title: Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies.
abstract: BACKGROUND
  Previous studies have shown that placebo response rates in antidepressant trials have been increasing since the 1970s. However, these studies have been based on outdated or limited datasets and have used inappropriate statistical methods. We did a systematic review of placebo-controlled randomised controlled trials of antidepressants to examine associations between placebo-response rates and study and patient characteristics.
  
  
  METHODS
  In this systematic review, we searched for published and unpublished double-blind randomised placebo-controlled trials of first-generation and second-generation antidepressants for acute treatment of major depression in adults (update: Jan 8, 2016). The log-transformed proportions of placebo response, defined as 50% or greater reduction in depression severity score from baseline, were meta-analytically synthesised for each year. We then looked for a structural break point in the secular changes in these characteristics through the years and examined the influence of the study year and other trial and patient characteristics on the response rates through meta-regression.
  
  
  RESULTS
  We identified 252 placebo-controlled trials (26 324 patients on placebo) done between 1978 and 2015. There was a structural break in 1991, and since then, the average placebo response rates in antidepressant trials have remained constant in the range between 35% and 40% (relative risk [RR] 1·00, 95% CI 0·97-1·03, p=0·99, for every 5-year increase). The length of the study and the number of study centres were significant factors (RR 1·03, 95% CI 1·01-1·05 for 1 more week in trial length; 1·32, 1·11-1·57 for multicentre vs single-centre trials).
  
  
  CONCLUSIONS
  Contrary to the widely held belief, the average placebo response rates in antidepressant trials have been stable for more than 25 years. This new evidence should have an effect on the interpretation of the scientific literature and the future of psychopharmacology, both from a clinical and methodological point of view.
  
  
  BACKGROUND
  Japan Society for Promotion of Science, Great Britain Sasakawa Foundation.
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan; Department of Clinical Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan.
authors.forename: Toshi A
authors.initials: TA
authors.lastname: Furukawa
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK. Electronic address: andrea.cipriani@psych.ox.ac.uk.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cipriani
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: Lauren Z
authors.initials: LZ
authors.lastname: Atkinson
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Leucht
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takeshima
authors.affiliation: Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hayasaka
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Department of Hygiene and Epidemiology, University of Ioannina, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Chaimani
authors.affiliation: Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Department of Hygiene and Epidemiology, University of Ioannina, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Salanti
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D006801:Humans; D015990:Placebo Effect; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation