that the vast majority of available treatments made the underlying condition worse. When a final and more complete version of his treatise was published in 1809, it distinguished in its title, Trait
e M
edico-Philosophique sur l’Ali
enation Mentale ou la Manie, between insanity in general and a new, more specific diagnosis of mania [1]. Once this distinction was made, and mania was separated out from idiocy dementia and melancholia, the rates of admission for mania settled at approximately 50% of all admissions in asylums in Europe and America until around 1900. While asylum nomenclature remained relatively constant for a century, there was an evolution in the thinking about insanity. The idea that there might be a distinct mood faculty that could be disordered in its own right was put forward in

Bipolar Disorder: Clinical and Neurobiological Foundations Edited by Lakshmi N. Yatham and Mario Maj © 2010 John Wiley & Sons, Ltd. ISBN: 978-0-470-72198-8

the 1830s by one of Pinel’s pupils, Jean-Dominique Etienne Esquirol, who described profound sadness – lypemanie – as a distinct disorder. The notion of a disease entity took shape in the 1850s when two of Esquirol’s pupils, Jean-Pierre Falret and Jules Baillarger, both described disorders that laid the basis for what became circular insanity. Falret outlined folie circulaire; Baillarger termed his disorder folie a double forme [2]. The idea that mania or insanity might give rise to protean manifestations had posed little difficulty, but as clinicians moved towards the concept of a disease entity, they had difficulties with the idea that two clinical states that looked so different might be presentations of the same underlying disease state. In their efforts to overcome these conceptual problems, both Falret and Baillarger posited a disorder with alternating cycles of mania and melancholia of fixed length and with fixed intervals between episodes. But crucially if neither the superficial features of mania nor the superficial features of melancholia accounted for the disorder, then some common ground between them must be responsible for the disorder. Some substrate must be diseased. The new disorder was not one that commanded clinical attention. Both men conceded that what they were describing was a rare condition. The condition described was moreover at this point not clearly a mood disorder. Others described alternating or circular insanity. None of these states were bipolar affective disorder, as that term would be understood today. The first to approach modern bipolar disorder was Karl Kahlbaum who in 1883 described cyclothymia. Where circular insanity was a psychotic disorder, with regular and stable features that led to degeneration, cyclothymia was for Kahlbaum a specific mood disorder from which patients could recover. Kahlbaum also introduced disease course as a classificatory principle, but this was resisted. Most academics at the time expected a localization of clinical features in different brain areas to provide the key to unlocking the mysteries of mental illness rather than disease course. However disease course was used by Charcot to distinguish between hysteria and Tourette’s syndrome, and later to distinguish between Alzheimer’s and Creutfeld-Jacob disease. 1

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Manic-depressive illness In 1899, building on a series of syndromes first outlined by Kahlbaum, and on his principle of disease course, but eschewing brain localization, Emil Kraepelin distinguished between two disease entities – dementia praecox and manicdepressive insanity [3]. Dementia praecox was a disorder of cognitive function where the sufferer never returns to normal. Within this group, Kraepelin included three disorders outlined by Kahlbaum – hebephrenia, catatonia and paranoia. Given that clinical course was to be the main determinant of disease status, if in the one case recovery was to be the exception, there had to be a contrasting state in which recovery was the norm. Manic-depressive illness therefore emerged as the foil to dementia praecox. Kraepelin’s manicdepressive illness was a disorder where sufferers recovered from acute episodes but were at risk of a relapse. For Kraepelin, a bipolar alternation between excitement and stupor could not be a classificatory principle in that a similar alternation happens in many states of dementia praecox or general paralysis of the insane. But periodic, circular and simple manias, in addition to melancholic disorders, could all be regarded as manifestations of the one illness if they showed a remitting course. Involutional melancholia brings out the rigidity with which Kraepelin held to a disease course criterion. These classic depressive psychoses had their onset over the age of 50, when patients typically presented with disturbed sleep and appetite, diurnal variation of mood and either paranoid, nihilistic or guilt-laden delusions. In 1899 Kraepelin thought that these patients were much less likely to recover than other patients with mood disorders. Clinicians now would have no doubt that this condition was a mood disorder. However, because involutional melancholia apparently failed to remit, it posed difficulties for Kraepelin. As a result, he kept involutional melancholia separate from manic-depressive illness until the eighth edition of his textbook. Kraepelin’s distinctions between two almost identical clinical presentations (involutional and non-involutional melancholias) and amalgamation of what appeared to be quite different clinical presentations (unipolar and bipolar affective disorders) produced an illness concept that almost certainly baffled many of his contemporaries. The puerperal psychoses further clouded the diagnostic picture. Kraepelin’s compelling descriptions of a characteristic confusion and fleeting hallucinatory features in these psychoses, as well as their unstable cycling states, made a good case for a separate diagnosis to either dementia praecox or manic-depressive illness. But his disease course criterion left him no option but to argue that they were in all cases either manic-depressive insanity or dementia praecox.

Between these puerperal psychoses and good prognosis psychoses with cycloid features, there was a group of patients accounting for close to 10% of admissions for serious mental illness, double the number of admissions for bipolar affective disorder, but these all disappeared from view, because polarity did not count for Kraepelin as a classificatory principle.

The reception of manic-depressive illness – the academic response When Kraepelin’s work was discussed both within and outside of Germany, it was largely in terms of dementia praecox. For a quarter of a century, there was little mention of manic-depressive illness. In America, Kraepelin’s clinical approach was welcomed by Adolf Meyer as the breakthrough psychiatry was waiting for, although he later criticized it as being too neurological, and failing to place the patient’s disorder within the context of their life story. In Britain, there were regular references to Kraepelin’s work at psychiatric meetings and in the academic literature, in a way that did not happen with other German formulations [4]. These references were to dementia praecox; some disliked the term dementia and some disliked praecox, but the concept was widely discussed, whereas manicdepressive illness was rarely raised. The French did not accept that all psychotic disorders had the same degenerative clinical course, distinguishing instead between acute and chronic psychoses and amongst a variety of chronic non-deteriorating psychoses. The discovery of chlorpromazine in France validated traditional distinctions between the chronic psychoses and schizophrenia, on the basis that schizophrenia was poorly responsive to antipsychotics [5]. Nevertheless, from 1900, dementia praecox swept rapidly into use for a number of reasons. First, many psychiatrists had been struggling with the same issues and had come up with variants of the same idea from primary dementia to adolescent insanity. Kraepelin’s formulation balanced simplicity and complexity. It was more complex than simply adolescent insanity but much simpler than making distinctions amongst the chronic psychoses, as the French and Kahlbaum had done. Second, before 1900, diagnoses across medicine were made on the basis of the visible presentations of patients at admission, giving rise to diagnoses of consumption, ague, debility or mania. These diagnoses were essentially descriptions of the presenting problem. Following the triumph of bacteriology, after 1900 there was a move to defer diagnoses to later in the course of the admission, after the appropriate laboratory tests had been done and there had been more time to consider which, amongst a number of differential diagnoses, best accounted for the features of the illness. This

From Mania to Bipolar Disorder

The reception of manic-depressive illness: a typical asylum The North Wales Asylum, which opened in 1848, offers an opportunity to look at the uptake of concepts like Kraepelin’s. In North West Wales, the overall population and ethnic mix was almost precisely the same in 2000 as it had been in 1900. Elsewhere, because of geography and rising wealth, a growing number of people had a choice of hospitals. Because of this choice, it is difficult to know how representative patients, ending up in the public or private asylums across the Western world between 1800 and 1950, were of the mental illness happening in their communities of origin. In North West Wales, because of enduring poverty and geography, those with mental illnesses had nowhere to go except to one asylum. The resulting asylum records and case registers for modern admissions shed light on a number of issues. The first is the impact of Kraepelin’s diagnoses of dementia praecox and manic-depressive illness on clinical practice within Britain. The second set of issues has to do with quantitative aspects of the syndromes underpinning Kraepelin’s diagnoses. The first thing that strikes any reader of the asylum records is that up until 1900 over 50% of patients admitted apparently had mania (Figure 1). As late as 1900, patients who were suicidal, patients with senility, and patients with what now would be called schizophrenia, were all labelled as manic. However, manic-depressive illness was not dramatically more common 100 years ago than it is now. The

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The Diagnosis of Mania as a Percentage of all Admissions to the North Wales Asylum: 1875-1924 60 50 40 30 20 10 0 20

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95

00

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85

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applied also to psychiatry, so that from 1900 diagnoses were less likely to be made on admission, bringing the likely chronicity of a patient’s illness to the fore as a diagnostic feature. The time was convenient for Kraepelin’s new ideas. In contrast, while there were many formulations of early onset dementia, Kraepelin’s manic-depressive illness concept was quite idiosyncratic. The new illness also introduced a new nomenclature. Why manic-depressive illness? Why not manic-melancholic disease, given that almost all the ‘depressions’ Kraepelin was faced with were melancholic in terms of their severity and clinical features? The answer may lie in a quirk in the man – he had a partiality for novelty. Melancholia was an old-fashioned word. Depression was creeping into use. The first major paper on depressive illness had come a few years earlier, in 1886, from the Danish neurologist Carl Lange [6]. When it came to manic-depressive insanity, Kraepelin’s concept may have ultimately survived, because he had picked a name that worked. Names as well as concepts have survival value. But it took a quarter of a century for the new illness to achieve recognition, as data from North Wales indicates.

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Fig. 1 The diagnosis of mania as a percentage of all admissions to the North Wales Asylum: 1875–1924.

explanation for this finding is, as outlined above, that a diagnosis of mania referred to any state of overactive insanity. Around 1900, primarily in response to Kraepelin’s impact, the use of mania as a diagnosis in North Wales began to fall, and it fell progressively to the current rate of less than 5% of patients. Two questions arise. First, when do modern diagnoses emerge in the records and, second, how many manics had what would now be diagnosed as having in fact bipolar affective disorder? The contrasting reception of dementia praecox and manic-depressive illness helps bring these points out and can be seen in the cases of Bessie Hughes and William Thomas. Bessie Hughes was a 17-year-old girl admitted on 16 October 1905 with hebephrenic and catatonic features. She was noted to be a good case of dementia praecox. The records indicate that up until then a case like Bessie’s would have been diagnosed as melancholia with stupor. The term dementia praecox thereafter rapidly came into use in North Wales, and was not replaced by schizophrenia in these records before 1949. In contrast, William Thomas had been admitted in 1891 at the age of 45, having been looked after at home by his family for a number of years. A businessman, who had travelled back and forth between Wales and Argentina, his family wondered if his first breakdown 17 years previously, from which he had recovered at home, had stemmed from an engagement to a Catholic woman, or whether it had been triggered by the general alarum that had accompanied an outbreak of Yellow Fever. He had recovered and continued working until his early 40s, when his family committed him to the asylum where he remained until his death. On admission, in contrast to most patients, he seemed far from manic in the sense of agitated or overactive. After some days, grandiosity and probable delusional beliefs became apparent. Periods of elation alternated with mute and almost catatonic states, and he settled down to a cycle of episodes of depression, followed by overactivity and periods of lucidity. In 1904, 13 years after admission, the notes

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indicate that his alternating states were being viewed as circular insanity. The reference to circular insanity is the first of its kind in these records, but the overall diagnosis remained mania and never became manic-depressive illness. In 1906, a national conference on the classification of insanity in Britain introduced a new set of diagnoses. This system proposed a new disorder, primary dementia, which was the equivalent of Kraepelin’s dementia praecox. The new national classification system subdivided mania and melancholia into recent, chronic and recurrent mania or melancholia, and introduced the term alternating insanity. None of these terms were used in North Wales but dementia praecox was and it was this that led to the fall in the frequency of diagnoses of mania. Within the affective disorders domain, RO, who was admitted in 1908 and discharged in 1909, was diagnosed with maniacal depressive insanity – a disorder not on the list. In fact, this odd use of words was a better description of his case than a diagnosis of manic-depressive insanity would suggest, in that he only presented on one occasion, showing features of agitated (or maniacal) depression without any alternation of mood. Despite the example of RO, except for clearcut cases of dementia praecox, other cases continued to be diagnosed as having mania or melancholia rather than alternating insanity or manic-depressive illness. It was not until the 1920s that we begin to find diagnoses of manic-depressive illness appearing. In September 1920, a 30-year-old sailor, RP, was admitted with grandiose beliefs and violent behaviour. He remained in hospital for over a year, during which time he had attacks of agitation at regular intervals. On discharge he was diagnosed as manic-depressive. This man was readmitted two years later and spent most of the following 15 years as an inmate of the asylum, during which time he was noted to have a clinical state that alternated from manic to depressive poles on a one month cycle. The diagnosis only came into regular use in 1924. In that year, three cases were diagnosed as manic-depressive. One was AA, whose records from 1924 outline a 60-year-old woman who had two admissions for what would now be diagnosed as psychotic depression – no hint of mania. ER, also admitted and diagnosed in 1924 as manic-depressive, had a postpartum psychosis. In 1924, WH had her tenth admission, and during this admission she was diagnosed as manic-depressive. There had been nine previous admissions starting from May 1900, mostly for mania, none of which led to this diagnosis. Later in the 1920s, the pattern of taking previous episodes into account takes hold, and also a willingness to make the diagnosis if the person during the course of one admission has distinct spells of elevated and depressed moods. In addition to mirroring the wider resistance to Kraepelin’s concept of manic-depressive illness, the asylum

records reveal a quantitative factor to this resistance. During the historical period 1875–1924, there were 3872 admissions from North West Wales. These came from 3172 patients. Amongst patients admitted for the first time during the 1875–1924 period, only 127 (4%) had what retrospectively appears to be a bipolar disorder. Against the background population of North West Wales, this rate of admission gives rise to 10 cases per million per year, a rate that remained constant across the 50-year period, and continues to hold true today [2,7]. In contrast, there were 1041 patients with non-affective psychoses, who between them had 1304 admissions, and 658 admissions from 568 individuals for severe depression or melancholia. These melancholias account for 17% of all admissions and over 80% of the manic-depressive cohort. Without inclusion in a larger manic-depressive group, bipolar patients would have been close to invisible, and this may have been a factor that led Kraepelin to collapse these disorders into one entity. From this perspective, it is clear why concepts such as folie circulaire, folie a double forme or alternating insanity were simply not used in a working asylum like Denbigh before 1900. Too few patients were involved. The viability of the modern concept of a bipolar affective disorder depends critically on the diagnosis of hypomanic or cyclothymic states in the community. Of the patients with retrospective bipolar diagnoses admitted to the North Wales Asylum, 60% were female, compared to the 66% Kraepelin reported. The average age of first admission was 32 years old, with the youngest admission being for a 17 year old. The average length of stay in hospital for any one episode was 6 months. Almost all patients went home well, with only a very small proportion having continuous fluctuations in clinical state that precluded discharge. This group of 127 patients had 345 admissions and on average each person had 4 admissions every 10 years. Today the district general hospital unit serving the same area has a slightly higher proportion of female admissions. The average age of first admission is 31 years old. The average length of stay is a month. But bipolar patients have 6.5 admissions every 10 years. There is therefore a substantial increase in admission prevalence [7]. In the 1875–1924 cohort, 80% of the admissions for bipolar disorder were for manic presentations. Today, over 50% of the admissions from bipolar patients are for depression. Thus either the presentation of the illness is changing, or treatment is having an impact on presentations, or we have a greater sensitivity to episodes of depression that would formerly not have led to admission. The records also shed light on involutional melancholia. When patients with melancholia admitted to North Wales Asylum between 1875 and 1924 were tracked for length of stay and rates of recovery, broken down by age, one

From Mania to Bipolar Disorder

might have expected, if Kraepelin was right, that those who had an episode of melancholia in their 50s and 60s would have much longer lengths of stay and a much lower rate of recovery. Also patients with melancholia in their 50s and 60s had a somewhat lower rate of recovery, but this was in fact governed by the greater likelihood that they would die in hospital from physical illness. The length of stay of those patients who did not die in hospital was the same as those who had an onset of the disorder earlier in life. Overall patients admitted in their 30s or 40s were 1.2 times more likely to recover than patients admitted in their 50s or 60s, hardly the behaviour of a distinct disorder [8]. Between 1875 and 1924, puerperal psychoses accounted for close to 10% of admissions of women of childbearing years and 3% of admissions overall (Table 1). This disorder was as common as bipolar affective disorder. Two different sets of women were admitted with postpartum psychoses. The larger of the two sets were women who had no mental illness prior to the postpartum period. A smaller group (20%) were women with a prior mental illness [9]. In the modern period, psychoses with a first onset in the postpartum period in North West Wales have all but vanished, while the incidence of postpartum psychoses in women with a pre-existing mental illness remains the same. Data from across Europe support these findings. If so, this would support claims that these disorders are distinct from other disorders. Alternately, if regarded as affective disorders, establishing the basis for the apparent decline in frequency of these disorders may have implications for other affective disorders.

Table 1 The incidence of postpartum psychoses in North West Wales: 1875–1924 vs. 1994–2005.

All Female Admissions All Women All Women of Child-Bearing Age All Postpartum Psychotic Admissions All Women with Postpartum Psychoses Women with no prior Mental Illness Women with Prior Mental Illness Postpartum Cases/All Admissions from Women of Child-Bearing Age All Postpartum Cases/1000 Births Postpartum Onset Cases/1000 Births All Postpartum Cases/100 000 Childbearing Yrs Postpartum Onset Cases/100 000 Childbearing Yrs

1875–1924

1994–2005

1946 1577 1100 103 101 80 21 9.2%

3956 1827 1032 7 7 1 6 0.68%

0.34 0.26 3.43

0.19 0.03 0.94

2.70

0.13

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The emergence of bipolar disorder A new chapter in the affective disorder story opened up in the psychotropic era. By this time, Manic-Depressive Illness had become a stable and accepted category, and anomalies such as calling someone who only ever had depressive episodes manic-depressive no longer registered. Two factors brought about a change. First, in 1954, Mogens Schou demonstrated that manic states responded to lithium. Second, in 1957, Karl Leonhard distinguished amongst affective disorders on the basis of polarity, separating manic-depressive illness from pure melancholia and pure depression. Several prominent European and American researchers picked up his lead. The effect of lithium appeared both to endorse the existence of a bipolar subgroup within manic-depressive illness, and put a premium on the diagnosis of a mood disorder rather than a psychotic disorder. Combined, these developments underpinned the emergence of bipolar disorder in the mid-1960s and its incorporation into DSM III in 1980. DSM III was badged as a neo-Kraepelinian revolution in psychiatry. As of 1980, bipolar disorder was still embedded within the affective disorders, of which depression was the most important. The research focus was on distinguishing between subtypes of depression so that biological markers might be discovered. The failure to discover such markers was widely attributed to the heterogeneity of the samples being studied and this had led to proposals to distinguish between neurotic and psychotic, primary and secondary, reactive and endogenous depressions and other distinctions including bipolar and unipolar depression. In the early 1970s, the bipolar/unipolar dichotomy looked amongst the less fruitful avenues of research, in that clinically there was less to distinguish bipolar and unipolar depression, for instance from neurotic and psychotic depressions or endogenous and reactive depressions. As of 1980, the effects of pharmacological and biological dissection of nervous disorders seemed more likely to lead to distinctions between ever smaller groups of disorders rather than the reverse. Lithium, for instance, seemed only helpful for a proportion of either manic-depressive or bipolar patients. In the decade from 1980 to the mid-1990s, manicdepressive illness and bipolar disorder co-existed, with Goodwin and Jamison’s 1990 monograph on the illness still entitled Manic-Depressive Illness [10]. It was only in 1992, with ICD 10, that the term bipolar disorder spread beyond America. But with the launch of Depakote as a moodstabilizer in 1995, the bipolar offspring ate its manicdepressive parent. The term mood-stabilizer essentially had not existed before 1995. Sedatives had been widely used to manage manic patients prior to that, but demonstrating a sedative effect in mania is quite different to showing a drug is

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prophylactic for bipolar disorder. Depakote was licensed for the treatment of mania but its adverts claimed it was a mood-stabilizer. Had Abbott said Depakote was prophylactic, they would have broken the law, as it had not been shown to be prophylactic but the term mood-stabilizer had no precise meaning. It suggested prophylaxis and this suggestion led to the use of Depakote and other anticonvulsants for maintenance purposes, despite a failure in controlled trials to demonstrate these agents are prophylactic. Bipolar disorder, in my view, has become more a brand than a well-grounded scientific term – as successful a brand as the creation of the terms tranquilizer and SSRI. A brand is something whose value lies in the perception of a consumer rather than in a tangible benefit. Where there had been almost no uses of the term mood-stabilizer before 1995, by 2000 there were over 100 articles per year featuring this term in their titles. The dramatic and rapid switch from Manic-Depressive Illness to Bipolar Disorder in the mid-1990s took place in the absence of any clinical or research facts to underpin the switch. The term bipolar disorder is rarely found in the titles of articles listed in Medline before 1992, but its use rapidly escalates from 1995 to reach 500 articles per year by 2005, while the term manic-depressive vanished. Estimates of the frequency of bipolar disorder in the population soared to a 100-fold compared with figures for admissions to the North Wales Asylum in the period from 1875 to 1924. The possibilities offered by ‘mood-stabilization’ and ‘bipolar disorder’ led companies producing second generation antipsychotics into the market, greatly expanding the use of these terms. Bipolar affective disorder is unquestionably a distinct clinical type; this does not mean it is necessarily a distinct disease entity. We still do not know enough about the bases for any remitting disorders to carve nature definitively at its joints in these domains. Many clinicians and scientists associate history with postmodernism, an all but psychiatric disorder in its own right, where academics refuse to concede there is any reality to human behaviours, or to the physical underpinnings of disorders of human behaviour. That which scientists regard as hard data or even facts, post-modernists treat as texts to be interpreted and re-interpreted without external constraint. The analysis of Kraepelin’s concept of manic-depressive illness outlined above demonstrates how complex his concept was, and how open to revision, but it also makes clear that clinical realities were once the primary determinant of clinical concepts. Concepts arose from the clinical material. In contrast, the post-modernism at which the marketing departments of pharmaceutical companies excel think nothing of shaping the clinical material to fit a marketing concept.

In the decade from 2000, all of the companies producing antipsychotics have targeted bipolar disorder as a means to enhance sales. The companies have recognised that to do this the attitudes of primary care physicians would have to change. Market research had shown that these doctors were reluctant to use antipsychotics, but they could be reeducated to the possibilities of mood-stabilizers. These were doctors who thought that bipolar disorder was a severe mental illness comparable to schizophrenia whose treatment appropriately was either in secondary care rather than primary care – they would need to be re-educated to recognise that many of the anxious and depressed patients going through their practices could be re-conceptualized as having bipolar disorder. These points are illustrated using the documents in the public domain from litigation involving Zyprexa, but a similar scenario applies to other drugs in the group. Thus: ‘As the current market leader in primary care, Zyprexa will continue to revolutionize the way complicated mood disorders are treated by primary care physicians. Just as Prozac revolutionized the treatment of depression in the late 1980s and throughout the 1990s, so too will Zyprexa forever change the way primary care physicians view and treat bipolar disorder’ [11]: The facts: up to 30% of patients with a diagnosis of depression or anxiety may actually have bipolar disorder [12].

