Bipolar Psychopharmacotherapy E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1076

Veröffentlichungsjahr: 2011

Beschreibung

"If a colleague were to ask me, "What would you recommend I read if I want to become a real expert on bipolarity?" I would respond Bipolar Psychopharmacotherapy: Caring for the Patient." Journal of Bipolar Disorders And the second edition is even better! Bipolar Psychopharmacotherapy covers both pharmacotherapy and the supportive role of psychotherapy, psychoeducation and social approaches to provide a broad integrative philosophy of care for bipolar patients. Extensive coverage is given to special management issues such as the pharmacological care of women with bipolar disorder, children and the elderly, as well as bipolar depression and suicide prevention. The mood swings that characterize bipolar disorder can now be better stabilized in most patients than in the past, but the illness must be carefully managed throughout a person's life. Pharmacotherapy is central to the acute treatment and long-term management and as there are several classes of drugs which are often prescribed concurrently, treatment issues are complex. This essential reference work features critical reviews of the existing literature, plus information on new treatments that have been reported at peer reviewed scientific meetings, often written by the pioneering experts on a particular treatment. The second-generation antipsychotics are now covered in separate chapters to provide in-depth coverage of these agents. There are also new chapters on the pharmacological treatments of mixed states and rapid cycling and novel therapeutic vistas.

Leseprobe

Contents

List of Contributors

Preface to the Second Edition

Chapter 1 The scope of bipolar disordersHagop S. Akiskal

1.1 Diagnostic and public health aspects

1.2 Psychological and social aspects

Appendix 1.A: Laboratory considerations in the clinical use of lithium

Chapter 2 Lithium treatment: Focus on long-term prophylaxisPaul Grof and Mogens Schou

2.1 Introduction

2.2 Cade’s pioneering study

2.3 Discovery of the prophylactic action of lithium

2.4 Practical issues

2.5 Are new and better prophylactic agents about to oust lithium?

2.6 Combination treatment

2.7 Prophylaxis in recurrent depressive disorder

2.8 The effect of lithium on the patients’ suicidal behavior

2.9 Benefits of prophylactic lithium treatment

2.10 Conclusion

Chapter 3 Valproate: Clinical pharmacological profileCharles L. Bowden and Vivek Singh

3.1 Historical background

3.2 Structure-activity relationships

3.3 Pharmacodynamic properties

3.4 Pharmacokinetics and metabolic clearance

3.5 Serum concentration and efficacy

3.6 Efficacy and indications

3.7 Efficacy in bipolar disorder

3.8 Combination strategy in acute mania

3.9 Prophylaxis in bipolar disorder

3.10 Treatment of bipolar depression

3.11 Valproate in treatment of bipolar disorder in children and adolescents

3.12 Use in bipolar illness comorbid with alcoholism

3.13 Bipolar disorder comorbid with ADHD

3.14 Bipolar disorder comorbid with borderline personality disorder

3.15 Adverse effects

3.16 Comparative adverse effects

3.17 Adverse effects in combination therapy, compared with monotherapy

3.18 Adverse effects by bodily system

3.19 Summary

Chapter 4 Pharmacological profile and clinical utility of lamotrigine in mood disordersMarc L.M. van der Loos, Joseph R. Calabrese, Willem A. Nolen and David J. Muzina

4.1 Introduction

4.2 Clinical pharmacology of lamotrigine

4.3 Lamotrigine and mood disorders

4.4 Safety

4.5 Clinical applications for lamotrigine in mood disorders

4.6 Summary

Chapter 5 Carbamazepine and other anticonvulsantsHeinz Grunze

5.1 Introduction

5.2 Conclusions

Chapter 6 Olanzapine in treatment for bipolar disorderMauricio Tohen, Giedra Campbell and Juan-Carlos Gómez

6.1 Introduction

6.2 Rationale in the clinical trial development of olanzapine

6.3 Efficacy in the treatment of acute mania

6.4 Efficacy in the treatment of bipolar depression

6.5 Efficacy in bipolar maintenance/relapse prevention

6.6 Safety and tolerability

6.7 Summary

Chapter 7 Haloperidol and other first generation antipsychotics in maniaJohn Cookson

7.1 Introduction

7.2 Acute tranquillization in mania

7.3 Sedation is not required for antipsychotics to improve mania

7.4 Chlorpromazine in mania

7.5 Haloperidol in mania

7.6 Hormone changes and mechanisms of antimanic effects of antipsychotics

7.7 Antipsychotics as mood stabilizers

7.8 Placebo-controlled studies in mania

7.9 Recent comparative trials without placebo

7.10 Pharmacoeconomics

7.11 Conclusions

Chapter 8 Clinical utility of clozapine in bipolar disorderV.E. Cosgrove, J.S. Seo, H. Yang and Trisha Suppes

