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.