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Open AccessReview Article

Antidepressants and the Placebo Effect

Published Online:February 28, 2015https://doi.org/10.1027/2151-2604/a000176

Abstract

Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed, their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close as any theory in the history of science to having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future.

References

  • Andrews, P. W. , Thomson, J. A. , Amstadter, A. , Neale, M. C. (2012). Primum non nocere: An evolutionary analysis of whether antidepressants do more harm than good. [Review]. Frontiers in Psychology, 3, 117 doi: 10.3389/fpsyg.2012.00117. First citation in articleCrossref, Google Scholar

  • Babyak, M. A. , Blumenthal, J. A. , Herman, S. , Khatri, P. , Doraiswamy, P. M. , Moore, K. A. , … Krishnan, K. R. (2000). Exercise treatment for major depression: Maintenance of therapeutic benefit at 10 months. Psychosomatic Medicine, 62, 633–638. First citation in articleCrossref, Google Scholar

  • Beutler, L. E. (1998). Prozac and placebo: There’s a pony in there somewhere. Prevention & Treatment, 1, 3c doi: 10.1037/1522-3736.1.2.13c. First citation in articleGoogle Scholar

  • Dobson, K. S. , Hollon, S. D. , Dimidjian, S. , Schmaling, K. B. , Kohlenberg, R. J. , Gallop, R. J. , … Jacobson, N. S. (2008). Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression. Journal of Consulting and Clinical Psychology, 76, 468–477. doi: 10.1037/0022-006X.76.3.468 First citation in articleCrossref, Google Scholar

  • Domar, A. D. , Moragianni, V. A. , Ryley, D. A. , Urato, A. C. (2013). The risks of selective serotonin reuptake inhibitor use in infertile women: A review of the impact on fertility, pregnancy, neonatal health and beyond. Human Reproduction, 28, 160–171. doi: 10.1093/humrep/des383 First citation in articleCrossref, Google Scholar

  • Fountoulakis, K. N. , Möller, H. J. (2011). Efficacy of antidepressants: A re-analysis and re-interpretation of the Kirsch data. International Journal of Neuro-Psychopharmacology, 14, 405. First citation in articleGoogle Scholar

  • Fournier, J. C. , DeRubeis, R. J. , Hollon, S. D. , Dimidjian, S. , Amsterdam, J. D. , Shelton, R. C. , Fawcett, J. (2010). Antidepressant drug effects and depression severity: a patient-level meta-analysis. Journal of the American Medical Association, 303, 47–53. doi: 10.1001/jama.2009.1943 First citation in articleCrossref, Google Scholar

  • Gartlehner, G. , Hansen, R. A. , Morgan, L. C. , Thaler, K. , Lux, L. , Van Noord, M. , … Lohr, K. N. (2011). Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder. Annals of Internal Medicine, 155, 772–785. doi: 10.1059/0003-4819-155-11-201112060-00009 First citation in articleCrossref, Google Scholar

  • Hollon, S. D. , DeRubeis, R. J. , Shelton, R. C. , Weiss, B. (2002). The emperor’s new drugs: Effect size and moderation effects. Prevention and Treatment, 5, 28 doi: 10.1037/1522-3736.5.1.528c First citation in articleCrossref, Google Scholar

  • Hunter, A. M. , Leuchter, A. F. , Morgan, M. L. , Cook, I. A. (2006). Changes in brain function (quantitative eeg cordance) during placebo lead-in and treatment outcomes in clinical trials for major depression. American Journal of Psychiatry, 163, 1426–1432. First citation in articleCrossref, Google Scholar

  • Kaptchuk, T. J. , Friedlander, E. , Kelley, J. M. , Sanchez, M. N. , Kokkotou, E. , Singer, J. P. , … Lembo, A. J. (2010). Placebos without deception: A randomized controlled trial in irritable bowel syndrome. PLoS One, 5, e15591 doi: 10.1371/journal.pone.0015591 First citation in articleGoogle Scholar

  • Kelley, J. M. , Kaptchuk, T. J. , Cusin, C. , Lipkin, S. , & Fava, M. (2012). Open-label placebo for major depressive disorder: A pilot randomized controlled trial. Psychotherapy and Psychosomatics, 81, 312–314. First citation in articleCrossref, Google Scholar

  • Khan, A. , Faucett, J. , Lichtenberg, P. , Kirsch, I. , Brown, W. A. (2012). A systematic review of comparative efficacy of treatments and controls for depression. PLoS One, 7, e41778 doi: 10.1371/journal.pone.0041778 First citation in articleGoogle Scholar

  • Khin, N. A. , Chen, Y. F. , Yang, Y. , Yang, P. , Laughren, T. P. (2011). Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. Journal of Clinical Psychiatry, 72, 464–472. doi: 10.4088/JCP.10m06191 First citation in articleCrossref, Google Scholar

  • Kirsch, I. (1998). Reducing noise and hearing placebo more clearly. Prevention & Treatment, 1, 7r doi: 10.1037/1522-3736.1.1.17r First citation in articleGoogle Scholar

  • Kirsch, I. (2009). The emperor’s new drugs: Exploding the antidepressant myth. London, UK: Bodley Head. First citation in articleGoogle Scholar

  • Kirsch, I. , Deacon, B. J. , Huedo-Medina, T. B. , Scoboria, A. , Moore, T. J. , Johnson, B. T. (2008). Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine, 5, e45 doi: 10.1371/journal.pmed.0050045 First citation in articleGoogle Scholar