8.1 Introduction

8.2 History

8.3 Clinical pharmacology of clozapine

8.4 Clozapine in bipolar disorders

8.5 Effective pharmacotherapy for bipolar disorder?

8.6 Case studies

Chapter 9 Risperidone and paliperidone in the treatment of bipolar disorderL. Ivo Caers and Joris Berwaerts

9.1 Introduction

9.2 Oral risperidone in bipolar mania

9.3 Paliperidone extended release (ER) in bipolar mania

9.4 Risperidone long-acting injectable (LAI) in the maintenance treatment of bipolar disorder

9.5 Elements of special interest

9.6 Summary and conclusions

Chapter 10 Quetiapine in bipolar disorderMauricio Kunz, Svante Nyberg and Lakshmi N. Yatham

10.1 Introduction

10.2 Pharmacology

10.3 Quetiapine in the treatment of acute mania

10.4 Quetiapine in the treatment of acute bipolar depression

10.5 Quetiapine in the maintenance treatment of bipolar disorder

10.6 Safety and tolerability of quetiapine

10.7 Summary

Chapter 11 Ziprasidone in the treatment of bipolar disorderThomas L. Schwartz, Stephen M. Stahl, Elizabeth Pappadopulos and Onur N. Karayal

11.1 Introduction

11.2 Ziprasidone and its proposed mechanism of action

11.3 Ziprasidone in treatment guidelines

11.4 Overview of ziprasidone efficacy from clinical trial data

11.5 Acute manic/mixed episodes

11.6 Acute depressive episodes

11.7 Long term maintenance treatment of bipolar disorder

11.8 Practical guidance on the use of ziprasidone in bipolar disorder

11.9 Safety and tolerability

11.10 Treatment of special populations

11.11 Summary and conclusions

Chapter 12 Aripiprazole in bipolar disorderAlessandra Nivoli and Eduard Vieta

12.1 Aripiprazole and its mode of action

12.2 Aripiprazole in treatment guidelines

12.3 Aripiprazole efficacy from clinical trial data

12.4 Aripiprazole safety and tolerability

12.5 Treatment of special populations

12.6 Pharmacogenetics of aripiprazole

Chapter 13 Asenapine in bipolar disorder Roger S. McIntyre

13.1 Introduction

13.2 Pharmacology

13.3 Human pharmacokinetics

13.4 Asenapine: Efficacy in bipolar mania and mixed states

13.5 Asenapine: Efficacy and tolerability during extension treatment

13.6 Summary and conclusion

Chapter 14 Complex combination therapy for long-term stability in bipolar disorder Robert M. Post

14.1 Introduction

14.2 Rationale for complex combination therapy in bipolar illness

14.3 Principles of building an effective therapeutic regimen

14.4 Conclusions

Chapter 15 The role of antidepressants in bipolar disorder Boghos I. Yerevanian

15.1 Introduction

15.2 Tricyclic antidepressants

15.3 MAO inhibitors

15.4 SSRIs

15.5 SNRIs: Venlafaxine, mirtazapine, duloxetine

15.6 Bupropion

15.7 Clinical and research implications

Chapter 16 Bipolarity in women: Therapeutic issuesSusan L. McElroy, Lesley M. Arnold and Lori L. Altshuler

16.1 Introduction

16.2 Epidemiology and gender distribution of the bipolar spectrum

16.3 Gender differences in phenomenology

16.4 Gender differences in course and outcome

16.5 Gender differences in comorbidity

16.6 Bipolar disorder and the reproductive cycle

16.7 Treatment of bipolar disorder in females

16.8 Summary

Chapter 17 Pediatric bipolar disorder: The promise of psychopharmacotherapyTiffany Thomas and Robert L. Findling

17.1 Introduction

17.2 Lithium

17.3 Anticonvulsants

17.4 Antipsychotics

17.5 Conclusion

Chapter 18 Treatment of bipolar disorder in old ageKenneth I. Shulman, Nathan Herrmann and Martha Sajatovic

18.1 Treatment of bipolar disorder in old age

18.2 Management of bipolar disorder in the elderly

18.3 Treatment of bipolar depression in older adults

18.4 The future

Chapter 19 Diagnosis and treatment of mixed statesAlan C. Swann

19.1 What is a mixed state?

19.2 General considerations for treatment strategies in mixed states

19.3 Treating mania in mixed states

19.4 Treating depression in mixed states

19.5 Nonpharmacological treatments

19.6 An Integrated model for treating mixed states

19.7 Conclusions

Chapter 20 Rapid cycling of bipolar patientsAthanasios Koukopoulos, G. Serra, F. Zazzara,A. E. Koukopoulos and G. Sani

20.1 Introduction

20.2 Epidemiological data

20.3 Spontaneous and induced rapid cycling

20.4 Temperament and rapid cycling

20.5 Course

20.6 Clinical picture of rapid cycling

20.7 Neurobiology of rapid cycling bipolar disorder: The role of dopamine D2 receptors, sensitization

20.8 Treatment

20.9 Discussion

Chapter 21 Novel therapeutic approaches for treating bipolar disorderRodrigo Machado-Vieira, Ioline Henter, Jacqueline Baumann, David Latov, Cristina Wheeler-Castillo and Carlos A. Zarate

