CLINICAL TRIALS IN PSYCHOPHARMACOLOGY
CONTENTS SECTION I: THE HEALTH CARE ENVIRONMENT AND MEDICATIONS 1 FDA REFORM: D´EJ`A VU ENCORE INTRODUCTION THE 1992 PRESCRIPTION DRUG USER FEE ACT ADDS FUNDS AND CHANGES FDA’S FOCUS PDUFA SHORTENS DRUG REVIEW TIMES AND ELIMINATES THE DRUG LAG PDUFA TIMETABLES FEED SAFETY CONCERNS FDA RESPONDS TO SAFETY CONCERNS THE PIPELINE PROBLEM THE 2007 FDA SCIENCE BOARD’S SUBCOMMITTEE ON SCIENCE AND TECHNOLOGY REPORT THE FDAAA OF 2007 REAUTHORIZE PDUFA AND PROVIDE NEW AUTHORITY TO ADDRESS SAFETY AND THE CRITICAL PATH INITIATIVE THE IMPACT OF PDFUA ON FDA COMPARATIVE MEDICAL BENE?TS, COMPARATIVE EFFECTIVENESS AND FDA FDA AND NON-INFERIORITY TRIALS FDA AND CMS DECISIONS ON MEDICARE COVERAGE PREEMPTION: FDA’S ROLE IN RELATION TO LIABILITY LITIGATION IN STATE COURTS FDA’S EXCLUSIVITY IN ALLOWING ACCESS TO EXPERIMENTAL DRUGS CONCLUSIONS 2 DO ANTIDEPRESSANTS CAUSE SUICIDE? SOME DE?NITIONAL PROBLEMS A BRIEF HISTORY OF THE CONCERNS OF SUICIDALITY CAUSED BY ANTIDEPRESSANTS POLITICS REARS ITS UGLY HEAD THE FDA RESPONDS WHAT CHANGES IN PUBLIC POLICY WROUGHT A FUNNY THING HAPPENED ON THE WAY TO THE FORUM MEANWHILE BACK AT THE RANCH MORAL (MAYBE) 3 THE GENOME, GENES AND BRAIN – TAILORED DRUGS ISSUES IN NEW DRUG DEVELOPMENT EARLY DEVELOPMENT OF PSYCHIATRIC PHARMACEUTICAL ENTITIES ADVANCES IN RESEARCH TECHNOLOGY REVIEW OF GENETICS ACTIVATION OF GENES BY SIGNAL TRANSDUCTION CASCADES THE HUMAN GENOME THE SEQUENCING OF THE GENOME DNA VARIATION GENES AND ILLNESS GENOMIC ?NDINGS, POTENTIAL TARGETS AND NEW DRUG DEVELOPMENT CONCLUSION 4 PATENTING AND LICENSING CONCERNS IN PSYCHIATRIC GENETICS GENETIC DIAGNOSES IN PSYCHIATRY THE EVOLVING PATENT LANDSCAPE IN PSYCHIATRY APPROACHES TO SOLVING POTENTIAL PROBLEMS 5 WOMEN’S ISSUES IN CLINICAL TRIALS HISTORY PERCEIVED ADVANTAGES OF EXCLUDING WOMEN CHANGE IN PERSPECTIVE HAVE THINGS CHANGED? PROGRESS SINCE REPORTED CURRENT DIF?CULTIES IN INCLUDING WOMEN CONTRACEPTION IN CLINICAL TRIALS DRUGS IN LACTATING WOMEN HOW OFTEN DO WOMEN TAKE DRUGS DURING PREGNANCY? ETHICAL ISSUES: RISK/BENE?T ANALYSIS ADEQUATE INFORMATION ADOLESCENT WOMEN RECRUITMENT AND RETENTION OF WOMEN SECTION II: CLINICAL TRIALS AND MOOD DISORDERS 6 ISSUES AND CLUES IN THE PHARMACOLOGICAL TREATMENT OF MOOD DISORDERS WHAT DO WE KNOW ABOUT MOOD DISORDERS THAT MAY BE RELEVANT FOR THEIR PHARMACOLOGICAL TREATMENT? ARE THERE CLUES FOR THE PHARMACOLOGICAL TREATMENT OF MOOD DISORDERS? PERSPECTIVES 7 BIPOLAR DISORDER TRIALS IN ACUTE MANIA TRIALS IN ACUTE BIPOLAR DEPRESSION TRIALS IN MAINTENANCE OF BIPOLAR DISORDER WHAT IS A MOOD STABILIZER? WHAT CONTROLLED TRIALS CANNOT TELL US ABOUT TREATMENT OF BIPOLAR DISORDER 8 SPECIAL ISSUES OF RESEARCH METHODOLOGY IN BIPOLAR DISORDER CLINICAL TREATMENT TRIALS EF?CACY–EFFECTIVENESS GAP TRIALS FOR DRUG REGISTRATION VERSUS THOSE THAT ARE MOST CLINICALLY INFORMATIVE THE NEED FOR DESIGNS THAT MORE OPTIMALLY INFORM CLINICAL PRACTICE ‘HIDDEN’ HIGH DEGREES OF TREATMENT RESISTANCE CONTROVERSY ABOUT OPTIMAL DESIGNS AND RATING INSTRUMENTS THE TRADITIONAL RCT IS EXPENSIVE, CUMBERSOME AND PRONE TO FAILURE ALTERNATIVE DESIGNS FOR PILOT AND