Scenarios like Donna’s have been put forward as typical: ‘Donna is a single mom, in her mid-30s appearing in your office in drab clothing and seeming somewhat ill at ease. Her chief complaint is “I feel so anxious and irritable lately”. Today she says she has been sleeping more than usual and has trouble concentrating at work and at home. However, several appointments earlier she was talkative, elated, and reported little need for sleep. You have treated her with various medications including antidepressants with little success. . . You will be able to assure Donna that Zyprexa is safe and that it will help relieve the symptoms she is struggling with’ [13]. There is clearly a nexus of nervous problems that patients endure in the community without ever coming to the attention of mental health services. Company marketers have been adept at framing the symptoms these give rise to in a manner most likely to lead to a script for the remedy of the day. Donna could have featured in adverts for tranquilizers from the 1960s to the 1980s, or for antidepressants in the 1990s, and would have probably been more likely to respond to either of these treatment groups than to an antipsychotic, and less likely to be harmed by them than by an antipsychotic. There have traditionally been difficulties in seeing these conditions simply as anxiety or as depression [14]. But

From Mania to Bipolar Disorder

while bipolar affective disorders probably exist in the community without coming to the attention of the secondary services, it flies in the face of a century of psychiatric thinking to see conditions that patients like Donna have as bipolar disorder. The concept of juvenile bipolar disorder flies even more in the face of a century of psychiatric thinking, but as of 2008, upwards of a million children in the United States, in many cases preschoolers, are on ‘mood-stabilizers’ for bipolar disorder, even though the condition remains unrecognized in the rest of the world [2]. While this was happening, the cycloid disorders, which provided sound clinical grounds to unpick or go beyond the Kraepelinian synthesis, remained neglected. Instead, in a return to a pre-Kraepelinian psychiatry, company marketing departments have used a template of a supposedly neo-Kraepelinian medical science to promote a form of bipolar disorder based more on the visible presentations of patients rather than on any valid classificatory basis. This new disorder would have been unrecognizable to Kraepelin, whose tombstone bears an inscription – ‘your name may vanish but your work remains’ – that has become ironic.

References 1. Pinel, P. (1809/2008) Medico-Philosophical Treatise on Mental Alienation (Trans G. Hickish, D., Healyand L.C.C. Charland), Wiley-Blackwell, Chichester. 2. Healy, D. (2008) Mania, in A Short History of Bipolar Disorder, Johns Hopkins University Press, Baltimore.

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3. Kraepelin, E. (1899) Psychiatrie, in Ein Lehrbuch f€ ur Studirende und Aertze. Barth, Leipzig (Translation S. Ayed), (1960), Science History Publications, Canton MA, p. 272. 4. Ion, R.M.and Beer, M.D. (2002) The British reaction to dementia praecox 1893–1913, part 1. Hist. Psychiatr., 13, 285–304, Part 2, 13, 419–432. 5. Pichot, P. (1982) The diagnosis and classification of mental disorders in French-speaking countries. Psychol. Med., 12, 475–492. 6. Lange, C.G. (1886) Om Periodiske Depressionstilstande, Jakob Lunds, Copenhagen. 7. Harris, M., Chandran, S., Chakroborty, N.and Healy, D. (2005) Service utilization in bipolar disorder, 1890 and 1990 compared. Hist. Psychiatry, 16, 423–434. 8. Farquhar, F., Le Noury, J., Tschinkel, S. et al. (2007) The incidence and prevalence of manic-melancholic syndromes in North West Wales: 1875–2005. Acta Psych. Scand, 115 (Suppl 433), 37–43. 9. Tschinkel, S., Harris, M., Le Noury, J.and Healy, D. (2007) postpartum psychosis: two cohorts compared, 1875–1924 & 1994–2005. Psychol. Med., 37, 529–536. doi: 10/1017/ S0033291706009202 10. Goodwin, F.K. and Jamison, K.R. (1990) Manic Depressive Illness, Oxford University Press, New York. 11. Zyprexa. Primary Care Sales Force Resource Guide (2002) Zyprexa MDL 1596, Plaintiffs’ Exhibit 01926, page 3. 12. Zyprexa. Primary Care Sales Force Resource Guide (2002) Zyprexa MDL 1596, Plaintiffs’ Exhibit 01926, page 6. 13. Zyprexa. Primary Care Sales Force Resource Guide (2002) Zyprexa MDL 1596, Plaintiffs’ Exhibit 01926, page 7. 14. Shorter, E. and Tyrer, P. (2003) Separation of anxiety and depressive disorders: blind alley in psychopharmacology and classification of disease. Br. Med. J., 327, 158–160.

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Clinical Features and Subtypes of Bipolar Disorder Fred K. Goodwin1 and D.Z. Lieberman2 1

Department of Psychiatry and Behavioral Sciences, Center on Neuroscience, Medical Progress, and Society, George Washington University Medical Center, Washington, DC, USA 2 Department of Psychiatry and Behavioral Sciences, George Washington University Medical Center, Washington, DC, USA

Introduction: the phenomenology of cyclicity and polarity The origins of the bipolar illness concept have been reviewed in the previous chapter by David Healy. Nevertheless, before discussing the clinical features and subtypes of bipolar disorder, it is worth reiterating a few salient points concerning the evolution of the bipolar illness construct. Kraepelin’s unitary concept of manic-depressive illness included all recurrent mood disorders, which were differentiated from dementia praecox by a family history of mood disorders, the episodic nature of the patient’s illness, and the relatively benign course and outcome. In 1957 Leonhard observed that manic-depressive patients with a history of mania (whom he termed bipolar) had a higher incidence of mania in their families as compared with those with recurrent depressions only (whom he termed monopolar) [1], a distinction that was validated by the extensive family history studies in the 1960s by Perris, and independently by Angst [2]. The bipolar–unipolar distinction was formally incorporated into the American diagnostic system, DSM. In 1980, the third edition (DSM-III) was subsequently carried forward into DSM-IV, and became explicit in the international classification system in ICD-10. Unfortunately, the structure of DSM-IV (see Figure 1), which breaks out bipolar disorder as a separate illness distinct from all other mood disorders (i.e. from the depressive disorders) obscures the fact that originally the bipolar–unipolar distinction was conceived of as a way to distinguish two forms of a recurrent illness. In other words, the DSM structure gives precedence to polarity over cyclicity, obscuring the reality that one rather common variant of unipolar illness is as recurrent or cyclic as bipolar illness. Furthermore, DSM-IV really has no language for the unipolar patient with frequent recurrences, since its ‘recurrent’ category is so broad as to include patients with only two depressions in a lifetime, comprising at least 80% of all patients with major depression (Figure 2).

Because cyclicity in DSM-IV-TR is largely restricted to the bipolar category, there is a tendency to include highly cyclic forms of unipolar depression within a ‘bipolar spectrum’. While common features can be observed amongst patients with diverse cyclic mood disorders, broadening the definition of ‘bipolar disorder’ to such a large degree may weaken the core concept of bipolar disorder. It may also de-emphasize some of the important clinical differences between unipolar and bipolar patients. For example, one proposed definition of bipolar spectrum disorder includes recurrent unipolar patients with an early onset of illness who have a family history of bipolar disorder in a first-degree relative [3]. This definition moves beyond the clinical phenomenology of bipolar disorder to a definition based on presumptive genetic vulnerability to elevated mood states.

Clinical features of affective episodes Under the current system, the diagnosis of bipolar disorder is based on symptom presentation and the natural course of the illness. Although progress has been made in advancing our understanding of the neurobiology and genetics of bipolar disorder, we are far from being able to validate the diagnosis and sharpen its boundaries by reference to an identified aetiologic agent or a characteristic pathophysiological abnormality. There are significant challenges associated with using symptoms as a basis for diagnosis. Some patients’ symptoms may correspond well with published diagnostic criteria, while others are more ambiguous. Over time, debate about what constitutes the core clinical features of mood episodes has been reflected in changing diagnostic criteria in the DSM and ICD. This debate is more than an academic exercise. Because diagnosis guides treatment decisions as well as the composition of research samples, the content of the diagnostic criteria has a profound impact on patient care, as well as on our ability to advance neurobiological and genetic research on mood disorders.

Mania Bipolar Disorder: Clinical and Neurobiological Foundations Edited by Lakshmi N. Yatham and Mario Maj © 2010 John Wiley & Sons, Ltd. ISBN: 978-0-470-72198-8

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Mania represents the primary defining feature of bipolar disorder. Although primary emphasis has been placed on

Clinical Features and Subtypes

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The Diagnosis of Mania as a Percentage of all Admissions to the North Wales Asylum: 1875-1924 60 50 40 30 20 10 0 20

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Fig. 1 DSM-IV classification of mood disorders. Note: NOS ¼ not otherwise specified. Reprinted with permission from Goodwin FK, Jamison KR: Manic Depressive Illness: Bipolar Disorders and Recurrent Depression. New York, NY, Oxford University Press, 2007.

the elevation of mood, Kraepelin described activation of motoric and cognitive processes that can be the more predominant features in some patients. For example, there has been an increasing appreciation for the role of irritability in the absence of euphoria [4]. Accordingly, DSM-IV-TR allows elevated, expansive or irritable mood in the core criterion A of the diagnostic definition (Box 1). While elevated mood is a fairly specific symptom of mania and hypomania, irritability can be more ambiguous because it

is also commonly seen in bipolar depressive episodes [5] and major depressive disorder [6]. Irritability can be defined as extreme reactions to relatively minute stimuli [7], or as a low threshold for experiencing anger in response to negative emotional events [8]. Irritability is particularly prominent in paediatric bipolar disorder, although lacking in specificity [8]. Thus in children irritability is present in a number of common diagnoses including attention deficit hyperactivity disorder, anxiety disorders, and oppositional

Affective Disorders

Depressive Disorders < 3 Episodes; Onset < age 30

Recurrent (Episodic) Affective Disorders > 3 Episodes; Onset < age 30 (Kraepelin’s manic-depressive illness)

Bipolar

BP-I

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BPNOS

Unipolar

Cyclothymia

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Nonpsychotic

Major Depression

Psychotic

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The Bipolar Spectruma

Fig. 2 Recurrence as the primary organizing feature of the affective disorders. Note: BP ¼ bipolar; NOS ¼ not otherwise specified. Reprinted with permission from Goodwin FK, Jamison KR: Manic Depressive Illness: Bipolar Disorders and Recurrent Depression. New York, NY, Oxford University Press, 2007.

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Chapter 2

Box 1 DSM-IV-TR Definition of a Manic Episode DSM-IV (p. 328) defines a manic episode as follows: Criterion A: A Manic Episode is a distinct period during which there is an abnormally and persistently elevated, expansive or irritable mood. This period of abnormal mood must last at least one week (or less if hospitalization is required). Criterion B: The mood disturbance must be accompanied by at least three additional symptoms from a list that includes inflated self-esteem or grandiosity, decreased need for sleep, pressure of speech, flight of ideas, distractibility, increased involvement in goal-directed activity or psychomotor agitation, and excessive involvement in pleasurable activities with a high potential for painful consequences. If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present. Criterion C: The symptoms do not meet criteria for a mixed episode. Criterion D: The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterized by the presence of psychotic features. Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (Copyright 2000). American Psychiatric Association.

defiant disorder. And, of course, some level of irritability is observed in the course of normal development. Overactivity, defined in the DSM as either increased goal directed activity or psychomotor agitation, is an optional criteria for the diagnosis rather than a core criterion A symptom. A study by Benazzi suggests that overactivity may play a more central role in the diagnosis than the DSMIV-TR organization implies [9]. In a sample of 213 patients, focusing the probing for history of hypomania on overactivity in addition to mood change reduced false-negatives for a bipolar II diagnosis. Using Angst’s diagnostic criteria for hypomania [10], which emphasizes overactivity rather than simply elevated mood, and comparing the results to the Structured Clinical Interview for DSM-IV, no significant differences were found between the two samples on age, gender, symptom structure of hypomania, number of episodes, episodes duration and level of functioning. Compared to elevated mood, overactive behaviour may be less vulnerable to the cognitive distortions associated with loss of insight that occurs during manic and hypomanic episodes, and therefore easier for patients to identify. The kind of psychomotor activation which is stereotyped, repetitive and purposeless, such as pacing and fidgeting (i.e. agitation) is, unfortunately, conflated with increased goal directed activity in DSM-IV-TR. Psychomotor agitation is also part of the criteria for major depressive disorder, and this overlap may serve to blur the distinction between the activation of mania and that of depression.

In order to meet the criteria for a manic episode, four or five out of nine criteria must be met. It is not necessary to have all of the symptoms listed, and for each individual patient certain symptoms may be more likely than others to accompany a manic episode. Patients may experience a degree of symptom consistency over the course of consecutive episodes. Capitalizing on this tendency, identifying personally relevant early signs of mania or hypomania is a common ingredient in a number of bipolar-specific psychotherapies, including psychoeducation [11], cognitive behavioural therapy [12], family-focused therapy [13] and interpersonal and social rhythm therapy [14]. These early symptoms, of which decreased need for sleep is a common example, may not be especially pathological in and of themselves. However, because they can be consistent and reliable predictors of serious affective decompensation, systematically documenting the nature of the symptoms, and developing a level of vigilance for their emergence, can create an opportunity for early intervention that may prevent an impending manic episode or decrease its severity. Formally evaluating the consistency of symptoms across episodes can be complex. Effects of medications, such as an antidepressant that can induce or heighten agitation, or a benzodiazepine that modulates the decreased need for sleep, may introduce variance. In addition, the timing of the assessment can lead to the presentation of differing symptoms. Carlson and Goodwin found substantial differences in symptomatology based on the stage of mania during which a subject was evaluated [15]. One study that attempted to control for these potentially confounding factors, evaluated 77 subjects during two discrete manic episodes, which occurred an average of two years apart. The authors reported that four symptom factors as well as manic severity were significantly correlated across episodes. The symptom factors were dysphoria, hedonic activation, psychosis and irritable aggression [16]. Psychotic symptoms that occur in the context of a manic episode may have special status as defining a specific subtype of bipolar disorder. Psychosis is generally associated with more severe symptoms of mania and possibly a less favourable long-term course [17]. The McLean-Harvard First-Episode Mania Study found that psychosis was a predictor of mania recurrence [18], and a recent two-year prospective study conducted in 14 European countries found that psychotic symptoms during the initial presentation predicted poor response to treatment, and chronicity of mania [19].

Depression Despite the predominance of depressive symptoms in bipolar disorder, there has been less quantitative study of the clinical features of bipolar depression than is the case for either mania or nonbipolar depression. Although the

Clinical Features and Subtypes

DSM-IV-TR does not distinguish between unipolar and bipolar depression (Box 2), studies that have compared the two generally find differences in the clinical presentations. The most widely replicated findings point to a picture of bipolar I depressed patients as having more mood lability, psychotic features, psychomotor retardation and comorbid substance abuse. In contrast, the typical unipolar patient in these studies had more anxiety, agitation, insomnia, physical complaints, anorexia and weight loss [20]. However, none of the contemporary studies of unipolar-bipolar differences match the samples for number of previous episodes (i.e. for cyclicity) and only a few even match for age of onset. Indeed, Benazzi has found that when unipolar and

Box 2 DSM-IV-TR Definition of a Major Depressive Episode DSM-IV (p. 320) defines a major depressive episode as follows: Criterion A1: The essential feature of a Major Depressive Episode is a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities. In children and adolescents, the mood may be irritable rather than sad. The individual must also experience at least four additional symptoms drawn from a list that includes changes in appetite or weight, sleep and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; or recurrent thoughts of death or suicidal ideation, plans or attempts. To count towards a Major Depressive Episode, a symptom must either be newly present or must have clearly worsened compared with the person’s pre-episode status. The symptoms must persist for most of the day, nearly every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational or other important areas of functioning. For some individuals with milder episodes, functioning may appear to be normal, but requires markedly increased effort. The mood in a Major Depressive Episode is often described by the person as depressed, sad, hopeless, discouraged or “down in the dumps”. Criterion A2: Loss of interest or pleasure is nearly always present, at least to some degree. Criterion A3: When appetite changes are severe (in either direction), there may be a significant loss or gain in weight or, in children, a failure to make expected weight gains may be noted. Criterion A4: The most common sleep disturbance associated with a Major Depressive Episode is insomnia. Criterion A5: Psychomotor changes include agitation (e.g. the inability to sit still, pacing, hand-wringing; or pulling or rubbing of the skin, clothing or other objects) or retardation (e.g. slowed speech, thinking and body movements; increased pauses before answering; speech that is decreased in volume, inflection, amount or variety of content, or muteness). Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (Copyright 2000). American Psychiatric Association.

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bipolar samples are matched for age of onset, many of the UP-BP differences disappear [21]. In bipolar II depression, some studies have found more atypical features such as hypersomnia, increased appetite, leaden paralysis and interpersonal rejection sensitivity compared to those with unipolar depression [3,22,23], but typically these studies also fail to control for cyclicity and age of onset. Compared to mania, the cumulative impact of syndromal and subsyndromal depression on role functioning is greater [24]. Thus a long-term study that evaluated bipolar patients over the course of 4 years found functional outcome was correlated with depressive but not manic symptoms [25]. Similarly, resource utilization and direct health care costs have been shown to be highest amongst bipolar depressed patients compared to those who were manic or mixed [26]. The impact of depressive symptoms on functioning is seen even in sub-syndromal presentations. In a study of bipolar patients that excluded patients who currently met the full DSM criteria for any acute mood episode, those with higher Hamilton Depression Rating Scale scores had poorer outcomes as measured by the psychosocial components of the Global Assessment of Functioning Scale [27].

Mixed states of bipolar disorder The DSM-IV-TR criteria for a mixed episode require a patient to meet the full criteria for both a manic episode and a major depressive episode (Box 3). Our knowledge of mixed states is more limited than it is for other manifestations of bipolar disorder because patients experiencing mixed episodes are often excluded from studies. This relative lack of knowledge is unfortunate because mixed states occur frequently. Although estimates vary, in one study, 40% of bipolar I inpatient admissions were for mixed episodes [28]. Mixed episodes may evolve from a depressive episode, a manic episode, or the mixed symptoms may emerge at the same time. Patients may also experience mixed symptoms when a bipolar depression is treated with an antidepressant [29]. However, this would fail to meet the strict criteria because symptoms that occur as a direct consequence of the effect of a substance are excluded by the DSM. A mixed episode may evolve into a major depressive episode, but it is uncommon for a mixed episode to become a pure mania. In an early study, patients who presented with a mixed episode accounted for 31% of 84 outpatients with manicdepressive disorder [30]. The mixed states were not associated with illness severity or cycling, but did correlate with sedative abuse and poor response to treatment. Himmelhoch and associates commented that ‘. . .drug abuse (particularly alcohol and sedatives) alters the clinical presentation of manic-depressive swings, and the impact of

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Chapter 2

Box 3 DSM-IV-TR and ICD-10 Definitions of a Mixed Episode DSM-IV (p. 333) defines a mixed episode as follows: Criterion A: A Mixed Episode is characterized by a period of time (lasting at least 1 week) in which the criteria are met both for a manic episode and for a major depressive episode nearly every day. The individual experiences rapidly alternating moods (sadness, irritability, euphoria) accompanied by symptoms of a manic episode and a major depressive episode. The symptom presentation frequently includes agitation, insomnia, appetite dysregulation, psychotic features and suicidal thinking. Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (Copyright 2000). American Psychiatric Association.

oversedation or withdrawal or both on a “pure” affective state is to make it dysphoric and mixed’. More recently, Goldberg and colleagues, evaluating the long-term effects of substance abuse on the course of bipolar I disorder, also found that substance abuse was more common amongst those who had mixed states [31]. The direction of causality could not be determined from this study. Compared to patients with pure mania, those with mixed mania have been found to have more prior mixed episodes, longer hospitalizations, higher rates of comorbid obsessivecompulsive disorder, and they are more likely to be female [32]. Dilsaver and colleagues found a highly significant difference in suicidality as measured by the Schedule for Affective Disorders and Schizophrenia suicide subscale between patients with pure and mixed mania. Only 1 of 49 manic patients was suicidal, compared to 24 of 44 with mixed mania [33]. One would expect that suicidality in bipolar disorder would be associated with depressed mood. Potential additional risk factors present in a mixed episode include higher levels of energy, impulsivity and irritability. A study of 191 psychiatric inpatients and outpatients confirmed this expectation. Suicidality, as measured by the Scale for Suicidal Ideation, was highest for patients with mixed phase presentations [34]. The Scale for Suicidal Ideation measures various dimensions of suicidality, including self-destructive thoughts or wishes, the extent of the wish to die, the desire to make an actual suicide attempt, and details of any plans. Actual suicide attempts during the index episodes were also measured, and like ideation, attempts were more common in the mixed patients. Suicidality was particularly correlated with hopelessness, which was highest during the mixed phase. It is important to note, however, that suicidality is often a poorly defined construct, and whether it

correlates with or predicts actual suicide is not at all clear. See Chapter 7, Suicide and Bipolar Disorder, for an in-depth discussion of this issue. Some authors have suggested that the DSM-IV-TR definition for a mixed episode is too narrow. Failure to meet the full criteria for a major depressive episode, even by a single symptom, results in a diagnosis of a manic state. However, patients who have prominent sub-syndromal depressive symptoms may differ in clinically important ways from those with pure mania. Consequently, other definitions have been developed. The broadest definition permits the presence of one or more depressive symptoms within a manic episode to be sufficient for diagnosis of a mixed episode [35]. Swann and colleagues, using a broad definition of this nature, found that the depressive symptoms responded poorly to lithium compared to the classic manic symptoms [36]. The depressive manic patients had better outcomes on divalproex. A moderate definition midway between the strict and broad criteria has been proposed, in which a mixed episode would be defined as a full manic presentation with three or more symptoms of depression [37]. Just as limited symptoms of depression can accompany a manic episode, limited symptoms of hypomania may be present during a depressive episode. Although there is no formal DSM-IV-TR category for a patient who is experiencing simultaneous or closely juxtaposed symptoms of depression and hypomania, it appears that it is common. The Stanley Foundation Bipolar Treatment Network prospectively studied more than 900 patients for up to seven years, and evaluated the co-occurrence of depressive and hypomanic symptoms. Amongst all visits in which patients had hypomanic symptoms, 57% met criteria for mixed hypomania defined as Young Mania Rating Scale score of 12 or higher and an Inventory of Depressive Symptomatology–Clinician-Rated Version score of 15 or higher [38]. The specific diagnostic entity, ‘depressive mixed state’, has been defined as a major depressive episode plus three or more intra-episodic hypomanic symptoms (DMX3). In a sample of 151 outpatients with major depressive disorder who were presenting with psychoactive drug-free major depressive episode, 23.1% met the criteria for DMX3 [39]. The presence of DMX3 was significantly associated with variables distinguishing bipolar from strictly defined unipolar disorders: younger age at onset; greater recurrence; more atypical features; more bipolar II family history. A number of reports suggest that the number and severity of depressive symptoms during mania or hypomania is a continuous rather than a modal phenomenon. In a study of 37 outpatients, depending on the threshold used, the prevalence of mixed features during a manic or hypomanic episode rose incrementally from 5–73% [40]. Patients who met one of the threshold criteria during a given episode were no more likely than chance to have a similar symptom

Clinical Features and Subtypes

constellation during a subsequent episode. The authors concluded that dichotomizing mania and mixed episodes based on the presence of a predefined number of depressive symptoms was not supported by the data.

Diagnostic subgroups of bipolar disorder Bipolar I In one version of a mood disorder spectrum, bipolar I disorder is at one end while recurrent unipolar major depressive disorder is at the other end. Characterized by manic or mixed episodes, patients with bipolar I disorder experience the highest levels of severity with respect to elevated mood. The National Comorbidity Survey Replication, a nationally representative survey of mental disorders amongst adults in the United States, estimated a lifetime prevalence of bipolar I disorder of 1.0% [41]. Unlike major depressive disorder, which is twice as prevalent in females, the prevalence of bipolar I disorder was approximately equal for males and females (0.8 and 1.1%, respectively). One gender difference that was noted was that men were more likely than women to be initially manic, but overall, both were more likely to have a first episode characterized by depression. The typical age of onset varied from the teens to early 40s, with a mean value of 18.2 years. Patients with bipolar I disorder experience substantial morbidity and mortality, and tend to function below the level of the general population, even in between episodes when mood is euthymic (see Chapter 8: Neurocognition and Bipolar Disorder). During a two-year follow-up of patients hospitalized for a psychotic affective episode (72.6% bipolar I), almost all of the subjects achieved syndromic recovery by the end of the study. However, functional recovery was 2.6 times less likely than syndromal recovery [42]. Most of those recovering syndromally did not recover functionally by two years. Patients who had an older age of onset of their mood disorder were more likely to experience functional recovery than those who were younger when they experienced their first episode, probably reflecting more cumulative time ill. Episodes of psychosis are common, affecting at some time 75% of patients with bipolar I disorder [43]. Psychotic features are most common in mixed presentations and least common during pure depressive episodes [44]. Patients who experience psychotic episodes may represent a distinct phenotype, and there appears to be genetic overlap between these patients and patients with schizophrenia (see Chapter 12: Genetics of Bipolar Disorder).