  • Kirsch, I. , Moore, T. J. , Scoboria, A. , Nicholls, S. S. (2002). The emperor’s new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention and Treatment, 5, 23 doi: 10.1037/1522-3736.5.1.523a First citation in articleCrossref, Google Scholar

  • Kirsch, I. , & Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention and Treatment, 1, 2a doi: 10.1037/1522-3736.1.1.12a First citation in articleGoogle Scholar

  • Klein, D. F. (1998). Listening to meta-analysis but hearing bias. Prevention & Treatment, 1, 6c doi: 10.1037/1522-3736.1.1.16c First citation in articleGoogle Scholar

  • Leber, P. (1998). Approvable action on Forrest Laboratories, Inc. NDA 20-822 Celexa (citalopram HBr) for the management of depression. Memoradum to the Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research. May 4 Washington, DC: FDA. First citation in articleGoogle Scholar

  • Melander, H. , Ahlqvist-Rastad, J. , Meijer, G. , Beermann, B. (2003). Evidence b(i)ased medicine – selective reporting from studies sponsored by pharmaceutical industry: Review of studies in new drug applications. British Medical Journal, 326, 1171–1173. First citation in articleCrossref, Google Scholar

  • NICE . (2004). Depression: Management of depression in primary and secondary care [Clinical practice guideline 23]. London, UK: National Institute for Health and Care Excellence Retrieved from www.nice.org.uk/page.aspx?o=235213 First citation in articleGoogle Scholar

  • Quitkin, F. M. , McGrath, P. J. , Stewart, J. W. , Ocepek-Welikson, K. , Taylor, B. P. , Nunes, E. , … Klein, D. F. (1998). Placebo run-in period in studies of depressive disorders: Clinical, heuristic and research implications. British Journal of Psychiatry, 173, 242–248. First citation in articleCrossref, Google Scholar

  • Rabkin, J. G. , Markowitz, J. S. , Stewart, J. W. , McGrath, P. J. , Harrison, W. , Quitkin, F. M. , & Klein, D. F. (1986). How blind is blind? Assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and phenelzine. Psychiatry Research, 19, 75–86. First citation in articleCrossref, Google Scholar

  • Raz, A. , Campbell, N. , Guindi, D. , Holcroft, C. , Déry, C. , Cukier, O. (2011). Placebos in clinical practice: A Pan-Canadian Review of attitudes and patterns of use between academic psychiatrists and non-psychiatrists. Canadian Journal of Psychiatry, 56, 198–208. First citation in articleGoogle Scholar

  • Rush, A. J. , Trivedi, M. H. , Wisniewski, S. R. , Nierenberg, A. A. , Stewart, J. W. , Warden, D. , … Fava, M. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. American Journal of Psychiatry, 163, 1905–1917. First citation in articleCrossref, Google Scholar

  • Rutherford, B. R. , Sneed, J. R. , Roose, S. P. (2009). Does study design influence outcome? Psychotherapy and Psychosomatics, 78, 172–181. First citation in articleCrossref, Google Scholar

  • Serretti, A. , Chiesa, A. (2009). Treatment-emergent sexual dysfunction related to antidepressants: A meta-analysis. Journal of Clinical Psychopharmacology, 29, 259–266. First citation in articleCrossref, Google Scholar

  • Simon, G. E. , VonKorff, M. (1997). Prevalence, burden, and treatment of insomnia in primary care. American Journal of Psychiatry, 154, 1417–1423. First citation in articleCrossref, Google Scholar

  • Teasdale, J. D. (1985). Psychological treatments for depression: How do they work? Behaviour Research and Therapy, 23, 157–165. First citation in articleCrossref, Google Scholar

  • Thase, M. E. (2002). Antidepressant effects: The suit may be small, but the fabric is real. Prevention & Treatment, 5, 32 doi: 10.1037/1522-3736.5.1.532c First citation in articleCrossref, Google Scholar

  • Tilburt, J. C. , Emanuel, E. J. , Kaptchuk, T. J. , Curlin, F. A. , Miller, F. G. (2008). Prescribing “placebo treatments”: Results of national survey of US internists and rheumatologists. British Medical Journal, 337, 1097–1100. doi: 10.1136/bmj.a1938 First citation in articleCrossref, Google Scholar

  • Turner, E. H. , Matthews, A. M. , Linardatos, E. , Tell, R. A. , Rosenthal, R. (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. New England Journal of Medicine, 358, 252–260. First citation in articleCrossref, Google Scholar

  • Wagstaff, A. J. , Ormrod, D. , Spencer, C. M. (2001). Tianeptine: A review of its use in depressive disorders. CNS Drugs, 15, 231–259. First citation in articleCrossref, Google Scholar

  • Wiegand, M. H. (2008). Antidepressants for the treatment of insomnia: A suitable approach? Drugs, 68, 2411–2417. First citation in articleCrossref, Google Scholar

  • Zimmerman, M. , Chelminski, I. , Posternak, M. A. (2005). Generalizability of antidepressant efficacy trials: Differences between depressed psychiatric outpatients who would or would not qualify for an efficacy trial. American Journal of Psychiatry, 162, 1370–1372. doi: 10.1176/appi.ajp. 162.7.1370 First citation in articleCrossref, Google Scholar