Current Psychiatry Reports

, Volume 13, Issue 6, pp 476–482 | Cite as

The Small Specific Effects of Antidepressants in Clinical Trials: What Do They Mean to Psychiatrists?

  • Michael E. Thase


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.


Antidepressants 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).


Papers of particular interest, published recently, have been highlighted as: •Of importance, ••Of major importance

  1. 1.
    Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry. 2009;66:848–56.PubMedCrossRefGoogle Scholar
  2. 2.
    Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45.PubMedCrossRefGoogle Scholar
  3. 3.
    Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252–60.PubMedCrossRefGoogle Scholar
  4. 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. 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. 6.
    Thase ME. Comparing the methods used to compare antidepressants. Psychopharmacol Bull. 2002; 36 Suppl 1:Suppl 1–17.Google Scholar
  7. 7.
    Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;12:52–62.Google Scholar
  8. 8.
    Thase ME. Treatment of severe depression. J Clin Psychiatry. 2000;61 Suppl 1:17–25.PubMedGoogle Scholar
  9. 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. 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. [2], 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
  11. 11.
    Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746–58.PubMedCrossRefGoogle Scholar
  12. 12.
    Quitkin FM, Rabkin JG, Gerald J, Davis JM, Klein DF. Validity of clinical trials of antidepressants. Am J Psychiatry. 2000;157(3):327–37.PubMedCrossRefGoogle Scholar
  13. 13.
    Thomson R. Side effects and placebo amplification. Br J Psychiatry. 1982;140:64–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Moncrieff J, Wessely S, Hardy R. Meta-analysis of trials comparing antidepressants with active placebos. Br J Psychiatry. 1998;172:227–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Thase ME. Do antidepressants really work? A clinicians’ guide to evaluating the evidence. Curr Psychiatry Rep. 2008;10:487–94.PubMedCrossRefGoogle Scholar
  16. 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
  17. 17.
    Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA. 2002;287(14):1840–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Khan A, Bhat A, Kolts R, Thase ME, Brown W. Why has the antidepressant-placebo difference in antidepressant clinical trials diminished over the past three decades? CNS Neurosci Ther. 2010;16(4):217–26.PubMedCrossRefGoogle Scholar
  19. 19.
    Engelhardt N, Feiger AD, Cogger KO, Sikich D, DeBrota DJ, Lipsitz JD, et al. Rating the raters: assessing the quality of Hamilton Rating Scale for Depression clinical interviews in two industry-sponsored clinical drug trials. J Clin Psychopharmacol. 2006;26:71–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Kobak KA, Kane JM, Thase ME, Nierenberg AA. Why do clinical trials fail? The problem of measurement error in clinical trials: time to test new paradigms? J Clin Psychopharmacol. 2007;27(1):1–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Kobak KA, Leuchter A, DeBrota D, Engelhardt N, Williams JB, Cook IA, et al. Site versus centralized raters in a clinical depression trial: impact on patient selection and placebo response. J Clin Psychopharmacol. 2010;30(2):193–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Gelenberg AJ, Thase ME, Meyer RE, Goodwin FK, Katz MM, Kraemer HC, et al. The history and current state of antidepressant clinical trial design: a call to action for proof-of-concept studies. J Clin Psychiatry. 2008;69:1513–28.PubMedCrossRefGoogle Scholar
  23. 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
  24. 24.
    Möller HJ. Antidepressants: controversies about their efficacy in depression, their effect on suicidality and their place in a complex psychiatric treatment approach. World J Biol Psychiatry. 2009;10(3):180–95.PubMedCrossRefGoogle Scholar
  25. 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
  26. 26.
    Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003;361(9358):653–61.PubMedCrossRefGoogle Scholar
  27. 27.
    Quitkin FM, Stewart JW, McGrath PJ, Tricamo E, Rabkin JG, Ocepek-Welikson K, et al. Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo. Br J Psychiatry Suppl. 1993;21:30–4.PubMedGoogle Scholar
  28. 28.
    Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord. 2000;58(1):19–36.PubMedCrossRefGoogle Scholar
  29. 29.
    Thase ME, Trivedi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 1995;12(3):185–219.PubMedCrossRefGoogle Scholar
  30. 30.
    Lotufo-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology. 1999;20(3):226–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Thase ME, Pritchett YL, Ossanna MJ, Swindle RW, Xu J, Detke MJ. Efficacy of duloxetine and selective serotonin reuptake inhibitors: comparisons as assessed by remission rates in patients with major depressive disorder. J Clin Psychopharmacol. 2007;27:672–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Mojtabai R, Olfson M. National patterns in antidepressant treatment by psychiatrists and general medical providers: results from the National Comorbidity Survey replication. J Clin Psychiatry. 2008;69(7):1064–74.PubMedCrossRefGoogle Scholar
  34. 34.
    Hollon SD, Jarrett RB, Nierenberg AA, Thase ME, Trivedi M, Rush AJ. Psychotherapy and medication in the treatment of adult and geriatric depression: which monotherapy or combined treatment? J Clin Psychiatry. 2005;66(4):455–68.PubMedCrossRefGoogle Scholar
  35. 35.
    Gaffan EA, Tsaousis I, Kemp-Wheeler SM. Researcher allegiance and meta-analysis: the case of cognitive therapy for depression. J Consult Clin Psychol. 1995;63:966–80.PubMedCrossRefGoogle Scholar
  36. 36.
    Luborsky L, Diguer L, Seligman D, Rosenthal R, Krause E, Johnson S, et al. The researcher’s own therapy allegiances: a “wild card” in comparisons of treatment efficacy. Clin Psychol Sci and Practice. 1999;6:95–106.CrossRefGoogle Scholar
  37. 37.
    Thase ME, Greenhouse JB, Frank E, Reynolds 3rd CF, Pilkonis PA, Hurley K, et al. Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry. 1997;54(11):1009–15.PubMedGoogle Scholar
  38. 38.
    Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000;342(20):1462–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Schramm E, van Calker D, Dykierek P, Lieb K, Kech S, Zobel I, et al. An intensive treatment program of interpersonal psychotherapy plus pharmacotherapy for depressed inpatients: acute and long-term results. Am J Psychiatry. 2007;164(5):768–77.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Philadelphia Veterans Affairs Medical Center, Perelman School of Medicine of the University of PennsylvaniaUniversity of Pittsburgh Medical CenterPhiladelphiaUSA

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