21.1 Introduction

21.2 The dynorphin opioid neuropeptide system

21.3 The purinergic system

21.4 The melatonergic system

21.5 The glutamatergic system

21.6 The tachykinin neuropeptides system

21.7 The glucocorticoid system

21.8 The arachidonic acid (AA) cascade

21.9 The endocannabinoid system

21.10 Oxidative stress and bioenergetics

21.11 The intracellular signaling pathways

21.12 Final remarks

Chapter 22 The pivotal role of psycho-education in the long-term treatment of bipolar disorderFrancesc Colom and Andrea Murru

22.1 Introduction

22.2 On the need for psycho-education

22.3 The five ingredients of psycho-education

22.4 Substance misuse avoidance

22.5 Early warning signs – detection

22.6 Lifestyle regularity (and miscellanea)

22.7 Psycho-education with the family

22.8 Long-term follow-up

22.9 The future

22.10 Funding sources and acknowledgments

Chapter 23 The role of treatment setting in the pharmacotherapy of bipolar disorderJean-Michel Azorin

23.1 Implementation of drug treatment according to phase and severity of illness

23.2 Pretreatment evaluation and monitoring of pharmacotherapy

23.3 Drug response and treatment setting

23.4 From efficacy to efficiency of pharmacotherapy in bipolar illness

Chapter 24 Pharmacological prevention of suicide in bipolar patientsZoltán Rihmer

24.1 Introduction

24.2 Mood disorders and suicidal behavior

24.3 Risk of suicidal behavior in bipolar disorders

24.4 Suicide prevention in bipolar disorders

Chapter 25 Overview of principles of caring for bipolar patientsHagop S. Akiskal and Kareen K. Akiskal

25.1 Introduction

25.2 The major players in bipolar disorder

25.3 Principles of caring

25.4 Special considerations for hypomanic and cyclothymic patients

25.5 Conclusion

Index

This edition first published 2011, © 2011 John Wiley & Sons

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Library of Congress Cataloging-in-Publication Data

Bipolar psychopharmacotherapy : caring for the patient / edited by Hagop Akiskal and Mauricio Tohen. – 2nd ed.p. ; cm.

Includes bibliographical references and index.ISBN 978-0-470-74721-6 (cloth)

1. Manic-depressive illness–Chemotherapy. 2. Lithium–Therapeutic use. 3. Antipsychotic drugs.4. Psychopharmacology. I. Akiskal, Hagop S. II. Tohen, Mauricio. [DNLM: 1. Bipolar Disorder–drug therapy. 2. Anticonvulsants–therapeutic use. 3. Antimanic Agents–therapeutic use. 4. Antipsychotic Agents–therapeutic use. 5. Bipolar Disorder–prevention & control. WM 207]RC516.B529 2011616.89’5–dc22

2010046388

A catalogue record for this book is available from the British Library.

This book is published in the following electronic formats: ePDF: 9780470975107; Wiley Online Library: 9780470975114; ePub: 9780470976982

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

We also dedicate it to Pierre Deniker and Mogens Schou for their pioneering research which made such caring possible.

“To my wife Dianne” – Mauricio Tohen

List of Contributors

Hagop S. Akiskal, International Mood Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA

Kareen K. Akiskal, International Mood Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA; French Depressive and Manic-Depressive Association, Rennes, France

Lori L. Altshuler, Department of Psychiatry and Behavioral Sciences, Veterans Affairs Greater Los Angeles Healthcare System, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Lesley M. Arnold, Department of Psychiatry and Behavioral Neuroscience, Women’s Health Research Program, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA

Jean-Michel Azorin, Department of Psychiatry, Ste Marguerite Hospital, 13274 Marseille Cedex 9, France

Jacqueline Baumann, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Joris Berwaerts, Johnson & Johnson Pharmaceutical Research & Development, LIC Beerse, Belgium; JB Titusville, NJ, USA

Charles L. Bowden, Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio TX 78229-3900, USA

L. Ivo Caers, Johnson & Johnson Pharmaceutical Research & Development, LIC Beerse, Belgium; JB Titusville, NJ, USA

Joseph R. Calabrese, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA

Giedra Campbell, Scientific Communications, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA

Francesc Colom, Head of Psychoeducation and Psychological Treatments Area, Barcelona Bipolar Disorders Program, IDIBAPS, Institute of Neurosciences, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain

John Cookson, The Royal London Hospital, Burdett House, Mile End Hospital, Bancroft Road, London E1 4DG, UK

V.E. Cosgrove, Stanford School of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA

Robert L. Findling, Division of Child and Adolescent Psychiatry, University Hospitals Case Medical Center, 10524 Euclid Avenue, Cleveland, OH 44106, USA

Juan-Carlos Gómez, Psychosis Global Development Team, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA

