Clinical Trials in Psychopharmacology

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.  

Acknowledgments. Introduction.

List of Contributors.

SECTION I: The Health Care Environment and Medications.

1. FDA Reform Déjà vu Encore (John J. Cohrssen).

1.1 Introduction.

1.2 The 1992 prescription drug user fee act adds funds and changes FDA’s focus.

1.3 PDUFA shortens drug review times and eliminates the drug lag.

1.4 PDUFA timetables feed safety concerns.

1.5 FDA responds to safety concerns.

1.6 The pipeline problem.

1.7 The 2007 FDA Science Board’s Subcommittee on Science and Technology report.

1.8 The FDAAA of 2007 reauthorize PDUFA and provide new authority to address safety and the critical path initiative.

1.9 The impact of PDFUA on FDA.

1.10 Comparative medical benefits, comparative effectiveness and FDA.

1.11 FDA and non-inferiority trials.

1.12 FDA and CMS decisions on medicare coverage.

1.13 Preemption: FDA’s role in relation to liability litigation in state courts.

1.14 FDA’s exclusivity in allowing access to experimental drugs.

1.15 Conclusions.

2. Do Antidepressants Cause Suicide (Marc Hertzman).

2.1 Some definitional problems.

2.2 A brief history of the concerns of suicidality caused by antidepressants.

2.3 Politics rears its ugly head.

2.4 The FDA responds to fear of its own shadow.

2.5 What changes in public policy wrought.

2.6 A funny thing happened on the way to the forum.

2.7 Meanwhile back at the ranch.

2.8 Moral (maybe).

3. The Genome, Genes and Brain - Tailored Drugs (Lawrence Adler).

3.1 Introduction.

3.2 Issues in new drug development.

3.3 Early development of psychiatric pharmaceutical entities.

3.4 Advances in research technology.

3.5 Review of genetics.

3.6 Activation of genes by signal transduction cascades.

3.7 The human genome.

3.8 The sequencing of the genome.

3.9 DNA variation.

3.10 Genes and illness.

3.11 Genomic findings, potential targets and new drug development.

3.12 Conclusion .

4. Patenting and Licensing Concerns in Psychiatric Genetics (Jorge A. Goldstein and Karen R. Markowicz).

4.1 Genetic diagnoses in psychiatry.

4.2 The evolving patent landscape in psychiatry.

4.3 Approaches to solving potential problems.

4.4 Conclusions.

5. Women’s Issues in Clinical Trials (Mary Seeman).

5.1 History.

5.2 Perceived advantages of excluding women.

5.3 Change in perspective.

5.4 Have things changed?.

5.5 Progress since 1993.

5.6 Reported current difficulties in including women.

5.7 Contraception in clinical trials.

5.8 Drugs in lactating women.

5.9 How often do women take drugs during pregnancy?.

5.10 Ethical issues: risk/benefit analysis.

5.11 Adequate information.

5.12 Adolescent women.

5.13 Recruitment and retention of women.

SECTION II Clinical Trials and Mood Disorders.

6. Issues and Clues in the Pharmacological Treatment of Mood Disorders (F. Jollant, A Ionita and P Courtet).

6.1 What do we know about mood disorders that may be relevant for their pharmacological treatment?.

6.2 Are there clues for the pharmacological treatment of mood disorders?.

6.3 Perspectives.

7. Bipolar Disorder (A. Bochetta).

7.1 Trials in acute mania.

7.2 Trials in acute bipolar depression.

7.3 Trials in maintenance of bipolar disorder.

7.4 What is a mood stabilizer?.

7.5 What controlled trials cannot tell us about treatment of bipolar disorder.

8. Special Issues of Research Methodology in Bipolar Disorder Clinical Treatment Trials (R. M. Post).

8.1 Introduction.

8.2 Efficacy–effectiveness gap.

8.3 Trials for drug registration versus those that are most clinically informative.

8.4 Needed for designs that more optimally inform clinical practice.

8.5 ‘Hidden’ high degrees of treatment resistance.

