Clinical trials in psychopharmacology : a better brain

422 Pages·2010·1.662 MB·English

by  Hertzman, Marc, Adler, Lawrence

Clinical Trials in
Psychopharmacology
A Better Brain
SECOND EDITION
Editors
Marc Hertzman
Research Psychiatrist and formerly Professor of Psychiatry,
George Washington University, USA
Lawrence Adler
University of Maryland School of Medicine, USA

Clinical Trials in
Psychopharmacology
SECOND EDITION

Clinical Trials in
Psychopharmacology
A Better Brain
SECOND EDITION
Editors
Marc Hertzman
Research Psychiatrist and formerly Professor of Psychiatry,
George Washington University, USA
Lawrence Adler
University of Maryland School of Medicine, USA
Thiseditionfirstpublished2010
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LibraryofCongressCataloguing-in-PublicationData
Clinicaltrialsinpsychopharmacology:abetterbrain/editors,MarcHertzman,LawrenceAdler.–2nded.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-0-470-74076-7(cloth)
1.Psychopharmacology.2.Psychotropicdrugs.3.Clinicaltrials.I.Hertzman,Marc.II.Adler,Lawrence.
[DNLM:1.PsychotropicDrugs.2.ClinicalTrialsasTopic.QV77.2C64162010]
RM315.C5572010
615(cid:1).78–dc22
2009031413
ISBN:978-0-470-74076-7
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
Typesetin10.5/12.5ptTimesbyLaserwordsPrivateLimited,Chennai,India.
PrintedinSingaporebyMarkonoPrintMediaPteLtd
Firstimpression – 2010
Contents
Acknowledgments xi
Introduction xiii
List of Contributors xv
SECTION I: The Health Care Environment and Medications 1
1. FDA Reform: De´ja` vu Encore 3
JohnJ.Cohrssen
1.1 Introduction 4
1.2 The1992prescriptiondruguserfeeactaddsfundsandchangesFDA’sfocus 7
1.3 PDUFAshortensdrugreviewtimesandeliminatesthedruglag 8
1.4 PDUFAtimetablesfeedsafetyconcerns 9
1.5 FDArespondstosafetyconcerns 11
1.6 Thepipelineproblem 12
1.7 The2007FDAScienceBoard’sSubcommitteeonScience
andTechnologyreport 17
1.8 TheFDAAAof2007reauthorizePDUFAandprovidenewauthorityto
addresssafetyandthecriticalpathinitiative 18
1.9 TheimpactofPDFUAonFDA 21
1.10 Comparativemedicalbenefits,comparativeeffectivenessandFDA 21
1.11 FDAandnon-inferioritytrials 23
1.12 FDAandCMSdecisionsonMedicarecoverage 24
1.13 Preemption:FDA’sroleinrelationtoliabilitylitigationinstatecourts 24
1.14 FDA’sexclusivityinallowingaccesstoexperimentaldrugs 24
1.15 Conclusions 25
2. Do Antidepressants Cause Suicide? 31
MarcHertzman
2.1 Somedefinitionalproblems 31
vi CONTENTS
2.2 Abriefhistoryoftheconcernsofsuicidalitycausedbyantidepressants 32
2.3 Politicsrearsitsuglyhead 35
2.4 TheFDAresponds 35
2.5 Whatchangesinpublicpolicywrought 36
2.6 Afunnythinghappenedonthewaytotheforum 39
2.7 Meanwhilebackattheranch 39
2.8 Moral(maybe) 40
3. The Genome, Genes and Brain – Tailored Drugs 43
LawrenceAdler
3.1 Introduction 43
3.2 Issuesinnewdrugdevelopment 44
3.3 Earlydevelopmentofpsychiatricpharmaceuticalentities 44
3.4 Advancesinresearchtechnology 45
3.5 Reviewofgenetics 46
3.6 Activationofgenesbysignaltransductioncascades 47
3.7 Thehumangenome 48
3.8 Thesequencingofthegenome 48
3.9 DNAvariation 48
3.10 Genesandillness 49
3.11 Genomicfindings,potentialtargetsandnewdrugdevelopment 50
3.12 Conclusion 55
4. Patenting and Licensing Concerns in Psychiatric Genetics 61
JorgeA.Goldstein andKarenR.Markowicz
4.1 Geneticdiagnosesinpsychiatry 62
4.2 Theevolvingpatentlandscapeinpsychiatry 63
4.3 Approachestosolvingpotentialproblems 76
4.4 Conclusions 83
5. Women’s Issues in Clinical Trials 87
MaryV.Seeman
5.1 History 87
