The contibution of clinical trials in psychiatry: beyond basic science

INVITED EDITORIAL

The contribution of clinical trials in psychiatry: beyond basic science

Andrew Nierenberg

MD. Medical director, Bipolar Clinic and Research Program, Massachusetts General Hospital, Boston, MA, USA. Associate director, Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA, USA. Associate professor, Harvard Medical School, Boston, MA, USA

To paraphrase Dickens, it is the best of times and the worst of times in psychiatric research. It is the best of times because of an explosion in basic brain science relevant for psychiatry: neurophysiology, neurocircuitry, neurogenesis, neuroprotection, structural and functional neuroimaging, genomics, genetic epidemiology, gene–environment interactions, pharmacogenomics, proteomics, and metabolomics. It is the worst of times because of the dearth of clinical trials assessing new psychiatric interventions: few new medications or novel psychotherapies are being developed for depression, bipolar disorder, schizophrenia, or anxiety disorders. Non–industry funding for clinical trials has, with few exceptions, diminished substantially in the past 5 years.

Similar to what had occurred in internal medicine a generation ago, psychiatry is (appropriately) concerned with understanding physiopathology to identify fundamental defects that can lead to new therapeutic targets and new therapeutics. But the number of psychiatric clinical trials that impact practice published in the literature has decreased. Furthermore, the value of clinical trials has been under assault, fueled by cynicism that negative results have been withheld by pharmaceutical companies and that these same companies have emphasized minimal benefits while hiding the risks of their products. Critics have castigated pharmaceutical companies for pursuing profit at the expense of patients' health.^1–3 With these issues at the forefront, what, then, (if any) is the continuing value of clinical trials?

Clinical trials generate essential, albeit imperfect, evidence for clinicians to make informed decisions for the care of their patients. Clinical trials are the ultimate method to test whether therapeutic interventions work and provide important data to guide clinicians to assess benefit/risk ratios. These trials put interventions to the test by minimizing bias (through randomization, controls, and blinding when appropriate) – and ask "is the study intervention better than alternatives (placebo or active controls)"? Treatments that appear theoretically appealing must pass through the crucible of clinical trials – just look back at the recent history of promising interventions that were unable to show sufficient efficacy in clinical trials (corticotrophin–releasing factor antagonists, repetitive transcranial magnetic stimulation, and pindolol for speeding up response to antidepressants, to name a few).

Clinical trials provide the evidence for "evidence based medicine." The phrase "evidence based medicine" is, however, peculiar. What is the alternative? Use non–evidence based medicine?⁴ Clinicians (should) practice psychiatry informed by clinical trials ("hard data"), clinical experience, and clinical reasoning (and in reality, use stories from colleagues).^5–8 But investigators limit the clinical utility of the results of clinical trials by reporting mean changes on scales without relevant data that would identify those patients who might benefit or worsen during treatment.⁹ Generalizability is another issue.¹⁰ Whereas some researchers have found that research and clinical patient populations are similar,^11–13 others have found that those who seek clinical treatment differ substantially from those who participate in research trials.¹⁴ Given that there may be important differences between clinical and research populations, clinicians tend to be cautious when generalizing research findings to daily practice and, by integrating their clinical experience with information from randomized controlled trials (RCT), and avoid turning evidence–based medicine into "evidence–biased medicine."¹⁵ Other critiques of RCT include: insensitive measures, problems with research raters, and the use of designs meant for medication registration rather than for guiding clinical practice.^16,17 Nevertheless, RCT, while imperfect, serve as an essential basis for informing clinical practice. The results should not be applied mindlessly and interpretation of results should take into account their limited external validity.

The majority of published psychiatric clinical trials are funded by and conducted for pharmaceutical companies. Companies conduct those trials that they deem in their best interest and consistent with their business models. Pharmaceutical companies are the source of most new medications in psychiatry and need to conduct those trials that ultimately will serve the public and their shareholders – a model that has been largely successful. Few, if any, psychiatric interventions originate with non–industry sources. Pharmaceutical companies will tend to avoid those clinical trials that might damage their business – and companies frequently avoid those clinical trials that directly compare medications that might risk making their product appear less competitive. The challenge is for companies to conduct clinical trials that not only get medications to market (registration trials) but for the field to conduct those trials that help with daily clinical practice, including the development and testing of psychosocial interventions. Foundations and governments play an essential role for funding these trials.

