title: Nocebo in clinical trials for depression: a meta-analysis.
abstract: 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.
authors.affiliation: Neurology Department, Athens Naval Hospital, 77A Vas. Sofias Avenue, 11521 Athens, Greece. Electronic address: dmitsikostas@ath.forthnet.gr.
authors.forename: Dimos D
authors.initials: DD
authors.lastname: Mitsikostas
authors.affiliation: First Psychiatric Department, Aeginition Hospital, Athens University, Athens, Greece.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Mantonakis
authors.affiliation: First Psychiatric Department, Aeginition Hospital, Athens University, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Chalarakis
mesh_terms: D000928:Antidepressive Agents / Q000009:adverse effects*; D003863:Depression / Q000188:drug therapy*; D003866:Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D064786:Nocebo Effect; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents
keywords: Adverse events; Clinical trials; Depression; Meta-analysis; Nocebo