8.6 Controversy about optimal designs and rating instruments.

8.7 The traditional RCT is expensive, cumbersome and prone to failure.

8.8 Alternative designs for pilot and proof of principle efficacy studies.

8.9 Statistical analysis of N-of-1 trials.

8.10 Statistical approaches to estimating necessary trial durations in individual patients.

8.11 Crossover trials for enhancing clinical informatics and statistical power.

8.12 Carryover effects.

8.13 Long-term trend for understudy of bipolar disorder compared to other major mental disorders.

8.14 Parallel and pressing design issues for childhood-onset bipolar illness.

8.15 Contradictory balance between inclusiveness (for generalizability) and homogeneity (for efficacy).

8.16 Assessing moderators and mediators.

8.17 Conclusions and implications.

9. The Utility of Low-dose Antidepressants (Monica L. Zilberman, Clarice Gorenstein and Valentim Gentil).

9.1 Introduction.

9.2 Low dose antidepressants for chief indications.

9.3 Antidepressant use for other indications.

9.4 Emotion regulation in healthy individuals.

9.5 Conclusion.

SECTION III Clinical Trials in Anxiety and Other Disorders.

10. Clinical Trials for Anxiety Disorders (Marco Mula and Gionata Strigaro).

10.1 Introduction.

10.2 Methodological issues in treatment research for anxiety disorders.

10.3 Panic disorder with/without agoraphobia.

10.4 Generalized anxiety disorder.

10.5 Social anxiety disorder.

10.6 Post-traumatic stress disorder.

10.7 Conclusions.

11. Pharmacological Trials for the Treatment of Substance Use Disorders (Lisa J. Merlo, Julia Arana and Amanda M. Stone).

11.1 Psychopharmacological trials for the treatment of substance use disorder.

11.2 Definitions of substance use disorders.

11.3 Introduction to psychopharmacotherapy for SUD.

11.4 Considerations in pharmacotherapy trials for SUDs.

11.5 Conclusions and future directions.

12. Clinical Psychopharmacology of Patients with Eating Disorders (James E Mitchell, Kristine Steffen, Scott Engel, Ross Crosby and James Roerig).

12.1 Introduction.

12.2 Diagnostic issues.

12.3 Methodological/statistical issues.

12.4 Pharmacotherapy trials.

12.5 Pharmacotherapy/psychotherapy combined trials.

12.6 Summary.

13. ADHD Clinical Trials (Anne Childress).

13.1 Introduction.

13.2 Lisdexamfetamine (Vyvanse).

13.3 Methylphenidate transdermal system (Daytrana).

13.4 Dexmethylphenidate (Focalin).

13.5 Dexmethylphenidate extended release (Focalin XR).

13.6 Atomoxetine (Strattera).

13.7 Extended release methylphenidate (Ritalin LA).

13.8 Modified release methylphenidate (Metadate CD).

13.9 Mixed amphetamine salts extended release (Adderall XR).

13.10 OROS methylphenidate (Concerta).

13.11 Guanfacine extended release.

13.12 SPD465.

13.13 Modafinil.

13.14 Bupropion XL.

13.15 Discussion.

14. Autism and Asperger’s Spectrum Disorders (Marc Hertzman).

14.1 Introduction.

14.2 Individual entities versus a spectrum disorder.

14.3 Recent psychopharmacological approaches to autism and Asperger’s spectrum disorders.

14.4 Recapitulation.

15. Pharmacological Treatments of Impulse Control Disorders (Helga Myrseth and Ståle Pallesen).

15.1 Impulse control disorders.

15.2 Pathological gambling.

15.3 Trichotillomania.

15.4 Kleptomania.

15.5 Pyromania.

15.6 Intermittent explosive disorder.

15.7 Conclusions.

SECTION IV Special Issues in Psychopharmacology.

16. Potential Benefits of Herbal Medicine for Schizophrenia: from Empirical Observations to Clinical Trials (Zhang-Jin Zhang, Qing-Rong Tan, Xue-Chu Zhen and Yao Tong).

16.1 Potential benefits of herbal medicine used in the treatment of schizophrenia.

16.2 Possible psychopharmacological mechanisms of herbal actions.

16.3 Search strategies for herbal agents having antischizophrenic potentials.

16.4 Specific issues in the conduct of herbal medicine trials in schizophrenia.

16.5 Conclusions.

17. Adverse Effects of Antipsychotics (Pierre Landry, Anne-Marie Rousseau, and Leila Skalli).

17.1 Introduction.

17.2 Pharmacology of adverse events.

17.3 Discontinuation symptoms.

17.4 Conclusion.

18. Meta Musings on Methodology (Marc Hertzman).

18.1 Criticisms of assumptions about clinical trials methodology.

18.2 Thoughts on alternative study designs.

18.3 Conclusion: standardization can be stultifying.

Index.