Cenobamate Improves Emotional Dysregulation, Impulsivity, and Apathy in Drug-Resistant Focal Epilepsy: A Longitudinal Neuropsychological Study

Introduction: Although effects on cognitive function have been reported during cenobamate (CNB) treatment, far less is known about how it may affect neuropsychological domains such as apathy, emotion dysregulation, and impulsivity. This prospective longitudinal study aims to assess psychopathological and cognitive changes after CNB introduction in adults with drug-resistant focal epilepsy, accounting for seizure outcome and burden of concomitant anti-seizure medication (ASM). Methods: We consecutively recruited adults with drug-resistant focal epilepsy who had undergone a comprehensive neuropsychological evaluation at baseline, before starting CNB, and at follow-up, 12 months after treatment introduction. The psychopathological battery included Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory, Difficulties in Emotion Regulation Scale (DERS-36), Barratt Impulsiveness Scale (BIS-11), Apathy Evaluation Scale (AES), and Quality of Life in Epilepsy Inventory (QoLIE-31). The cognitive assessment comprised Rey Auditory Verbal Learning Test (RAVLT), Digit-Span, Rey-Osterrieth Complex Figure Test, WEIGL, FAS, Stroop Color and Word Test, and Symbol Digit Modalities Test (SDMT). We applied linear mixed-effects models adjusted for responder status and total concomitant ASM defined daily dose (DDD) ratio. Results: Our cohort included 27 individuals (16 female; mean age 42.4 ± 16.7 years) showing a 74% responder rate with 30% achieved seizure freedom at follow-up. CNB treatment was associated with favorable changes in BDI-II (q = 0.009), DERS-36 (q = 2.36 × 10-5), BIS-11 (q = 6.30 × 10-8), AES (q = 4.87 × 10-5), and QoLIE-31 (q = 0.009). RAVLT-Immediate performance likewise improved (q = 0.004), whereas SDMT worsened over time (q = 0.002); the remaining domains were unchanged. These effects remained significant after adjustment for responder status and total concomitant ASM DDD ratio: BDI-II [β (95% CI) = - 0.582 (- 0.943, - 0.221)], DERS-36 [β (95% CI) = - 0.550 (- 0.739, - 0.361)], BIS-11 [β (95% CI) = - 0.932 (- 1.144, - 0.719)], AES [β (95% CI) = - 1.001 (- 1.330, - 0.673)], QoLIE-31 [β (95% CI) = 0.488 (0.185, 0.791)], RAVLT-Immediate performance [β (95% CI) = 0.446 (0.255, 0.636)], and SDMT [β (95% CI) = - 0.294 (- 0.425, - 0.163)]. Conclusion: Adjunctive CNB was correlated with psychopathological improvements alongside domain-specific cognitive changes, independent of seizure outcome and concomitant ASM burden. These findings further expand current knowledge on CNB impact and tolerability profile.