The National Institutes of Mental Health in the United States recently completed three large effectiveness trials that were planned in the late 1990's: CATIE, STEP–BD, and STAR*D to compare or evaluate interventions for schizophrenia, bipolar disorder, and depression, respectively. Each study has its strengths and limitations, supporters and detractors. But the overall mission of these studies was to conduct clinical trials that would not have been supported by industry and that would advance the treatment of serious mental illnesses. These types of effectiveness studies provide a different form of information than registration trials and provide additional evidence to guide clinical practice. Each of these large trials left behind an established infrastructure that morphed into clinical trials networks for future studies (schizophrenia, bipolar, and depression trials networks).

Psychiatric clinical trials designed with internal and external validity that inform clinical practice are expensive to conduct but essential if clinicians are to have the data to provide optimal care for their patients. We will need continued funding and manpower to conduct clinical trials that will enhance public health. Continued funding needs the support of the public and especially advocacy groups. Continued investments in research training programs that develop clinical researchers are needed to continue to serve the public interest. In summary, psychiatric clinical trials are necessary to advance clinical practice.

References

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2. Angell M. The truth about the drug companies: how they deceive us and what to do about it. New York: Random House; 2005.

3. Kassirer JP. On the take: how medicine's complicity with big business can endanger your health. New York: Oxford University; 2005.

4. Isaacs D, Fitzgerald D. Seven alternatives to evidence based medicine. BMJ. 1999;319(7225):1618.

5. Devereaux PJ, Yusuf S. The evolution of the randomized controlled trial and its role in evidence–based decision making. J Intern Med. 2003;254(2):105–13.

6. Goldner EM, Bilsker D. Evidence–based psychiatry. Can J Psychiatry. 1995;40(2):97–101.

7. Sackett DL. Evidence–based medicine. Semin Perinatol. 1997;21(1):3–5.

8. Sackett DL, Rosenberg WM. On the need for evidence–based medicine. J Public Health Med. 1995;17(3):330–4.

9. Horwitz RI, Singer BH, Makuch RW, Viscoli CM. Can treatment that is helpful on average be harmful to some patients? A study of the conflicting information needs of clinical inquiry and drug regulation. J Clin Epidemiol. 1996;49(4):395–400.

10. Treatment Research in Mental Illness: Improving the Nation's Public Mental Health Care through NIMH Funded Interventions Research. Report of the National Advisory Mental Health Council's Workgroup on Clinical Trials. http://www.nimh.nih.gov/council/interventions_research.cfm. p. 4.

11. Carroll KM, Nich C, McLellan AT, McKay JR, Rounsaville BJ. 'Research' versus 'real–world' patients: representativeness of participants in clinical trials of treatments for cocaine dependence. Drug Alcohol Depend. 1999;54(2):171–7.

12. Rapaport MH, Frevert T, Babior S, Zisook S, Judd LL. A comparison of demographic variables, symptom profiles, and measurements of functioning in symptomatic volunteers and an outpatient clinical population. Psychopharmacol Bull. 1995;31(1):111–4.

13. Stirman SW, DeRubeis RJ, Crits–Christoph P, Brody PE. Are samples in randomized controlled trials of psychotherapy representative of community outpatients? A new methodology and initial findings. J Consult Clin Psychol. 2003;71(6):963–72.

14. Braslow JT, Duan N, Starks SL, Polo A, Bromley E, Wells KB. Generalizability of studies on mental health treatment and outcomes, 1981 to 1996. Psychiatr Serv. 2005;56(10):1261–8.

15. Schelling FA. Clinical trials: deliberations on their essence and value. J Eval Clin Pract. 2004;10(2):291–6.

16. Fava G. The intellectual crisis of psychiatric research. Psychother Psychosom. 2006;75(4):202–8.

17. Wise TN. Curiosity and crisis. Psychother Psychosom. 2006;75(4):199–201.

Publication Dates

• Publication in this collection
  06 Sept 2007
• Date of issue
  Apr 2007