Nocebo in Alzheimer's disease; meta-analysis of placebo-controlled clinical trials

• Nocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome.
• In RCTs for Alzheimer's disease one out of fifteen patients treated with placebo drops out because of AEs.
• In RCTs for Alzheimer's disease three out of five patients treated with placebo experience adverse events.
• Nocebo deserves much more attention when designing clinical trials.

Background and purposeNocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in Randomized Controlled Studies (RCTs) for Alzheimer's Disease (AD).MethodsAfter a systematic Medline search for RCTs for AD pharmacological treatments, we assessed the number of placebo-treated patients reporting at least one AE and the number of discontinuations because of placebo intolerance and searched for factors correlating to nocebo's extent.ResultsData were extracted from 20 RCTs fulfilling our search criteria. Of 3049 placebo-treated patients, 57.8% (95% CI: 50.1%–66.7%) reported at least one AE and 6.6% (95% CI: 5.3%–8.4%) discontinued placebo treatment because of AEs. All patients participating in these RCTs reported similar AEs independently of the study arm they belonged. Nocebo AE rate and dropout rate were positively related to study population size. The rates of AEs and dropouts because of AEs were parallel between placebo and active arms of RCTs (r = 0.812, p < 0.001 and r = 0.787, p < 0.001, respectively). Effectiveness rates correlated significantly to ΑΕs rate and dropout rate because of AEs in placebo treated patients (r = 0.787, p < 0.001 and r = 0.812, p < 0.001, respectively).ConclusionIn RCTs for AD one out of fifteen patients treated with placebo dropped out because of AEs and three out of five experienced AEs indicating that adherence and effectiveness may be adversely affected with additional implications for clinical practice. The principal implications of this paper are that nocebo deserves much.