Systematic Review and Meta-analysis: Placebo Response in Randomized Controlled Trials of Tourette's Disorder Medications

Objective: To examine the magnitude of placebo response in randomized controlled trials (RCTs) of medications for Tourette's disorder.

Method: CENTRAL, Embase, PubMed, PsycInfo, Web of Science, WHO ICTRP, and ClinicalTrials.gov databases were searched to identify placebo-controlled RCTs assessing pharmacological interventions for Tourette's disorder. Standardized mean change and standardized mean difference were calculated for within-group (placebo, drug) and between-group (drug-placebo) change in tics. Data were pooled in random-effects meta-analysis. Meta-regressions were performed to identify study-level characteristics that could be differentially associated with placebo, drug, and drug-placebo response.

Results: Searchers identified 13,775 records, and 50 RCTs involving 1,566 participants were included in the placebo meta-analysis. Placebo response was medium to large (standardized mean change: -0.62; 95% CI: -0.75, -0.5; I² = 76%; τ² = 0.14). Several factors were associated with larger placebo responses (eg, non-US RCT, industry sponsorship, number of centers and participants). However, there was a moderate-to-high correlation between placebo and drug response (ρ = 0.66; 95% CI: 0.47, 0.79), and factors associated with larger placebo response were also generally associated with larger drug responses. There was not a significant correlation between placebo response and drug-placebo differences (ρ = -0.05; 95% CI: -0.32, 0.22), and factors associated with larger placebo response generally did not interfere in drug-placebo differences.

Conclusion: The magnitude of placebo response in Tourette's disorder may be large, but similar to that in other child and adolescent psychiatric conditions. Clinical researchers may manipulate study-level factors to diminish placebo response (eg, carefully selecting study sites and keeping them at the minimum feasibility). However, drug-placebo differences may not increase as drug response will likely diminish as well.

Study preregistration information: Comparative Efficacy, Tolerability, and Acceptability of Pharmacological Interventions for Chronic Tic Disorders Including Tourette's Syndrome in Children, Adolescents, and Adults: Protocol for a Systematic Review and Network Meta-analysis; https://www.crd.york.ac.uk; CRD42022296975.

Diversity & inclusion statement: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science.