Clinical Trials in Psychopharmacology (eBook)

Dr. Hertzman, a psychopharmacologist, previously Professor of Psychiatry at George Washington University, is now in private practice. Before that he was a Division Director for the National Institute on Alcohol Abuse and Alcoholism and served as their representative to the US government task force which originated US policy on clinical trials. His publications, in addition to the first edition of this book, include work on Mood Disorders, Anxiety, and Autism Spectrum Disorders. He has also been a Principal Investigator on clinical trials for more than thirty years. Dr Adler is the Owner/Director of Clinical Insights and Clinical Assistant Professor of Psychiatry at the University of Maryland. He is Board-certified in Psychiatry and Geriatric Psychiatry, and is a Certified Physician Investigator. From 1983 - 1998 he conducted research into the genetics and epidemiology of schizophrenia. He has been involved in clinical trials since 1993.

Clinical Trials in Psychopharmacology 3
Contents 7
Acknowledgments 13
Introduction 15
List of Contributors 17
SECTION I: The Health Care Environment and Medications 19
1. FDA Reform: D´ej`a vu Encore 21
1.1 Introduction 22
1.2 The 1992 prescription drug user fee act adds funds and changes FDA’s focus 25
1.3 PDUFA shortens drug review times and eliminates the drug lag 26
1.4 PDUFA timetables feed safety concerns 27
1.5 FDA responds to safety concerns 29
1.6 The pipeline problem 30
1.7 The 2007 FDA Science Board’s Subcommittee on Science and Technology report 35
1.8 The FDAAA of 2007 reauthorize PDUFA and provide new authority to address safety and the critical path initiative 36
1.9 The impact of PDFUA on FDA 39
1.10 Comparative medical benefits, comparative effectiveness and FDA 39
1.11 FDA and non-inferiority trials 41
1.12 FDA and CMS decisions on Medicare coverage 42
1.13 Preemption: FDA’s role in relation to liability litigation in state courts 42
1.14 FDA’s exclusivity in allowing access to experimental drugs 42
1.15 Conclusions 43
2. Do Antidepressants Cause Suicide? 49
2.1 Some definitional problems 49
2.2 A brief history of the concerns of suicidality caused by antidepressants 50
2.3 Politics rears its ugly head 53
2.4 The FDA responds 53
2.5 What changes in public policy wrought 54
2.6 A funny thing happened on the way to the forum 57
2.7 Meanwhile back at the ranch 57
2.8 Moral (maybe) 58
3. The Genome, Genes and Brain – Tailored Drugs 61
3.1 Introduction 61
3.2 Issues in new drug development 62
3.3 Early development of psychiatric pharmaceutical entities 62
3.4 Advances in research technology 63
3.5 Review of genetics 64
3.6 Activation of genes by signal transduction cascades 65
3.7 The human genome 66
3.8 The sequencing of the genome 66
3.9 DNA variation 66
3.10 Genes and illness 67
3.11 Genomic findings, potential targets and new drug development 68
3.12 Conclusion 73
4. Patenting and Licensing Concerns in Psychiatric Genetics 79
4.1 Genetic diagnoses in psychiatry 80
4.2 The evolving patent landscape in psychiatry 81
4.3 Approaches to solving potential problems 94
4.4 Conclusions 101
5. Women’s Issues in Clinical Trials 105
5.1 History 105
5.2 Perceived advantages of excluding women 108
5.3 Change in perspective 108
5.4 Have things changed? 109
5.5 Progress since 1993 110
5.6 Reported current difficulties in including women 111
5.7 Contraception in clinical trials 112
5.8 Drugs in lactating women 113
5.9 How often do women take drugs during pregnancy? 114
5.10 Ethical issues: risk/benefit analysis 114
5.11 Adequate information 115
5.12 Adolescent women 115
5.13 Recruitment and retention of women 115
SECTION II: Clinical Trials and Mood Disorders 121
6. Issues and Clues in the Pharmacological Treatment of Mood Disorders 123
6.1 What do we know about mood disorders that may be relevant for their pharmacological treatment? 124
6.2 Are there clues for the pharmacological treatment of mood disorders? 127
6.3 Perspectives 134
7. Bipolar Disorder 143
7.1 Introduction 144
7.2 Trials in acute mania 145
7.3 Trials in acute bipolar depression 148
7.4 Trials in maintenance of bipolar disorder 150
7.5 What is a mood stabilizer? 152
7.6 What controlled trials cannot tell us about treatment of bipolar disorder 153
8. Special Issues of Research Methodology in Bipolar Disorder Clinical Treatment Trials 167
8.1 Introduction 168
8.2 Efficacy–effectiveness gap 169
8.3 Trials for drug registration versus those that are most clinically informative 169
8.4 The need for designs that more optimally inform clinical practice 170