Paul Grof, Mood Disorders Center of Ottawa, Smyth Medical Building, 1929 Russell Road, Ottawa, ON K1G 4G3, Canada

Heinz Grunze, Academic Psychiatry, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE46BE, UK

Ioline Henter, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Nathan Herrmann, Department of Psychiatry, Faculty of Medicine, Sunnybrook Health Sciences Center, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada

Onur N. Karayal, Pfizer Inc., 235 East 42nd Street, New York, NY 10017, USA

A.E. Koukopoulos, Azienda Ospedaliera Sant’Andrea, Università La Sapienza Roma, Rome, Italy

Athanasios Koukopoulos, Centro Lucio Bini Roma, 42, Via Crescenzio, 00193 Rome, Italy

Mauricio Kunz, Department of Psychiatry, Mood Disorders Centre, University of British Columbia, Vancouver, Canada

David Latov, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Rodrigo Machado-Vieira, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

Susan L. McElroy, Lindner Center of HOPE, Mason and Department of Psychiatry, and Behavioral Neuroscience University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA

Roger S. McIntyre, Departments of Psychiatry and Pharmacology and Institute of Medical Science, University of Toronto; Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto M5T 2S8, Canada

Andrea Murru, Barcelona Bipolar Disorders Program, IDIBAPS, Institute of Neurosciences, Hospital Clinic, 08036 Barcelona, Spain

David J. Muzina, Department of Psychiatry and Psychology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA

Alessandra Nivoli, Bipolar Disorders Program, Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS-CIBERSAM, Villarroel 170, Barcelona 08036 Catalonia, Spain

Willem A. Nolen, Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Svante Nyberg, Neuroscience TA, AstraZeneca R&D, Södertälje, Sweden

Elizabeth Pappadopulos, Department of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY 11004, USA

Robert M. Post, The George Washington University, 5415 West Cedar Lane, Suite 201B, Bethesda, MD 20814, USA

Zoltán Rihmer,, Department of Clinical and Theoretical Mental Health, and Department of Psychiatry and Psychotherapy, Semmelweis University, Faculty of Medicine, Budapest, Hungary.

Martha Sajatovic, Department of Psychiatry, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, 10524 Euclid Avenue, Cleveland, OH 44106, USA

G. Sani, Azienda Ospedaliera Sant’Andrea, Università La Sapienza Roma, Rome, Italy Mogens Schou, Deceased prior to the publishing of the 2nd edition of this book

Thomas L. Schwartz, Treatment Resistant Depression and Anxiety Disorders Program, SUNY Upstate Medical University, Syracuse NY 13210, USA

Kenneth I. Shulman, Department of Psychiatry, Faculty of Medicine, Sunnybrook Health Sciences Center, University of Toronto, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada

J.S. Seo, Stanford School of Medicine, Stanford University Medical Center, 291 Campus Drive MC 5216, Stanford, CA 94305-5101, CA, USA

G. Serra, Azienda Ospedaliera Sant’ Andrea, Universitä La Sapienza Roma, Rome, Italy

Vivek Singh, Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio TX 78229-3900, USA

Stephen M. Stahl, Department of Psychiatry, University of California San Diego, 9500 Gilman Drive # 9116-A, La Jolla, CA 92093-9116-A, USA; Department of Psychiatry, University of Cambridge, Cambridge, UK

Trisha Suppes, VA Palo Alto Health Care System, Palo Alto; Stanford University Medical Centre, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA

Alan C. Swann, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, 1300 Moursund Street, Houston TX 77030, USA

Tiffany Thomas, Division of Child and Adolescent Psychiatry, University Hospitals Case Medical Center, 10524 Euclid Avenue, Cleveland, OH 44106, USA

Mauricio Tohen, Department of Psychiatry, Division of Mood and Anxiety Disorders, University of Texas Health Science Centre at San Antonio, 7730 Floyd Curl Drive, San Antonio, TX 78229, USA

Marc L.M. van der Loos, Department of Psychiatry, Isala Klinieken, Location Sophia, Zwolle, The Netherlands

Eduard Vieta, Bipolar Disorders Program, Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS-CIBERSAM, Villarroel 170, Barcelona 08036, Catalonia, Spain

Cristina Wheeler-Castillo, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

H. Yang, Stanford School of Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA

Lakshmi N. Yatham, UBC Department of Psychiatry, UBC Hospital, The University of British Columbia, 2255 Wesbrook Mall, Vancouver BC V6T2AI, Canada

Boghos I. Yerevanian, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

Carlos A. Zarate, Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA

F. Zazzara, Centro Lucio Bini Roma, 42, Via Crescenzio, 00193 Rome, Italy

Preface to the Second Edition

Although few new drugs have been introduced since the first edition of this book five years ago, the field of bipolar pharmacotherapy has grown sober and hopefully wiser. With the FDA approval of new indications for existing agents, we actually have an embarrassment of riches.

