Episode duration and severity as predictors of placebo response in major depressive disorder

The purpose of this study was to examine the effects of two patient-level factors, episode duration and severity, on placebo response in antidepressant clinical trials. To do this we conducted a secondary analysis of seven 8-week, randomized, double-blind, placebo-controlled trials of desvenlafaxine (50–400 mg/d) for acute major depressive disorder ( n = 3647). Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale. Subgroup variables were used to stratify participants according to episode severity (baseline depression score) and chronicity (episode duration ≥ 24 months). Effects on response rates were tested with logistic regression models. Chronicity and severity were unrelated; both variables were associated with lower placebo response rates, but neither moderated the efficacy of desvenlafaxine over placebo, as evidenced by nonsignificant subgroup-treatment interactions. Overall, the results suggest that chronicity and severity are general prognostic indicators and did not support the notion that drug-placebo differences could be meaningfully increased by selectively recruiting clinical trial participants based on these criteria. © 2026 The Authors.