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

Abstract

Introduction: Psychotropic medications are frequently prescribed alongside trauma-focused psychotherapy for post-traumatic 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 (EMDR) therapy, 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 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.