Bipolar II Bipolar II disorder, first described by Dunner, Gershon and Goodwin [45], is characterized by at least one major depres-

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sive episode with one or more hypomanic episodes, as opposed to the manic or mixed episodes seen in bipolar I disorder. As discussed in the section on hypomania, the criteria are essentially the same as for mania; however, the manifestations are less severe. Patients diagnosed with hypomania do not require hospitalization, are not psychotic, and do not experience marked impairment in social or occupational functioning. Bipolar II disorder is described in DSM-IV-TR, but not in ICD-10. DSM-IV-TR requires hypomanic episodes to last a minimum of 4 days. This durational criterion is largely arbitrary and may not represent the best choice. Reducing the duration to two days increases the sensitivity of diagnosis, and a recent study found no differences in characteristics of patients with bipolar II disorder, whether the two or four day duration was used [46]. Using the two-day minimum duration adequately distinguishes bipolar II patients from those with major depressive disorder based on external validators such as family history and course of illness [47]. Using the more restrictive DSM-IV criteria, the National Comorbidity Survey Replication study estimated that the lifetime prevalence of bipolar II disorder was 1.1%; approximately equal to bipolar I disorder, which was 1% [41] (See Chapter 6: Epidemiology of Bipolar Disorder). The Zurich Study found an additional 2.8% of patients who experienced brief hypomania [48]. In one sample, patients with bipolar II disorder (diagnosed using the two-day duration criterion) comprised approximately half of patients who presented for treatment with a major depressive episode [49]. Bipolar II disorder is sometimes viewed as a milder form of bipolar disorder. However, the cumulative effect of the illness is no less severe than bipolar I disorder. Although mania is characterized by greater symptom intensity than hypomania, bipolar II disorder has a more chronic course, and is associated with greater episode frequency, comorbidity, suicidal behaviour [50], and more time spent depressed [51]. Bipolar II disorder can be difficult to recognize because by definition hypomanic episodes do not cause marked functional impairment. Patients may not identify episodes of hypomania as pathological, or view them as related to episodes of depression. Alternatively, episodes may manifest as brief periods of irritability and agitation, which may not be easily recognized as hypomania. As a result, misdiagnosis is common, especially when a clinician fails to include a member of the family in the intake diagnostic evaluation process. A chart review of 85 patients found that bipolar disorder was misdiagnosed as unipolar depression in 37% of patients who first saw a mental health professional after their first episode of elevated mood [52]. A inpatient study found a similar result. Bipolar disorder was misdiagnosed as unipolar depression in 40% of patients [53]. Family and genetic data suggest that there is a true separation of bipolar I and II into separate categories, as

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Chapter 2

opposed to a more continuous spectrum. Bipolar II disorder clusters within families, and appears to ‘breed true’, as evidenced by the finding that bipolar II patients have more bipolar II and unipolar relatives, and fewer bipolar I relatives compared to patients with bipolar I [54,55]. Bipolar II disorder also appears to be phenomenologically stable. In a 10-year follow-up study, only 7.5% of a sample of patients with bipolar II disorder experienced a full manic episode, compared to 66.4% of patients with bipolar I disorder [56]. By far the predominant polarity of bipolar II disorder is depression. A prospective study of the natural history of the weekly symptomatic status of bipolar II patients conducted over more than 10 years found that during times when patients experienced mood symptoms, depression was 39 times more common than hypomania (50.3% vs. 1.3%). Overall, patients were symptomatically ill 53.9% of the weeks studied [46]. A similar result was seen in patients with bipolar I disorder; however the imbalance between symptoms of depression and symptoms of mania or hypomania was not as great. That is, bipolar I patients were symptomatic 47.3% of the weeks, and depressive symptoms were 3.6 times more common than manic/hypomanic symptoms [57]. The greater predominance of depression in bipolar II disorder may contribute to the higher rates of suicidal behaviour seen in this illness. A study of psychiatric inpatients found that a prior history of a suicide attempt and suicide after discharge were more frequent amongst bipolar II patients compared to those with bipolar I disorder [45]. Similar results have been found with outpatients [58] although not all studies agree.

Cyclothymia Cyclothymia, like bipolar II disorder, is characterized by attenuated severity of symptoms in the context of a high degree of chronicity. Patients with cyclothymia experience numerous periods with hypomanic symptoms and periods with depressed symptoms that do not meet the full criteria for a major depressive disorder. Emphasizing chronicity, the diagnostic criteria require that patients are not symptom-free for more than two months at a time. Cyclothymia may be a precursor to other forms of bipolar disorder, rather than a stable diagnostic entity in itself. In a study of the natural course of cyclothymia, 35% developed full syndromal depression, hypomania or mania during drug-free follow-up [59]. Compared to patients with a definite history of mania, cyclothymic patients had milder symptoms of abnormal mood and cognition. Most showed sleep disturbances and fluctuating levels in the quality of work or school productivity. Cyclothymic patients reported periods of irritability or aggressiveness, patterns of frequent shifts in interests or plans, and drug or alcohol abuse.

Episodic promiscuity or extra-marital affairs were reported by 40% of the sample, and 25% reported joining new movements with zeal, followed by subsequent disappointment. Because of the high level of chronicity, it can be difficult to distinguish cyclothymia from personality disorders.

Conclusion The current definitions and classification schemes of bipolar disorder remain a work in progress. While the diagnoses have relatively high inter-rater reliability, there is considerable heterogeneity within each diagnostic category. Recognizing the various manifestations, which may reflect differing positions on a spectrum or alternatively genuine subgroups, can be important to treatment selection as our pharmacologic armamentarium continues to expand. Some mood stabilizing medications may work best in a specific subpopulation of patients with a bipolar diagnosis. Alternatively, some mood stabilizing treatments may be effective in a population that does not meet the current bipolar criteria, but is nevertheless characterized by recurrent affective illness that falls within the broader Kraeplinian manic-depressive conceptualization. As our understanding of this group of disorders continues to evolve, continued development of evidence-based approaches to treatment will require accurate and detailed descriptions of clinical trial samples that go beyond simple diagnosis.

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patients with bipolar I disorder. Bipolar Disord., 4 (6), 398–405. Altshuler, L.L., Gitlin, M.J., Mintz, J. et al. (2002) Subsyndromal depression is associated with functional impairment in patients with bipolar disorder. J. Clin. Psychiatry, 63 (9), 807–811. Kr€ uger, S., Young, L.T. and Br€ aunig, P. (2005) Pharmacotherapy of bipolar mixed states. Bipolar Disord., 7 (3), 205–215. Dilsaver, S.C. and Swann, A.C. (1995) Mixed mania: apparent induction by a tricyclic antidepressant in five consecutively treated patients with bipolar depression. Biol. Psychiatry, 37 (1), 60–62. Himmelhoch, J.M., Mulla, D., Neil, J.F. et al. (1976) Incidence and signficiance of mixed affective states in a bipolar population. Arch. Gen. Psychiatry, 33 (9), 1062–1066. Goldberg, J.F., Garno, J.L., Leon, A.C. et al. (1999) A history of substance abuse complicates remission from acute mania in bipolar disorder. J. Clin. Psychiatry, 60 (11), 733–740. McElroy, S.L., Strakowski, S.M., Keck, P.E. Jr et al. (1995) Differences and similarities in mixed and pure mania. Compr. Psychiat., 36 (3), 187–194. Dilsaver, S.C., Chen, Y.-W., Swann, A.C. et al. (1994) Suicidality in patients with pure and depressive mania. Am. J. Psychiatry, 151 (9), 1312–1315. Valtonen, H.M., Suominen, K., Mantere, O. et al. (2007) Suicidal behaviour during different phases of bipolar disorder. J. Affect Disord., 97 (1–3), 101–107. Marneros, A. (2001) Origin and development of concepts of bipolar mixed states. J. Affect. Disord., 67 (1–3), 229–240. Swann, A.C., Bowden, C.L., Morris, D. et al. (1997) Depression during mania. Treatment response to lithium or divalproex. Arch. Gen. Psychiatry, 54 (1), 37–42. McElroy, S., Keck, P. Jr, Pope, H. Jr et al. (1992) Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am. J. Psychiatry, 149 (12), 1633–1644. Suppes, T., Mintz, J., McElroy, S.L. et al. (2005) Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon. Arch. Gen. Psychiatry, 62 (10), 1089–1096. Akiskal, H.S. and Benazzi, F. (2003) Family history validation of the bipolar nature of depressive mixed states. J. Affect. Disord., 73 (1), 113–122. Bauer, M.S., Whybrow, P.C., Gyulai, L. et al. (1994) Testing definitions of dysphoric mania and hypomania: prevalence, clinical characteristics and inter-episode stability. J. Affect Disord., 32 (3), 201–211. Merikangas, K.R., Akiskal, H.S., Angst, J. et al. (2007) Lifetime and 12-month prevalence of bipolar spectrum disorder in the national comorbidity survey replication. Arch. Gen. Psychiatry, 64 (5), 543–552. Tohen, M., Hennen, J., Zarate, C.M. Jr et al. (2000) Two-year syndromal and functional recovery in 219 cases of firstepisode major affective disorder with psychotic features. Am. J. Psychiatry, 157 (2), 220–228. Tohen, M., Waternaux, C.M. and Tsuang, M.T. (1990) Outcome in Mania. A 4-year prospective follow-up of 75 patients

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utilizing survival analysis. Arch. Gen. Psychiatry, 47 (12), 1106–1111. Dilsaver, S.C., Chen, Y.W., Swann, A.C. et al. (1997) Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania. Psychiatry Res., 73 (1–2), 47–56. Dunner, D.L., Gershon, E.S. and Goodwin, F.K. (1976) Heritable factors in the severity of affective illness. Biol. Psychiatry, 11 (1), 31–42. Judd, L.L., Akiskal, H.S., Schettler, P.J. et al. (2003) A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch. Gen. Psychiatry, 60 (3), 261–269. Benazzi, F. (2007) Testing predictors of bipolar-II disorder with a 2-day minimum duration of hypomania. Psychiatry Res., 153 (2), 153–162. Angst, J. (1998) The emerging epidemiology of hypomania and bipolar II disorder. J. Affect Disord., 50 (2–3), 143–151. Benazzi, F. (1999) Prevalence of bipolar II disorder in atypical depression. Eur. Arch. Psychiatry Clin. Neurosci., 249 (2), 62–65. Vieta, E. and Suppes, T. (2008) Bipolar II disorder: arguments for and against a distinct diagnostic entity. Bipolar Disord., 10 (1 Pt 2), 163–178. Suppes, T. and Dennehy, E.B. (2002) Evidence-based longterm treatment of bipolar II disorder. J. Clin. Psychiatry, 63 (Suppl 10), 29–33.

52. Ghaemi, S.N., Boiman, E.E. and Goodwin, F.K. (2000) Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J. Clin. Psychiatry, 61 (10), 804–808; quiz 809. 53. Ghaemi, S.N., Sachs, G.S., Chiou, A.M. et al. (1999) Is bipolar disorder still under-diagnosed? Are antidepressants overutilized? J. Affect Disord., 52 (1–3), 135–144. 54. Fieve, R.R., Go, R., Dunner, D.L. and Elston, R. (1984) Search for biological/genetic markers in a long-term epidemiological and morbid risk study of affective disorders. J. Psychiatr. Res., 18 (4), 425–445. 55. Coryell, W., Endicott, J., Reich, T. et al. (1984) A family study of bipolar II disorder. Br. J. Psychiatry, 145, 49–54. 56. Coryell, W., Endicott, J., Maser, J.D. et al. (1995) Long-term stability of polarity distinctions in the affective disorders. Am. J. Psychiatry, 152 (3), 385–390. 57. Judd, L.L., Akiskal, H.S., Schettler, P.J. et al. (2002) The longterm natural history of the weekly symptomatic status of bipolar I disorder. Arch. Gen. Psychiatry, 59 (6), 530–537. 58. Goldring, N. and Fieve, R.R. (1984) Attempted suicide in manic-depressive disorder. Am. J. Psychother, 38 (3), 373–383. 59. Akiskal, H.S., Djenderedjian, A.M., Rosenthal, R.H. and Khani, M.K. (1977) Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am. J. Psychiatry, 134 (11), 1227–1233.

CHAPTER

3

The Long-Term Course and Clinical Management of Bipolar I and Bipolar II Disorders Lewis L. Judd1 and Pamela J. Schettler2 1 2

Department of Psychiatry, University of California at San Diego (UCSD), La Jolla, CA, USA Mood Disorders Research Group, Department of Psychiatry, University of California at San Diego (UCSD), La Jolla, CA, USA

Introduction It is surprising that mood disorders, with their fundamental tendency for episodes to recur during the life cycle, have had so few prospective longitudinal studies of their longterm course of illness. Apart from studies by Jules Angst et al. covering 20 years or more of the life span [1,2], most long-term studies of the course of bipolar illness have been derived from the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS) [3–17]. The vast majority of treatment studies for bipolar disorders are short-term, and until recently have focused primarily on resolution of acute manic episodes. If any follow-up course is examined, it rarely extends beyond two years. Over a decade ago, our research group at the University of California, San Diego, in conjunction with our collaborators from the NIMH CDS, designed a series of studies to describe and delineate the long-term course of mood disorders. Initially, we investigated the long-term course of unipolar major depressive disorder (MDD) [18–20]. We found that unipolar MDD tends to be a chronic lifelong illness, not an illness of single isolated acute major depressive episodes surrounded by long periods of symptom free euthymia. Furthermore, we found that the long-term course of the disorder is expressed symptomatically along a continuum of depressive symptom severity, primarily involving minor, dysthymic and subsyndromal depression. Each increase or decrease in depressive symptom severity, including subsyndromal depressive symptoms, is associated with a progressive and significant increase or decrease in psychosocial impairment [20]. Recovery from a major depressive episode (MDE) with ongoing residual depressive symptoms is associated with significantly faster episode relapse, as well as with a more chronic future course of illness [21,22]. Following our work on unipolar MDD, we designed another series of investigations of patients with bipolar disor-

ders [11–17,23]. The purpose of these studies was to fill the enormous gap in empirical data concerning the long-term course and the life impacts of bipolar I (BP-I) and bipolar II (BP-II) disorders. While findings from these eight peer-reviewed studies have been reported individually in scientific publications, the present chapter afforded an opportunity to compile all of our findings about the long-term symptomatic and episodic course of bipolar I and bipolar II disorders and their associated psychosocial impairment. When first published, our analyses of the weekly symptom status of bipolar CDS patients during up to 20 years of follow-up provided the field with a uniquely detailed and comprehensive picture of the long-termcourseofbipolardisorders.Whilethepresentchapter is primarily based upon our data, we also reference reports by other groups, whose work in this rapidly advancing field of research supports, complements or extends our observations. The findings presented here have strong implications for how bipolar illnesses should be managed over time. Recommendations for this are presented at the conclusion of this chapter.

Methods of the NIMH CDS The data for these publications is derived from the clinical mood disorder cohort of the NIMH CDS [24,25]. This study is unique in that it obtains prospective, naturalistic, systematic, long-term follow-up data on the weekly symptom status of a very large cohort of patients with mood disorders diagnosed using research-based criteria. Patients entered the study in a major affective episode, during a three-year period from 1978 to 1981. Some of these subjects have now been followed for 27 years. Findings reported in this chapter were derived from data extending up to 20 years of followup, with an average of 15 years per subject, for 291 patients with bipolar I or bipolar II disorder.

Subjects Bipolar Disorder: Clinical and Neurobiological Foundations Edited by Lakshmi N. Yatham and Mario Maj © 2010 John Wiley & Sons, Ltd. ISBN: 978-0-470-72198-8

Subjects entered the CDS as inpatients or outpatients at one of five tertiary care centres, while experiencing an active 17

18

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Chapter 3

affective episode. All of the patients in the CDS were required to be Caucasian (genetic hypotheses were being tested), speak English, have an IQ score of at least 70, and have no evidence of any organic brain syndrome or terminal medical illness. Written informed consent was obtained for participation in the research. Patients in the CDS received a diagnosis using the Research Diagnostic Criteria (RDC) [26], based on Schedule for Affective Disorders and Schizophrenia interviews [27] and on a review of medical records. They were included in the present analysis if they met criteria for bipolar I (definite) or bipolar II (definite or probable) at entry. Since we found no difference in clinical, demographic or follow-up characteristics of patients with bipolar II disorder who had hypomanic episodes lasting 1 week or more (definite BP-II) versus three to six days (probable BP-II) [12], we combined both groups into the BPII cohort. Consistent with DSM-IV criteria [28], we excluded N ¼ 25 patients (6.8%) who had no MDD by the end of follow-up (unipolar manic/hypomanic patients and those with lifetime mania/hypomania plus minor depression/ dysthymia but no MDD). For those patients who switched from unipolar MDD to BP-I or BP-II during follow-up, their data on psychosocial impairment were included, starting from the time of their first lifetime manic or hypomanic episode [15]. Patients who ever met RDC criteria for schizophrenia or schizoaffective disorder were excluded. Interview forms rated with poor or very poor reliability of weekly symptom status or monthly psychosocial impairment were excluded from the analysis (3% of follow-up forms). The resulting analysis sample included 158 patients with BP-I (lifetime MDD and mania) and 133 patients with BP-II (lifetime MDD and hypomania, but no mania). Demographic and clinical characteristics are shown in Table 1.

Weekly psychiatric symptom ratings As described in greater detail elsewhere [11–13], trained professional raters interviewed patients every six months for the first five years and then yearly thereafter, using variations ofthe Longitudinal Interval Follow-up Evaluation (LIFE) [29]. During these semi-structured interviews, chronological memory prompts are used to obtain information on changes in weekly symptom severity for all mood and other mental disorders. This information, supplemented by available medical records, is integrated into weekly Psychiatric Status Ratings that have scale values anchored to diagnostic thresholds for RDC mental disorders. The CDS raters undergo rigorous training, resulting in intraclass correlation coefficients of 0.90 for reliability of psychiatric symptom ratings, 0.95 for recovery from major affective episodes, and 0.88 for subsequent appearance of affective symptoms [29]. For the analyses reported here, each week’s psychiatric symptom ratings for all affective conditions were combined and classified into one of eight mutually exclusive symptom

Table 1 Demographic and clinical characteristics of patients with BP-I and BP-II disorders in the NIMH CDS.

Demographics Age Female Married/Living Together Some College Intake Episode Inpatient Severity – Worst Week Global Assessment Scale (GAS) score Last Available Follow-up (years)

BP-I (N ¼ 158)

BP-II (N ¼ 133)

P Value

Mean (sd) Range % %

38.2 (12.6) 17–79 60.1 44.9

35.2 (12.7) 17–74 67.6 42.1

0.18 0.63

%

60.1

57.1

0.61

% Mean (sd)

88.6 33.6 (10.7)

66.9 37.1 (9.2)

<0.001 0.004

Mean (sd) Range

15.2 (4.7) 2.5–20.0

15.2 (4.9) 2.5–20.0

0.89

0.04

severity categories. These are three levels of severity of symptoms in the pure depressive spectrum, namely major depression (MDD), minor depression/dysthymia (MinD) and subsyndromal depression (SSD); three levels of symptom severity in the pure manic spectrum, namely mania, hypomania (Hyp.) and subsyndromal hypomania (SSH); cycling or mixed polarity (indicating change in polarity or coexistence of both manic and depressive symptoms within a given month); or the asymptomatic status (no affective symptoms, return to usual self). To analyze monthly psychosocial impairment ratings in relation to affective symptom severity and polarity, the weekly symptom status categories were then combined and coded with the most severe level of symptom severity (separately for the depressive and the manic spectrum) that occurred during any week of each one-month period of psychosocial ratings. Based on the worst level of affective symptoms recorded in that month, the entire month was then categorized into one of three levels of pure depressive symptom severity, three levels of pure manic/hypomanic symptom severity, a combination of depressive and manic/hypomanic symptoms, or asymptomatic status (no affective symptoms, return to usual self for the entire month).

Characteristics of the long-term course of bipolar illness In the remainder of this chapter, we summarize our findings about the fundamental characteristics of the long-term

The Long-Term Course and Outcome

course of bipolar I and bipolar II disorders based on the weekly affective symptom status data described above. The chapter ends with recommendations for treatment implications derived from these findings. The remainder of the chapter is organized in the following sections: 1 Chronicity of the Course of Bipolar Illness 2 Dynamic and Changeable Affective Symptom Course of Bipolar Illness 3 Affective Symptom Expression Along a Dimensional Continuum of Symptom Severity 4 Dominance of Affective Symptoms Below Syndromal Threshold of Major Depression and Mania 5 Dominance of Depressive Episodes and Symptoms 6 Psychosocial Impairment Associated with Bipolar Disorders 7 Clinical Importance of Bipolar II Disorder 8 Incomplete Recovery from Major Affective Episodes As a Predictor of Early Episode Relapse/Recurrence 9 Conclusions About the Long-Term Course of Bipolar Illness 10 Implications for the Long-Term Clinical Management of BP-I and BP-II Disorders.

Chronicity of the course of bipolar illness It is generally understood that bipolar disorders, with their repeat episodes, are chronic in nature. However, a unique picture of just how chronic these disorders really are emerged from these studies. As seen from Table 2, the Table 2 Lifetime chronicity of BP-I and BP-II disorders in the NIMH CDS.

Prior to Intake Age of Onset of First Lifetime Affective Episode First Episode before Age 21 Number of Previous Episodes (Including the Intake Episode) During Follow-up % Wks Symptomatic during
20 Yrs of Follow-up Number of Episodes during 10 Yrs after End of Intake Episode

BP-I

BP-II

P Value

Mean (sd) Range

23.6 (10.4) 1–62

22.1 (10.5) 1–64

0.22

%

49.4

53.4

0.50

Median

5.5

5.0

0.52

Mean (sd)

46.6 (34.1)

55.8 (33.1)

0.06

Median

2.5

4.0

0.05

|

19

illness begins early in life, with mean age of onset of first affective episode in the low 20s for both bipolar I and bipolar II disorders, and approximately half the samples experiencing their first affective episode before age 21. Patients entering the CDS with either bipolar disorder had already experienced a median of five separate affective episodes (including the index/intake episode). During the first 10 years of follow-up after the end of the intake episode, patients with bipolar I disorder experienced a median of 2.5 episodes and those with bipolar II disorder experienced a median of four episodes; this difference was marginally significant (P ¼ 0.05). This is consistent with Angst et al.’s findings from a 27-year follow-up of a large cohort of patients hospitalized between 1959 and 1963 and evaluated at five-year intervals thereafter [2]. Those authors found that the risk of recurrence of bipolar disorders (0.4 episodes per year) was about twice that of unipolar depressive patients (0.2 episodes per year); that the risk of recurrence was slightly higher for BP-II than for BP-I; and that the risk of recurrence for all groups was constant over the life span, up to the age of 70. A new measure of chronicity, which we have been advocating for the study of both unipolar MDD and bipolar disorder, is the total percentage of weeks when subjects experience any level of affective symptoms from their illness – in other words, the percentage of time the illness is active. Measurement of total time symptomatic, regardless of the symptom severity or whether an individual is in an episode, is a more sensitive measure of illness chronicity than time in episodes, since we have demonstrated that bipolar (and unipolar) patients, even when meeting consensus criteria for ‘recovery’, frequently experience subsyndromal affective symptoms [17,21]. As shown in Table 2, patients with bipolar I disorder were symptomatic from their illness during 47% of follow-up weeks and bipolar II patients were symptomatic 56% of the time. It is very clear that bipolar disorders, both BP-I and BP-II, are intensely chronic with the patients being afflicted from the illness approximately half of the time, during up to 20 years of prospectively observed follow-up.

