Table Of ContentMilestones in Drug Therapy
MDT
Series Editors
Prof. Dr. Michael J. Parnham PhD Prof. Dr. J. Bruinvels
Director of Preclinical Discovery Sweelincklaan 75
Centre of Excellence in Macrolide Drug Discovery NL-3723 JC Bilthoven
GlaxoSmithKline Research Centre Zagreb Ltd. The Netherlands
Prilaz baruna Filipovića 29
HR-10000 Zagreb
Croatia
Bipolar Depression:
Molecular Neurobiology, Clinical
Diagnosis and Pharmacotherapy
Edited by Carlos A. Zarate Jr. and Husseini K. Manji
Birkhäuser
Basel . Boston . Berlin
Editors
Carlos A. Zarate Husseini K. Manji
Mood Disorders Research Unit Laboratory of Molecular Pathophysiology
Laboratory of Molecular Pathophysiology National Institute of Mental Health
National Institute of Mental Health Porter Neuroscience Research Center
Mark O. Hatfield Clinical Research Center Building 35, Room 1C-917
Unit 7SE, Rm. 7-3445 36 Convent Drive, MSC 3711
10 Center Drive Bethesda, Maryland 20892
Bethesda, Maryland 20892 USA
USA
Advisory Board
J.C. Buckingham (Imperial College School of Medicine, London, UK)
R.J. Flower (The William Harvey Research Institute, London, UK)
A.G. Herman (Universiteit Antwerpen, Antwerp, Belgium)
P. Skolnick (DOV Pharmaceuticals Inc., Hackensack, NJ, USA)
Library of Congress Control Number: 2008935771
Bibliographic information published by Die Deutsche Bibliothek
Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed
bibliographic data is available in the internet at http://dnb.ddb.de
ISBN: 978-3-7643-8566-8 Birkhäuser Verlag AG, Basel – Boston – Berlin
The publisher and editor can give no guarantee for the information on drug dosage and administration
contained in this publication. The respective user must check its accuracy by consulting other sources of
reference in each individual case.
The use of registered names, trademarks etc. in this publication, even if not identified as such, does not
imply that they are exempt from the relevant protective laws and regulations or free for general use.
This work is subject to copyright. All rights are reserved, whether the whole or part of the material
is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation,
broadcasting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of
use, permission of the copyright owner must be obtained.
© 2009 Birkhäuser Verlag AG, P.O. Box 133, CH-4010 Basel, Switzerland
Part of Springer Science+Business Media
Printed on acid-free paper produced from chlorine-free pulp. TFC ∞
Printed in Germany
ISBN 978-3-7643-8566-8 e-ISBN 978-3-7643-8567-5
9 8 7 6 5 4 3 2 1 www. birkhauser.ch
V
Contents
List of contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI
Section A:Bipolar depression:Clinical phenotype and course of illness
Andreas Marneros
The historyof bipolar disorders ............................... 3
Gordon B. Parker and Kathryn Fletcher
Theclinical diagnosis of bipolar depression ..................... 17
Tamas Treuer and Mauricio Tohen
Course and outcome of bipolar disorder – focusing on depressive
aspects .................................................. 29
Zoltán Rihmer
Suicide and bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Section B:Bipolar depression:Neurobiology
Thomas G.Schulze and Francis J. McMahon
The genetic basis of bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Jun-Feng Wang and L. Trevor Young
Understanding the neurobiology of bipolar depression . . . . . . . . . . . . . 77
Wallace C. Duncan,Jr
Non-pharmacological treatments and chronobiological aspects of
bipolar disorder:implications for novel therapeutics . . . . . . . . . . . . . . 95
Jonathan Savitz and Wayne C. Drevets
Neuroimaging studies of bipolar depression:therapeutic implications . 117
VI Contents
Section C:Acute and long-term treatment of bipolar disorder
Gary S. Sachs,Louisa G. Sylvia and Hannah G. Lund
Pharmacological treatment of acute bipolar depression . . . . . . . . . . . . 147
Keming Gao,David E. Kemp and Joseph R. Calabrese
Pharmacological treatment of the maintenance phase of bipolar
depression:focus on relapse prevention studies and the impact
ofdesign on generalizability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Harold A. Sackeim
Non-pharmacological somatic treatments for bipolar depression . . . . . 179
Carlos A. Zarate Jr and Husseini K. Manji
