Nocebo in clinical trials for depression: a meta-analysis

Nocebo refers to adverse events (AEs) related to negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo-controlled randomized clinical trials (RCTs). We sought to examine the AEs following placebo administration in RCTs for depression (D). After a systematic Medline search for RCTs in depression published in the last decade we assessed percentages of placebo-treated patients reporting at least one AE or discontinuing due to placebo intolerance and searched for factors influencing nocebo's extent. Data were extracted from 21 RCTs fulfilling search criteria. Of 3255 placebo-treated patients, 44.7% (95% CI: 22.3-68.3%) reported at least one AE, and 4.5% (95% CI: 3.4-5.8%) discontinued placebo treatment due to intolerance. AE rates in placebo and active drug treated patients were correlated quantitatively (r=0.915, p<0.001) and qualitatively, but not dropout rates (r=0.047). We conclude that almost one out of 20 placebo treated patients discontinued treatment due to AEs, indicating a significant nocebo in trials for depression treatment adversely affecting adherence and efficacy of current treatments in clinical practice, with additional implications for trial designing.