The generation of the senior editor, who started practicing in the early 1970s, had only lithium, the sole agent approved by the FDA specifically for the treatment of what was then called manic-depressive illness. And in a sense we were lucky because we had many years to learn how best to use this agent for the prophylaxis of the disruptive mood episodes of patients with this devastating condition. There was great enthusiasm, even though there were then very few clinical centers in North America where lithium was prescribed. The enthusiasm was due to the fact that lithium was – and still is – a very special agent, at that time unlike any other in our field. We had to follow strict protocols for its use and limit it largely to those who had the ‘classical’ presentations of the illness. Lithium helped ‘medicalize’ psychiatry because one had to be a well-trained physician to use it properly. Although some patients who were misinformed about the dangers of lithium shunned this product (just like some psychiatrists), many more wanted to have a therapeutic trial. Thus, it became a sign of prestige to be offered a trial with this ‘miraculous’ agent. Part of the mystique was that it was not a drug – it was a natural product. Unfortunately, it is not free of risk: despite proper work-up and expert follow-up, 25 years later a very small minority of patients may develop kidney or thyroid dysfunction. We, nonetheless, continue to believe that even with the availability of newer agents every bipolar patient, properly screened, needs to be evaluated for the benefits of a properly conducted lithium trial. With the publication of systematic long-term data from the BALANCE study in the UK (Lancet 375:385–395,2010), sceptics have been reminded of the benefits of lithium.

The anticonvulsant agents that are psychoactive with ‘mood stabilizing’ properties have been widely studied and were the first agents to provide an alternative to lithium, either as monotherapy or in combination with lithium. Although ‘polypharmacy’ has gained a bad reputation, it has become the standard in the treatment of many diseases such as hypertension and epilepsy: these conditions have indeed served as a model for combination therapy in psychiatry. Combination therapy has actually raised bipolar psychopharmacotherapy into an art form in the hands of experts, and we have therefore devoted a chapter to extensive coverage of its proper application. Mood and bipolar clinics nowadays depend on such experts to supervise the work of young psychiatrists. One can say that bipolar clinics have helped to make bipolarity a psychiatric subspecialty – almost. Such clinics conduct research not only on pharmaceutical aspects, but also on biomarkers of clinical response, as well as long-term observational studies of patient cohorts, and the development of psychoeducational and innovative psychotherapies specifically geared for bipolar disorder.

Enter the atypical antipsychotics, the main class of agents introduced in the last decade for bipolar disorder. Classical neuroleptics were very effective for acute mania, in fact they were the first pharmacological agents used in the treatment of bipolar mania over 60 years ago, but extrapyramidal, endocrine as well as depressive side effects limited their use. They can, however, still be used in selected patients, especially for acute treatment and in the elderly. That is why atypical antipsychotics have been welcomed in clinical practice, even though they are not entirely free of the limitations of the neuroleptics – and most bring their own liabilities in terms of metabolic side effects.

This edition builds on the comprehensive scope of the first edition in that we cover different classes of agents as well as different populations, namely children, women, and older patients. In view of major recent advances in atypical agents, each (including Clozapine) is now covered in a separate chapter, and the newer agents (including Asenapine) have been added to our coverage in separate chapters. A unique feature of this edition is the two chapters devoted to the pharmacological treatment of mixed states and rapid cycling, the forms of bipolar disorder which are all too common in current practice and often challenging for the patient, family, and psychiatrist. Although the use of antidepressants remains controversial in bipolar disorder, and certainly antidepressant monotherapy in bipolar illness is generally contra-indicated, in practice they are not infrequently combined with mood-stabilizing agents; for this reason a chapter meticulously summarizing the pros and cons of antidepressant use in bipolar disorder graces this new edition. We are also pleased that a team of clinical scientists from the National Institute of Mental Health, Bethesda, brings to this edition the latest expertise in novel and experimental approaches to the treatment of bipolarity.

As in the first edition – which also appeared in Spanish (2007) and Turkish (2009) – our monograph devoted to bipolar pharmacotherapy opens with a chapter on the scope of bipolar disorders from clinical and epidemiologic-public health perspectives. Suicide prevention, the major evidence for which comes from Hungary which has pioneered this field, is also described from such a dual perspective. We conclude with an expanded and extensively revised chapter on the principals of caring for bipolar patients and their families in a mood (bipolar) clinic; this chapter extends beyond the chapter on psychoeducation to weave, in association with the individual pharmacotherapy chapters, an even broader integrative philosophy of care for bipolar patients than in the first edition. The substantive advances in bipolar psychopharmacotherapy in the last five years have caused the book to grow from 19 to 25 chapters, which cover essentially all efficacious treatments for bipolar disorder with the exception of electroconvulsive and stimulation-modulation therapies.

We thank the staff at Wiley-Blackwell, in particular, Joan Marsh, who closely worked with the editors and the authors to achieve these goals. Nearly all authors represent pioneers, from both industry and academia, in the development of the individual drugs or therapeutic topics or modalities covered in this book. We sorely miss the late Mogens Schou who opened, with his ground-breaking research, one of the most glorious pages in the history of psychopharmacotherapy with his extensive research on lithium. For this reason the new edition has a dedication to him and the late Professor Pierre Deniker (who, with Jean Delay), led the introduction of Chlorpromazine, the first neuroleptic, into psychiatry.