Dynamic and changeable affective symptom course of bipolar illness Angst and his colleagues reported that BP-II patients experience a slightly higher number of episodes per year than BP-I patients [1,2]. In a 2003 paper [14], we confirmed and extended these findings by comparing BP-I and BP-II patients on the number, duration and percentage of weeks spent in each type of affective episode, during a 10-year period after the end of their intake episode. In this study, both bipolar groups spent about 30% of the time in major or minor mood disorder episodes. BP-II patients tended to have more episodes (mean (sd) ¼ 4.2 (2.6) vs. 3.3 (2.5);

20

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Chapter 3

Table 3 Dynamic follow-up course of BP-I and BP-II disorders in the NIMH CDS.

Total Changes in Symptom Status (Changes in Severity and/or Polarity) Changes per Yr Mean (sd) More than % 5 Times per Yr Changes in Symptom Polarity Changes per Yr More than 5 Times per Yr

Mean (sd) %

BP-I

BP-II

5.9 (7.7) 35.6

3.8 (4.9) 22.5

3.5 (7.5) 19.3

1.5 (4.2) 5.6

P ¼ 0.052), including significantly more episodes of MDD and significantly more episodes of minor depression or dysthymia. BP-I patients, on the other hand, had significantly more episodes with cycling/mixed polarity (some depression and some mania/hypomania). During this 10-year period, the duration of each type of episode was slightly (non-significantly) longer for patients with BP-II than for those with BP-I. When data on episode status is supplemented with weekly data on change in the entire spectrum of affective symptom categories, the results show a strikingly high number of changes in symptom status per year for bipolar patients. As seen in Table 3, the mean total number of changes per year in symptom status (symptom severity and/or polarity) is nearly 6 for BP-I patients and approximately 4 for BP-II patients. By contrast, we found that unipolar MDD patients in the CDS changed depressive symptom severity level only

Hyp. 5% SSH 3%

Mania 2% Mixed 6%

Affective symptom expression along a dimensional continuum of symptom severity Over the long-term course, affective symptoms in bipolar disorder are expressed along a dimensional continuum of progressively increasing symptom severity, ranging from subsyndromal, through minor depressive and hypomanic affective symptoms, to symptoms at the full syndromal severity of mania and major depression. Figure 1 shows the percentage of weeks of follow-up that BP-I and BP-II subjects in the CDS spent in each of eight mutually exclusive symptom categories – three levels of depressive symptom severity, three levels of manic/hypomanic symptom severity, symptoms of mixed polarity and the asymptomatic status [13]. BP-I patients were without symptoms of the illness 53% of the time, and BP-II patients were asymptomatic only 44% of the time. This is a striking confirmation of

Hyp. 1% SSH .4%

Mixed 2.5%

MDD 13%

MDD 9% MinD 13%

two times per year [18], corroborating Angst’s findings of greater change in bipolar patients compared to unipolar patients [1,2]. Shifts per year in symptom polarity are defined by a patient shifting from symptoms in the depressive spectrum to the manic spectrum or vice versa. On average, BP-I patients change polarity between three and four times per year and BP-II patients change between one and two times per year. Examination of shifts across the entire spectrum of affective symptoms complements the picture of long-term course based on episode status alone, and shows that BP-I is the more dynamic and changeable of the two disorders, while BP-II is characterized by greater chronicity and more frequent episodes. It is noteworthy that a subset of each group suffers from a highly changeable course that could be labelled as rapid cycling. What is presented here is a rather dramatic picture of the changeable and quixotic nature of the naturalistic course of bipolar disorders.

Asymptomatic 53%

Asymptomatic 44% MinD 25%

SSD 9% SSD 14%

Bipolar I

Bipolar II

Fig. 1 Mean percent weeks in each category of affective symptoms during long-term follow-up.

The Long-Term Course and Outcome

the highly chronic nature of BP-II. We found that the great majority of bipolar patients experience the full range of categories of symptom severity of both depressive and manic symptoms during their course of illness. This, combined with the information on changeability of course (above), shows that bipolar patients not only change episode status frequently, but move and flow from one category of symptom severity and polarity to another during the course of their illness. Observing bipolar patients serially or cross-sectionally is like taking a snapshot of an ongoing movie. When seen at one point in time, patients may be in an episode of mania or depression, while at another time they are likely to be experiencing minor or subsyndromal affective symptoms, and at yet another time they may be free of symptoms and euthymic. It is only when the entire, continuous symptomatic course is recorded and analyzed, that a true picture of the long-term symptomatic course of bipolar disorders can be seen.

Dominance of affective symptoms below syndromal threshold of major depression and mania Contained in Table 4 are the mean percent of follow-up weeks at the threshold of major depression or mania versus the mean percent weeks beneath that threshold – that is with symptoms at or below the threshold for minor depression or hypomania. As can be seen, most of the symptomatic course of both BP-I and BP-II disorder is below the syndromal threshold. Even though bipolar disorder is traditionally defined by episodes at the syndromal threshold of major depression or mania, most of the illness occurs over time at a mild or moderate level of affective symptom severity. These data on the dominance of subthreshold symptoms during the course of bipolar illness complement our previous findings, derived from the NIMH Epidemiological Catchment Area (ECA) study [30]. The original authors of the ECA reported that the lifetime prevalence of bipolar I disorder was 0.8%, and bipolar II disorder was 0.5% for

Table 4 Dominance of subthreshold symptoms during long-term follow-up of patients with BP-I and BP-II disorders in the NIMH CDS.

Percent of Wks with Symptoms beneath the Threshold of MDE/Mania Percent of Wks with Symptoms at the Threshold of MDE/Mania Subthreshold/Threshold

BP-I

BP-II

Mean

34.2

43.2

Mean

12.3

12.6

Ratio

<3 : 1

>3 : 1

|

21

a combined lifetime prevalence of bipolar illness of 1.3% [31]. With our reanalysis of the ECA data adding subthreshold hypomanic symptoms [23], the lifetime prevalence figures increased substantially, from 1.3 to 6.4% for the bipolar spectrum. In that study, having had symptoms at the subsyndromal hypomanic level at some time in one’s life was found to be associated with significantly greater health service utilization for mental/emotional or substance abuse problems, as well as greater use of welfare and disability benefits. Subsyndromal symptoms are particularly important when they are present during an episode of the opposite polarity. Angst et al. [32] and others [33,34] have pointed out that, in persons with a history of major or even mild depression, subsyndromal hypomanic symptoms are an important indicator of bipolarity that needs to be considered during diagnosis and treatment. Investigators analyzing the NIMH STEP-BD data found that two-thirds of the 1380 subjects presenting with bipolar I or II depressive syndromes also had subsyndromal manic/hypomanic symptoms at intake, and that these were markers for a more severe form of bipolar illness [33]. Further analysis of the STEP-BD data has shown that use of adjunctive antidepressants in these subjects does not speed recovery from the index depression compared to mood stabilizers alone, and it may even increase the severity of the manic symptoms [34].

Dominance of depressive episodes and symptoms As the new picture of the long-term symptomatic course of bipolar illness began to emerge, the high prevalence of depressive episodes and symptoms was very striking. While bipolar illness has traditionally been defined and treated with a focus on the often chaotic episodes of mania, these comprise a relatively small portion of the total symptomatic course of illness. Table 5 shows the percent of weeks during long-term follow-up that bipolar patients in the CDS spent with depressive episodes and symptoms, compared

Table 5 Dominance of depressive episodes and symptoms during long-term follow-up of patients with BP-I and BP-II disorders in the NIMH CDS.

Percent of Wks with Depressive Episodes and Symptoms Percent of Wks with Manic/Hypomanic Episodes and Symptoms Depression/Mania

BP-I

BP-II

Mean

30.6

51.9

Mean

9.8

1.4

Ratio

3:1

37 : 1

22

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Chapter 3

to all weeks with manic/hypomanic episodes and symptoms. The ratio of depression to mania (D:M) in BP-I is approximately 3 : 1. The ratio in BP-II is dramatically different, with approximately 52% of the weeks involving depressive episodes and symptoms and only 1.4% of weeks when BP-II patients experience hypomanic episodes and subsyndromal hypomanic symptoms – resulting in a ratio of depressive to hypomanic symptom spectrum of 37 : 1. This provides compelling data supporting the conclusion that BP-I is primarily a depressive illness and that BP-II is almost exclusively a chronic depressive illness. This is interesting, since most of the scientific effort in the study of bipolar disorder has focused on the management of manic or mixed polarity symptoms, with far less attention to depressive episodes and symptoms. It is an important fact that depression is far more prevalent during the course of bipolar illness. Other investigators have documented the importance of depression in the long-term course of BP-I disorder. Turvey et al. [10] found that individual CDS patients with BP-I tended to have consistency across prospectively observed episodes in terms of their starting polarity, that episodes beginning with major depression were significantly longer than those beginning with mania, and that patients whose first prospectively observed episode began with depression had a significantly worse follow-up course. More recently, the 10-year McLean-Harvard First Episode Project & International Consortium for Bipolar Disorder Research found that most early morbidity after first lifetime onset of bipolar I disorder is associated with depression, and that initial depression or mixed states predict more depressive symptoms and greater overall morbidity during subsequent follow-up [35]. Coryell et al. recently reported [36] that early onset age predicts greater depressive morbidity in BP-I patients during CDS follow-up, and that depressive symptoms increasingly predominate as individuals move through their third, fourth and fifth decades of BP-I illness.

Psychosocial impairment associated with bipolar disorders Data summarized in this section are from the first investigation that we are aware of, studying psychosocial impairment associated with every level of affective symptom severity, as well as periods of euthymia in a large cohort of BP-I and BP-II patients followed prospectively for many years [15]. In Figure 2, mean ratings of global psychosocial impairment associated with various symptom status categories are presented. Results were generated by mixed regression analysis, used to model the relationship between monthly psychosocial ratings and the severity and polarity of affective symptoms within those months, as individual patients experience different symptom status categories

during long-term follow-up. The height of the bars represents mean level of impairment, and the error bars represent the 95% confidence intervals of those means, from the mixed regression analysis. As clearly conveyed in Figure 2, affective symptom severity and psychosocial disability fluctuate together during the course of bipolar illness. As we found for unipolar MDD [20], every stepwise increase or decrease in depressive symptom severity is associated with a corresponding significant, stepwise increase or decrease in psychosocial impairment in both BP-I and BP-II disorders. When subjects with either disorder have no mood disorder symptoms, no impairment is present and psychosocial functioning is rated as good. When the same patients are experiencing subsyndromal depressive symptoms, they have mild impairment; during months with symptoms at the level of minor depression or dysthymia, their psychosocial impairment is rated between mild and moderate; and when bipolar patients are experiencing symptoms at the syndromal threshold of major depression, their psychosocial functioning is rated as moderately impaired. Even subsyndromal depressive symptoms are associated with significantly more impairment than the asymptomatic (euthymic) status, for both BP-I and BP-II disorder. There is a similar picture of stepwise increases in psychosocial impairment associated with stepwise increases in manic symptom severity, for patients with BP-I disorder. By contrast, for those with BP-II disorder, hypomanic and subsyndromal hypomanic symptoms are not associated with significant increases in psychosocial impairment, and may even enhance psychosocial function. This is consistent with Akiskal’s and others’ findings that minimal disability, and possibly even enhanced psychosocial functioning, frequently occurs during subsyndromal and syndromal hypomanic periods of bipolar II disorder, which may make it difficult to diagnose hypomania [37–40]. Figure 2 also conveys that depressive symptoms, which have been seen to dominate the course of both bipolar disorders, are at least as disabling as symptoms of comparable severity in the manic/hypomanic spectrum. Data from these studies shows that much of the psychosocial disability associated with BP-I and BP-II is derived from symptoms in the depressive spectrum. This is in striking contradiction to the traditional view that mania and manic symptoms are more disabling than depression. The figure further shows that within each level of depressive symptom severity, BP-II is associated with a level of psychosocial impairment comparable to BP-I disorder. These findings again underscore the importance of depressive symptoms in BP-II. What should be very encouraging to all is the fact that when affective symptoms are abated and the patient with either BP-I or BP-II is asymptomatic, no psychosocial impairment is noted and the patient’s function is rated as normalized.

The Long-Term Course and Outcome

Mean Global Impairment Rating

Asymptomatic

Marked

5

Depressive Spectrum

|

23

Manic Spectrum

Patients with Bipolar I Disorder (N=158)

Impairment

4

Moderate Impairment

3

Mild Impairment

2

No Impairment

1 Asympt.

Mean Global Impairment Rating

5

SSD SSH

MinD Hypom.

MDD Mania

Patients with Bipolar II Disorder (N=133)

Marked Impairment

4

Moderate Impairment

3

Mild Impairment

2

No Impairment

1 Asympt.

SSD SSH

MinD Hypom.

Clinical importance of bipolar II disorder Bipolar II disorder is generally considered to be the lesser of the two bipolar subtypes and some think it is of little clinical significance; as a result, it not treated as often as it should be. Findings presented here provide strong evidence that these impressions of BP-II disorder are incorrect. CDS subjects with BP-II were symptomatic during 56% of weeks during an average of 15 years of follow-up; this is evidence of even greater symptomatic chronicity than for patients with BP-I disorder, who were symptomatic during 47% of weeks in their long-term course. Furthermore, BP-II patients spent approximately the same mean percentage of follow-up weeks at the full syndromal threshold of MDE as BP-I patients spent with MDE/mania [mean (sd) ¼ 12.6 (15.9) vs. 12.3 (14.6); P ¼ 0.834]. They also spent significantly more weeks with symptoms of minor depression/dysthymia or hypomania [mean (sd) ¼ 27.0 (23.3) vs. 20.1 (21.2); P ¼ 0.036]. In our study comparing the episodic course of BP-I and BP-II patients in the CDS [14], we found that those with BP-II had significantly longer intake episodes (P < 0.001), and 18% even had psychotic symptoms. They also had marginally more episodes during follow-up (P ¼ 0.052),

MDD

Fig. 2 Mean global impairment rating at each level of affective symptom severity (single polarity months).

including significantly more episodes of MDD and minor depression/dysthymia (P < 0.001 for both). Patients with BP-II disorder experienced depressive symptoms during more than half of follow-up weeks, and depressive symptoms outweighed the percent of hypomanic symptoms in a ratio of 37 : 1 (compared to a ratio of 3 : 1 for patients with BP-I disorder). This is notable because all levels of depressive symptoms, as indicated in the last section, are associated with significant psychosocial impairment. When we examined psychosocial disability averaged across all ill and well periods during the long-term course of illness for patients with BP-I and BP-II disorders [16], the mean levels of global disability for the two bipolar groups were identical and reflected a mild level of impairment. Both groups experienced some degree of impairment during nearly 60% of months during follow-up (58.3% for BP-I; 59.1% for BP-II), which included moderate to severe impairment during 30% of long-term follow-up (31.3% for BPI; 30.3% for BP-II). Impairment for both bipolar groups was slightly higher than for unipolar MDD patients (53.8% of months with some impairment, including 25.8% with moderate to severe impairment during long-term follow-up).

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We did not find any difference in BP-II disorder defined on the basis of hypomanic episodes that are longer (7 days or more) compared to shorter (from two to six days) [12]. We and others [32,39] have suggested that hypomanic episodes of either duration are part of the same disease process. Despite the evidence that bipolar II disorder is a ‘real’ disorder, with its intensely chronic and depressive nature and its association with significant psychosocial impairment, treatment of BP-II tends to be overlooked [13]. Table 6 provides cogent data on somatic treatment by symptom severity and polarity categories. Within 5 of 7 symptom categories, including the asymptomatic status when patients often require maintenance treatment for prophylaxis of future episodes, CDS patients with BP-II disorder were prescribed somatic treatment significantly less often than those with BP-I disorder. This was the case even during periods when patients were experiencing symptoms at the level of major depression; BP-II patients were treated only half the time, compared to three-quarters of the time for patients with BP-I during MDE periods. Data presented here clearly shows that bipolar II disorder is not the lesser of the two bipolar subtypes, but is a serious and intensely depressive disorder in its own right, and warrants the same level of clinical management that is given to bipolar I disorder.

Incomplete recovery from major affective episodes as a predictor of early episode relapse/recurrence We previously reported that the presence of ongoing residual subsyndromal depressive symptoms following recovery from a MDE in unipolar MDD patients, although meeting the consensus definition of ‘recovery’, is associated with significantly faster episode relapse/recurrence when

Table 6 Mean percent of weeks with any prescribed somatic treatment for BP-I vs. BP-II disorder, by affective symptom category during long-term follow-up. Affective Symptom Category

BP-I

BP-II

P Value

Levels of Depressive Severity Subsyndromal Depressive Symptoms Minor Depression/Dysthymia Major Depressive Disorder

75.9% 77.2% 76.0%

51.9% 56.9% 60.4%

<0.001 <0.001 0.003

Levels of Hypomanic Severity Subsyndromal Hypomania Hypomania

91.1% 80.7%

53.3% 55.3%

0.003 0.068

Cycling/Mixed Polarity Symptoms (All Levels of Severity)

79.9%

58.8%

0.137

Asymptomatic Status (Prophylaxis)

73.7%

43.5%

<0.001

compared to full asymptomatic recovery [21,22]. We hypothesized that the same would be true in bipolar illness – namely, that residual affective symptoms seen following resolution of major affective episodes in bipolar patients would also be associated with significantly faster relapse/ recurrence of the next major affective episode. Similar to our unipolar MDD papers [21,22], ‘recovery’ for our investigation in the bipolar cohort [17] also followed the current consensus definition of eight or more consecutive weeks asymptomatic or with minimal residual affective symptoms. However, dividing recovery into these two levels, we found (Figure 3) that those bipolar patients recovering from their intake MDE/manic episodes with residual affective symptoms experienced a subsequent major affective episode over five times faster than asymptomatic recoverers (median 24 weeks vs. 123 weeks, respectively; p < 0.001). We also found that those whose recovery was marked by residual affective symptoms had a significantly more chronic and severe future course. Recovery status (asymptomatic vs. residual symptoms) proved to be the strongest correlate of time to major affective episode relapse/recurrence for the bipolar cohort (p < 0.001), followed by a history of three or more affective episodes before intake (p ¼ 0.007). No other variable of the 13 examined was significantly associated with time to relapse/recurrence, once the Bonferroni correction was applied. We concluded that in bipolar disorder, the presence of residual symptoms after the resolution of a major affective episode indicates that the individual is at significant risk for rapid relapse and/or recurrence, strongly suggesting that the illness is still active. Recently, a panel of experts in bipolar disorder proposed a standardized set of definitions for patient status for use in clinical trials [41]. These include ‘remission’, defined as having no or only minimal symptoms of the affective episode for one week, and ‘sustained remission’, defined as maintaining this status for eight consecutive weeks. Our finding that ‘recovery’ with residual affective symptoms predicts much faster episode relapse in unipolar [21,22] and bipolar [17] patients, however, argues for a stricter definition of episode remission based on achieving abatement of all symptoms of the episode. Berk et al. [42] re-analysed data from four pharmacologic treatment studies using a definition of remission based on achieving a Clinical Global Impression-Bipolar Version (CGI-BP) severity score of 1 (representing ’normal, not at all ill’). Compared to the current consensus definition of recovery, which allows minimal affective symptoms to be present, these authors conclude that the stricter definition of remission, while more difficult to attain, is more clinically meaningful. We fully agree and have been advocating this since 1998 [21]. The minimum time (number of consecutive weeks) at this status needed to define a stable state of recovery needs to be determined through empirical study, and may be as short as four weeks. A stable recovery state in bipolar disorder,

Cumulative % of Subjects Remaining Free of Major Affective Episode Relapse/Recurrence

The Long-Term Course and Outcome 100

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25

Asymptomatic Recovery (N = 163) Recovery with Residual Affective Symptoms (N = 60)

75

50

Median Weeks Well

(95% Confidence Interval)

123

(89 - 179)

24

(19 - 31)

25

0

0

200

400

600

800

1000

Weeks from End of Intake MDE/Mania to Next Major Affective Episode Wilcoxon Chi Square = 35.81; P < 0.0001; Hazard Ratio = 3.36 (95% CI = 2.25 - 4.98) Judd et al., Arch Gen Psychiatry, 2008

we believe, is achieved only when the asymptomatic status is reached for a sufficient period of time for the patient to be free of risk for relapse into the previous syndromal episode.

Conclusions about the long-term course of bipolar illness From these data, we conclude that bipolar illness disorders are chronic, primarily lifelong illnesses, with strong tendencies for relapse and recurrence of major and minor affective episodes. Syndromal level episodes are interspersed with euthymic periods, during which subsyndromal symptoms are often present. The long-term symptomatic expression of bipolar disorders is dimensional in character, along a continuum of depressive and manic/hypomanic symptom severity. Affective symptoms beneath the threshold of mania and major depression dominate the course of bipolar disorders on a 3 : 1 basis. Psychosocial impairment changes in a step-wise fashion with each increase or decrease in depressive symptom severity in either bipolar I or bipolar II disorder, and with each increase or decrease in manic symptom severity in bipolar I disorder. When patients are completely without symptoms (asymptomatic), psychosocial impairment is no longer seen and the patient’s psychosocial function normalizes and is rated as good. The longterm course of bipolar disorders is very dynamic and changeable, with patients frequently moving from one level of symptom severity to another and from one polarity to another. Depressive episodes and symptoms dominate the course of BP-I (3 : 1 ratio) and BP-II (37 : 1 ratio). Although both bipolar disorders are primarily depressive in nature, bipolar II disorder is fundamentally a chronic depressive illness. As such, BP-II is not merely the lesser of the two bipolar disorders, but is a more serious illness than previ-

Fig. 3 Comparison of asymptomatic versus residual symptom recovery on time to next major affective episode (N ¼ 223 patients with bipolar I or bipolar II disorder). Reprinted from Judd et al., Arch Gen Psychiatry 2008; 65(4):386–394. Copyright
(2008) American Medical Association. All rights reserved.

ously thought. Asymptomatic recovery from major affective episodes is associated with a significantly longer delay in episode relapse or recurrence, as well as a more benign future course of illness. The methodology of our studies, which takes into account the full range of affective symptom severity and polarity on a weekly basis, should be considered by other researchers interested in studying the long-term course of bipolar and unipolar disorders. Collection of such prospective data by trained clinical raters, using empirically established semistructured interviews such as the LIFE [29], not only provides the basis for accurate identification of the start and end of all types of affective episodes (including those below the syndromal level of MDE and mania), but also provides a complete picture of the true illness burden associated with all levels of affective symptoms, during and between episodes. The empirical findings on the long-term course of bipolar illness summarized here suggest certain principles for effective long-term clinical management strategies. These are the focus of the final section of this chapter.

Implications for the long-term clinical management of BP-I and BP-II disorders There are scores of studies presenting useful empirical data on a wide variety of pharmacological agents, and combinations of agents, used to treat acute bipolar episodes; these have been summarized in recent review papers [43,44]. Early studies focused primarily on the treatment of mania [45], but as the predominance of depression that we have reported [11–13] has gained acceptance, controlled medication trials increasingly address the treatment and prevention of bipolar episodes of depression as well [46–48],

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including mixed polarity episodes consisting of depression with concurrent subsyndromal manic/hypomanic symptoms [33]. Most of these studies are concerned with pharmacological agents to treat BP-I. It has generally been assumed that depression in BP-II responds to the same agents used to treat depression in BP-I, and that hypomania is likely to respond to the same agents that are used for mania. Recently, controlled studies have begun to be conducted examining medication effectiveness for BP-II [49]. The NIMH CDS, on which this chapter is largely based, is a naturalistic study, not a controlled treatment investigation. Some studies have examined the impact of particular classes of medication on course and outcome for unipolar [50–52] and bipolar [53–55] patients in the CDS. However, conclusions about medication selection, dosage schedules and medication combinations should be drawn with caution and confirmed only through reports of controlled clinical trials. By ’naturalistic’ is meant that patients were followed systematically while on and off medications, which were given according to the standards and protocols at each of the five academic centres where they entered the CDS in 1978 through 1981, or practices at other facilities where they received treatment during 20 years of follow-up. Somatic treatments throughout this time were systematically recorded, along with the frequency of various types of ‘talk therapy’ and any periods of hospitalization. Treatments given are likely to be consistent with the best available clinical practices at the particular time and would have changed as new medications, and combinations of medications, came into use. There is little doubt that modern psychopharmacology, with its increasing numbers of mood stabilizing medications to treat bipolar illness, has revolutionized the management of these serious disorders. It has made these devastating illnesses into treatable diseases and it is no longer necessary for bipolar patients to spend significant parts of their lifetime hospitalized. Findings about the long-term course of bipolar disorders, developed using the unique CDS database, highlight the need for certain approaches to the clinical management of bipolar disorders. In the remainder of this chapter we outline a series of therapeutic strategies and health system requirements for effectively treating bipolar patients and supporting those closest to them. As many clinicians have already discovered, these therapeutic principles are proving very useful for controlling and managing these difficult, potentially devastating, chronic disorders, and for normalizing patients’ functioning and well-being.

