Concomitant Psychotropic Medication is Associated with Reduced Outcomes of Trauma-Focused Psychotherapy for Post-Traumatic Stress Disorder

Introduction: Psychotropic medications are frequently prescribed alongside trauma-focused psychotherapy for posttraumatic stress disorder (PTSD), yet their impact on treatment response remains uncertain. This study emulated target trials to examine the association between psychotropic co-medication at treatment onset and psychotherapy outcomes in a real-world PTSD cohort. Methods: A prospective cohort of 6,125 adults with chronic or delayed-onset PTSD received a standardized 2–8 day trauma-focused psychotherapy program, including daily prolonged exposure and eye movement desensitization and reprocessing, at a Dutch psychotrauma center (2021–2024). Target trial emulation with double machine learning with inverse probability of treatment weighting estimated the effects of specific psychotropic co-medications versus non-use on changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores (range, 0–80) from pre- to post-treatment. Results: Mean CAPS-5 scores improved by 25.7 points (Cohen’s d=–2.30). Psychotropic co-medication (n=1,382) was associated with reduced symptom improvement compared with non-use (model-estimated difference = –2.52 points; relative reduction = –9.4%, 95% CI = –10.0 to –8.9; d=–1.11, E=10.0). This effect that persisted at 6- month follow-up (d=–0.42). Antidepressants overall (d=–0.28; follow-up d=–0.56), amitriptyline (d=–0.51), and mirtazapine (d=–0.29) were consistently associated with poorer outcomes across sensitivity analyses. Similar patterns were observed for anticonvulsants, mood stabilizing anticonvulsants, antipsychotics, fluoxetine, zolpidem, and zopiclone. Sensitivity analyses and E-values indicated robustness to unmeasured confounding. Conclusion: Several psychotropic co-medications were associated with reduced outcomes of evidence-based trauma-focused psychotherapy for PTSD. By identifying this as a potentially modifiable factor, psychotherapy outcomes may be optimized. Trials are warranted to evaluate whether tapering or substituting these agents improves outcomes.