Twenty years after ‘Listening to Prozac but hearing placebo’. Do we hear placebo even louder?
More details
Hide details
Submission date: 2018-09-11
Final revision date: 2018-11-04
Acceptance date: 2018-12-06
Online publication date: 2019-03-06
Publication date: 2019-03-07
Health Psychology Report 2019;7(1):1–8
An active placebo is a substance that produces side effects similar to an active ingredient while not producing the same intended therapeutic effect. The aim of this study is to review the literature on the hypothesis of the active placebo response as a mechanism of action of antidepressants.
It was found that persons who expect the occurrence of side effects of a pure placebo taken under the guise of an antidepressant present a higher degree of depressive symptoms than persons who do not expect the occurrence of side effects.
There are reasons to believe that the entirety or part of the difference in the effectiveness of antidepressants and placebo is due to the fact that participants of the clinical trials correctly guess which study group they have been assigned to.
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Washington: APA Publishing.
Angoa-Pérez, M., Kane, M. J., Briggs, D. I., Herrera-Mundo, N., Sykes, C. E., Francescutti, D. M., & Kuhn, D. M. (2014). Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype. ACS chemical neuroscience, 5, 908–919.
Aronson, R., Offman, H. J., Joffe, R. T., & Naylor, C. D. (1996). Triiodothyronine augmentation in the treatment of refractory depression: a meta-analysis. Archives of General Psychiatry, 53, 842–848.
Barbui, C., Cipriani, A., Patel, V., Ayuso-Mateos, J. L., & van Ommeren, M. (2011). Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis. British Journal of Psychiatry, 198, 11–16.
Bauer, M., & Döpfmer, S. (1999). Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. Journal of Clinical Psychopharmacology, 19, 427–434.
Bąbel, P. (2006). Placebo i nocebo. Próba integracji [Placebo and nocebo. An attempt to integrate the terms]. Przegląd Psychologiczny, 49, 141–156.
Beck, A. T., & Alford, B. A. (2009). Depression: Causes and treatment. Philadelphia: University of Pennsylvania Press.
Capezzani, L., Ostacoli, L., Cavallo, M., Carletto, S., Fernandez, I., Solomon, R., Pagani, M., & Cantelmi, T. (2013). EMDR and CBT for cancer patients: Comparative study of effects on PTSD, anxiety, and depression. Journal of EMDR Practice and Research, 7, 134–143.
Cowen, P. J. (2008). Serotonin and depression: pathophysiological mechanism or marketing myth? Trends in Pharmacological Sciences, 29, 433–436.
Cuijpers, P., Li, J., Hofmann, S. G., & Andersson, G. (2010). Self-reported versus clinician-rated symptoms of depression as outcome measures in psychotherapy research on depression: a meta-analysis. Clinical Psychology Review, 30, 768–778.
Dawes, R. M. (1998). “Listening to Prozac but hearing placebo”: Commentary on Kirsch and Sapirstein. Prevention & Treatment, 1.
Deacon, B. J., & Spielmans, G. I. (2017). Is the efficacy of “antidepressant” medications overrated? In S. O. Lilienfeld & I. D. Waldman (Eds.), Psychological science under scrutiny (pp. 250–270). Hoboken, NJ: John Wiley & Sons, Inc.
Dolińska, B. (2011). Placebo. Dlaczego działa coś, co nie działa? [Placebo. Why it works when it doesn’t work?]. Sopot: Smak Słowa.
Driessen, E., Cuijpers, P., de Maat, S. C., Abbass, A. A., de Jonghe, F., & Dekker, J. J. (2010). The efficacy of short-term psychodynamic psychotherapy for depression: a meta-analysis. Clinical Psychology Review, 30, 25–36.
Dydak, K., Sliwinska-Mosson, M., & Milnerowicz, H. (2016). Psilocybin as an alternative medicine for patients suffering from depression. Psychiatria i Psychologia Kliniczna, 16, 165–170.
Edmond, T., Rubin, A., & Wambach, K. G. (1999). The effectiveness of EMDR with adult female survivors of childhood sexual abuse. Social Work Research, 23, 103–116.
Ernst, E. (1995). St. John’s Wort, an anti-depressant? A systematic, criteria-based review. Phytomedicine, 2, 67–71.
Faria, V., Gingnell, M., Hoppe, J. M., Hjorth, O., Alaie, I., Frick, A., Hultberg, S., Wahlstedt, K., Engman, J., Månsson, K. N. T., Carlbring, P., Andersson, G., Reis, M., Larsson, E. M., Fredrikson, & M., Furmark, T. (2017). Do you believe it? Verbal suggestions influence the clinical and neural effects of escitalopram in social anxiety disorder: a randomized trial. EBioMedicine, 24, 179–188.