Paradigm shift from acute to chronic disorders The first and perhaps most important treatment implication based on the CDS data presented here is the shift from understanding bipolar disorders as a series of acute, isolated affective episodes, to the recognition that they are

fundamentally chronic, lifelong illnesses. This necessitates a paradigm shift in the overall approach to managing bipolar disorders. We have established that, while patients with BP-I or BP-II disorder spend only 12 or 13% of longterm follow-up at the syndromal level of MDE or mania, they are symptomatic from their illnesses and psychosocially impaired during over half of their course of illness. This underscores the inherently chronic nature of bipolar illness. Recognizing the chronicity of these disorders is the first step to realizing that patients need to be treated with long-term treatment strategies such as those used for type II diabetes, chronic coronary artery disease and so on. Similarly, chronic illnesses such as BP-I and BP-II also require long-term chronic treatment strategies.

Principles for the long-term clinical management of bipolar disorders Following is a series of suggestions based on the data we have reported here, outlining strategies for how bipolar illness can best be managed throughout the patient’s life cycle. It is beyond the scope of this chapter to provide a comprehensive review of the large number of important medication and psychosocial treatment studies for bipolar disorder. Rather, we have referenced selected studies that are relevant to specific treatment recommendations: 1 Provide accurate, evidence-based information on the clinical characteristics and treatment of bipolar illness. It is essential, at the very beginning of treatment, to initiate an educational programme for patients, spouses, families and significant others concerning the clinical characteristics of bipolar illness, including its chronicity and very strong tendencies for episode relapse and recurrence. Special emphasis should be placed on identifying early warning signs or symptoms that may usher in an impending affective episode, together with the need to contact the clinician at the first appearance of these signs. We have noted that bipolar patients often move from an asymptomatic status to an active illness state, with progressive increases in affective symptom severity. Often, a given patient will experience the same unique symptom or set of symptoms as a precursor to each impending episode. Care should be taken by the clinician to identify the signal symptoms for each individual patient, and the patient needs to be instructed to contact the attending clinician as soon as possible when the signal symptoms appear. In addition, the process of education provides an ideal opportunity to create a treatment team made up of the clinician (as leader), the bipolar patient and willing significant others – all of whose goal is to restore and maintain full recovery for the patient. It is essential for those on the team to maintain open communication about the patient’s status, help monitor treatment adherence and provide support during times of crisis and other difficulties (see No. 5 below, on clinical monitoring, for details).

The Long-Term Course and Outcome

2 The necessity for strict adherence to the therapeutic regimen prescribed should be emphasized to patients, spouses, family members and significant others. It is paramount to highlight to the patient and all concerned the need for scrupulous adherence to the prescribed treatment regimens, both medication and psychosocial, thatare needed for effective treatment during both short-term and long-term management phases of the bipolar disorder. The necessity of complying with all recommended treatments should be clearly explained and discussed with the patient and significant others, so they can understand the importance of these approaches for reducing acute symptoms, stabilizing patients and maximizing their psychosocial functioning and well-being, together with preventing future episodes. 3 Explain the need for extended long-term medication regimens. We and others have found it useful to conceptualize the treatment of mood disorders, including bipolar disorders, in terms of different phases of treatment: First, acute treatment is aimed at amelioration of acute symptoms of the index episode. Second, continuation treatment extends beyond symptom resolution of the index episode, and is aimed at preventing return of the index episode (relapse), as well as achieving a stable state of recovery of at least four weeks asymptomatic, if possible. Third, the maintenance phase of treatment is focused on prevention of future new episodes (recurrence), as well as elimination of psychosocial dysfunction and impaired sense of wellbeing that is associated with even the most minor subsyndromal symptoms. The medications used (singly or in combination) during these treatment phases, along with their dosage schedule, need to be individually tailored to each patient. In deciding what medications to prescribe, clinicians need to consider the latest published research findings as well as the patient’s current symptom status, previous clinical history (including their patterns of cyclicity and risk for depressive vs. manic relapse), their past and current medication response, and their experience of adverse side effects. In some cases it is advisable to continue or maintain the patient indefinitely on the same medication(s) and at the same dosage that proved effective for achieving resolution of their acute episode [56]. 4 Combined treatment with medication and adjunctive psychosocial intervention is optimum. It is becoming increasingly recognized that bipolar disorders typically pose enormous short-term and long-term challenges for patients and their families, despite the best available medication regimens [35,57]. Recently, a considerable body of evidence has been building, demonstrating the effectiveness of psychosocial intervention programmes for improving both acute and long-term outcomes in bipolar illness [58–70]. At a recent roundtable [65], experts in the field concluded that, as with other chronic mental disorders, an integrated approach is best, which includes individualized programmes of psychosocial intervention (such as cogni-

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tive-behavioural therapy, interpersonal and social rhythm therapy, and family therapy), along with extended longterm medication regimens. These combined approaches are effective during acute, continuation and maintenance phases of treatment. The main psychosocial intervention modalities for which there is currently some empirical evidence include the following: cognitive-behavioural therapy, which is focused on assisting patients in modifying dysfunctional cognitions and behaviours; interpersonal and social rhythm therapy, which is aimed at improving interpersonal role and occupational functioning, and regularizing daily biological and social rhythms; and family therapy, which aims at reducing high levels of stress and conflict within the patient’s family and teaching effective strategies for coping with bipolar disorder. Another modality, group psychoeducation, provides a forum for sharing accurate, evidence-based information on the clinical characteristics and course of bipolar disorders, available treatment strategies and the necessity for strict adherence to the prescribed treatment. It is also an ideal opportunity to organize and empower the treatment team (clinician, patient, family and significant others), which has proven invaluable in helping to monitor the bipolar patient and keep them episode and symptomfree. From recent reviews of controlled clinical trials on psychosocial interventions for treatment of bipolar disorders [62,64–67], it now appears that specific psychosocial intervention modalities are most effective, depending on the time when they are introduced (acute, continuation or maintenance treatment phase), the clinical status of the patient, the past history of episode polarity and the presence of comorbid conditions. These efforts are promising and await results of further randomized controlled clinical trials confirming or extending these early observations. In the meantime, it is recommended that integrated pharmacological and psychosocial therapies be used for BP-I and BP-II during all three phases of treatment, with the specific modalities selected and applied based upon the most recent publications in this rapidly expanding area of research. 5 Clinical monitoring should be available on a regular ongoing basis. It is important for physicians who are caring for bipolar patients to maintain contact with those patients, even though they may appear to be euthymic and doing well during certain periods. Regular contact is necessary to evaluate current clinical status, adherence to treatment and patients’ psychosocial well-being. There should be clear two-way communication between the clinician and patient to address questions about medication compliance, dosage adjustments and any adverse side effects, along with checking to see whether the patient needs ‘booster’ sessions of their psychosocial treatment. An effective treatment team is indispensable for maintaining this communication. Many academic centres have organized mood disorder clinics, where knowledgeable clinicians or case managers maintain

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Chapter 3

frequent contact with the patient and other members of the treatment team to monitor patients’ clinical status and early signs of impending affective episodes. It is not sufficient to treat the bipolar patient for an acute affective episode, then discharge them with instructions to return if bipolar symptoms recur. A necessary component of the long-term maintenance strategy consists of ongoing contact, careful clinical monitoring and management, and a partnership within the entire treatment team to keep the patient well and functioning optimally. 6 Treat affective episodes and symptoms to their full symptom abatement. The presence of ongoing residual affective symptoms following ‘recovery’ from a major affective episode, even though it meets consensus criteria for remission, has now been shown to be associated with early episode relapse and a less benign future course of illness [17,21,22]. This indicates that the illness is still active and that until all symptoms of the index episode are fully resolved, the episode is not yet over. These findings support the idea that the optimal goal for treatment of bipolar episodes, as for unipolar MDD, should be to eliminate all residual affective symptoms, restore good psychosocial function, and achieve a sustained state of full recovery. 7 Treat depressive episodes and symptoms with equal priority and rigour as manic episodes and symptoms. Until recently, most of the clinical and research emphasis in bipolar disorders has been on the treatment of acute manic episodes. We have provided evidence here that the course of BP-I and BP-II is largely depressive. Since we published these findings [11–13], recent reports have addressed medication issues specifically for controlling the depressive phases of bipolar disorder [46–48]. As data about the highly depressive course of bipolar illness becomes more widely disseminated, we anticipate that there will be increased numbers of treatment studies focusing on bipolar depression. 8 Treat bipolar II with the same priority and rigour as bipolar I disorder. These studies underscore both the clinical importance and the disabling nature of bipolar II disorder, together with the fact that it is treated significantly less often than bipolar I disorder, even at the same levels of affective symptom severity. Bipolar II disorder is equally impairing as bipolar I disorder, because of its intensely chronic and depressive nature [16]. Patients with bipolar II disorder deserve and need equal therapeutic priority and the same methodical treatment rigour as those with bipolar I disorder, throughout their lifetime.

Summary of the expanded goals for the long-term management of bipolar disorders The first step in the treatment of patients with bipolar disorders is to ameliorate the severe symptoms of an acute affective episode. To this we now add the need to treat even

residual symptoms of the episode to their full abatement, where possible. Our findings about the chronicity of bipolar disorders underscore the importance of ongoing clinical monitoring and long-term maintenance treatment to prevent affective episode relapse and recurrence, as well as the need to treat even minor and subsyndromal affective symptoms in order to reduce the overall chronicity of the illness. Our findings of psychosocial impairment associated with all levels of affective symptom severity highlight the treatment goal of restoring bipolar patients to their optimal level of psychosocial functioning. In summary, the focus of treatment has shifted from the reduction of severe symptoms of acute episodes, to maintaining patients as symptom-free and optimally functioning as possible throughout their lifetime.

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The Long-Term Course and Outcome 13. Judd, L.L., Schettler, P.J., Akiskal, H.S. et al. (2003) Long-term symptomatic status of bipolar I vs. bipolar II disorders. Int. J. of Neuropsychopharm., 6, 127–137. 14. Judd, L.L., Akiskal, H.S., Schettler, P.J. et al. (2003) The comparative clinical phenotype and long-term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders? J. Affect. Disord., 73, 19–32. 15. Judd, L.L., Akiskal, H.S., Schettler, P.J. et al. (2005) Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch. Gen. Psychiatry, 62, 1322–1330. 16. Judd, L.L., Schettler, P.J., Solomon, D.A. et al. (2008) Psychosocial disability and work role function compared across the long-term course of bipolar I, bipolar II and unipolar major depressive disorders. J. Affect. Disord., 108, 49–58. 17. Judd, L.L., Schettler, P.J., Akiskal, H.S. et al. (2008) Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Arch. Gen. Psychiatry, 65, 386–394. 18. Judd, L.L., Akiskal, H.S., Maser, J.D. et al. (1998) A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch. Gen. Psychiatry, 55, 694–700. 19. Judd, L.L.,and Akiskal, H.S., (2000) Delineating the longitudinal structure of depressive Illness: beyond clinical subtypes and duration thresholds (Anna-Monika-Prize paper). Pharmacopsychiatry, 33, 3–7. 20. Judd, L.L., Akiskal, H.S., Zeller, P.J. et al. (2000) Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch. Gen. Psychiatry, 57, 375–380. 21. Judd, L.L., Akiskal, H.S., Maser, J.D. et al. (1998) Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. J. Affect. Disord., 50, 97–108. 22. Judd, L.L., Paulus, M.J., Schettler, P.J. et al. (2000) Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? Am. J. Psychiatry, 157, 1501–1504. 23. Judd, L.L. and Akiskal, H.S. (2003) The prevalence and disability of bipolar spectrum disorders in the U.S. population: reanalysis of the ECA database taking into account subthreshold cases. J. Affect. Disord., 73, 123–131. 24. Katz, M.M. and Klerman, G.L. (1979) Introduction: overview of the Clinical Studies Program. Am. J. Psychiatry, 136, 49–51. 25. Katz, M.M., Secunda, S.K., Hirschfeld, R.M. and Koslow, S. H. (1979) NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression. Arch. Gen. Psychiatry, 36, 765–771. 26. Spitzer, R.L., Endicott, J. and Robins, E. (1977) Research Diagnostic Criteria for a Selected Group of Functional Disorders, 3rd edn, Biometrics Research Division, New York State Psychiatric Institute, New York. 27. Spitzer, R.L. and Endicott, J. (1979) Schedule for Affective Disorders and Schizophrenia (SADS), 3rd edn, Biometrics Research Division, New York State Psychiatric Institute, New York.

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28. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, 4th edn, American Psychiatric Association, Washington, DC. 29. Keller, M.B., Lavori, P.W., Friedman, B. et al. (1987) The Longitudinal Interval Follow-up Evaluation: a comprehensive method for assessing outcome in prospective longitudinal studies. Arch. Gen. Psychiatry, 44, 540–548. 30. Regier, D.A., Myers, J.K., Kramer, M. et al. (1984) The NIMH Epidemiologic Catchment Area (ECA) Program: historical context, major objectives and study population characteristics. Arch. Gen. Psychiatry, 41, 934–941. 31. Regier, D.A., Farmer, M.E., Rae, D.S. et al. (1990) Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA, 264, 2511–2518. 32. Angst, J., Gamma, A., Benazzi, F. et al. (2003) Toward a redefinition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J. Affect. Disord., 73, 133–146. 33. Goldberg, J.F., Perlis, R.H., Bowden, C.L. et al. (2009) Manic symptoms during depressive episodes in 1.380 patients with bipolar disorder: findings from the STEP-BD. Am. J. Psychiatry, 166, 173–181. 34. Goldberg, J.F., Perlis, R.H., Ghaemi, S.N. et al. (2007) Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am. J. Psychiatry, 164, 1348–1355. 35. Salvatore, P., Tohen, M., Khalsa, H.M. et al. (2007) Longitudinal research on bipolar disorders. Epidemiol. Psichiatr. Soc., 16, 109–117. 36. Coryell, W., Fiedorowicz, J., Solomon, D. and Endicott, J. (2009) Age transitions in the course of bipolar I disorder. Psychol. Med., 39, 1247–1252. 37. Akiskal, H.S. and Akiskal, K. (1988) Re-assessing the prevalence of bipolar disorders: clinical significance and artistic creativity. Psychiatrie et Psychobiologie, 3, S29–S36. 38. Akiskal, H.S., Bourgeois, M.L., Angst, J. et al. (2000) Reevaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J. Affect. Disord., 59 (suppl 1), S5–S30. 39. Akiskal, H.S. (2002) Classification, diagnosis and boundaries of bipolar disorders, in Bipolar Disorder (eds M. Maj, H.S. Akiskal, J.J. Lopez-Ibor and N. Sartorius), John Wiley & Sons, London, pp. 1–52. 40. Jamison, K.R., Gerner, R.H., Hammen, C. and Padesky, C. (1980) Clouds and silver linings: positive experiences associated with primary affective disorders. Am. J. Psychiatry, 137, 198–202. 41. Hirschfeld, R.M., Calabrese, J.R., Frye, M.A. et al. (2007) Defining the clinical course of bipolar disorder: response, remission, relapse, recurrence, and roughening. Psychopharmacol. Bull., 40, 7–14. 42. Berk, M., Ng, F., Wang, W.V. et al. (2008) The empirical redefinition of the psychometric criteria for remission in bipolar disorder. J. Affect. Disord., 106, 153–158. 43. CME Institute of Physicians Postgraduate Press, Inc. (2008) Easing the burden of bipolar disorder: from urgent situations

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to remission. Prim. Care Companion J. Clin. Psychiatry, 10, 391–402, [also available on-line at psychiatrist.com]. Fountoulakis, K.N. and Vieta, E. (2008) Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int. J. Neuropsychopharmacol., 11, 999–1029. Grunze, H., Vieta, E., Goodwin, G.M. et al. (2009) The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J. Biol. Psychiatry, 10, 85–116. Bowden, C.L. (2005) A different depression: clinical distinctions between bipolar and unipolar depression. J. Affect. Disord., 84, 117–125. Bowden, C.L. (2005) Treatment options for bipolar depression. J. Clin. Psychiatry, 66 (Suppl 1), 3–6. Kemp, D.E., Muzina, D.J., McIntyre, R.S. and Calabrese, J.R. (2008) Bipolar depression: trial-based insights to guide patient care. Dialogues Clin. Neurosci., 10, 181–192. Benazzi, F. (2007) Bipolar II disorder: epidemiology, diagnosis and management. CNS Drugs, 21, 727–740. Dawson, R., Lavori, P.W., Coryell, W.H. et al. (1998) Maintenance strategies for unipolar depression: an observational study of levels of treatment and recurrence. J. Affect. Disord., 49, 31–44. Leon, A.C., Keller, M.B., Warshaw, M.G. et al. (1999) Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects. Am. J. Psychiatry, 156, 195–201. Leon, A.C., Solomon, D.A., Mueller, T.I. et al. (2003) A 20-year longitudinal observational study of somatic antidepressant treatment effectiveness. Am. J. Psychiatry, 160, 727–733. Coryell, W., Winokur, G., Solomon, D. et al. (1997) Lithium and recurrence in a long-term follow-up of bipolar affective disorder. Psychol. Med., 27, 281–289. Coryell, W., Solomon, D., Leon, A.C. et al. (1998) Lithium discontinuation and subsequent effectiveness. Am. J. Psychiatry, 155, 895–898. Coryell, W., Arndt, S., Turvey, C. et al. (2001) Lithium and suicidal behavior in major affective disorder: a case-control study. Acta Psychiatr. Scand., 104, 193–197. Kupfer, D.J., Frank, E., Perel, J.M. et al. (1992) Five-year outcome for maintenance therapies in recurrent depression. Arch. Gen. Psychiatry, 49, 769–773. Solomon, D.A., Keitner, G.I., Miller, I.W. et al. (1995) Course of illness and maintenance treatments for patients with bipolar disorder. J. Clin. Psychiatry, 56, 5–13.

58. Keller, M.B. (2004) Improving the course of illness and promoting continuation of treatment of bipolar disorder. J. Clin. Psychiatry, 65 (Suppl 15), 10–14. 59. Frank, E., Kupfer, D.J., Thase, M.D. et al. (2005) Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch. Gen. Psychiatry, 62, 996–1004. 60. Swann, A.C. (2005) Long-term treatment in bipolar disorder. J. Clin. Psychiatry, 66 (Suppl 1), 7–12. 61. Miklowitz, D.J. and Johnson, S.L. (2006) The psychopathology and treatment of bipolar disorder. Annual Rev. Clin. Psychol., 2, 199–235. 62. Miklowitz, D.J. (2006) A review of evidence-based psychosocial interventions for bipolar disorder. J. Clin. Psychiatry, 67 (Suppl 11), 28–33. 63. Miklowitz, D.J., Otto, M.W., Frank, E. et al. (2007) Intensive psychosocial intervention enhances functioning in patients with bipolar depression: results from a 9-month randomized controlled trial. Am. J. Psychiatry, 164, 1340–1347. 64. Soares-Weiser, K., Bravo Vergel, Y., Beynon, S. et al. (2007) A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder. Health Technol. Assess., 11, iii–iv, ix–206. 65. Keck, P.E. Jr, McIntyre, R.S. and Shelton, R.C. (2007) Bipolar depression: best practices for the outpatient. CNS Spectr., 12 (Suppl 20), 1–14. 66. Sachs, G.S. (2008) Psychosocial interventions as adjunctive therapy for bipolar disorder. J. Psychiatr. Pract., 14 (Suppl 2), 39–44. 67. Miklowitz, D.J. (2008) Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am. J. Psychiatry, 165, 1408–1419. 68. Frank, E., Soreca, I., Swartz, H.A. et al. (2008) The role of interpersonal and social rhythm therapy in improving occupational functioning in patients with bipolar I disorder. Am. J. Psychiatry, 165, 1559–1565. 69. Solomon, D.A., Keitner, G.I., Ryan, C.E. et al. (2008) Preventing recurrence of bipolar I mood episodes and hospitalizations: family psychotherapy plus pharmacotherapy versus pharmacotherapy alone. Bipolar. Disord., 10, 798–805. 70. Colom, F., Vieta, E., Sanchez-Moreno, J. et al. (2009) Group psychoeducation for stabilised bipolar disorders: 5-year outcome of a randomised clinical trial. Br. J. Psychiatry, 194, 260–265.

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Comorbidity in Bipolar Disorder: A Focus on Addiction and Anxiety Disorders Mark A. Frye1 and Giulio Perugi2 1 2

Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA Department of Psychiatry, University of Pisa; Institute of Behavioural Sciences ‘G. De lisio’, Carrara, Italy

Introduction Bipolar affective disorder is an illness with substantial morbidity and mortality, characterized by episodic recurrence of mania/hypomania and major depression. Our current DMS- IV TR and ICD-10 based diagnoses have operationalized criteria for the specific diagnosis of bipolar I, II, and not otherwise specified with delineating course specifiers and subtype patterns. As recently reviewed by Soreca et al. [1], these criteria fail to capture the dimensional aspects and multisystem involvement of bipolar disorder. Mulitsystem or comorbid symptoms and disease, not defined as core or primary symptoms related to mood disorder, are highly prevalent and clinically relevant in the management of bipolar disorder. Two comorbid conditions that are the focus of this chapter, substance use, particularly alcohol and nicotine dependence, and anxiety disorders, clearly impact the course of bipolar illness.

