Meta-Analysis of Placebo Response in Adult Antidepressant Trials
Roughly 80% of the symptom improvement experienced on antidepressants in clinical trials is also observed in the placebo comparison group. Understanding the correlates of placebo improvement and response is important to designing efficient and successful trials of future antidepressants.
The objective of this meta-analysis was to investigate the magnitude of placebo symptom improvement and placebo response rates in second-generation antidepressant trials of depression, anxiety, and obsessive-compulsive disorder.
We searched PubMed on 10 June, 2016, with no date or language limits, to identify randomized placebo-controlled trials of second-generation antidepressants in adults with depression, anxiety, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the magnitude of placebo symptom improvement using standardized mean difference and placebo response rate. Stratified subgroup analysis and meta-regression were utilized to examine the effect of diagnostic indication and correlates of placebo symptom improvement.
The meta-analysis included 164 trials involving 19,591 participants. Magnitude of placebo improvement and placebo response rates varied significantly between diagnostic indications. The magnitude of placebo improvement was much lower in obsessive-compulsive disorder (standardized mean difference = 0.58, 95% confidence interval 0.36–0.79) than in depression (standardized mean difference = 1.22, 95% confidence interval 1.12–1.32) or anxiety (standardized mean difference = 1.01, 95% confidence interval 0.90–1.12) trials. There was a large amount of heterogeneity in placebo improvement between studies (Q = 899, df = 110, p < 0.001, I2 = 88%). A greater number of study sites and a later publication year were associated with a greater magnitude of placebo improvement and response rate. Presence of a placebo lead-in and absence of non-US sites were associated with a reduced magnitude of placebo improvement. Trial duration was positively associated with the magnitude of placebo improvement in depression trials but negatively associated with the magnitude of placebo improvement in anxiety and obsessive-compulsive disorder trials.
Magnitude of placebo symptom improvement differed significantly based on diagnostic indication with improvement being significantly less in obsessive-compulsive disorder than anxiety and depression. Some trial characteristics were associated with a greater magnitude of placebo improvement in trials across disorders but others were disorder specific.
The authors are grateful to Chad Beyer and Kiley Cappetta for their assistance in the study selection and data extraction.
Compliance with Ethical Standards
No sources of funding were received for the preparation of this article.
Conflict of interest
Michael H. Bloch receives research support from Therapix Biosciences, Neurocrine Biosciences, Janssen Pharmacueticals, and Biohaven Pharmaceuticals. He also gratefully acknowledges additional research support from NIH, NARSAD, and the Patterson Foundation. Fenghua Li, Madeeha Nasir, and Baris Olten have no conflicts of interest that are directly relevant to the content of this article. This article was completed in compliance with the recommendations for the Conduct, Reporting, Editing and Publication of Scholarly work in Medical Journals’ issued by the International Committee for Medical Journal Editors.
- 3.Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress Anxiety. 2010;27(5):417–25.CrossRefPubMedGoogle Scholar
- 23.Locher C, Koechlin H, Zion SR, Werner C, Pine DS, Kirsch I, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(10):1011–20.CrossRefPubMedPubMedCentralGoogle Scholar