Potential novel treatments for bipolar depression . . . . . . . . . . . . . . . . . 191
Section D:Treatment of bipolar disorder in special populations
John L. Beyer and K. Ranga R. Krishnan
Late-onset bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Robert L. Findling
Treatment of childhood-onset bipolar disorder ................... 241
Patricia Roy and Jennifer L. Payne
Treatment of bipolar disorder during and after pregnancy . . . . . . . . . . 253
Carlos A. Zarate Jr and Husseini K. Manji
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
VII
List of contributors
John L. Beyer, Duke University Medical Center, Durham, NC 27710, USA;
e-mail:[email protected]
Joseph R. Calabrese, Department of Psychiatry, Bipolar Disorder Research
Center in Mood Disorders Program, University Hospitals Case Medical
Center,Case Western Reserve University School of Medicine,10524 Euclid
Avenue,12th Floor,Cleveland,Ohio 44106,USA; e-mail:joseph.calabrese@
uhhospitals.org
Wayne C. Drevets,Section on Neuroimaging in Mood and Anxiety Disorders,
NIH/NIMH DIRP,15K North Dr.,Bethesda,MD 20892,USA
Wallace C. Duncan, Mood and Anxiety Disorders Program, National Institute
of Mental Health,Bethesda,Maryland 20892,USA
Robert L. Findling, Department of Psychiatry, University Hospitals Case
Medical Center, 10524 Euclid Avenue, Cleveland, Ohio 44106, USA;
e-mail:[email protected]
Kathryn Fletcher, School of Psychiatry, University of New South Wales,
Sydney,NSW 2031,Australia; e-mail:[email protected]
Keming Gao, Department of Psychiatry, Bipolar Disorder Research Center in
Mood Disorders Program, University Hospitals Case Medical Center, Case
Western Reserve University School of Medicine,10524 Euclid Avenue,12th
Floor,Cleveland,Ohio 44106,USA; e-mail:[email protected]
David E. Kemp,Department of Psychiatry,Bipolar Disorder Research Center
in Mood Disorders Program, University Hospitals Case Medical Center,
Case Western Reserve University School of Medicine, 10524 Euclid
Avenue, 12th Floor, Cleveland, Ohio 44106, USA; e-mail: kemp.david@
gmail.com
K. Ranga R. Krishnan,Duke University Medical Center,Durham,NC 27710,
USA
Hannah G. Lund, Bipolar Clinic and Research Program, Massachusetts
General Hospital,50 Staniford St,Suite 580,Boston,MA 02114,USA
Husseini K. Manji, Laboratory of Molecular Pathophysiology, National
Institute of Mental Health, Porter Neuroscience Research Center, Building
35, Room 1C-917, 36 Convent Drive, MSC 3711, Bethesda, Maryland
20892,USA; e-mail:[email protected]
Andreas Marneros, Klinik und Poliklinik für Psychiatrie, Psychotherapie und
Psychosomatik, Martin-Luther-Universität Halle-Wittenberg, 06097 Halle,
Germany; e-mail:[email protected]
Francis J. McMahon, Unit on the Genetic Basis of Mood and Anxiety
Disorders, Mood & Anxiety Disorders Program, National Institute of
VIII List of contributors
Mental Health, National Institutes of Health, Dept. of Health & Human
Services,Bethesda,MD 20892,USA
Gordon B. Parker, Black Dog Institute, Prince of Wales Hospital, Sydney,
NSW 2031,Australia; e-mail:[email protected]
Jennifer L. Payne,Johns Hopkins School of Medicine,550 N. Broadway,Suite
305,Baltimore,MD 21205,USA; e-mail:[email protected]
Zoltán Rihmer, Department of Clinical and Theoretical Mental Health, and
Department of Psychiatry and Psychotherapy, Semmelweis Medical
University, Kútvölgyi Clinical Centre, Kútvölgyi út 4, 1125 Budapest,
Hungary; e-mail:[email protected]
Patricia Roy,Johns Hopkins School of Medicine,550 N. Broadway,Suite 305,
Baltimore,MD 21205,USA; e-mail:[email protected]
Gary S. Sachs, Bipolar Clinic and Research Program, Massachusetts General
Hospital, 50 Staniford St, Suite 580, Boston, MA 02114, USA; e-mail:
[email protected]
Harold A. Sackeim, 4 Grant’s Path, Poughquag, NY 12570, USA; e-mail:
[email protected]
Jonathan Savitz, Section on Neuroimaging in Mood and Anxiety Disorders,
NIH/NIMH DIRP, 15K North Dr., Bethesda, MD 20892, USA; e-mail:
[email protected]
Thomas G. Schulze, Unit on the Genetic Basis of Mood and Anxiety
Disorders, Mood & Anxiety Disorders Program, National Institute of
Mental Health, National Institutes of Health, Dept. of Health & Human
Services,Bethesda,MD 20892,USA; e-mail:[email protected]
Louisa G. Sylvia, Bipolar Clinic and Research Program, Massachusetts
General Hospital,50 Staniford St,Suite 580,Boston,MA 02114,USA
