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 But analyses of the published data and the unpublished data that were hidden by the drug companies reveal that most (if not all) of the benefits are due to the placebo effect.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 to any theory in the history of science 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.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Andrews PW, Thomson JA, Amstadter A, Neale MC (2012) Primum non nocere: an evolutionary analysis of whether antidepressants do more harm than good. Front Psychol 3:117. doi:10.3389/fpsyg.2012.00117
Babyak MA, Blumenthal JA, Herman S, Khatri P, Doraiswamy PM, Moore KA et al (2000) Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med 62:633–638
Beutler LE (1998) Prozac and placebo: there’s a pony in there somewhere. Prevention Treatment 1, 0003c
Chen JA, Papakostas GI, Youn S, Baer L, Clain AJ, Fava M, Mischoulon D (2011) Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group. J Clin Psychiatry 72(12):1669–1676
Dobson KS, Hollon SD, Dimidjian S, Schmaling KB, Kohlenberg RJ, Gallop RJ et al (2008) Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression. J Consult Clin Psychol 76(3):468–477
Domar AD, Moragianni VA, Ryley DA, Urato AC (2013) The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. Hum Reprod 28(1):160–171. doi:10.1093/humrep/des383
Fountoulakis KN, Möller HJ (2011) Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. Int J Neuropsychopharmacol 14(3):405
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC et al (2010) Antidepressant drug effects and depression severity: a patient-level meta-analysis. J Am Med Assoc 303(1):47–53
Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M et al (2011) Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder. Ann Intern Med 155(11):772–785. doi:10.1059/0003-4819-155-11-201112060-00009
Hollon SD, DeRubeis RJ, Shelton RC, Weiss B (2002) The emperor’s new drugs: effect size and moderation effects. Prevention Treatment 5:Article 27. Available on the World Wide Web: http://www.journals.apa.org/prevention/volume5/pre0050027c.html
Huedo-Medina TB, Johnson BT, Kirsch I (2012) Kirsch et al.’s (2008) calculations are correct: reconsidering Fountoulakis & Möller’s re-analysis of the Kirsch data. Int J Neuropsychopharmacol 1(1):1–6
Hunter AM, Leuchter AF, Morgan ML, Cook IA (2006) Changes in brain function (quantitative EEG cordance) during placebo lead-in and treatment outcomes in clinical trials for major depression. Am J Psychiatr 163(8):1426–1432
Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP et al (2010) Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS ONE 5(12):e15591. doi:10.1371/journal.pone.0015591
Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M (2012) Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother Psychosom 81(5):312–314
Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown WA (2012) A systematic review of comparative efficacy of treatments and controls for depression. PLoS ONE 7(7):e41778. doi:10.1371/journal.pone.0041778
Khin NA, Chen YF, Yang Y, Yang P, Laughren TP (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. J Clin Psychiatry 72(4):464
Kirsch I (1998) Reducing noise and hearing placebo more clearly. Prevention Treatment 1(2):7r. doi:10.1037/1522-3736.1.1.17r
Kirsch I (2009) The emperor’s new drugs: exploding the antidepressant myth. The Bodley Head, London
Kirsch I, Sapirstein G (1998) Listening to prozac but hearing placebo: a meta-analysis of antidepressant medication. Prevention Treatment 1, 0002a. doi:10.1037/1522-3736.1.1.12a
Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002) The emperor’s new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention Treatment 5, 23
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5(2):e45. doi:10.1371/journal.pmed.0050045
Klein DF (1998) Listening to meta-analysis but hearing bias. Prevention Treatment 1, 0006c
Leber, P (1998) NDA 20-822 Celexa (citalopram HBr) for the management of depression. Memorandum to the Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research. Approvable action on Forrest Laboratories, Inc, Washington, DC
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. Br Med J 326:1171–1173
NICE (2004) Depression: management of depression in primary and secondary care. Clinical practice guideline No 23. www.nice.org.uk/page.aspx?o=235213. Accessed 24 May 2005
Quitkin FM, McGrath PJ, Stewart JW, Ocepek-Welikson K, Taylor BP, Nunes E et al (1998) Placebo run-in period in studies of depressive disorders: clinical, heuristic and research implications. Br J Psychiatry 173:242–248
Rabkin JG, Markowitz JS, Stewart JW, McGrath PJ, Harrison W, Quitkin FM et al (1986) How blind is blind? Assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and phenelzine. Psychiatry Res 19:75–86
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. Can J Psychiatry 56(4):198–208
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatr 163:1905–1917
Rutherford BR, Sneed JR, Roose SP (2009) Does study design influence outcome? Psychother Psychosom 78(3):172–181
Serretti A, Chiesa A (2009) Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol 29(3):259–266
Simon GE, VonKorff M (1997) Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatr 154(10):1417–1423
Teasdale JD (1985) Psychological treatments for depression: how do they work? Behav Res Ther 23:157–165
Thase ME (2002) Antidepressant effects: the suit may be small, but the fabric is real. Prevention Treatment 5(32)
Tilburt JC, Emanuel EJ, Kaptchuk TJ, Curlin FA, Miller FG (2008) Prescribing “placebo treatments”: results of national survey of US internists and rheumatologists. Br Med J 337:1097–1100. doi:10.1136/bmj.a1938
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R (2008) Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358:252–260
Wagstaff AJ, Ormrod D, Spencer CM (2001) Tianeptine: a review of its use in depressive disorders. CNS Drugs 15:231–259
Wiegand MH (2008) Antidepressants for the treatment of insomnia: a suitable approach? Drugs 68(17):2411–2417
Zimmerman M, Chelminski I, Posternak MA (2005) Generalizability of antidepressant efficacy trials: differences between depressed psychiatric outpatients who would or would not qualify for an efficacy trial. Am J Psychiatr 162(7):1370–1372. doi:10.1176/appi.ajp.162.7.1370
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Kirsch, I. (2014). The Emperor’s New Drugs: Medication and Placebo in the Treatment of Depression. In: Benedetti, F., Enck, P., Frisaldi, E., Schedlowski, M. (eds) Placebo. Handbook of Experimental Pharmacology, vol 225. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44519-8_16
Download citation
DOI: https://doi.org/10.1007/978-3-662-44519-8_16
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-44518-1
Online ISBN: 978-3-662-44519-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)