Bipolar Disorder: Clinical and Neurobiological Foundations

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Bipolar Disorder: Clinical and Neurobiological Foundations

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

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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 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





List of Contributors


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


2 Clinical Features and Subtypes of Bipolar


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




Ivan J. Torres and Gin S. Malhi 83


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

Robert M. Post and Marcia Kauer-Sant’Anna

17 Molecular Biology of Bipolar Disorder



18 Mitochondrial Dysfunction and Oxidative


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


Timothy Dinan and Michael Bauer Disorder

21 Treatment Adherence in Bipolar Disorder




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


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


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


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


14 Functional Magnetic Resonance Imaging,

David Healy Disorder



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





23 Pharmacological Treatment of Bipolar


31 Psychoeducation as a Core Element of


Allan H. Young and Charles B. Nemeroff

32 Cognitive-Behavioural Therapy for Bipolar


Alan C. Swann




36 Bipolar Disorder in Women


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

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


37 Phenomenology and Treatment of Bipolar

I Disorder in Children: A Critical Review

Mark S. George


Gabrielle A. Carlson and Elizabeth B. Weller

30 Novel Therapeutic Strategies for Bipolar

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


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

28 Bipolar Disorder and Safety Monitoring



David J. Miklowitz 35 Collaborative Care for Bipolar Disorder

Ihsan M. Salloum, Luca Pani and Tiffany Cooke



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


33 Interpersonal and Social Rhythm Therapy for


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


Francesc Colom and Lesley Berk

24 Practical Pharmacological Maintenance

Treatment of Bipolar Disorder

Psychological Approaches for Bipolar Disorders


38 Bipolar Disorder in the Elderly


Martha Sajatovic and Lars Vedel Kessing Index



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


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



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



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



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].



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 Traite 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, Traite Medico-Philosophique sur l’Alienation 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



Chapter 1

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


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





















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.


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



Chapter 1

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



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





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



Chapter 1

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.



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.



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


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

Clinical Features and Subtypes



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





















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)









Major Depression



Depressive Disorder-NOS


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.



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.



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



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-



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



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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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



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





% Mean (sd)

88.6 33.6 (10.7)

66.9 37.1 (9.2)