PROOF OF PRINCIPLE EF?CACY STUDIES STATISTICAL ANALYSIS OF N-OF-1 TRIALS STATISTICAL APPROACHES TO ESTIMATING NECESSARY TRIAL DURATIONS IN INDIVIDUAL PATIENTS CROSSOVER TRIALS FOR ENHANCING CLINICAL INFORMATICS AND STATISTICAL POWER CARRYOVER EFFECTS LONG-TERM TREND IN STUDIES OF BIPOLAR DISORDER COMPARED TO OTHER MAJOR MENTAL DISORDERS PARALLEL AND PRESSING DESIGN ISSUES FOR CHILDHOOD-ONSET BIPOLAR ILLNESS CONTRADICTORY BALANCE BETWEEN INCLUSIVENESS (FOR GENERALIZABILITY) AND HOMOGENEITY (FOR EF?CACY) ASSESSING MODERATORS AND MEDIATORS CONCLUSIONS AND IMPLICATIONS 9 THE UTILITY OF LOW-DOSE ANTIDEPRESSANTS LOW DOSE ANTIDEPRESSANTS FOR CHIEF INDICATIONS ANTIDEPRESSANT USE FOR OTHER INDICATIONS EMOTION REGULATION IN HEALTHY INDIVIDUALS SECTION III: CLINICAL TRIALS IN ANXIETY AND OTHER DISORDERS 10 CLINICAL TRIALS FOR ANXIETY DISORDERS METHODOLOGICAL ISSUES IN TREATMENT RESEARCH FOR ANXIETY DISORDERS PANIC DISORDER WITH/WITHOUT AGORAPHOBIA GENERALIZED ANXIETY DISORDER SOCIAL ANXIETY DISORDER POST-TRAUMATIC STRESS DISORDER ACKNOWLEDGMENT 11 PHARMACOLOGICAL TRIALS FOR THE TREATMENT OF SUBSTANCE USE DISORDERS PSYCHOPHARMACOLOGICAL TRIALS FOR THE TREATMENT OF SUBSTANCE USE DISORDERS DE?NITIONS OF SUBSTANCE USE DISORDERS INTRODUCTION TO PSYCHOPHARMACOTHERAPY FOR SUDS CONSIDERATIONS IN PHARMACOTHERAPY TRIALS FOR SUDS CONCLUSIONS AND FUTURE DIRECTIONS 12 CLINICAL PSYCHOPHARMACOLOGY OF PATIENTS WITH EATING DISORDERS DIAGNOSTIC ISSUES METHODOLOGICAL/STATISTICAL ISSUES PHARMACOTHERAPY TRIALS PHARMACOTHERAPY/PSYCHOTHERAPY COMBINED TRIALS SUMMARY 13 ADHD CLINICAL TRIALS LISDEXAMFETAMINE (VYVANSE) METHYLPHENIDATE TRANSDERMAL SYSTEM (DAYTRANA) DEXMETHYLPHENIDATE (FOCALIN) DEXMETHYLPHENIDATE EXTENDED RELEASE (FOCALIN XR) ATOMOXETINE (STRATTERA) EXTENDED RELEASE METHYLPHENIDATE (RITALIN LA) MODI?ED RELEASE METHYLPHENIDATE (METADATE CD) MIXED AMPHETAMINE SALTS EXTENDED RELEASE (ADDERALL XR) OROS METHYLPHENIDATE (CONCERTA) GUANFACINE EXTENDED RELEASE MODA?NIL BUPROPION XL DISCUSSION 14 AUTISM AND ASPERGER’S SPECTRUM DISORDERS INDIVIDUAL ENTITIES VERSUS A SPECTRUM DISORDER RECENT PSYCHOPHARMACOLOGICAL APPROACHES TO AUTISM AND ASPERGER’S SPECTRUM DISORDERS RECAPITULATION 15 PHARMACOLOGICAL TREATMENTS OF IMPULSE CONTROL DISORDERS IMPULSE CONTROL DISORDERS PATHOLOGICAL GAMBLING TRICHOTILLOMANIA KLEPTOMANIA PYROMANIA INTERMITTENT EXPLOSIVE DISORDER SECTION IV: SPECIAL ISSUES IN PSYCHOPHARMACOLOGY 16 POTENTIAL BENE?TS OF HERBAL MEDICINE FOR SCHIZOPHRENIA: FROM EMPIRICAL OBSERVATIONS TO CLINICAL TRIALS POTENTIAL BENE?TS OF HERBAL MEDICINE USED IN THE TREATMENT OF SCHIZOPHRENIA POSSIBLE PSYCHOPHARMACOLOGICAL MECHANISMS OF HERBAL ACTIONS SEARCH STRATEGIES FOR HERBAL AGENTS HAVING ANTISCHIZOPHRENIC POTENTIALS SPECI?C ISSUES IN THE CONDUCT OF HERBAL MEDICINE TRIALS IN SCHIZOPHRENIA ACKNOWLEDGMENTS 17 ADVERSE EFFECTS OF ANTIPSYCHOTICS PHARMACOLOGY OF ADVERSE EVENTS DISCONTINUATION SYMPTOMS 18 META MUSINGS ON METHODOLOGY BRIEF HISTORY OF THE CLINICAL TRIAL CRITICISMS OF ASSUMPTIONS ABOUT CLINICAL TRIALS METHODOLOGY THOUGHTS ON ALTERNATIVE STUDY DESIGNS CONCLUSION: STANDARDIZATION CAN BE STULTIFYING