Ketamine-assisted psychotherapy for posttraumatic stress disorder: a systematic review and individual participant data meta-analysis of predictors of treatment effects

Introduction: Ketamine combined with psychotherapy has shown promise in treating posttraumatic stress disorder (PTSD), but predictors of clinical benefit remain unclear. In this systematic review and individual participant data meta-analysis (IPDMA), we examined patient- and treatment-level predictors of PTSD symptom change after combined treatment. Methods: Eligible studies combined ketamine with psychotherapy in adults with PTSD. The primary outcome was PTSD symptom change on the PTSD Checklist for DSM-5 (PCL-5). We fit linear mixed-effects models with a random intercept for study and fixed effects for age, sex, baseline PCL-5, number of ketamine sessions, number of psychotherapy sessions, administration route, and treatment duration. Sex-stratified analyses and a quality-restricted sensitivity analysis were conducted. Results: Twelve studies (533 participants) were included; nine were of poor quality. Greater improvement was associated with more psychotherapy (β = 1.03 per session) and more ketamine sessions (β = 1.15 per session), higher baseline symptom severity (β = 0.50 per PCL-5 point), and shorter treatment duration (β = −0.58 per week). Between-study heterogeneity was non-trivial (ICC ≈ 0.15). In sex-stratified models, number of psychotherapy sessions, baseline severity, and shorter treatment duration remained associated with improvement in both sexes. In the sensitivity analysis (n = 63), baseline severity was the only significant predictor of treatment outcome. Conclusion: Higher baseline PTSD severity was the most robust predictor of symptom reduction. Session intensity and treatment timing may matter, but associations should be interpreted cautiously given the predominance of poor-quality studies and require replication in prospective trials with standardized protocols and longer follow-up.