The Small Specific Effects of Antidepressants in Clinical Trials: What Do They Mean to Psychiatrists?
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Although antidepressants continue to be a mainstay for clinicians who treat people suffering from depressive disorders, there have recently been articles published in both the scientific literature and the popular press that have raised questions about the utility of this class of medications. This paper briefly examines recent meta-analyses that have reported small drug versus placebo differences in randomized controlled trials and, from the perspective of a prescribing psychiatrist, discusses the clinical significance of these findings. It is concluded that antidepressants do have relatively modest effects (as compared with placebo) in contemporary randomized controlled trials, and that the contribution of placebo-expectancy factors to individual outcomes is often underestimated. Nevertheless, it is also concluded that the modest benefits of antidepressants in grouped datasets obscure large, specific, and very meaningful therapeutic effects for 10% to 20% of those treated with antidepressants.
KeywordsAntidepressants Placebo Meta-analysis Randomized controlled trials RCT Clinical trials Psychiatrists
Dr. Thase has served as a consultant for Alkermes, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Dey Pharma, Forest Laboratories, Gerson Lehrman Group, GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante, Merck & Co. (formerly Schering-Plough and Organon Pharmaceuticals USA), Neuronetics, Novartis, Otsuka Pharmaceutical Co., Ortho-McNeil Pharmaceuticals (Johnson & Johnson), Pamlab, Pfizer (formerly Wyeth-Ayerst International), PGxHealth, Shire US, Supernus Pharmaceuticals, Takeda Pharmaceuticals North America, and Transcept Pharmaceuticals; has received grant support from the Agency for Healthcare Research and Quality, Eli Lilly and Company, Forest Pharmaceuticals, GlaxoSmithKline, the National Institute of Mental Health, Otsuka Pharmaceutical Co., and Sepracor; has received honoraria from AstraZeneca, Bristol-Myers Squibb, Dey Pharma, Eli Lilly and Company, Merck & Co., Pfizer (formerly Wyeth-Ayerst International); has received royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton & Company; has received payment for development of educational presentations (including service on speakers’ bureaus) from Pfizer and Bristol-Myers Squibb; and has held stock/stock options in MedAvante. His wife has been employed by Embryon (formerly Advogent).
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- 4.• Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010; 303: 47–53. This meta-analysis of individual patient data from six placebo-controlled studies of antidepressants confirmed that the effects of antidepressants were small for patients with mild to moderate depression. Google Scholar
- 5.Khan A, Leventhal RM, Khan SR, Brown WA. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol. 2002;24:1–3.Google Scholar
- 6.Thase ME. Comparing the methods used to compare antidepressants. Psychopharmacol Bull. 2002; 36 Suppl 1:Suppl 1–17.Google Scholar
- 7.Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;12:52–62.Google Scholar
- 9.•• Kirsch I. The Emperor’s New Drugs: Exploding the Antidepressant Myth. New York: Basic Books, 2010. The findings reported in this book were widely featured in the lay press. Written for the general public, the book provides an excellent overview of the placebo response and its relevance to the treatment of depression. Google Scholar
- 10.• Fountoulakis KN, Möller HJ. 2010. Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. Int J Neuropsychopharmacol 2011; 14: 405–12. This meta-analysis uses the same dataset as did Kirsch et al. , with several different statistical assumptions. Their findings are somewhat more positive, though they still demonstrate that antidepressants have relatively modest effects in grouped data. Google Scholar
- 16.Depression Guideline Panel. Clinical Practice Guideline Number 5: Depression in Primary Care: Treatment of Major Depression. Rockville, MD. US Department of Health and Human Services, Public Health Service, Agency for Healthcare Policy and Research, 1993; 2; AHCPR publication 93–0551.Google Scholar
- 23.National Institute for Clinical Excellence (NICE). 2004. Depression: management of depression in primary and secondary care. Clinical practice guideline no. 23. National Institute for Clinical Excellence, London.Google Scholar
- 25.• Thase ME, Larsen KG, Kennedy SH. Assessing the “true” effect of active antidepressant therapy versus placebo in patients with major depressive disorder using a mixture model. Br J Psychiatry 2011 (in press). This meta-analysis of placebo-controlled studies of escitalopram demonstrated that a modest average effect in grouped data obscures a large effect for 15% to 20% of patients. Google Scholar