8.5 ‘Hidden’ high degrees of treatment resistance 171
8.6 Controversy about optimal designs and rating instruments 172
8.7 The traditional RCT is expensive, cumbersome and prone to failure 174
8.8 Alternative designs for pilot and proof of principle efficacy studies 174
8.9 Statistical analysis of N-of-1 trials 177
8.10 Statistical approaches to estimating necessary trial durations in individual patients 178
8.11 Crossover trials for enhancing clinical informatics and statistical power 179
8.12 Carryover effects 182
8.13 Long-term trend in studies of bipolar disorder compared to other major mental disorders 183
8.14 Parallel and pressing design issues for childhood-onset bipolar illness 184
8.15 Contradictory balance between inclusiveness (for generalizability) and homogeneity (for efficacy) 185
8.16 Assessing moderators and mediators 185
8.17 Conclusions and implications 187
9. The Utility of Low-dose Antidepressants 197
9.1 Introduction 197
9.2 Low dose antidepressants for chief indications 198
9.3 Antidepressant use for other indications 198
9.4 Emotion regulation in healthy individuals 202
9.5 Conclusion 203
SECTION III: Clinical Trials in Anxiety and Other Disorders 207
10. Clinical Trials for Anxiety Disorders 209
10.1 Introduction 209
10.2 Methodological issues in treatment research for anxiety disorders 210
10.3 Panic disorder with/without agoraphobia 215
10.4 Generalized anxiety disorder 216
10.5 Social anxiety disorder 217
10.6 Post-traumatic stress disorder 218
10.7 Conclusions 219
10.8 Acknowledgment 220
11. Pharmacological Trials for the Treatment of Substance Use Disorders 225
11.1 Psychopharmacological trials for the treatment of substance use disorders 226
11.2 Definitions of substance use disorders 226
11.3 Introduction to psychopharmacotherapy for SUDs 227
11.4 Considerations in pharmacotherapy trials for SUDs 237
11.5 Conclusions and future directions 245
12. Clinical Psychopharmacology of Patients with Eating Disorders 251
12.1 Introduction 251
12.2 Diagnostic issues 252
12.3 Methodological/statistical issues 255
12.4 Pharmacotherapy trials 258
12.5 Pharmacotherapy/psychotherapy combined trials 264
12.6 Summary 264
13. ADHD Clinical Trials 269
13.1 Introduction 269
13.2 Lisdexamfetamine (Vyvanse) 271
13.3 Methylphenidate transdermal system (Daytrana) 273
13.4 Dexmethylphenidate (Focalin) 274
13.5 Dexmethylphenidate extended release (Focalin XR) 275
13.6 Atomoxetine (Strattera) 277
13.7 Extended release methylphenidate (Ritalin LA) 279
13.8 Modified release methylphenidate (Metadate CD) 279
13.9 Mixed amphetamine salts extended release (Adderall XR) 280
13.10 OROS methylphenidate (Concerta) 282
13.11 Guanfacine extended release 284
13.12 SPD465 285
13.13 Modafinil 285
13.14 Bupropion XL 286
13.15 Discussion 287
14. Autism and Asperger’s Spectrum Disorders 291
14.1 Introduction 291
14.2 Individual entities versus a spectrum disorder 292
14.3 Recent psychopharmacological approaches to autism and Asperger’s spectrum disorders 295
14.4 Recapitulation 301
15. Pharmacological Treatments of Impulse Control Disorders 307
15.1 Impulse control disorders 307
15.2 Pathological gambling 309
15.3 Trichotillomania 310
15.4 Kleptomania 317
15.5 Pyromania 319
15.6 Intermittent explosive disorder 322
15.7 Conclusions 322
SECTION IV: Special Issues in Psychopharmacology 327
16. Potential Benefits of Herbal Medicine for Schizophrenia: from Empirical Observations to Clinical Trials 329
16.1 Introduction 330
16.2 Potential benefits of herbal medicine used in the treatment of schizophrenia 330
16.3 Possible psychopharmacological mechanisms of herbal actions 337
16.4 Search strategies for herbal agents having antischizophrenic potentials 338
16.5 Specific issues in the conduct of herbal medicine trials in schizophrenia 339
16.6 Conclusions 345
16.7 Acknowledgments 345
17. Adverse Effects of Antipsychotics 355
17.1 Introduction 355
17.2 Pharmacology of adverse events 356
17.3 Discontinuation symptoms 387
17.4 Conclusion 388
18. Meta Musings on Methodology 399
18.1 Brief history of the clinical trial 399
18.2 Criticisms of assumptions about clinical trials methodology 401
18.3 Thoughts on alternative study designs 404
18.4 Conclusion: standardization can be stultifying 406
Index 409

"this is a valuable addition to the monographs on clinical trial methodology and should be essential reading for all those undertaking trials of psychotropic drugs. The chapters are clearly written, the references are up-to-date and the volume comes at a price of under £50" (Human Psychopharmacology, 2010)