5.2 Perceivedadvantagesofexcludingwomen 90
5.3 Changeinperspective 90
5.4 Havethingschanged? 91
5.5 Progresssince1993 92
5.6 Reportedcurrentdifficultiesinincludingwomen 93
5.7 Contraceptioninclinicaltrials 94
5.8 Drugsinlactatingwomen 95
5.9 Howoftendowomentakedrugsduringpregnancy? 96
5.10 Ethicalissues:risk/benefitanalysis 96
CONTENTS vii
5.11 Adequateinformation 97
5.12 Adolescentwomen 97
5.13 Recruitmentandretentionofwomen 97
SECTION II: Clinical Trials and Mood Disorders 103
6. Issues and Clues in the Pharmacological Treatment of Mood
Disorders 105
FabriceJollant,Ade´laIonitaandPhilippeCourtet
6.1 Whatdoweknowaboutmooddisordersthatmayberelevantfortheir
pharmacologicaltreatment? 106
6.2 Aretherecluesforthepharmacologicaltreatmentofmooddisorders? 109
6.3 Perspectives 116
7. Bipolar Disorder 125
AlbertoBocchetta
7.1 Introduction 126
7.2 Trialsinacutemania 127
7.3 Trialsinacutebipolardepression 130
7.4 Trialsinmaintenanceofbipolardisorder 132
7.5 Whatisamoodstabilizer? 134
7.6 Whatcontrolledtrialscannottellusabouttreatmentofbipolardisorder 135
8. Special Issues of Research Methodology in Bipolar Disorder
Clinical Treatment Trials 149
RobertM.Post
8.1 Introduction 150
8.2 Efficacy–effectivenessgap 151
8.3 Trialsfordrugregistrationversusthosethataremostclinicallyinformative 151
8.4 Theneedfordesignsthatmoreoptimallyinformclinicalpractice 152
8.5 ‘Hidden’highdegreesoftreatmentresistance 153
8.6 Controversyaboutoptimaldesignsandratinginstruments 154
8.7 ThetraditionalRCTisexpensive,cumbersomeandpronetofailure 156
8.8 Alternativedesignsforpilotandproofofprincipleefficacystudies 156
8.9 StatisticalanalysisofN-of-1trials 159
8.10 Statisticalapproachestoestimatingnecessarytrialdurations
inindividualpatients 160
8.11 Crossovertrialsforenhancingclinicalinformaticsandstatisticalpower 161
8.12 Carryovereffects 164
8.13 Long-termtrendinstudiesofbipolardisordercomparedtoothermajor
mentaldisorders 165
viii CONTENTS
8.14 Parallelandpressingdesignissuesforchildhood-onsetbipolarillness 166
8.15 Contradictorybalancebetweeninclusiveness(forgeneralizability)and
homogeneity(forefficacy) 167
8.16 Assessingmoderatorsandmediators 167
8.17 Conclusionsandimplications 169
9. The Utility of Low-dose Antidepressants 179
MonicaL.Zilberman,ClariceGorenstein andValentimGentil
9.1 Introduction 179
9.2 Lowdoseantidepressantsforchiefindications 180
9.3 Antidepressantuseforotherindications 180
9.4 Emotionregulationinhealthyindividuals 184
9.5 Conclusion 185
SECTION III: Clinical Trials in Anxiety and Other Disorders 189
10. Clinical Trials for Anxiety Disorders 191
MarcoMulaandGionataStrigaro
10.1 Introduction 191
10.2 Methodologicalissuesintreatmentresearchforanxietydisorders 192
10.3 Panicdisorderwith/withoutagoraphobia 197
10.4 Generalizedanxietydisorder 198
10.5 Socialanxietydisorder 199
10.6 Post-traumaticstressdisorder 200
10.7 Conclusions 201
10.8 Acknowledgment 202
11. Pharmacological Trials for the Treatment of Substance Use
Disorders 207
LisaJ.Merlo,JuliaAranaandAmandaM.Stone
11.1 Psychopharmacologicaltrialsforthetreatmentofsubstanceusedisorders 208
11.2 Definitionsofsubstanceusedisorders 208
11.3 IntroductiontopsychopharmacotherapyforSUDs 209
11.4 ConsiderationsinpharmacotherapytrialsforSUDs 219
11.5 Conclusionsandfuturedirections 227
12. Clinical Psychopharmacology of Patients with Eating Disorders 233
JamesEMitchell,KristineSteffen,ScottEngel,RossCrosby
andJamesRoerig
12.1 Introduction 233
12.2 Diagnosticissues 234