Discontinuing Psychotropic Medication Before Trauma-Focused Psychotherapy for PTSD: A Policy-Driven Target Trial Emulation

Background and rationale A previous prospective cohort study of more than 6,000 patients receiving standardized intensive trauma-focused psychotherapy for PTSD at a high-volume psychotrauma expertise center during 2021-2024 found that concomitant use of several psychotropic medications was associated with smaller reductions in PTSD symptoms (https://doi.org/10.1159/000549259). Analyses adjusted for 27 baseline covariates. Psychotropic co-medication overall was associated with reduced symptom improvement compared with non-use, and this association persisted at 6-month follow-up. Antidepressants overall, amitriptyline, and mirtazapine showed consistent associations with poorer outcomes across sensitivity analyses. Anticonvulsants, antipsychotics, mood-stabilizing anticonvulsants, fluoxetine, zolpidem, and zopiclone showed similar negative associations, although estimates were less consistent across sensitivity analyses.

An important threat to causal inference in comparisons of psychotropic medication users with non-users is confounding by indication: patients receiving psychotropic medication had greater baseline PTSD symptom severity and psychiatric comorbidity. The present study will address this problem by comparing patients using a specific medication under two different clinical policies: patients who continued that medication during psychotherapy in 2021-2024 and patients for whom discontinuation of the same medication will be initiated before psychotherapy under the revised 2026 policy. Together with adjustment for baseline differences, this same-medication comparison will substantially improve clinical comparability. The principal remaining alternative explanation is a secular change in psychotherapy outcomes or patient characteristics between the historical and post-policy periods, which will be examined in dedicated sensitivity analyses. This design will significantly reduce residual confounding and strengthens the plausibility of a causal interpretation.

The purpose of this policy-driven natural experiment will therefore be to investigate whether tapering and discontinuing selected psychotropic medications before intensive trauma-focused psychotherapy, when clinically appropriate, is associated with greater improvement in PTSD symptoms than continuation of the same medications during psychotherapy.

Study design This will be an observational target trial emulation based on a policy-driven natural experiment. In September 2026, the center PSYTREC (Zeist, the Netherlands) will introduce a revised clinical medication-review protocol in which current and recent psychotropic medication use and treatment indication are systematically verified using available clinical and pharmacy information.

The target medications are amitriptyline, mirtazapine, quetiapine, topiramate, zolpidem, and zopiclone when prescribed off-label for PTSD-related symptoms. Under the revised policy, tapering and discontinuation before psychotherapy are initiated when clinically appropriate and safe. Medication management remains part of routine clinical care rather than a randomized research intervention. Tapering schedules are individualized according to medication, dose, duration of use, symptoms, withdrawal effects, and clinical circumstances. Psychotherapy can be postponed or the medication strategy modified when clinically necessary.