Effectiveness of adjunctive low‐dose clobazam in adults with focal drug‐resistant epilepsy and incomplete response to cenobamate: A real‐world study

OBJECTIVE: Cenobamate (CNB) is a highly effective antiseizure medication (ASM) for focal drug-resistant epilepsy (DRE); nevertheless, even with CNB treatment and optimized therapy, a substantial proportion of patients continued to experience seizures. Preliminary observations suggest that clobazam (CLB), a 1,5-benzodiazepine, may enhance CNB efficacy. We aimed to evaluate the real-world effectiveness and safety of adjunctive low-dose CLB in adults with focal DRE who continued to have incomplete seizure control despite CNB. METHODS: We conducted a retrospective single-center study including adults with focal DRE treated with CNB ≥200 mg/day who subsequently received adjunctive CLB due to persistent seizures despite CNB therapy. Seizure outcomes, responder rates, treatment retention, adverse drug reactions (ADRs), and changes in concomitant ASM burden were assessed at approximately 3, 6, 9, and 12 months after CLB initiation. RESULTS: Eighty-five patients were included (median disease duration, 12 years; median of 6 prior ASM failures). Median seizure reduction from CLB initiation improved from 80.0% at 3 months to 95.8% at 12 months (p < 0.001 at all time points). Responder rates (≥50% reduction) ranged from 72.9% to 82.1%, and approximately one-third of patients achieved seizure freedom across follow-up. The 12-month retention rate was 83.1%. Modifications in concomitant ASM burden were minor and descriptive, without implying a meaningful reduction in polytherapy. ADRs were mostly mild to moderate, predominantly somnolence, with low discontinuation rates. SIGNIFICANCE: Adjunctive low-dose clobazam was associated with rapid and sustained seizure reduction in adults with focal DRE who had incomplete seizure control on CNB. The combination was generally well tolerated and was associated with no meaningful reduction in polytherapy. These findings support a potential pharmacokinetic-pharmacodynamic interaction between CNB and CLB and highlight the role of mechanism-driven polytherapy in refractory epilepsy. PLAIN LANGUAGE SUMMARY: This study looked at adults with hard-to-treat focal epilepsy whose seizures were not fully controlled by cenobamate. Adding a low dose of clobazam to their existing treatment helped most patients reduce the number of seizures, with many achieving near-complete control. The combination was generally well tolerated, and most patients were able to continue therapy over 1 year. These findings suggest that strategically combining these two medicines can improve seizure control in patients who remain resistant to standard treatments.