We believe that the best weapon against the stigma of mental illness is research and the development of efficacious treatments for which this book stands as witness. We believe that drug development can improve further with synergistic efforts of scientists from industry and academia. Allies in this battle are the patients themselves, their families, and the clinical professionals privileged to care for them. This book is dedicated to them as well.

Hagop AkiskalMauricio Tohen

CHAPTER 1 The Scope of Bipolar Disorders

Hagop S. Akiskal

University of California at San Diego, CA, USA

1.1 DIAGNOSTIC AND PUBLIC HEALTH ASPECTS

Recent advances in the epidemiology, psychopathology, and pharmacotherapy of bipolar disorders have led to a greater recognition of this illness in all of its varieties (Akiskal et al., 2000; Maj et al., 2002; Goodwin and Jamison, 2007). The lifetime risk for bipolar conditions is about 1% for the core (bipolar I) phenotype, making it at least equal in prevalence to schizophrenia. A higher percentage of acute psychiatric hospital admissions is now being assigned to the category of mania, and recognition of clinically attenuated outpatient forms of the illness (soft bipolar spectrum) is increasing. The latter (Bipolar II and beyond) is now estimated to be at least three to four times more prevalent than bipolar I (Angst et al., 2003; Judd and Akiskal, 2003; Hirschfeld et al., 2003); the current US prevalence of bipolar spectrum disorders, including bipolar I, is estimated at 4–5% (Merikangas et al., 2007).

Reasons for the current focus on the entire diagnosable range of bipolar conditions are several. Predominant among these is the tendency of diagnostic practice to follow the availability of effective treatment modalities (Lehmann, 1969). After the discovery of chlorpromazine, North American psychiatrists were tacitly encouraged to elicit subtle degrees of formal thought disorder from their patients so as to bring them the benefits of this new class of drugs. By the early 1970s, schizophrenia had become more or less synonymous with psychosis. With the advent of lithium carbonate treatment and its well-documented efficacy for bipolar disorders, this trend became reversed in favor of bipolar disorders. Beginning with DSM-III (American Psychiatric Association, 1980), the concept of schizophrenia has been largely restricted to a core group of deteriorating psychotic disorders, while mood disorders have been broadened to include even those with mood-incongruent psychotic features that may or may not coincide with affective episodes. This diagnostic approach reflects more than just therapeutic fashion; it is supported by familial aggregation, course, and outcome (Akiskal, 2002). Available evidence indicates that mood disorders are often recurrent and, especially in bipolar conditions, can lead to considerable impairment in developmental, conjugal, and social spheres. The public health significance of bipolar disorder is summarized in Table 1.1. The most important of these is suicide, seen in as many as 20% of those who receive inadequate or no

Table 1. 1 Public health aspects of bipolar disorder.

Lifelong cyclical illness1.0–1.5% of populationPeak onset 15–30 years5–10 year delay in correct diagnosisFrequent hospitalizationRepeated hospitalizationRepeated conjugal disruption: promiscuityRepeated job change/lossFinancial disastersAlcohol/substance abuse50% nonadherence to medicationIncreased cardiovascular mortalitySuicide (highest within 10 years of illness onset)

treatment, and must be considered a preventable complication (Khuri and Akiskal, 1983; Akiskal, 2007). It now appears that bipolar II may account for a disproportionately large portion of suicidal morbidity and mortality among bipolar disorders (Rihmer et al., 1990; Rihmer and Pestality, 1999; Akiskal, 2007), emphasizing the importance of early and accurate diagnosis.

At the “softest” end of the spectrum, milder degrees of bipolar disorder – subsumed under the rubrics of cyclothymic disorder (Akiskal et al., 1977) and bipolar disorder not otherwise specified – are now categorized as mood disorders rather than being grouped with neurotic or personality disorders. Although these seemingly attenuated and “atypical” variants may not be easily distinguishable from nonaffective personality disorders, the clinician is advised to err on the side of affective diagnosis because of treatment implications, including their potential to engage in suicidal acts (Azorin et al., 2010).

External validating strategies – such as family history, course, and inter-episodic temperamental features – are often necessary to confirm the diagnosis of the bipolar spectrum (Akiskal, 2003). The most established of bipolarity beyond classic mania and bipolar I (Akiskal, 1999) is the bipolar II type, so-named originally by Dunner, Gershon, and Goodwin (1976). Like diabetes type II, its onset is often insidious, but its ravages no less devastating than that of the psychotic forms of the illness. This is particularly true for cyclothymic depression, a variant of bipolar II we have termed bipolar II½ (Akiskal et al., 2006), arising from a cyclothymic temperament, it pursues an unstable course; and is likely to be misdiagnosed as axis II cluster B (Akiskal, 2004). These patients represent the “dark side” of bipolarity (Akiskal, Hantouche, and Lancrenon, 2003; Hantouche, Angst, and Akiskal, 2003).