Alcohol abuse and dependence Since the Kraepelian observation nearly 90 years ago [2], contemporary epidemiologic studies, including the Epidemiologic Catchment Area (ECA) study, the National Comorbidity Study (NCS), the National Comorbidity SurveyReplication (NCS-R) and the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), have reported rates of alcohol abuse or dependence in bipolar disorder that are consistently higher than the general population and/or most other axis I disorders [3–8]. A subscale analysis of the ECA study [3] remarkably showed that BPI and BPII populations had the highest lifetime prevalence rate of alcohol abuse or dependence (46.2 and 39.2%, respectively) followed by schizophrenia (33.7%), panic disorder (28.7%), unipolar depression (16.5%) and the general

Bipolar Disorder: Clinical and Neurobiological Foundations Edited by Lakshmi N. Yatham and Mario Maj © 2010 John Wiley & Sons, Ltd. ISBN: 978-0-470-72198-8

population (13.8%). A lifetime diagnosis of alcohol dependence was associated with significantly increased risk of having mania in both men (Odds ratio ¼ 12.03) and women (Odds ratio ¼ 5.3) [4]. These epidemiological studies suggest that some aspect of bipolar disorder, in comparison to other serious mental illness, is associated with high rates of developing alcoholism. Clinical studies done over the past 50 years [9–13] have confirmed similar lifetime prevalence rates (8–42%). It is important to emphasize that careful assessment for dual diagnosis, ideally with a structured diagnostic interview, is critical to confirm the comorbidity. The diagnosis of bipolar illness in the presence of active substance use, in this case alcohol abuse or dependence, can be made in any or all of the following criteria: (1) the presence of a historical manic, hypomanic or depressed episode while not drinking (DSM-IV early partial or complete remission); (2) a manic, hypomanic or depressed episode that predated the onset of alcohol abuse or dependence; and (3) a manic, hypomanic or depressed episode with high moderate to severe mood symptoms with minimal drinking [14]. This is relevant as a recent study by Stewart and colleagues [15] recently examined clinical diagnoses of bipolar disorder in 21 patients participating in a community-based substance treatment programme and found only 9 out of 21 were found to have concordance with a structured diagnostic interview. A second retrospective analysis by Goldberg and associates [16], of records of 85 adults admitted to a private dual disorders chemical dependency programme, found that only 33% of individuals with suspected bipolar diagnoses actually met DSM-IV criteria, utilizing a structured diagnostic interview. Careful assessment needs to be done to confirm the dual diagnosis. Despite high prevalence rates of alcoholism in bipolar disorder, gender and specific mood state analyses have received less contemporary systematic study. As originally described by Kraepelin in 1921, alcoholism could be found in about a quarter of men with bipolar disorder ‘but it is to be

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regarded as the consequence of debaucheries committed in excitement, not as a cause’. These initial reports underscore the observation that drinking tends to be associated with acute mania. Dipsomania was also a clinical description of increased alcohol consumption during mania [17]. As most of these early studies focused predominantly on male inpatients at VA hospitals, very little is known about bipolar outpatients and bipolar women and mood state dependent drinking behaviour. In more contemporary samples, gender differences in prevalence rate, relative risk and clinical correlates of alcohol dependence in bipolar disorder have been reported. In clinical samples, gender differences in prevalence rate, relative risk and clinical correlates of alcohol dependence in bipolar disorder have been reported. Compared to bipolar men, bipolar women have an increased odds ratio of developing alcohol abuse or dependence compared to gender matched controls [18]. Compared to bipolar alcoholic men, bipolar alcoholic women have increased illness burden characterized by mixed mania, depressive episodes, polarity shifts, less time spent euthymic [18,19], history of physical and/or sexual abuse [20], increased anxiety burden including social phobia, post-traumatic stress disorder [21,22], higher rates of incarceration [23] and a greater number of maximum drinks in a 24-hour period (HallFlavin 2008 [24]). Any and all of these clinical correlates may be the reason that bipolar women do not seek medical attention for the substance use disorder. From the NESARC study, the lifetime prevalence of substance use disorders in bipolar disorder was significantly greater amongst those women with lifetime anxiety disorders; this increased risk was not identified in bipolar men [25]. Whereas it is generally known that women are more likely to seek help than men, the health care utilization pattern of bipolar I men and women with alcohol dependence appears to be different. In a second NESARC post-hoc analysis, bipolar I disorder is more likely to go untreated in men, and addiction treatment is more likely to go untreated in bipolar women. This differential pattern of gender and health care utilization in dual diagnosis patients will be relevant in how we clinically monitor patients in initial diagnostic assessment and longitudinal follow-up. Future studies should be developed to better understand and correct the under-utilization of addiction programmes for patients with bipolar disorder and to identify clinical correlates that predispose bipolar women to binge drinking.

Comorbid alcoholism and bipolar course of illness It is increasingly clear that co-occurring alcohol use disorders in bipolar disorder phenomenologically changes the illness presentation. As reviewed by [26], bipolar patients

with co-occurring alcohol use disorders in comparison to bipolar patients without co-occurring alcohol use disorders have higher rates of mixed or dysphoric mania, rapid cycling, increased manic and depressed symptom severity, and higher levels of novelty seeking, suicidality, aggressivity and impulsivity. Whatever the aetiology of the association, it is apparent that substance use may precede formal symptoms of bipolar illness and subsequently complicate the bipolar course of illness. A case controlled study by Black et al. [27] reported that patients with ‘complicated mania’ (mania accompanied with an antecedent or current nonaffective psychiatric disorder, including alcohol abuse) were significantly less likely to both obtain a therapeutic trial of lithium during hospitalization for mania and achieve recovery at hospital discharge. Poor lithium outcome measures have been consistently reported when bipolar disorder is comorbid with current substance use of even a history of alcoholism ([13,28–30]; Keller et al., 1986 [31]). Interestingly, the Aagaard and Vestergaard study is the only one that identified substance use disorders as predictive of noncompliance, but not non-response. Thus, to date, it is unclear whether the lithium non-responsivity in co-occurring bipolar disorder and alcohol abuse/dependence is related to: (4) lack of aggressive mood stabilization such that subsyndromal symptoms are being self treated with alcohol; (5) side-effect intolerability promoting medication non-compliance and relapse; (6) solely non-compliance promoting relapse; or (7) the high prevalence rate of rapid cycling and dysphoric mania, which by itself, can present with higher rates of lithium failure. Further studies are needed to better identify risk factors of relapse (mood and/or alcohol) and whether, in addition to mood stabilization prophylaxis, aggressive treatment for bipolar illness can be a prophylaxis against alcohol abuse relapse.

Treatment implications for dual diagnosis bipolar disorder and alcoholism Despite landmark epidemiological studies highlighting extensive comorbidity between alcohol use disorders and bipolar disorder, recent retrospective data would suggest that patients with bipolar disorder represent the minority of patients (
3%) in residential alcohol addiction treatment (Hall Flavin et al., unpublished data). These findings are similar to secondary analyses of the NESARC survey that reported that subjects with bipolar I (12.5%) and bipolar II (3%) disorder were a minority representation of subjects who sought treatment for their alcohol use disorder within the past year [32]. Individuals with undiagnosed, unstable or untreated bipolar disorder may be less motivated or viewed as less favourably to successfully engage and benefit

Comorbidity in Bipolar Disorder

from the specialized addiction treatment. Also, access to primary chemical dependency treatment services may be less available because of programme availability or reimbursement issues. It may also be that most chemical dependency treatment programmes, even those targeting the need of those with substantial psychiatric comorbidity, require a degree of behavioural stabilization that may decrease the likelihood of intervention in a chemical dependency setting during a period of acute decompensation, when substance use might be at its peak. Despite a high prevalence rate, patients with bipolar disorder and active alcohol abuse/dependence are routinely excluded from controlled clinical trials, leaving clinicians with little evidence-based medicine or randomized controlled studies to guide treatment. This routine exclusion may be related in part to the difficulties of confirming a diagnosis of bipolar disorder in the context of active drinking, but as well may be due to a lack of hypothesis-driven study designs or a lack of validated assessment tools to reliably quantify patterns of alcohol use.

Nicotine dependence The morbidity and mortality of smoking-related illnesses are substantial. Cigarette smoking is the leading preventable cause of illness and premature death in the United States. This public health problem is only magnified in patients with major mental illness and in particular in patients with bipolar disorder. The National Comorbidity Survey (NCS) reported a 1990–1992 prevalence rate of nicotine dependence amongst individuals with bipolar disorder more than twice (69 vs. 29%) that of the general population [33]. In the more recent 2001–2002 NESARC study, the 12-month prevalence rate of nicotine dependence in patients with bipolar I (35%) and II (33%) disorder was more than three-fold higher than the 12.8% prevalence rate in patients with no psychiatric comorbidity (OR 3.9 BPI, OR 3.5 BPII [7]. It is estimated that dually diagnosed nicotine dependent patients comprise more than 40% of the US tobacco market. The NCS and NESARC landmark epidemiological studies would suggest that while the prevalence of tobacco use has decreased over the course of a decade, the decrease has been less substantial in the bipolar patient population. The NCS quit rate for nicotine dependent patients without additional mental illness was 43%; the quit rate for bipolar disorder was significantly reduced at (17%) and was the lowest of all Axis I diagnoses (panic disorder ¼ 41%, major depression ¼ 38%, dysthymia ¼ 37%, alcohol abuse or dependence ¼ 34%, social phobia ¼ 33%, generalized anxiety disorder ¼ 33%, drug abuse or dependence ¼ 32%, post-traumatic stress disorder ¼ 28%). These reason that patients with bipolar disorder are not benefitting from smoking cessation therapies in the same

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way as the general population or other anxiety disorders is not known.

Bipolar disorder course of illness and nicotine dependence Nicotine impacts the course of bipolar illness in such a way where the illness is more virulent and less response to mood treatment interventions. Bipolar patients with nicotine dependence, in comparison to bipolar patients without nicotine dependence, have higher rates of mixed episodes, suicide attempts, rapid cycling, additional drug and alcohol comorbidity, greater severity of mood symptoms, and lower rates of response to mood stabilizing pharmacotherapy [34–36]. Despite the severity of mania and smoking rates as high as 70% [37], it is clear that when bipolar patients are symptomatic of their illness, they are far more likely to be depressed than manic [38,39]. In comparison to acute mania, bipolar depressive episodes are longer and more likely to be functionally disabling [40]. Recent data would suggest higher rates of hazardous drinking in bipolar patients when depressed (Abulseoud et al., 2008 [41]). To our knowledge, this phenomenon has not been systematically studied with tobacco dependence. Finally, there is increasing recognition that sub-syndromal bipolar depression (significant symptoms but not meeting DSM-IV criteria for major depressive episode) are not only a prodrome to syndromal relapse [37], but they themselves are highly prevalent and functionally disabling [38]. Moreover, subsyndromal depressive symptoms have consistently predicted poorer outcomes in smoking cessation trials (Niaura et al., 2001 [112]). The NCS and NESARC landmark epidemiological studies would suggest that while the prevalence of tobacco use has decreased over the course of a decade, the decrease has been less substantial in the bipolar patient population. This clearly has significant public health implications. It is likely that the presence of nicotine dependence plus limited access to preventative medical services may put bipolar patients at greater risk for cancer. There has been very little systematic study in this regard, but one linkage analysis based on a psychiatric inpatient diagnosis of bipolar disorder and a cancer national database, did report a significant increased standardized incidence ratio (SIR) for cancer in both bipolar women (SIR ¼ 1.75, 95% CI ¼ 1.31 to 2.18) and bipolar men (SIR ¼ 1.59, 95% CI 1.01 to 2.17, [42]). Furthermore, at least one Swedish registry study has reported increased standardized mortality ratios (SMR ¼ observed deaths/expected deaths) for respiratory death in bipolar men (3.1) and women (3.2), respectively [43]. While many of these excess deaths may be directly related to infection, it is generally assumed that these are preventable smokingrelated deaths (i.e. lung cancer, chronic obstructive pulmonary disease).

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Treatment considerations in bipolar disorder with nicotine dependence There has been remarkable progress in developing therapeutic interventions for patients with tobacco dependence [44]. Currently, there are three pharmacotherapies approved by the US Food and Drug Administration (FDA) for smoking cessation: nicotine replacement systems (gum, patch, nasal spray, inhaler and lozenge), sustained release bupropion or Zyban (aminoketone antidepressant also approved for major depression and seasonal affective disorder) and varenicline or Chantix (a4b2 nicotinic acetylcholine receptor partial agonist). According to the Public Health Service-sponsored Clinical Practice Guideline on treatment of tobacco dependence, counselling and behavioural therapies are considered the standard of care for smoking cessation treatment (SCT) [45]. These behavioural interventions have been shown to be effective in combination with smoking cessation pharmacotherapy in the general population [45–48]. In November 2007, the FDA issued an early communication on post-marketing surveillance reports of suicidal thinking associated with varenicline. In February 2008, the FDA issued an alert highlighting revisions to the Warning and Precaution section of the Chantix package insert. These changes are described as neuropsychiatric symptoms and included: behaviour change, agitation, depressed mood, suicidal ideation, and attempted and completed suicide. Most of these symptoms occurred during treatment but in some cases, symptoms developed following withdrawal of varenicline. These surveillance data cannot establish direct cause and effect. To date, there is one case report each for a vareniclineassociated manic and hypomanic episode [49,50]. A recent National Health Service pre-post comparison of abstinence rates by [51] reported 4-week abstinence rates that were higher with varenicline therapy than nicotine replacement therapy. Varenicline was equally effective in those with and without mental illness. In this study of more than 400 subjects, 27% of them (111) reported they were currently receiving treatment for mental illness. Of those, the primary diagnosis were depression (n ¼ 64), bipolar disorder (n ¼ 14), pyschosis (n ¼ 7), psychotic depression (n ¼ 24) and eating disorder (n ¼ 2). This is important preliminary data, suggesting that abstinence rates are similar if not better and that there are no significant adverse events of higher rate in mentally ill dually diagnosed nicotine dependent patients. SCTs need to be developed and optimized for the dually diagnosed. To date, there are no controlled evaluations of any SCT amongst patients with bipolar disorder. Furthermore, the trials of varenicline and other smoking-cessation clinical trials have excluded individuals with bipolar disorder. However, as compared to the general population, smoking cessation has been reported to be more difficult for

many individuals with psychiatric illness [52,53]. This may in part be related to mood symptoms and that for some patients, nicotine is acting as antidepressant. There is preclinical and clinical data documenting that cigarette smokers have reduced monoamine oxidase (MAO) activity [54]; this could potentially be optimized through MAO inibition (i.e. pharmacological mechanism of action of the several antidepressants, such as tranylcopromine or phenelzine). Several [55–57], but not all [58,59] studies in unipolar depression have reported a significant occurrence of depression following smoking cessation; the occurrence of depression seems to be related to a history of prior depressive episodes, persistent withdrawal symptoms and more difficulty with cessation. This has not been studied in bipolar disorder. Comorbidity of bipolar disorder and alcohol use disorder and nicotine dependence is a common clinical presentation and presents with significant challenges. The bipolar course of illness phenomenologically changes when addiction is present. Further work is encouraged to study these specific patterns (i.e. rapid cycling, dysphoric mania) and aetiology of comorbidity directionality (primary vs. secondary drug use) in controlled clinical trials. The question yet to be answered is whether an earlier and/or accurate diagnosis of bipolar disorder can prevent or at least attenuated the degree of subsequent addiction comorbidity or whether bipolar symptoms at onset that are diagnosed and treated can in fact attenuate or minimize the development of addiction comorbidity as a later manifestation of bipolar illness and the impact of self-medication.

Anxiety disorders Epidemiological, clinical and familial studies provide compelling evidence that anxiety disorders (ADs) may be the most prevalent psychiatric comorbidity amongst patients with Bipolar Disorder (BPD). Moreover, anxious comorbidity in individuals with BPD is associated with an intensification of symptoms, increased risk of alcohol and drug abuse, inadequate treatment response, poor functional outcome and suicidality.

Epidemiological and clinical data The reliability of lay interviewers diagnosing ADs in community-based samples is well established, while the reliability of identifying BPD cases with a predominantly mixed/dysphoric presentation is not ideal with the currently available diagnostic interviews [6,60]. Clinical studies indicate that AD comorbidity may be more prevalent in mixed and ‘softer’ expressions of BPD (or bipolar spectrum) [61–63], suggesting that community-based epidemiological studies may underestimate the prevalence of AD comorbidity in BPD subpopulations.

Comorbidity in Bipolar Disorder

Chen and Dilsaver [64], analysing the ECA database, reported lifetime rates of OCD amongst probands with bipolar and unipolar disorder of 21.0 and 12.2%, respectively. Furthermore, a significant association between comorbid OCD and suicidality was reported. In the NCS [5,65], the estimated lifetime prevalence of any AD in BPD was estimated at 92.9% (odds ratio, OR ¼ 31.2). Specific phobia was the most prevalent AD comorbidity (66.6%). while Panic Disorder (PD) was the least prevalent (33.1%). The reported risk of comorbid PD and Social Phobia (SoP) is higher in BPD (Odds Ratios of 11.0 vs. 4.6, respectively) compared to unipolar disorder (Odds Ratios of 7.0 vs. 3.6, respectively). In a European sample, (Angst, 1998 [113]) reported higher rates of comorbidity with PD, SoP and Obsessive-Compulsive Disorder (OCD) in subjects meeting DSM-IV hypomania, recurrent brief hypomania and sporadic brief hypomania compared to population controls. In summary, results from community-based epidemiological studies indicate that respondents screening positive for BPD are also more likely to screen positive for an AD. The co-occurrence of AD in BPD populations is associated with suicidality and possibly an earlier age of onset of bipolar illness. Concerning clinical studies, several investigations have reported on the prevalence of ADs amongst bipolar patients. Rihmer et al. [66] described the prevalence of AD comorbidity amongst 2953 primary care patients with a diagnosable mood disorder. The estimated prevalence of any comorbid AD was lowest amongst persons with BPD-I and highest in the BPD-II patient group. The prevalence of comorbid ADs for the MDD group was intermediary between the two BPD subgroups. This finding is consistent with the observation that softer expressions of BPD are often camouflaged as anxious depression in the primary care setting [67]. MacQueen et al. [68] reported that the prevalence of any AD comorbidity in BPD was higher in subsyndromal (80.6%) than in syndromal (54%) and euthymic (38.6%) phases. In contrast, Dilsaver and Chen [69] reported that SoP and PD presenting during a bipolar episode were highly associated with suicidality, particularly in depressive phases. These observations suggest that in some patients, anxiety comorbidity is most pronounced at the extremes of affective excursions, while in others, anxiety may present primarily as an ‘interepisodic’ disturbance. McElroy et al. [70] reported anxiety (n ¼ 122, 42%) and substance use disorders (n ¼ 122, 42%) as the most frequent lifetime comorbid disorders in BPD. There was no significant difference in AD comorbidity between patients with BPD-I and BPD-II. The reported lifetime and current prevalences of ‘any AD’ was 42 and 30%, respectively. Lifetime Axis I comorbidity was associated with early age of onset of

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BPD symptoms, progressive severity of illness and a family history of alcoholism and drug abuse. Current anxiety comorbidity was also associated with reduced occupational functioning, a history of rapid cycling and a shortening of well intervals. The prevalence of AD and its correlates was investigated in the first 500 patients (BPDI n ¼ 360, BPDII n ¼ 115) enrolled in the Systematic Treatment Enhancement Program for BPD (STEP-BPD) [22]. The prevalences of any lifetime AD for the entire sample were greater amongst patients with BPD-I (51.2%) versus BPD-II (30.5%). The age of onset of BPD was significantly lower for patients with any lifetime AD than in patients without AD (15.6 vs. 19.4 years, respectively). Patients with a lifetime AD also had less education, shorter time euthymic, lower rates of recovery and elevated rates of lifetime suicide attempts. It was also reported that BPD with comorbid ADs had a higher prevalence of alcohol and substance use disorders. The presence of multiple ADs was independently associated with added impairment in quality of life and functioning. Consistently with other reports, the presence of a lifetime AD was significantly associated with an increased number of suicide attempts [22]. The association between ADs and alcohol and substance use disorders is an additional theme that emanates from the BPD literature. Bauer et al. [71] examined the prevalence and the correlates of comorbid substance use disorders and ADs in a sample of inpatients with BPD (n ¼ 348). ADs were associated with earlier age at onset, rapid cycling, higher probability of reporting depressive symptoms, higher rates of prior suicide attempts, greater number of prior-year episodes, higher severity of illness scores and lower quality of life. The negative effect of ADs in BPD was particularly evident in patients with BPD who also had a comorbid substance abuse disorder. Goodwin et al. [72] also reported the association between AD and substance use disorders in BPD. In particular, PD was associated with an increased prevalence of cocaine, sedative and stimulant use disorders. Relatively fewer studies have reported the prevalence of BPDs amongst AD populations. ADs are often a phenomenological antecedent to overt BPD; this calls for careful screening for BPD amongst children and adolescents reporting to health care providers with prominent anxiety symptoms [73]. A history of manic or hypomanic episodes has been observed in patients with PD-Agoraphobia [74]. The development of mania or hypomania in response to treatment with serotonin reuptake inhibitors has also been widely described in OCD case series and reports [75,76]. In a clinical study of 345 outpatients with OCD [77], lifetime comorbidity with BPD (primarily bipolar II) was 16%. Finally, patients with SoP have been found to have high rates of BPD (Himmeloch, 1998 [114]). In a Pisa-San Diego collaborative study [62,63], major depression was the most common comorbid disorder in a

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large sample of patients with AD. However, bipolar II disorder resulted widely associated with SoP (21.1%), OCD (17.7%) and in a lesser extent with PD (5.0%). The relative neglect in clinical and epidemiological research for the comorbidity between bipolar spectrum disorders and AD is especially due to underdiagnosis of bipolar II disorders (often misdiagnosed as unipolar or personality disorders) in patients with AD. It has been documented that current official diagnostic systems grossly underestimate bipolar II and related disorders and that clinicians specifically trained in bipolar II outperformed routine interviewers in such structured interviews as the SADS or the SCID [78]. Although this point goes against the grain in the literature on structured interviewing, it is consistent in suggesting that the proper identification of BPDII requires a more sophisticated approach in diagnosis.

Comorbid ADs and clinical presentation of bipolar disorder The co-occurrence of BPD and ADs seems to result in something more complex than a simple add-on effect. Multiple comorbidity and consequent symptomatological instability appear as the most relevant consequence of the anxious-bipolar co-existence [62,63]. Because of that, many of these patients receive diagnoses of borderline, narcisistic, histrionic personality disorders that in some cases prevent them from receiving adequate pharmacological treatment [79]. Increased risk of mixed states, suicidal behaviour and alcohol and drug abuse are other important prognostic implications. ADs are associated with multiple indices of poor outcome in BPD. Gaudiano and Miller [80] evaluated comorbid ADs in BPD patients, and their association with bipolar illness severity, chronicity and treatment response. Patients with BPD-AD were more likely to report severe depression, chronic illness course and negative treatment outcomes. Henry et al. [81] also reported that ADs comorbidity was associated with an earlier age of BPD onset and lower response to anticonvulsants. Boylan et al. [82] observed that BPD patients with comorbid AD had an earlier age at onset, higher frequency of rapid cycling and a higher usage of benzodiazepine treatment. Moreover, BPD patients with comorbid ADs had significantly higher rates of substance abuse or dependence, illness severity and chronicity, and a lower mean Global Assessment of Functioning (GAF) score. Different temporal relationship seems to characterize the occurrence of hypomania in individual AD subtypes [83]. Usually SoP chronologically preceded hypomanic episodes and disappeared when the latter episodes supervened. By contrast, PD and OCD symptomatology, even when preceding hypomanic episodes, often persisted during such episodes. Interestingly, a relevant proportions

of all onsets of panic attacks, in patients with comorbid PD and BPD, were during (hypo)mania [83]. These findings are consistent with the hypothesis that, at least in some patients, SoP, and to some extent OCD, seem to lie on a broad affective continuum of inhibitory restraint versus disinhibited hypomania. By contrast, PD, in the context of an (hypo)manic episode, might be interpreted as a dysphoric or mixed evolution of the symptomatology. In order to confirm these observations, further investigations should focus on the prospective assessment of patients with concomitant ADS and BPD. Indeed, retrospective methodology utilized in most clinical studies makes it difficult to ascertain the extent to which antidepressants, the most common treatment for severe AD, could explain the anxiety-bipolar comorbidity. Investigations on differential patterns of comorbidity may provide important information in distinguishing more homogeneous clinical subtypes of affective disorders from the biological, genetic and therapeutic point of view. Preliminary evidence support the hypothesis that differential risk for PD comorbidity is a promising tool in order to discern heterogeneous genetic subtypes of BPD. MacKinnon et al. [84] evaluated 528 members of 57 families ascertained for a genetic linkage study of bipolar disorder. Out of 57 bipolar probands, 10 had comorbid PD; in their relatives PD co-segregated with bipolar disorder (in particular Bipolar II and cyclothymia) at a significantly higher rate than expected by chance, suggesting that comorbid PD might be a specific marker for a familial subtype of BPD. Bipolar OCD patients represent more frequently than the non-bipolar, abuse of alcohol, sedatives, stimulants and caffeine, as well as episodic course of the AD, a greater number of major depressive episodes and suicide attempts). Moreover, they currently reported significantly higher rate of sexual obsessions and a significantly lower rate of order rituals [85]. These observations would seem to indicate that bipolar comorbidity has a strong influence on the longitudinal course and complications of OCD. In particular, long-term episodic course of OCD resulted, related to family history for mood disorders, lifetime comorbidity for panic and bipolar II disorders and late age at onset. Evidence based on a single family pedigree [86] suggests a genetic linkage between OCD and BPD, while other studies indicate increased prevalence of OCD in bipolar probands and high rates of obsessional traits in the offspring of bipolar probands [87]. Coryell [88] reported an equal incidence (2.3%) of mania in families of probands with OCD and in families with a bipolar disordered member. These findings are consistent with the hypothesis that, at least in some cases, episodic course of OCD is related to cyclical affective disorders. In a more theoretical vein, episodic OCD symptoms, in a substantial minority of cases, may be considered the phenotypic expression of an underlying affective genotype.