Furukawa, T. A., Streiner, D., Young, L. T., & Kinoshita, Y. (2001). Antidepressants plus benzodiazepines for major depression. London: The Cochrane Library.
Gençöz, F., Gençöz, T., & Soykan, A. (2007). Psychometric properties of the Hamilton Depression Rating Scale and other physician-rated psychiatric scales for the assessment of depression in ESRD patients undergoing hemodialysis in Turkey. Psychology, Health & Medicine, 12, 450–459.
Greenberg, R. P., Bornstein, R. F., Fisher, S., Zborowski, M. J., & Greenberg, M. D. (1994). A meta-analysis of fluoxetine outcome in the treatment of depression. The Journal of Nervous and Mental Disease, 182, 547–551.
Gu, Q., Dillon, C. F., & Burt, V. L. (2010). Prescription drug use continues to increase: US prescription drug data for 2007-2008. NCHS Data Brief, 42, 1–8.
Hamilton, M. (1986). The Hamilton rating scale for depression. In M. Hamilton (Ed.), Assessment of depression (pp. 143–152). Heidelberg: Springer.
Hieronymus, F., Lisinski, A., Nilsson, S., & Eriksson, E. (2017). Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression. Molecular Psychiatry, 23, 1731–1736.
Hofmann, S. G., Asnaani, A., Vonk, I. J., Sawyer, A.T., & Fang, A. (2012). The efficacy of cognitive behavioral therapy: A review of meta-analyses. Cognitive Therapy and Research, 36, 427–440.
Hughes, S., Lacasse, J., Fuller, R. R., & Paulding-Givens, J. (2017). Adverse effects and treatment satisfaction among online users of four antidepressants. Psychiatry Research, 255, 78–86.
Huneke, N. T., Walsh, A. E., Brown, R., Browning, M., & Harmer, C. J. (2017). No evidence for an acute placebo response on emotional processing in healthy volunteers. Journal of Psychopharmacology, 31, 1578–1587.
Hypericum Depression Trial Study Group (2002). Effect of Hypericum perforatum (St John’s wort) in major depressive disorder: a randomized controlled trial. Journal of the American Medical Association, 287, 1807–1814.
Jakobsen, J. C., Katakam, K. K., Schou, A., Hellmuth, S. G., Stallknecht, S. E., Leth-Møller, K., & Krogh, J. (2017). Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and trial sequential analysis. BMC Psychiatry, 17, 58.
Jensen, J. S., Bielefeldt, A. Ø., & Hróbjartsson, A. (2017). Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: A methodological overview. Journal of Clinical Epidemiology, 87, 35–46.
Keller, M. B., Ryan, N. D., Strober, M., Klein, R. G., Kutcher, S. P., Birmaher, B., Hagino, O. R., Koplewicz, H., Carlson, G. A., Clarke, G. N., Emslie, G. J., Feinberg, D., Geller, B., Kusumakar, V., Papatheodorou, G., Sack, W. H., Sweeney, M., Wagner, K. D., Weller, E. B., Winters, N. C., Oakes, R., & McCafferty, J. P. (2001). Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 762–772.
Khan, A., Fahl Mar, K., Faucett, J., Khan Schilling, S., & Brown, W. A. (2017). Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987-2013. World Psychiatry, 16, 181–192.
Kirsch, I. (2014). Antidepressants and the placebo response. Zeitschrift für Psychologie, 222, 128–134.
Kirsch, I. (2009). The Emperor’s New Drugs. London: The Bodley Head.
Kirsch, I., & Sapirstein, G. (1998). Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment, 1.
Klein, D. F. (1998). Listening to meta-analysis but hearing bias. Prevention & Treatment, 1.
Klemow, K. M., Bilbow, E., Grasso, D., Jones, K., McDermott, J., & Pape, E. (2011). Medical attributes of St. John’s wort (Hypericum perforatum). In I. F. F. Benzie & S. Wachtel-Galor (Eds.), Herbal Medicine (2nd ed., pp. 757–780). Boca Raton, FL: CRC Press/Taylor & Francis.
Koszewska, I. (2003). Dziurawiec zwyczajny w leczeniu depresji [St. John’s wort in the treatment of depression]. Farmakoterapia w Psychiatrii i Neurologii, 1, 45–54.
Kube, T., & Rief, W. (2017). Are placebo and drug-specific effects additive? Questioning basic assumptions of double-blinded randomized clinical trials and presenting novel study designs. Drug Discovery Today, 22, 729–735.