The American Psychiatric Association Diagnostic Manual of Mental Disorders, even in its last published edition (DSM-IV, 2000), does not recognize hypomanic or manic switches occurring during pharmacotherapy, electroconvulsive therapy, phototherapy, and sleep deprivation as indicators of bipolar disorder. These patients are obviously not unipolar MDD, nor are they classified under bipolar NOS. Therefore, this common clinical phenomenon is voted by the DSM Committee out of existence. Since at least 1983, there has been good evidence that such switching of antidepressants requires bipolar family history (Akiskal et al., 2000; Akiskal, Hantouche, and Lancrenon, 2003). They are best regarded as less penetrant forms of bipolar disorder (bipolar III). Diagnostic studies of depressive states with mood swings in the setting of multiple drug abuse, particularly that of stimulants, is controversial, but we contend that many of these individuals belong to a provisional bipolar type III-½ (Akiskal and Pinto, 1999; Maremmani et al., 2003; Camacho and Akiskal, 2005). This is relevant in a book on advances in bipolar disorder, because many of these patients respond favorably to anticonvulsant mood stabilizers. Finally, I would like to mention bipolar type IV, which refers to individuals who develop depression later in life from a lifelong background of hyperthymic temperament (hypomanic traits without clear cut episodes); their bipolar status might be inferred from familial bipolarity (Cassano et al., 1992). It is uncertain how DSM-V in progress will deliberate on the status of bipolar spectrum disorders. Suffice it to say that their public health significance (that is,, early diagnosis and treatment) warrants a more appropriate nosological designation than the inglorious dumping ground of “bipolar NOS.”

In a French national study (see Table 1.2), 65% of all major depressions belonged to the bipolar spectrum, of which the most prevalent were the bipolar II and II½ phenotypes (Akiskal et al., 2005b, 2006). These considerations are important, because nearly all pharmacologic treatments covered in this book – certainly those approved by regulatory bodies – pertain to bipolar I. Thus, there is a wide gap between the psychopharmacology of bipolar disorder and the public health significance of the phenotypes observed in the community and the clinic.

Lithium was the first specific agent for bipolar disorder for clinical use. This was four decades ago. Many other agents have been approved since then, almost all of them in the last decade. They are all covered in this book. Lithium medicalized psychiatry in bringing significant attention to the course of bipolar disorder. Its importance should not be overshadowed by these new developments. Many patients, especially those in the “core” classic form of the illness (mania-depression free interval type, (Koukopoulos et al., 1995; Goodwin and Jamison, 2007)), do respond to lithium. Its judicious use, often in combination with other agents in rational polypharmacy, requires intimate knowledge of its physiological and medical characteristics. Regrettably, young psychiatrists are not

Table 1.2 Bipolar spectrum subtypes in the French EPIDEP study (n = 493): validation by bipolar family history.

 N%Bipolar I418.4Bipolar II6112.4Bipolar II-½16433.5Bipolar III285.7Bipolar IV224.5Total31964.5

Akiskal et al., J Affect Disord, 2005b.

having adequate experience with this agent. A summary of the medical workup of patients in preparation of lithium use (see Akiskal, 1999) is given in Appendix 1.A.

1.2 PSYCHOLOGICAL AND SOCIAL ASPECTS

The long term, essentially life-long, nature of bipolar disorder, and its vicissitudes dictate continuity of treatment and long-term caring. To solve practical problems in the patients’ lives requires caring that goes beyond medications and psychotherapy, to include the family, significant others, and the community.

Bipolar disorder continues to be poorly understood by both the public and doctors. More often than not, a bipolar child is classified as having conduct disorder or ADHD (Dilsaver, Henderson-Fuller, and Akiskal, 2003). A teenager’s suicide attempt is mis-attributed to problems of the heart, adolescent crisis, or substance abuse; promiscuous behavior is blamed on early “sexual abuse.” Bipolar patients from time to time describe their parents as “monsters” or “emotionally-abusive,” which some psychotherapists accept on blind faith without ever talking to the parents or significant others. Bipolar II patients are often diagnosed as unipolar and/or borderline personality (Akiskal, 2004), treated with antidepressant without mood stabilizers, resulting in tragic aggravation of the course of the illness (Akiskal and Mallya, 1987; Akiskal et al., 2005a). Excessive spending or squandering of one’s economic resources and pathological generosity may lead to financial ruin before bipolarity is considered.

Polls of members of the Depressive and Manic-Depressive Association in the U.S. have shown a latency of 10 years from the onset of symptoms until the correct diagnosis of bipolar disorder (Hirschfeld, Lewis, and Vornik, 2003). Early diagnosis is critical, because suicide in bipolar patients often occurs within this early period. The comfort, support, destigmatization, information, and advocacy provided by such a conglomeration of patients, families, and community leaders (many of whom are themselves bipolar) represents a novel approach in the rehabilitation of the bipolar patient into society. This is a humane and just cause.

