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Meta-Analysis
. 2025 Jul;45(7):363-371.
doi: 10.1007/s40261-025-01451-w. Epub 2025 Jun 19.

Association of Placebo Response with Effect Size in Randomized, Double-Blind Clinical Trials of Antidepressants in Children and Adolescents: A Systematic Review and Meta-analysis

Risa Okubo  1 , Kazuhiro Matsui  2 , Mamoru Narukawa  2
Affiliations
Meta-Analysis

Association of Placebo Response with Effect Size in Randomized, Double-Blind Clinical Trials of Antidepressants in Children and Adolescents: A Systematic Review and Meta-analysis

Risa Okubo et al. Clin Drug Investig. 2025 Jul.

Abstract

Background and objective: Many randomized clinical trials (RCTs) of antidepressants in children and adolescents have failed to demonstrate their efficacy. This study examined the association between the placebo response and effect size in RCTs of antidepressants in children and adolescents assessed using the Children's Depression Rating Scale-Revised (CDRS-R).

Methods: PubMed and ClinicalTrials.gov databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants for the acute treatment of major depressive disorder in children and adolescents. The outcome for the present study was the mean change in the CDRS-R total score from baseline to the primary assessment time-point for the placebo and active drug arm. The effect size was calculated using Hedges' g.

Results: The analysis included 21 RCTs. There was a correlation between larger effect size and smaller placebo response. In clinical trials with fluoxetine, effect sizes were significantly greater in those with a placebo lead-in period than in those without.

Conclusions: The difference between the active drug and placebo was maximized when the placebo response was reduced. The placebo lead-in period was an important factor for obtaining superior results in clinical trials of antidepressants in adolescents and children evaluated using the CDRS-R.

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Conflict of interest statement

Declarations. Funding: This study was not supported by any external funding. Conflicts of Interest: The authors declare no conflicts of interest. Risa Okubo is an employee of Janssen Pharmaceutical K.K. Data Availability: All data generated or analyzed during this study are included in this article and its supplementary information files. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Code Availability: Not applicable. Author Contributions: Risa Okubo and Mamoru Narukawa designed the study and interpreted the data. Kazuhiro Matsui performed the data analysis. Risa Okubo drafted the manuscript. Mamoru Narukawa and Kazuhiro Matsui revised the manuscript. All authors have approved the submitted version of the manuscript and agreed to be accountable for any part of the work.

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