Efficacy and safety of novel antiseizure medications as adjunctive treatment of focal epilepsy: An updated network meta-analysis

OBJECTIVE: Antiseizure medications (ASMs) are the cornerstone of epilepsy treatment. However, evidence on direct comparison of ASMs is lacking. This network meta-analysis evaluated the comparative efficacy and safety of approved and investigational add-on third-generation ASMs for focal epilepsy in adolescents and adults. METHODS: Data were retrieved through an extensive literature search of PubMed, Embase, Cochrane Library, and ClinicalTrial.gov databases from inception through August 2025. Findings were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline (CRD420251180027). Primary efficacy outcomes were ≥50 % and 100 % responder rates at 12-weeks maintenance duration. Secondary outcomes were corresponding responder rates at 8-weeks maintenance duration. Tolerability was assessed as retention rate. Treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were the safety outcomes. RESULTS: The literature search retrieved 345 studies, of which 35 studies were included. All ASMs showed significantly higher responder rates compared with placebo. Significantly higher 100 % responder rate was observed with cenobamate (CNB; 400mg/d: Risk ratio [RR] 15; 95 % CI, 7.0-39; 200mg/d: RR 8.7; 95 % CI, 3.9-22) at a maintenance duration of 12 weeks and 8 weeks (400mg/d: RR 15; 95 % CI, 7.0-41; 200mg/d: RR 8.6; 95 % CI, 4.0-24). All ASMs showed a patient retention rate comparable with placebo. For overall TEAEs, brivaracetam (BRV; 50mg/d) and BRV ranked the lowest for individual and pooled doses, respectively; placebo ranked the highest in both cases. For TEAEs leading to treatment discontinuation, CNB ranked lower than the placebo. SIGNIFICANCE: All approved and investigational ASMs were effective add-on treatments for focal epilepsy, with CNB demonstrating the greatest likelihood of achieving seizure freedom.