Comorbidity in Bipolar Disorder

As regards the relationships between SoP and BPD, in a clinical study by Himmelhoch [89], 18 patients with FS had a significant improvement of social anxiety after a treatment with MAOI (phenelzine) and RIMA (moclobemide). Out of 32 of these subjects, 14, along with the complete remission of social phobic symptomatology, developed a hypomanic episode, both according to clinical judgement and structured evaluation. On the basis of this observation, the author hypothesized that SoP might actually belong, at least in some cases, to a bipolar spectrum. It is notable that Himmelhoch concluded that social phobia’s special relationship with bipolar II disorder became evident only when social anxiety was ‘perturbed by the central actions of stimulating antidepressants’. Protracted social anxiety may represent, along with inhibited depression, the opposite of hypomania. Moreover, the increased susceptibility to alcohol use in some patients with SP might be related more to the presence of a bipolar diathesis [90,91], with marked reactivity to the ethanol, than to the social-phobic symptomatology per se. This hypothesis is compatible with the observation of Himle et al. [92], on SoP patients without a comorbid BPD, where alcohol use did not reduce social anxiety in performance situations and was not associated by better performance. The socializing and disinhibiting effect that many SoP patients report with alcohol use might therefore be mediated by increased confidence as part of hypomania facilitated by alcohol. The correct identification of SoP-bipolar comorbidity has relevant clinical implications as far as other concomitant disorders, symptomatological features, course and complications are concerned. Severity and generalization of the SoP symptoms, multiple comorbidity and alcohol abuse appear to be the most relevant consequences of SoPbipolar coexistence. Likewise, clinicians must investigate whether or not BPD is a comorbid condition in patients presenting with SoP. The suspicion of bipolar comorbidity should be even greater if patients presented multiple comorbidity or have been previously refractory to treatment. In summary, comorbidity with ADs in the bipolar spectrum population is associated with several indices of severity, such as a more severe subtypes of BPD, an earlier age at onset, mixed state presentations, an intensification of symptoms, poor symptomatic and functional recovery, higher rates of alcohol and substance use disorders, suicidal behaviour, diminished response to pharmacological treatment, decreased quality of life and unfavourable course and outcome.

Treatment implications of anxious comorbidity The lack of information about anxious-bipolar connections may have a negative impact on treatment choice and man-

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agement. Most of the controlled trials on BPD excluded patients with comorbid ADs and vice versa; as a consequence, the empirical basis for treating patients with anxious-bipolar comorbidity are almost exclusively founded on anecdotal reports and open clinical experiences. Overall, lithium has not been studied in AD. Some useful suggestions can be derived from clinical experiences with mood stabilizers and anti-AD agents. Bipolar patients with high anxiety ratings are less likely to respond to lithium [93]. The association of anxiety with suicidality, and less favourable treatment responses in BPD patients, has been consistently reported [22,94]. Feske et al. [94] examined the correlates of acute treatment response in 124 BPD-I patients. Anxiety symptomatology was associated with a longer time to remission in both depression and mania. Moreover, nonremitting patients were more likely to report a history of panic attacks, current or past anxiety, more severe depression and a greater number of previous affective episodes. Patients reporting a history of panic attacks also required a higher mean number of medications to achieve symptomatic remission. Controlled data suggests valproate may be more effective than lithium in mania associated with depressive features, even when the depressive features are mild [95]. Since anxiety symptoms are often seen in mixed states and may even be related to depression in mania, future studies should evaluate anxious features as possible predictors of response of mania to valproate (and other antimanic agents). Regarding AD, valproate has been used successfully in the treatment of panic disorder [96]. In addition, in an open-label study, Calabrese and Delucchi [97] noted 6that rapid-cycling BPD patients with comorbid panic attacks described reduction in their panic symptoms with valproate treatment. In addition, one open-label study [98] and one case report [99] have suggested that valproate may be helpful in the treatment of some patients with OCD, especially those with associated bipolar or epileptiform features. As regards the use of carbamazepine in AD, Uhde et al. [100] did not find carbamazepine to be an efficacious treatment for panic disorder in a double-blind, placebocontrolled study of 14 patients. In OCD, Koopowitz and Berk [101] reported beneficial results with the use of carbamazepine in two patients, while Swinson and Joffe [102] found carbamazepine was ineffective in an open-label study. Gabapentin has shown preliminary evidence of efficacy in the treatment of anxiety but not BPD. In ADs, Gabapentin has been shown to be superior to placebo in one small controlled study on SoP [103], and in another controlled study on severe PD [104]. The predictors of response to gabapentin as adjunctive treatment has been evaluated in 43 patients with BPD, who were resistant to standard moodstabilizers [90,91]. Gabapentin was administered as an

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adjunctive treatment for an eight-week period, in combination with other mood stabilizers, benzodiazepines, antidepressants and neuroleptics. Of 43 patients, 18 (41.9%), who began treatment, were considered responders; in particular gabapentin showed antidepressant and anxiolytic properties. Comorbid PD and alcohol abuse (and to a lesser extent SoP) were the best predictors of response. This finding might has relevant clinical implications as concern the treatment of anxious bipolar comorbidity, but it should be confirmed in controlled clinical trials. As regard anti-anxiety agents, Benzodiazepines are relatively safe and well tolerated when used in combination with mood stabilizers. However, long-term benzodiazepine use may be problematic in most patients, due to development of tolerance, physical dependence and withdrawal phenomena. Antidepressants are often used in the treatment of AD and bipolar depression. However, these compounds may worsen the course of the mood disorder by precipitating mania, mixed states, or rapid cycling (for review see [105]). Antidepressant-induced (hypo)manic symptoms have been reported to occur specifically in the course of treatment of virtually all AD, including obsessive compulsive disorder, panic disorder, and social phobia [106,107,114]. In BPD, prophylactic treatment with mood stabilizers may prevent antidepressant-induced switching [107,108]. When treating comorbid bipolar and AD, it is imperative to begin treatment with a mood stabilizer. Indeed, initiating an antidepressant before adequate mood stabilization has been achieved could worsen the anxiety symptoms by exacerbating the BPD. The efficacy of typical and atypical antipsychotics in the treatment of primary or comorbid AD or anxiety symptoms in major depressive or bipolar disorders was recently reviewed [109]. Six trials in primary generalized anxiety disorder (GAD), 15 in refractory OCD, 8 in posttraumatic stress disorder (PTSD), 6 in neurosis with the HAM-A, 1 in SoP and 2 in anxiety symptoms in bipolar depression were identified. Gao et al. [109] concluded that, except for trifluoperazine, there is no large, well-designed study of antipsychotics in the treatment of primary or comorbid anxiety symptoms or disorders. Most of the less welldesigned studies showed that other typical antipsychotics might be superior to placebo or as effective as benzodiazepines in the treatment of GAD and other anxiety conditions. In most studies, risperidone, olanzapine and quetiapine augmentation to antidepressants was superior to placebo in treating refractory OCD and PTSD. Both olanzapine and quetiapine significantly reduced anxiety, compared to placebo in studies of bipolar depression. The efficacy of these agents in various anxiety conditions needs to be further investigated with large, well-designed comparison studies.

In the treatment of comorbid BPD and PD, it appears reasonable to utilize as a first choice mood stabilizers who have been shown to possess some antipanic efficacy, such as valproate or adjunctive gabapentin. In patients with persistent and disabling ADs, the combination with antidepressants can be considered. Less information is available for comorbid BPD and SoP. A small positive study on gabapentin in SoP seems indicate the possible efficacy of this drug [103]. The combination of mood stabilizers such as lithium, valproate and carbamazepine with SSRIs, RIMAs or IMAOs might reduce the number of switches in these patients. However, there is almost no information on long-term outcome of patients with comorbid BPD and SoP treated with drug combinations. Bipolar OCD are amongst the most difficult patients to treat. No mood stabilizers has been shown to exert any antiOCD activity, and the effective anti-OCD pharmachological treatments (high doses of clomipramine or SSRIs) have high potential for inducing (hyo)manic switches and increasing cyclicity in BPD patients. Combination of different mood stabilizer (lithium plus antiepileptics) is often necessary, and in some cases the combination with antidepressants supposed less likely to induce rapid-cycling (i.e. MAOIs) can be utilized. However, many of these patients present residual OCD symptomatology and very severe manic or mixed episode (aggressive, hostile mood) that may require hospitalization. In some cases the combination with atypical antipsychotics (risperidone, olanzapine, quetiapine or aripiprazole) can be taken into account. Indeed, even if in some cases atypical antipsychotics has been reported to exacerbate OCD symptomatology [110,111], in others these drugs display a mood-stabilizing, anti-aggressive activity, which permit also an effective treatment of OCD symptoms. In summary, the coexistence of anxiety and bipolar spectrum disorders is a substantial clinical issue affecting a large number of patients. The frequent comorbidity between BPD and ADs has also been reported in epidemiologic samples and primary care setting, indicating that clinical referral bias is unlikely to be the main explanation for this phenomenon. Accurate diagnosis is a central concern, in patients presenting with BPD, the clinician must screen for all ADs. Likewise, clinicians must investigate whether or not BPD is a comorbid condition in patients presenting with AD. The suspicion of bipolar comorbidity should be even greater if patients presented multiple ADs, alcohol or substance abuse or have been previously refractory to treatment. The correct identification of anxious-bipolar comorbidity has relevant clinical implications as far as BPD symptomatology, course and complications are concerned. Symptomatological instability, multiple comorbidity, in particular alcohol and substance abuse, and suicidality appear as the

Comorbidity in Bipolar Disorder

most relevant consequences of anxious-bipolar coexistence. No firm recommendations can be made as to which mood stabilizer would be best for which BPD patient, based on his or her particular comorbid AD. Nonetheless, several impressions emerge from the available literature. Generally, the data support the use of valproate as the mood-stabilizer of choice for patients with comorbid PD and possibly OCD, especially if associated with prominent anxiety symptoms, mixed features and/or rapid cycling. Antidepressants, while proven effective in PD, OCD and SP, may worsen the course of BPD, especially if initiated before treatment with a moodstabilizer. If antidepressants are to be used in patients with concurrent BPD and ADs, adequate mood stabilization should first be achieved, and antidepressants then added cautiously while patients are monitored carefully for emerging symptoms of hypomania or mania. Atypical antipsychotics are widely utilized as mood stabilizing agents. On the other hand, they have not yet been systematically studied in AD, and have been hypothesized to exacerbate PD and OCD because of their serotonergic antagonistic properties.

Conclusion The use of the term comorbidity in psychiatry is questionable and raises fundamental questions regarding the validity of the utilized diagnostic criteria and classification system. The study of comorbidity in BD, however, provides an opportunity to address important clinical and research questions. Epidemiological and clinical studies have documented the high lifetime rates and risks related to substance use and AD comorbidity in BD patients. This triad of diagnoses is associated with several indices of BD severity such as earlier age at onset, mixed presentations, severity of symptoms, poor symptomatic and functional recovery, suicidal behaviour, diminished acute response to pharmacological treatment, decreased quality of life and an unfavourable course and outcome. Comorbidity of BPD with substance use disorders and AD can be challenging to diagnose and optimally treat. Further work is encouraged to study these specific patterns (i.e. rapid cycling, dysphoric mania) and aetiology of comorbidity directionality (primary vs. secondary drug use) in controlled clinical trials. The identification of temporal priority in comorbid BD may provide a more refined view of the association between BD and comorbid syndromes. Coexisting conditions, whose onset precedes BD, often occurring with AD, may obscure essential elements of the primary diagnosis, thus diminishing the possibility of early detection and timely intervention. A question yet to be answered is whether an earlier and/or accurate diagnosis of BPD can

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prevent or at least attenuate the degree of subsequent substance use disorder or whether bipolar symptoms at onset that are diagnosed and treated can in fact attenuate or minimize the development of addiction as a later manifestation of bipolar illness. Finally, despite intensified efforts to clinically characterize substance use and anxiety comorbidity in BD, the empirical base informing therapeutic decisions in the comorbid bipolar patient remains largely inadequate, as a consequence of the routine exclusion of patients with such a comorbidity from the largest randomized clinical trials for all phases of bipolar illness.

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population but do not necessarily hamper smoking cessation. J. Clin. Psychiat., 65 (2), 169–176. Hirschfeld, R.M., Williams, J.B., Spitzer, R.L. et al. (2000) Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am. J. Psychiatry, 157, 1873–1875. Shoaib, A.M. and Dilsaver, S.C. (1995) Panic disorder in subjects with pure mania and depressive mania. Anxiety, 1, 302–304. Perugi, G., Toni, C. and Akiskal, H.S. (1999) AnxiousBipolar comorbidity: diagnostic and treatment challenges. Psychiat. Clin. N. Am., 22 (3), 565–583. Perugi, G., Akiskal, H.S., Ramacciotti, S. et al. (1999) Depressive comorbidity of panic, social phobic and obsessive-compulsive disorders re-examined: is there a bipolar connection? J. Psychiat. Res., 33, 53–61. Chen, Y.W. and Dilsaver, S.C. (1995) Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders. Psychiatric Res., 59, 57–64. Kessler, R. (1999) Comorbidity of unipolar and bipolar depression with other psychiatric disorders in a general population survey, in Comorbidity in Affective Disorders (ed. M. Tohen), Marcel Dekker Inc., New York, pp. 1–25. Rihmer, Z., Szadoczky, E., Furedi, J. et al. (2001) Anxiety disorders comorbidity in bipolar I, bipolar II and unipolar major depression: results from a populationbased study in Hungary. J. Affect. Disord., 67 (1–3), 175–179. Manning, J.S., Haykal, R.F., Connor, P.D. and Akiskal, H.S. (1997) On the nature of depressive and anxious states in a family practice setting: The high prevalence of bipolar II and related disorders in a cohort followed longitudinally. Compr. Psychiatry, 38, 102–108. MacQueen, G.M., Marriott, M., Begin, H. et al. (2003) Subsyndromal symptoms assessed in a longitudinal, prospective follow-up of a cohort of patients with bipolar disorder. Bipolar Disord., 5, 349–355. Dilsaver, S.C. and Chen, Y.W. (2003) Social phobia, panic disorder and suicidality in subjects with pure and depressive mania. J. Affect. Disord., 77, 173–177. McElroy, S.L., Altshuler, L.L., Suppes, T. et al. (2001) Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am. J. Psychiatry, 158, 420–426. Bauer, M.S., Altshuler, L., Evans, D.R. et al. (2005) for the VA Cooperative Study # 430 Team. Prevalence and distinct correlates of anxiety, substance and combined comorbidity in a multi-site public sector sample with bipolar disorder. J. Affect. Disord., 85, 301–315. Goodwin, R.D., Stayner, D.A., Chinman, M.J. et al. (2002) The relationship between anxiety and substance use disorders among individuals with severe affective disorders. Compr. Psychiatry, 43, 245–252. Masi, G., Perugi, G., Millepiedi, S. et al. (2007) Clinical and research implications of panic-bipolar comorbidity in children and adolescents. Psychiatry Res., 153 (1), 47–54.

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74. Savino, M., Perugi, G., Simonini, E. et al. (1993) Affective comorbidity in panic disorder: is there a bipolar connection? J. Affect. Disord., 28, 155–163. 75. Rhimer, Z., Barsi, J., Belso, N. et al. (1996) Antidepressant induced hypomania in obsessive-compulsive disorder. Int. Clin. Psychopharm., 11, 203–205. 76. Kruger, S., Cooke, R.G., Hasey, G.M. et al. (1995) Comorbidity of obsessive-compulsive disorder in bipolar disorder. J. Affect. Disord., 34, 117–120. 77. Perugi, G., Akiskal, H.S., Pfanner, C. et al. (1997) The clinical impact of bipolar and unipolar affective comorbidity on obsessive-compulsive disorder. J. Affect. Disord., 46, 15–23. 78. Dunner, D.L. and Kai Tay, L. (1993) Diagnostic reliability of the history of hypomania in bipolar II patients with major depression. Compr. Psychiatry, 34, 303–307. 79. Perugi, G. and Akiskal, H.S. (2002) The soft bipolar spectrum redefined: focus on the cyclothymic, anxious-sensitive, impulse-dyscontrol and binge-eating connection in Bipolar II and related conditions. Psychiatr. Clin. North Am., 25 (4), 713–737. 80. Gaudiano, B.A. and Miller, I.W. (2005) Anxiety disorder comorbidity in bipolar I disorder: relationship to depression severity and treatment outcome. Depress Anxiety, 21, 71–77. 81. Henry, C., Bulke, D., Bellivier, F. et al. (2003) Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood-stabilizers. J. Clin. Psychiatry, 64, 331–335. 82. Boylan, K.R., Bieling, P.J., Marriott, M. et al. (2004) Impact of comorbid anxiety disorders on outcome in a cohort of patients with bipolar disorder. J. Clin. Psychiatry, 65, 1106–1113. 83. Perugi, G., Akiskal, H.S., Toni, C. et al. (2001) The temporal relationship between anxiety disorders and (hypo)mania: a retrospective examination of 63 panic, social phobic and obsessive-compulsive patients with comorbid bipolar disorder. J. Affect. Disord., 67, 199–206. 84. MacKinnon, D.F., McMahon, F.J., Simpson, S.G. et al. (1997) Panic Disorder with familial bipolar disorder. Biol. Psychiatry, 42, 90–95. 85. Perugi, G., Akiskal, H.S., Gemignani, A. et al. (1998) Episodic course in obsessive compulsive disorder. Eur. Arch. Psychiatr. Clin. Neurosci., 248, 240–244. 86. Dilsaver, S.C. and White, K. (1986) Affective disorder and associated psychopathology: a family history study. J. Clin. Psychiatry, 47, 162–169. 87. Klein, D.N., Depue, R.A. and Slater, J.F. (1985) Inventory identification of cyclothymia. IX. Validation in offspring of bipolar I patients. Arch. Gen. Psychiatry, 43, 441–445. 88. Coryell, W. (1981) Obsessive compulsive disorder and primary unipolar depression. J. Nerv. Ment. Dis., 169, 220–224. 89. Himmelhoch, J.M. (1998) Social Anxiety, hypomania and the bipolar spectrum: data, theory and clinical issues. J. Affect. Disord., 50, 203–213. 90. Perugi, G., Toni, C., Frare, F. et al. (2002) Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity? J. Clin. Psychopharmacol., 22 (6), 584–591.

91. Perugi, G., Frare, F., Madaro, D. et al. (2002) Alcohol Abuse In Social Phobic Patients: Is There A Bipolar Connection? J. Affect. Disord., 68, 33–39. 92. Himle, J.A., Abelson, J.L., Haghightgou, H. et al. (1999) Effect of alcohol on social phobic anxiety. Am. J. Psychiatry, 156, 1237–1243. 93. Young, L.T., Cooke, R.G., Robb, J.C. et al. (1993) Anxious and non-anxious bipolar disorder. J. Affect. Disorder, 29, 49–52. 94. Feske, U., Frank, E., Mallinger, A.G. et al. (2000) Anxiety as a correlate of response to the acute treatment of bipolar I disorder. Am. J. Psychiatry, 157, 956–962. 95. Swann, A.C., Bowden, C.L., Morris, D. et al. (1997) Depression during mania: treatment response to lithium or divalproex. Arch. Gen. Psychiatry, 54, 37–42. 96. Lum, M., Fontaine, R., Elie, R. and Ontiveros, A. (1990) Divalproex sodium’s anti-panic effect in panic disorder: a placebo-controlled study. Biol. Psychiatry, 27, 164A–165. 97. Calabrese, J.R. and Delucchi, G.A. (1990) Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder. Am. J. Psychiatry, 147, 431–434. 98. Deltito, J.A. (1994) Valproate pretreatment for the difficultto-treat patient with OCD. J. Clin. Psychiatry, 55, 500. 99. Cora-Locatelli, G., Greenberg, B.D., Martin, J.D. and Murphy, D.L. (1998) Valproate monotherapy in an SRI-intolerant OCD patient. J. Clin. Psychiatry, 59, 82. 100. Uhde, T.W., Stein, M.B. and Post, R.M. (1988) Lack of efficacy of carbamazepine in the treatment of panic disorder. Am. J. Psychiatry, 145, 1104–1109. 101. Koopowitz, L.F. and Berk, M. (1997) Response of obsessive compulsive disorder to carbamazepine in two patients with comorbid epilepsy. Ann. Clin. Psychiatry, 9, 171–173. 102. Swinson, R.P. and Joffe, R.T. (1987) Carbamazepine in obsessive-compulsive disorder. Biol. Psychiatry, 22, 1169–1171. 103. Pande, A.C., Davidson, J. and Jefferson, J. (1999). Treatment of social phobia with gabapentin: a placebo controlled study. J. Clin. Psychopharm., 19, 341–348. 104. Pollack, M.H., Matthews, J. and Scott, E.L. (1998) Gabapentin as a potential treatment for anxiety disorders. Am. J. Psychiatry, 155 (7), 992–993. 105. Ghaemi, S.N., Wingo, A.P., Filkowski, M.A. and Baldessarini, R.J. (2008) Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr. Scand., 118 (5), 347–356. 106. Sholomskas, A.J. (1990) Mania in a panic disorder patient treated with fluoxetine. Am. J. Psychiatry, 147, 1090–1091. 107. Jann, M.W., Bitar, A.H. and Rao, A. (1982) Lithium prophylaxis of tricyclic-antidepressant-induced mania in bipolar patients. Am. J. Psychiatry, 139 (5), 683–684. 108. Kane, J.M., Quitkin, F.M., Rifkin, A. et al. (1982) Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness. Arch. Gen. Psychiatry, 39, 1065–1069. 109. Gao, K., Muzina, D., Gajwani, P. and Calabrese, J.R. (2006) Efficacy of typical and atypical antipsychotics for primary

Comorbidity in Bipolar Disorder and comorbid anxiety symptoms or disorders: a review. J. Clin. Psychiatry, 67 (9), 1327–1340. 110. Baker, R.W., Chengappa, K.N., Baird, J.W. et al. (1992) Emergence of obsessive compulsive symptoms during treatment with clozapine. J. Clin. Psychiatry, 53 (12), 439–442. 111. de Haan, L., Beuk, N., Hoogenboom, B. et al. (1997) Obsessive-compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of 113 patients with recent-onset schizophrenia or related disorders. J. Clin. Psychiatry, 58, 119–122.

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112. Niaura R, Britt DM, Shadel WG, Goldstein M, Abrams D, & Brown R. (2001). Symptoms of depression and survival experience among three samples of smokers trying to quit. Psychology of Addictive Behaviors, 15, 13–17. 113. Angst, J. (1998) The emerging epidemiology of hypomania and bipolar II disorder. J. Affect. Disord., 50 (2-3), 143–151. 114. Himmelhoch, J.M. (1998) Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical issues. J. Affect. Disord., 50 (2–3), 203–213.

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DSM-V Perspectives on Classification of Bipolar Disorder Jan Fawcett Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, NM, USA

It is customary to periodically revise our diagnostic system in the field of psychiatry. This custom is justified on the assumption that over a period of time new information is developed. DSM classifications have been updated over time, periods ranging from 7 to 12 years or more in response to new information concerning the course, treatment response and more recently the familial transmission, genetic factors, biological markers and even neural substrates associated with specific diagnostic categories, as research efforts at all levels yield more information. There is also an implicit assumption that from use of the established criteria in clinical practice and research over time, ‘design flaws’ inherent in any system will become evident and call for revision to further enhance the clinical utility, reliability and validity of the diagnostic categories.

