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

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

CENTRAL, Embase, PubMed, PsycInfo, Web of Science, WHO ICTRP, and ClinicalTrials.gov databases were searched up to September, 2023 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.

Literature searches 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.

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.

This study utilized data from 50 placebo-controlled clinical trials involving 1,566 participants of medicines for Tourette's disorder to determine the magnitude and correlates of improvement during treatment with placebo. Individuals in the placebo arm experienced considerable improvement throughout the duration of clinical trials, and there were also several study-level factors that were associated with greater improvement in the placebo arm. However, those factors were also generally associated with larger improvement in the drug arm and did not interfere with drug-placebo differences, which inform whether treatments were efficacious or not. The findings are relevant for designing and conducting pharmacological randomized controlled trials in Tourette's disorder.

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/PROSPERO/view/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.