Mauricio Tohen,Lilly Research Laboratories,Indianapolis IN 46285; McLean
Hospital, Harvard Medical School, Belmont MA 02184, USA; e-mail:
[email protected]
Tamas Treuer, Lilly Hungaria Kft., Madacs Imre u. 13–14, 1075 Budapest,
Hungary; e-mail:[email protected]
Jun-Feng Wang, Department of Psychiatry, University of British Columbia,
2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1; e-mail:
[email protected]
L. Trevor Young, Department of Psychiatry, University of British Columbia
2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1; e-mail:
[email protected]
Carlos A. Zarate, Mood Disorders Research Unit, Laboratory of Molecular
Pathophysiology, National Institute of Mental Health, Mark O. Hatfield
Clinical Research Center, Unit 7SE, Rm. 7-3445, 10 Center Drive,
Bethesda,Maryland 20892,USA; e-mail:[email protected]
IX
Acknowledgements
The editors gratefully acknowledge the contributions of our book project coor-
dinator, Ioline Henter. Her editing abilities, organizational assistance, and
attention to detail were integral to the preparation of this volume. We also wish
to acknowledge the support of Detlef Klüber and his colleagues at Birkhäuser
Publishing, who accepted our delays with good-natured patience, and whose
professionalism made them a pleasure to work with. Our thanks also go out to
the research staff of the 7 Southeast Unit and the Outpatient Clinic at the
National Institute of Mental Health (NIMH-NIH).
XI
Foreword
Bipolar disorder is a major public health problem,a reality reflected in its posi-
tion as the sixth leading cause of disability worldwide in 15 to 44-year olds –
the age range most associated with the onset of the disorder. Two-thirds of this
disability can be traced to the depressive phase of the disorder. While it is
beyond question that treatments for the depressive phase of bipolar disorder
represent the major unmet need for patients with bipolar disorder and their cli-
nicians alike,it is striking how out of balance the medication development for
this disorder has been. With one exception, every drug developed for bipolar
disorder has entered the market as a treatment for acute mania,so that we now
havenearly a dozen agents proven to work for this indication.
What proven treatments do we have for bipolar depression? There are two
with FDA indications for the acute treatment of bipolar depression, but only
one of them is a drug,the other being a combination of two drugs marketed in
asingle pill. The one monotherapy that has been proven to the satisfaction of
regulatory agencies is quetiapine, and yet, in spite of its ability to separate
from placebo in its effect on core depressive symptoms,the size of the overall
quetiapine effect in bipolar depression comes substantially from its ability to
improvesleepand reduce anxiety.
What about monotherapies that can prevent or attenuate new episodes of
depression when used as maintenance treatments? One agent – lamotrigine –
is effectivein reducing the time to intervention for new episodes of depression
among patients with bipolar disorder studied following remission from acute
mania or acute depression; in addition,the older maintenance data on lithium
suggest that that drug has at least a moderate ability to prevent or attenuate
depressive episodes. Placebo-controlled “maintenance” studies of olanzapine
and aripiprazole monotherapy show that the great bulk of the difference
between drug and placebo occurs in the continuation phase of treatment,i.e. in
the first few months after a manic episode (primarily by preventing relapse
back into the index manic episode). However, the ability of any atypical
antipsychotic to prevent or attenuate new episodes of depression has not yet
been established.
What about the host of “traditional” antidepressants – both the older tri-
cyclic and MAO inhibitor classes and the newer “second-generation” SSRIs,
SNRIs, bupropion and a few others? None of these “traditional” antidepres-
sants has ever been FDA-approved for bipolar depression. Indeed,in all of the
numerous large studies conducted in the process of registering these drugs as
antidepressants,patients with bipolar disorder were excluded. And recent large
randomized studies of patients with bipolar disorder in the depressive phase
