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

Abstract

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. 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. 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. 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.