Lacasse, J. R., & Leo, J. (2015). Challenging the narrative of chemical imbalance. In B. Probst (Ed.), Critical Thinking in Clinical Diagnosis and Assessment (pp. 275–282). New York: Springer.
Le Noury, J., Nardo, J. M., Healy, D., Jureidini, J., Raven, M., Tufanaru, C., & Abi-Jaoude, E. (2015). Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. British Medical Journal, 351, h4320.
Linde, K., Berner, M. M., & Kriston, L. (2008). St John’s wort for major depression. Cochrane Database of Systematic Reviews, 4.
Lund, K., Vase, L., Petersen, G. L., Jensen, T. S., & Finnerup, N. B. (2014). Randomised controlled trials may underestimate drug effects: balanced placebo trial design. Public Library of Science One, 9, e84104.
Moncrieff, J., Wessely, S., & Hardy, R. (2004). Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews, 1.
Netz, Y. (2017) Is the comparison between exercise and pharmacologic treatment of depression in the clinical practice guideline of the American College of Physicians evidence-based? Frontiers in Pharmacology, 8, 257.
NHMRC (2015). NHMRC Statement: Statement on Homeopathy. Retrieved from [accessed 09.2017].
Osher, Y., & Belmaker, R. H. (2009). Omeg-3 fatty acids in depression: A review of three studies. CNS Neuroscience & Therapeutics, 15, 128–133.
Ostroff, R. B., & Nelson, J. C. (1999). Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. The Journal of Clinical Psychiatry, 60, 256–259.
Rabkin, J. G., Markowitz, J. S., Stewart, J., McGrath, P., 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.
Ramel, W., Goldin, P. R., Carmona, P. E., & McQuaid, J. R. (2004). The effects of mindfulness meditation on cognitive processes and affect in patients with past depression. Cognitive Therapy and Research, 28, 433–455.
Reuters (2015). Analysis of GSK’s Seroxat antidepressant finds key data was held back. Retrieved from [accessed March 16, 2017].
Rutherford, B. R., Wall, M. M., Brown, P. J., Choo, T. H., Wager, T. D., Peterson, B. S., Chung, S., Kirsch, I., & Roose, S. P. (2016). Patient expectancy as a mediator of placebo responses in antidepressant clinical trials. American Journal of Psychiatry, 174, 135–142.
Rybakowski, J. (2011). Leki stosowane w chorobach afektywnych [Pharmacological treatment in affective disorders]. In M. Jarema & J. Rabe-Jabłońska (Eds.), Psychiatria: podręcznik dla studentów medycyny [Psychiatry for medical students] (pp. 457–534). Warszawa: Wydawnictwo Lekarskie PZW.
Siwak, S., Oronowicz-Jaśkowiak, W., & Oronowicz-Jaśkowiak, A. (2017). Efekt leczenia antydepresantami może sprowadzać się do wzmocnionego efektu placebo. Przegląd literatury [The effect of treatment with antidepressant drugs is equivalent to the enhanced placebo effect. The empirical support of the Irving Kirsch’s theory]. In E. Bajek & B. A. Nowak (Eds.), Choroby XXI w. – analiza współczes-.
nej sytuacji zdrowotnej [Diseases of the 21st century - analysis of the current health situation] (pp. 133–141). Lublin: Wydawnictwo Naukowe Tygiel.
Sneed, J. R., Rutherford, B. R., Rindskopf, D., Lane, D. T., Sackeim, H. A., & Roose, S. P. (2008). Design makes a difference: a meta-analysis of antidepressant response rates in placebo-controlled versus comparator trials in late-life depression. The American Journal of Geriatric Psychiatry, 16, 65–73.
Stahl, S. (1994). 5HT1A receptors and pharmacotherapy. Is serotonin receptor down-regulation linked to the mechanism of action of antidepressant drugs? Psychopharmacology Bulletin, 30, 39–43.
Viksveen, P., Relton, C., & Nicholl, J. (2017). Depressed patients treated by homeopaths: a randomised controlled trial using the “cohort multiple randomised controlled trial” (cmRCT) design. Trials, 18, 299.
Zhang, Z. J., Tan, Q. R., Tong, Y., Li, Q., Kang, W. H., Zhen, X. C., & Post, R. M. (2008). The effectiveness of carbamazepine in unipolar depression: a double-blind, randomized, placebo-controlled study. Journal of Affective Disorders, 109, 91–97.
Copyright: © Institute of Psychology, University of Gdansk This is an Open Access journal, all articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.