7468tpCast.indd 1 3/31/10 10:20:11 AM March22,2010 8:59 spi-b890 9inx6in b890-fm 7468tpCast.indd 2 3/31/10 10:20:13 AM Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. PHARMACOTHERAPY FOR DEPRESSION AND TREATMENT-RESISTANT DEPRESSION Copyright © 2010 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher. For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher. ISBN-13 978-981-4287-58-6 ISBN-10 981-4287-58-X Typeset by Stallion Press Email: [email protected] Printed in Singapore. XiaoLing - Pharmacotherapy for Depression.pm1d 8/2/2010, 6:21 PM March22,2010 8:59 spi-b890 9inx6in b890-fm IdedicatethisbooktomychildrenYanniandEllie. George IamextremelygratefultomywifeStefania andoursonGiovanni fortheirincrediblesupportofmywork. Maurizio March22,2010 8:59 spi-b890 9inx6in b890-fm March22,2010 8:59 spi-b890 9inx6in b890-fm About the Authors George I. Papakostas GeorgeI.PapakostasisAssociateProfessorofPsychiatryatHarvard MedicalSchoolandDirectorofTreatment-ResistantDepressionStu- diesintheDepartmentofPsychiatryatMassachusettsGeneralHos- pital in Boston, Massachusetts, USA. The focus of Dr. Papakostas’ researchincludesthepharmacotherapyofmajordepressivedisorder includingtreatment-resistantdepression,thestudyofthe“placebo” effectanditsrelevancetoclinicaltrialdesigninmajordepressivedis- order,andthestudyofclinicalandbiologicpredictors,moderators, and mediators of treatment outcome in major depressive disorder. Dr. Papakostas has received numerous national and international research awards from sources including the American College of Neuropsychopharmacology, the Collegium Internationale Neu- ropsychopharmacologium,theNewClinicalDrugEvaluationUnit of the National Institute of Mental Health, the American Psychi- atric Association, the World Federation of Societies of Biological Psychiatry, the American Academy of Clinical Psychiatrists, the InternationalCollegeofPsychosomaticMedicine,andtheAmerican FoundationforSuicidePrevention.Heistheauthororco-authorof over 150 clinical and scientific publications and book chapters, his publications appearing in prominent journals, including the Amer- ican Journal of Psychiatry, Biological Psychiatry, the Journal of Clinical Psychiatry,andthe JournalofClinicalPsychopharmacology. Heisalso ontheeditorialboardofthejournalPsychiatryResearch,andafield editorforpsychopharmacologyfortheWorldJournalofBiologicalPsy- chiatry.Dr.PapakostasisofteninvitedthroughouttheUnitedStates vii March22,2010 8:59 spi-b890 9inx6in b890-fm viii PharmacotherapyforDepressionandTreatment-ResistantDepression and abroad to lecture on a wide range of topics pertaining to the treatmentofdepression.Todate,hehasdeliveredmorethan100lec- turesatnationalorinternationalmeetingsinmorethan30countries. Dr. Papakostas attended Medical School at the New York University School of Medicine. He completed his residency in adult psychiatry at Massachusetts General Hospital and McLean Hospital, and a fellowship in Clinical Neuropsychopharmacology atMassachusettsGeneralHospitalthatwasfundedbytheAmerican CollegeofNeuropsychopharmacology. Maurizio Fava Dr.FavaobtainedhismedicaldegreefromtheUniversityofPadova School of Medicine, USA, and completed a residency training in endocrinologyatthesameuniversity.Aftercompletingaresidency traininginpsychiatryattheMassachusettsGeneralHospital(MGH), hehasbeenDirectoroftheMGHDepressionClinicalandResearch Programsince1990atthesamehospital.UnderDr.Fava’sdirection, the MGH Depression Clinical and Research Program has become oneofthemosthighlyregardeddepressionprogramsinthecountry. Dr.Favahasauthoredorco-authoredmorethan400originalarticles publishedinmedicaljournalswithinternationalcirculation.Hehas alsoeditedfivebooks,andpublishedmorethan50chaptersand500 abstracts. Dr. Fava is also a well-known national and international speaker,andhasalsobeentherecipientofmanyhonorsandawards. He is currently Executive Vice Chair for the MGH Department of Psychiatry, Executive Director, MGH Clinical Trials Network and Institute,andDirectoroftheMGHDepressionClinicalandResearch Program,andProfessorofPsychiatryatHarvardMedicalSchool. March22,2010 8:59 spi-b890 9inx6in b890-fm Preface Major depressive disorder (MDD) is a highly prevalent and, often, chronic illness, which has been shown to result in considerable patientsufferinganddistress,aswellassignificantdisability,mor- bidity and mortality. Despite more than half a century of intensive research, contemporary therapies for MDD demonstrate, at best, modestoverallefficacy,mostoftenresultingineitheracompletelack oforinsufficientsymptomimprovement.Inaddition,thetolerability profile of all contemporary pharmacotherapies for MDD, although greatlyimprovedsincetheirfirstappearanceinthemid-1950s,can oftencontributetopoortreatmentadherence,aswellaspatientdis- comfortanddisability.Furthermore,manypatientswhoexperience robustantidepressanteffectsmaystillsufferarelapseorrecurrence ofMDDshortlyafterthefulleradicationofsymptoms,anddespite full compliance with their treatment. As a result, patients with depressionoftendescribefeelingsasiftheyarecaughtinavicious cycle, with only brief periods of complete symptom recovery that arenotsufficientindurationtoallowforareturntothepre-morbid leveloffunctioning. When depression strikes, clinicians, patients, their families and their loved ones are on the front line. Supporting them are those working vigorously to enhance our ability to effectively treat depression: those working in academic clinical care and research centers, government sources including the National Institutes of Health, the pharmaceutical industry, as well as private donors and fundraisers. This book is intended as a review on the state of our knowledge regarding pharmacologic treatments for depres- sion. It is divided into four parts. The first three parts focus on ix