Background and Objective <p>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).</p> Methods <p>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’ <i>g</i>.</p> Results <p>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.</p> Conclusions <p>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.</p>