An overall view of the DSM-V process Thus, the effort to revise the present DSM-IV classification for a planned DSM-V classification intended for publication in 2012, was undertaken in 2007 by the American Psychiatric Association under the direction of David Kupfer MD and Darrel Regier MD. Having been assigned the task of addressing the area of mood disorders, a Mood Disorders Work Group of knowledgeable volunteers was formed, which has been meeting both face-to-face and more frequently by conference calls reviewing the DSM-V classification and relevant scientificclinical literature. Where deemed necessary, we would elect to conduct secondary data analyses directed at specific questions, identify issues for possible revision as well as to recommend field trials to test the feasibility of certain proposed changes. We have also been challenged to reconsider the structure of the overall DSM-V, and to consider new ways to classify disorders that would reflect changes in clinical knowledge or practice as well as emerging knowl-

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edge from neurogenetic, neuroimaging and clinical research findings. Our task is to come up with a revised diagnostic classification that reflects emerging information relevant to validity of disorders and improves clinical utility in a format that, in an age of rapidly emerging new information, will not become obsolete by the time of its publication and will lend itself to the incorporation of emerging findings. We proceeded with this awe-inspiring charge. There is a hope that the resulting DSM-V would be in the greatest possible harmony with the emerging ICD 11 classification of psychiatric disorders. An effort was made to form groups of individuals, with expertise in the study of each group of disorders, into members of diagnostic category workgroups. Suggested revisions and changes reached by consensus in the workgroups will be passed on to a task force chaired by Drs Kupfer and Regier, which will be made up of Diagnosis Work Group Chairs, and various leaders and consultants in psychiatry. which have the task of visualizing the overall structure of the merging DSMV classification for approval, deferral or modification. The Mood Disorders Workgroup covers the categories major depressive disorder and bipolar disorder and all related diagnoses. We divided into sub-workgroups to more effectively work on these sub-categories in parallel. In this process, it was determined that other relevant behavioural dimensional candidates, such as suicide risk, the role of comorbid anxiety and several related categories such as seasonal affective disorder and premenstrual dysphoric disorder deserved thoughtful consideration. To deal with these issues, further sub-workgroups made up of members of the Mood Disorders Workgroup, as well as liaison members from other overlapping workgroups, such as anxiety, personality and psychotic disorders, were sought, supplemented with appointed advisors with specific expertise and research experience in these clinical areas who could make specific valuable contribution to our deliberations and recommendations, were all recruited to participate in this multilayered process. Each sub-workgroup, such as the Bipolar Sub-workgroup, regularly report their areas of discussion, and preliminary

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recommendations to and receives feedback from the entire membership of Mood Disorders Workgroup on conference calls and in face-to-face meetings as the process moves forward. This creates an iterative process where preliminary decisions are revisited by the sub-workgroups and periodically discussed in the entire mood workgroup and when approved, will be forwarded to the task force as recommendations to be considered for inclusion in the new DSM-V structure. This complex and iterative process of seeking and discussing information on questions raised by a review of the overall structure, that is the possibility and feasibility of adding a suicide risk dimension or severity dimension for anxiety to a mood disorder diagnosis, or raised by review of possible specific criteria changes such as the required duration of a symptom, for example the required duration of hypomania for bipolar II disorder and the definition of a mixed depressive state, is proceeding and being discussed by both the major depression and bipolar sub-workgroups, as well as the overall Mood Disorders Workgroup. Because of the resulting six sub-workgroups, with conference calls ranging from every two to four weeks, as well as various related group calls and adding in the task force group calls, an average of two to four calls each week occur in this process. The workgoups meet for face-to-face discussions for two days about every six months.

Ongoing work on bipolar disorder for DSM-V Understanding the review process should make it clear that there is much discussion and evaluation of possible changes for bipolar disorder in DSM-V, though few final decisions have been made at this point in the process. The members of the Bipolar Sub-workgroup include the Sub-workgroup Chairperson Trish Suppes MD, Jules Angst MD, Ray DePaulo MD, Ellen Frank PhD, Ellen Leibenluft MD, who are members of the full Mood Disorders Workgroup, which includes Bill Coryell MD, Lori Davis, MD, David Goldberg MD, James Jackson PhD, Ken Kendler MD, Mario Maj MD, Michael Phillips MD, Carlos Zarate MD and myself, as well as liaisons members from other work groups and advisors, such as Alan Swann MD who had input concerning the issue of mixed states in the Bipolar Subworkgroup and Norman Rosenthal who wrote a review of seasonal affective disorder. Liaison members from other groups, such as Kimberly Yonkers, Uli Witchen and Joen Oldham, also participated at various stages.

Criteria for recommending a change in DSM-IV The Mood Disorders Workgroup agreed on a memorandum that described criteria for recommending a change in

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DSM-IV to the task force. In summary form, this memorandum stated that a recommendation for a signuifiucant change must be sponsored by a workgroup member who would provide a rationale for the change and a review of the literature or other database analyses supporting the change. The greater the significance of the change proposed, the greater the data required to support the change. Unintended consequences of any change and how those changes would be offset by the advantages of the change would be considered. A two-thirds vote of the workgroup would be required for the proposal to be forwarded to the task force for their consideration of the recommendation.

Bipolar disorder Based on discussions of the Bipolar Sub-workgroup and the Mood Disorders Workgroup some interesting issues have emerged. This work is going on at more than one conceptual level. A review of the DSM-IV criteria, such as the possible need to include increased energy or overactivity in the diagnostic criteria and how that could best be accomplished, has been discussed [18].

Bipolar spectrum A consideration of the meaning and relevance of the distinction of mania from hypomania, as well as the utility and validity of the concept of bipolar spectrum disorder, is going on simultaneously and receiving discussion. These discussions are occurring with an awareness of a plethora of articles published over the past 15 years, raising the question of sub-threshold manic symptoms not being recognized by DSM-IV, which would alter the balance of patients diagnosed on the bipolar spectrum, increasing the rate of bipolar spectrum patients to approach the rates of patients diagnosed with true unipolar disorder [1–8,10–12,14–16,18–21,33,35,36,38,40,44,45,50,57,60,62] Some of these articles have suggested that the four-day requirement for the diagnosis of bipolar II disorder in DSM-IV, has resulted in many bipolar spectrum patients being diagnosed as unipolar depression as opposed to a two-day duration of hypomanic symptoms [4,12,16,43,62]. These publications remind us that the original concept of manic depressive disorder included patients on the basis of recurrent affective episodes and not only the occurrence of a full syndrome manic episode [5]. The literature on bipolar spectrum has also pointed out that by having criteria that are too restrictive for the recognition of manic symptoms, may lead patients to suffer from symptoms for years without a correct diagnosis of bipolar disorder and effective treatment [21,36]. For example, the criteria requiring a fourday duration of hypomania has been criticized as a barrier to the correct and timely diagnosis of bipolar disorder by some authors [4,12,62]. Studies have pointed out the negative

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consequences in many patients of ineffective responses and increased risk for suicidal behaviour from the use of antidepressant medications, without consideration of the need for concomitant treatment with mood-stabilizing medications [4,16,19,43,62]. On the other hand, a problem of overdiagnosis of bipolar disorder diagnosis has been raised by Zimmerman et al. [65]. These investigators present results of 700 patients interviewed with the SCID, which is based on DSM-IV criteria. They found that fewer than half of the patients, who reported they had been diagnosed previously with bipolar disorder, were diagnosed with bipolar disorder based on a SCID interview. Patients who self-reported a previous diagnosis of bipolar disorder that was not confirmed by the SCID did not have a significantly higher morbid risk for bipolar disorder than the patients who were negative for bipolar disorder by self-report and the SCID. This finding does not answer the question of what are the best supported criteria for a bipolar diagnosis, but addresses the manner in which various clinicians apply the criteria.

could be improved at the borders of major depression and mild or moderate manifestations of mania, hypomania or mixed states, so that patients who are actually suffering from a bipolar spectrum disorder could be earlier diagnosed and treated. On the other hand, a very high proportion of patients diagnosed with major depression may have isolated (not concurrent) manic symptoms over their course without developing bipolar disorder. In addition, with respect to a bipolar spectrum, it has been found that the clinical outcome of bipolar I and bipolar II patients is distinct enough to merit designation into these categories.

Rapid cycling bipolar disorder Thus far, the specifier of rapid cycling bipolar disorder with the DSM-IV criteria of four affective episodes in the past year has been found to be clinically useful without need of modification by the workgroup.

Bipolar depression Mixed episodes The issue of mixed manic-hypomanic and depressive states is being considered with a trend toward extending mixed states across the entire severity range of bipolar bisorder. According to DSM-IV, a mixed episode occurs only as a part of bipolar disorder, and it requires the presence of full major depression and full mania, although the literature suggests that mixed depressive states are being found throughout the spectrum of bipolar patients, as well as in patients diagnosed with unipolar depression [9,13,17,22,24,27,30,33,37,42,52,58]. Of course, there are questions of the borders between bipolar and recurrent unipolar disorder. It has been found that the incidence of unipolar depression is as great or greater than bipolar disorder in family members, while the incidence of bipolar disorder is greater in families with bipolar disorder than those without [8,25,38,63]. The issues of bipolar spectrum, and sub-threshold bipolar states, as well as the capturing of episodes of mixed states, could have a significant effect on the proportion of patients diagnosed as in the bipolar spectrum versus unipolar depression. However, a report of an analysis comparing the course of BP I versus BP II patients concluded that the phenotypes of bipolar I and bipolar II disorder are likely to exist in a disease spectrum, but since they are sufficiently distinct in their long-term outcomes (more severe episodes in BP I patients and more chronic course with a predominance of depression in BP II patients), they are best classified as two separate subtypes in official classification syndromes [39]. It appears that a significant proportion of patients classified as unipolar major depressive may ultimately be found to be in the bipolar spectrum, and perhaps they could be classified on a severity spectrum. It seems that diagnosis

Bipolar depression and its clinical characteristics relative to treatment outcome is also a concern. Is it the same as unipolar major depression or are there differences that should be recognized? The data from the large STEP-BD study showing that adjunctive SSRI antidepressants or buprorion versus placebo added double blind to mood stabilizers or atypical antipsychotics in bipolar depressed patients, showed that the efficacy as measured by durable recovery of these antidepressants was only 23% versus a 27% response for placebo over 26 weeks [53]. Further reports from STEP-BD find that anidepressants do not assist in depressive recovery in bipolar depression accompanied by symptoms of mania, and are likely to increase symptoms of dysphoria, irritablity and middle waking, [34]. The STEPBD studies of antidepressant efficacy and effectiveness certainly raise questions as to differences in treatment response, particularly in those patients with the presence of depression with manic symptoms (mixed depression) or a history of mood switching in past trials of antidepressants [6,34,48]. Another study of self reported mood switching, within 12 weeks of starting antidepressant medications, found that 44% reported at least one episode in the 338 bipolar patients studied [49]. The risk of treatment-emergent mania was found to be greatest in bipolar patients with a short duration of illness, multiple past antidepressant trials and a past history of switch with at least one antidepressant. A treatment study of 176 adult outpatients with bipolar depression over 10 weeks found that 85 responded to treatment, 45 did not respond and 46 patients had treatment-emergent mania or hypomania [30]. YMRS items of increased motor activity, pressured speech and racing thoughts were significantly associated with the outcome of mood switching in this sample. This chapter suggests that

DSM-V Perspectives on Classification

screening for mild manic symptoms would help predict patients likely to develop manic symptomatology in response to antidepressant treatment. It is interesting that some of the same symptoms are noted in patients diagnosed with unipolar major depression who later develop manic or hypomanic behaviour. Perhaps more sensitive criteria for mixed depressive and mixed manic or hypomanic states would help to sort out candidates with bipolar depression from those with unipolar depression more accurately and earlier in their course. Is bipolar depression really the same condition as unipolar depression? If not, is there a difference in symptom criteria? The Collaborative Depression Study, reported an 11-year follow-up of major depression revealing an 8.6% rate of conversion to bipolar II disorder and a 3.9% conversion rate to bipolar I Disorder – total conversion rate 12.5% [6]. The patients who converted were found to have early onset of depression, high rates of substance abuse and a high incidence of social turmoil and antisocial acts. Mood labiality alone was the most sensitive predictor (86%), though of lower sensitivity (42%). ‘Habitual self’ descriptions of temperamental instability attained a predictive sensitivity of 91%. A study reported in 2007 of 744 outpatients followed since 1981–1986, found an incidence of lifetime mania of 27%, significantly associated with three factors: age of onset of depression, family history of mania and increased psychotic symptoms [48]. Another study reported on a 15-year follow-up of 74 patients with an average age of 23, were hospitalized for major depression and found that 27% had developed on or more distinct patterns of hypomania, while an additional 19% had at least one episode of bipolar I mania [26]. These investigators found that young patients with psychotic features were at particularly high risk for eventually developing mania. A recent study of 269, predominantly outpatients diagnosed as unipolar major depression and followed over 5 years, reported that 8.9% of patients diagnosed with unipolar major depression that then had a switch into symptoms of mania or hypomania and 2.8% switched to Type I when treated with antidepressant medications, also contribute to this issue [59]. One treatment study of unipolar depressed inpatients found a manic/hypomanic switch rate of 13.1%, and then compared these patients with 245 patients who did not show any switch [49]. The patients who developed a switch in response to antidepressants tended to be male and to have a higher proportion of family history of bipolar disorder. Mitchell and colleagues [45] have pointed out that while there is no ‘point of rarity’ between bipolar depression and unipolar major depression, there are clinical characteristics that are more common in each form of depression. Features more common in patients who ‘convert’ or later develop hypo/manic symptoms are: ‘atypical’ symptoms such as hypersomnia, hyperphagia, and leaden paralysis, psychomotor retardation, psychotic features and/or path-

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ological guilt and lability of mood. Bipolar depressed patients are more likely to have an earlier age of onset of their first depressive episode, to have more prior episodes of depression, to have shorter episodes of depression and a family history of bipolar disorder. Unipolar depression patients were found to have initial insomnia/reduced sleep, appetite or weight loss, normal or increased activity levels, somatic complaints, later age of onset of first episodes, prolonged episodes and no family history of bipolar disorder. The authors suggest that a ‘probabilistic’ approach to the diagnosis of bipolar/unipolar depression be developed, based on the appearance of these clinical characteristics. A subsequent study by the same group [46,47] of 217 patients with bipolar disorder with standardized interviews with a comparison with a Stanley Foundation Bipolar Disorders Network (SFBN) sample, as well as a STEP-BD sample, found sociodemographic similarities across the three samples, between samples for positive family history of bipolar disorder (40%) and unipolar depression (55%). The comparison also found similar proportions with the STEP-BD sample reporting earlier age of onset and the SFBN sample reporting higher numbers of overall episodes, but psychotic episodes and suicide attempts were less common than in the Australian sample. A recent study by Goldberg et al. [35], of 1380 STEP-BD bipolar patients with depressive episodes, found that two-thirds of this sample had concurrent manic symptoms, most often distractibility, flight of ideas, or racing thoughts and psychomotor agitation. Patients with mixed features were more likely to have an early age of onset, rapid cycling in the past year, suicide attempts and more days in the preceeding year with irritability or mood elevation. The authors conclude that manic symptoms often accompany bipolar depression, but are often overlooked when they appear less prominent than depressive features and subsyndromal manic symptoms during bipolar I or II depression demarcate a more common, severe and complex clinical state than pure bipolar depression.

Schizoaffective disorder The diagnosis of schizo-affective disorder is a contentious problem shared by the Mood Disorders Workgroup and the Psychosis Workgroup. While in its current form it has turned out to have rather low reliability, it has been found by Tohen et al. to be the most commonly used second diagnosis in a group of patients initially diagnosed as psychosis NOS. Currently, it seems that the Psychosis Workgroup is recommending that it be dropped and diagnosed by using the diagnosis of schizophrenia with a behavioural dimension of mania or depression. Because schizoaffective disorder is one of the most frequently used diagnoses, at this point it has been decided that the diagnosis will be retained in DSM-V changes in the wording of

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the criteria which will hopefully increase the reliability of this diagnosis. The psychosis Workgroup has currently proposed to retaine the diagnosis because of the frequency of its use, with changes in the diagnostic criteria aimed at making the diagnosis more reliable than it currently is.

Paediatric bipolar disorder The issue of diagnosing bipolar disorder in children is also a major issue. Bipolar disorder has a serious prognosis and often requires treatment with powerful medications that may have serious side effects and in some cases long-term medical risks, so when relying on symptom presentations and history as contrasted with laboratory tests, having the most effective diagnostic criteria is of great concern. It appears that irritability, although certainly common in bipolar disorder at all ages, is quite a promiscuous symptom across a range of diagnoses and may not be very useful in discriminating bipolar disorder from other disorders. Separating bipolar disorder from ADHD and Oppositional Defiant Disorder in children is a concern [55]. A recent study of 637 youths with a 10 item scale demonstrated good discrimination between bipolar disorder and attention deficit disorder, and showed that parents most notice elated mood, high energy, irritability and rapid changes in mood and energy as the prominent features of juvenile bipolar disorder [56,64]. The question has been raised whether children with bipolar disorder manifest shorter (as short as four hours) episodes occurring frequently over periods such as four days. This would suggest the possibility of different criteria for paediatric bipolar disorder than those currently in place for adults. On the other hand, there are obvious concerns for overdiagnosis as there must be a balance of overdiagnosis versus Underdiagnosis of paediatric bipolar disorder. A field test of criteria and further discussions with the Developmental/Lifespan Issues Task Force Committee will be required to decide this issue. A recent eight-year follow-up study of children diagnosed with bipolar disorder, showing an over 40% of recurrent mania once they are over the age of 18, provides a much needed confirmation of the potential for the accurate diagnosis of bipolar disorder in children [32]. However, concern has been expressed regarding the method of diagnosis utilized for the over-18 group in this study. It is also of great interest and importance that this study also documented a very high incidence (over 90%) of ultradian cycling (cycles of a minimum of four-hour switches) with an interview that is sensitive to this phenomenon, suggesting that it is common, but often not captured in clinical interviews. A study critically reviewing the phenomenology of paediatric bipolar disorder, the specificity of symptoms and the validity of the diagnostic construct found good support, but areas of disagreement over the use of elated mood versus irritability, and the limitations of the entity of bipolar dis-

order NOS in children [31,64]. A recent report, looking at the relative incidence of childhood-onset bipolar disorder reported by adult bipolar patients, found a 61% incidence in US patients compared with 30% report of childhood in the Netherlands or Germany [30,51]. This study found twice the genetic/familial risk for affective disorder and twice the incidence in childhood adversity in the United States. In a group of 480 adult outpatients carefully diagnosed with bipolar disorder, 14% reported an onset before age 12 and 36% reported onset in adolescence. The childhood-onset group reported an average 16-year delay until they received treatment, and both the childhood-onset and adolescentonset group had more episodes, more comorbidity and a more severe course [41]. It appears that childhood-onset bipolar onset diagnosis may not be made early enough, but that there might be disagreement around the milder forms (bipolar disorder NOS) that require attention to assure accurate, but timely diagnosis and treatment.

Behavioural dimensions In addition to an ongoing review of criteria for the diagnosis of bipolar mania, hypomania, depression, mixed states and various age-related presentations, the concept of being able to convey more useful clinical information by combining behavioural dimensions with diagnostic categories and how to do this and at the same time maintain clinical utility, is under consideration [7,61]. One candidate is a universal behavioural dimension, which might be rated as a severity dimension across diagnoses, is the presence of comorbid anxiety that emerges with the disorder, rather than as a primary comorbid anxiety disorder. Even the presence of a comorbid anxiety disorder might mean more if rated on a simple severity scale as done using the SADS-C psychic anxiety scale, which rates severity using both the intensity experienced by the patient as well as the time of the patient’s day dominated by anxiety [27]. The basis for this consideration is the fact that comorbid severe anxiety is not widely recognized as a high priority treatment target, while recent studies show that it is a robust predictor of poor outcome and suicidal behaviour in bipolar disorder and the range of affective disorders. Studies have shown it is very prevalent (40–50%) in bipolar disorder. If the patient meets criteria for a diagnosable anxiety disorder, this diagnosis can be made as a comorbid Axis I diagnosis, but not uncommonly the anxiety symptoms may emerge with the bipolar symptomatology and be ignored diagnostically and by under-treatment of a bipolar patient with comorbid anxiety, resulting in poor outcomes and an elevation of suicide risk [55,56]. It has also been reported that a comorbid anxiety disorders diagnosis predicts an increased risk of suicide (HR ¼ 1.81) in bipolar patients [54]. Fawcett et al. [29] found that severity of psychic anxiety in both bipolar and unipolar patients was signifi-

DSM-V Perspectives on Classification

cantly correlated with suicide risk over one year from the time of assessment. (See Chapter 7, Suicide and Bipolar Disorder). Recently, Coryell et al., studied the severity of psychic and somatic anxiety measured at baseline by the SADS-C rating scale, which was found significantly linearily correlated with time spent in a depressive episode stepwise by severity rating, over a 20-year follow-up period. Psychic anxiety severity was the strongest single correlate of time spent in depressive episodes of a 20-year follow-up [23]. It is interesting that a similar report concerning poor outcomes with antidepressant treatment has been recently made from the STAR
D study of treatment outcome in patients with unipolar major depression. Anxiety severity has also be related to poor outcome in unipolar depressive patients treated in the STAR
D Study [28]. This data supports the addition of a psychic anxiety dimension to all of the mood disorder diagnoses, including bipolar spectrum disorder has well as perhaps across other diagnostic categories. This clinically significant behavioural dimension, which is extrinsic to criteria for the diagnosis, would call attention to the need for treatment of anxiety symptoms and further collection of data on the significance of co-existing anxiety severity for each diagnostic category, without prematurely changing criteria for the diagnostic category. A simple scale, such as the SADS-C, would lend itself to easy use by clinicians that would not be a burden, but would increase the data available for treatment planning. A decision to add extrinsic (supraordinate) as well as intrinsic (criteria symptom severity dimensions) dimensional severity measures would be a major change in the conceptual structure of DSM-V, if adopted. Adding certain extrinsic behaviour dimensions, such as severity of psychic anxiety and severity and immediacy of suicide risk, could result in an important increase in relevant clinical information conveyed and improve the treatment of patients as well as lead to further valuable research outcome data, which could result in further progress. It has become clearer that the criteria presently used for the diagnosis of bipolar disorder as well as other diagnoses may limit our clinical perspective, by limiting the focus of our treatment efforts in such a way as to ignore important clinical dimensions presently not included in the diagnostic criteria, but which are critical to our patient’s clinical outcome. These issues are complex and raise the issue of clinical utility, which is a major consideration in the DSM-V process. A concept of bipolar disorder as a spectrum spanning a range of severity from very severe, psychotic behaviour to a recurrent disorder with subtle and short-lived 1–2 day bouts of hypomania followed by long episodes of depression, to traits of mood instability and periodic flamboyant behaviour that may not require treatment, may be more effective in arriving at severity cut points. True severity may also depend on comorbid symptomatology, such as substance

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abuse or anxiety severity as well as measures of disability. Such a choice might expand the numbers of patients formerly diagnosed with unipolar depression who receive an early bipolar diagnosis and result in a considerable increase in bipolar spectrum diagnoses in patients with recurrent mood disorders, relative to unipolar major depression. Adding behavioural dimensions across bipolar disorder and other diagnostic categories might considerably expand our treatment efforts and provide new targets for treatment and treatment development, resulting in improved outcomes for mood disorder and patients with other disorders. The DSM-V will need to be able to serve many masters. Busy clinicians will want it to be as simple and easy to use as possible and will not want to be burdened with changes that do not result in an obvious improvement in their practice. Research investigators will guard against changes that will diminish the value of previously collected large datasets resulting from any major changes in criteria and will set a high threshold of data driven support for proposed changes. Others will be wedded by years of hard work to certain clinical concepts and will demand solid empirical support for changes. Insurers and health care payers will be sensitive to changes, which might increase utilization and treatment expense. Ultimately, it is my hope that DSM-V can move the field ahead, with a diagnostic system that will improve treatment and encourage research in areas that need the greatest attention, by addressing newly developed knowledge and the inevitable ‘design flaws’ that result in any diagnostic system. Hopefully, we can help clinicians to be more responsive to important facets and contribute to more effective treatment of the disorders we treat.

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Chapter 5

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