Given that a proportion of bipolar individuals have artistic and leadership talents (Akiskal and Akiskal, 1988), sophisticated clinical management of bipolarity can potentially safeguard the adaptive capacity and contributions that gifted bipolar people provide to society. Although psychotically ill (bipolar) patients are represented in the media as being creative, this is a destigmatization campaign at best and glamorizing madness at worst. Achievement and creativity are attributes of the “softer” spectrum represented in the attenuated temperamental expressions of bipolarity often involving and extending into bipolar II (Akiskal and Akiskal, 1988, 2005).

To what extent cognitive dysfunction in bipolar illness precedes clinical onset is not entirely settled. Nor is it known how it specifically impacts functioning and creativity. These are new vistas of scientific investigation (Torres et al., 2010; Frangou, 2009; Germana et al., 2010; Giakoumaki et al., 2010). Goodwin and Jamison (2007), based on animal studies, raise the possibility that early treatment with certain agents used in bipolar disorder might increase neuronal growth and thereby contribute to better cognitive functions. This is an open field of investigation for the next generation of neuroscientists and psychopharmacologists in this area (Burdick et al., 2007; Goldberg and Chengappa, 2009).

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

APPENDIX 1.A: LABORATORY CONSIDERATIONS IN THE CLINICAL USE OF LITHIUM

More than any other development, the introduction of lithium has emphasized the role of physicianship in psychiatry. The scientific literature and clinical wisdom on the therapeutic aspects of this salt have been well summarized in a monograph by Jefferson et al. (1983). The success of lithium treatment is dependent on the thoroughness of the initial workup, on dosage titration procedures, and on appropriate monitoring throughout therapy.

The type of workup depends on the age of the patient and concurrent medical conditions (Table 1.3). In young (less than 40 years), physically healthy subjects, preparation for lithium therapy should include medical history (especially focused on neurologic, renal, cardiac, gastrointestinal, endocrine, and cutaneous systems), physical examination, and laboratory evaluation focusing on electrolytes and thyroid. In older patients or those with a history of cardiac disease, a baseline electrocardiogram (EKG) should be obtained and an electroencephalogram (EEG) performed if brain disease is suspected; if there is a history of renal disease, thorough evaluation of baseline kidney function is mandatory. Given rigorous indications for lithium, major medical illness, and abnormalities in laboratory indices do not necessarily contraindicate its use; they do dictate, however, greater medical vigilance, including frequent determination of blood levels and use of lower doses.

Table 1.3 Recommended laboratory workup of patients considered for lithium therapy.

Healthy <40 yearsAll othersWeightEKGCBCEEGT4/TSHTRH testFBS/serum electrolytes24-h urine volumeUrinalysisUrine concentration testBUN/creatinineCreatinine clearance

A short-term lithium trial in the controlled environment of a hospital is relatively easy to administer and is recommended for acutely manic, medically ill, or elderly subjects. In outpatient practice, the physician must make sure that the patient and significant others understand the importance of adherence to periodic laboratory procedures and monitoring of side effects.

Lithium is rapidly and completely absorbed from the gastrointestinal tract and peaks in the serum in about 1.5–2.0 (standard preparation) or 4.0–4.5 hours (slow release preparation), depending on age. Its half-life varies from 24 to 36 hours; steady state is reached in about four days. Lithium is not protein-bound and is excreted unchanged almost entirely through the kidneys. It can be safely combined with most classes of drugs except diuretics and nonsteroidal anti-inflammatory agents (other than aspirin), which tend to increase the serum lithium level.

Acutely manic- and possibly bipolar depressive-patients have a high tolerance for lithium and preferentially retain it during the first 10 days while excreting sodium; a regular diet is recommended. Postpubertal bipolar patients, who typically have excellent glomerular function, require higher doses to achieve the same level of equilibrium in the serum. The reverse is true in the geriatric age group. Elderly subjects with adequate glomerular function can benefit considerably from judicious lithium use. However, greater medical vigilance is required for this group; initial doses should be low (150–300 mg/day), with frequent clinical and laboratory monitoring to maintain blood levels in the lower range (0.3–0.8 mEq/l). Special attention must be paid to signs of sinus node dysfunction (bradycardia) or neurotoxicity; the latter is particularly likely in patients with concurrent neurologic disease or sedative and alcohol abuse.

In healthy subjects who achieve good episode prevention, quarterly serum levels (12 hours after the last dose) and serum creatinine are generally sufficient; thyroid indices must be obtained at least once a year. For elderly or medically compromised patients, laboratory tests should be repeated as dictated by the medical condition, with frequent serum lithium levels; the dosage should be kept at the lowest possible level compatible with prophylaxis.

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CHAPTER 2 Lithium Treatment: Focus on Long-Term Prophylaxis

Paul Grof and Mogens Schou