Roughly one-third of people with epilepsy remain drug-resistant despite appropriate antiseizure medication, a state associated with higher injury, mortality, and health-care use. Depression and anxiety affect about one quarter to one third of this population and worsen seizure control and utilization.

Contemporary guidance indicates that selective serotonin reuptake inhibitors (SSRIs) are generally safe in epilepsy and not associated with seizure worsening, though vigilance for pharmacokinetic interactions with enzyme-inducing antiseizure medicines is required. Population and meta-analytic data suggest seizure risk with newer antidepressants is low overall and varies by molecule, underscoring the need for real-world comparative data in drug-resistant cohorts. This study emulates a target trial to estimate the effects of initiating SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) on seizure-related outcomes.

We used TriNetX to assemble a cohort of patients with an incident epilepsy diagnosis. Patients were classified as SSRI/SNRI-exposed if they received any SSRI/SNRI prescription within the 14-day window around the index date; all others were classified as unexposed. In both groups, we excluded patients prescribed fewer than two anti-seizure medications and those who received any other anti-depressive medication during the 1-year period before or after the index date. We then performed propensity-score matching on 23 covariates spanning demographics, comorbidities, laboratory values, healthcare utilization behaviors, and concomitant medications. Cox proportional-hazards models were used to estimate hazard ratio for outcomes over 1 year of follow-up.

Among 654,392 patients, propensity-score matching yielded 127,089 per group. Relative to matched controls, exposure was associated with modestly higher healthcare utilization, including outpatient visits, hospitalizations, and emergency department visits, and with increased risks of out-of-hospital brain injury and benzodiazepine use. However, all-cause mortality and critical care use were lower in the exposed group.

Antidepressant use was associated with modest increases in minor adverse events but lower rates of severe outcomes. Prospective randomized trials are warranted.