Depression burden and differential treatment effects in PTSD and substance use disorder comorbidity: findings from Project Harmony

Background: Depression commonly co-occurs with posttraumatic stress disorder (PTSD) and substance use disorders (SUDs), yet it remains unclear whether depression meaningfully alters treatment response for individuals with PTSD/SUD. Prior studies have examined depression as an individual predictor with mixed findings but no studies to date have evaluated depression’s moderating role across a broad range of PTSD/SUD treatment modalities using harmonised individual patient data (IPD).Objective: To determine whether baseline depression moderates within- and post-treatment changes in PTSD symptom severity, alcohol use, and drug use across trauma-focused, SUD focused, integrated and pharmacologic interventions in a large PTSD/SUD IPD treatment dataset.Method: Data were drawn from Project Harmony, an individual patient data meta-analysis of 36 randomised controlled trials. Latent PTSD, alcohol, and drug use severity outcomes were estimated using moderated nonlinear factor analysis. Treatment effects were evaluated longitudinally using multilevel models with propensity score weighting. Depression was examined as both an individual-level and study-level moderator.Results: Analyses did not detect moderation of individual-level depression across outcomes. In contrast, study-level depression burden significantly moderated selected treatment effects, such that the proportion of participants with depression within each original RCT shaped treatment response. In studies with higher depression burden, trauma-focused psychotherapy produced stronger post-treatment reductions in PTSD symptom severity and alcohol use but smaller in-treatment improvements. Integrated trauma-focused psychotherapy demonstrated comparatively better in-treatment PTSD outcomes. High-depression contexts yielded attenuated PTSD improvements and mixed effects on alcohol use for SUD-focused psychotherapy.Conclusion: Analyses did not detect evidence that baseline depression, as operationalised within this harmonised dataset, moderated treatment response at the individual level. In contrast, study-level depression burden was associated with differential treatment effects across treatment modalities. These findings suggest that characteristics of treatment populations may influence comparative treatment performance and warrant further investigation in implementation and comparative effectiveness research.