Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta‐Analysis

Abstract Background Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. Objective The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. Methods A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta‐regression were performed to explore modifying factors. Results Twenty‐four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of −0.79 (95% confidence interval [CI] −0.99 to −0.59; I 2 = 67%). Forty‐four percent (95% CI 27% to 63%; I 2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. Conclusion There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. Systematic review registration PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.