The Effects of Cenobamate and Its Dosage on Cognition: A Retrospective Longitudinal Study in 84 Individuals with...

Previous studies on cenobamate (CNB) have generally reported neutral to positive effects on objective cognitive performance in patients with epilepsy, but are limited to dosages up to 250 mg/day. However, a case report (Witt et al. in Neurocase 30:91-96, 2024) noted severe memory deterioration at 400 mg/day.

The purpose of this study was to examine dose-dependent effects of CNB on cognition.

In this retrospective longitudinal real-world study, executive functions and episodic memory were assessed in adult patients with pharmacoresistant epilepsy during CNB therapy and compared with baseline. Subgroups were stratified by daily CNB doses of ≥ 300 mg versus < 300 mg. Executive functions were assessed using the EpiTrack^®, verbal memory via the VLMT or an abbreviated version, and figural memory with the DCS-R.

The study included 84 patients, 24 (28.6%) of them with a CNB dose of ≥ 300 mg. With a mean CNB dose of 200.6 ± 114.3 mg (range 12.5-400.0 mg), seizure freedom was achieved in 11.9% with no significant difference between the lower and the higher dose group. Repeated measures analysis of covariance (ANCOVA) revealed a significant decline in executive functions at ≥ 300 mg (n = 84; F = 6.35, p = 0.014) compared to baseline. Changes were correlated with CNB dose (r = - 0.31, p = 0.004). Individual level analyses indicated that 50.0% of patients on higher versus 16.7% on lower CNB doses deteriorated according to reliable change indices (RCI). In a subgroup undergoing extensive memory testing, verbal retention showed a significant negative, dose-independent effect at the group level (n = 22; F = 7.95, p = 0.011), with intraindividual declines in 28.6% (≥ 300 mg) versus 13.3% (< 300 mg). Other memory parameters were unaffected.

The results of this real-world study investigating objective cognitive performance under CNB suggest possible, partially dose-dependent negative effects of CNB on cognition. Daily CNB doses of ≥ 300 mg were associated with a significant decline in executive functions. Furthermore, a dose-independent negative effect on verbal retention was observed in a subgroup of patients undergoing extensive memory assessment. Given the limitations of retrospective audits, our findings prompt further, larger scope studies to confirm the results. However, a careful balance between seizure control at the lowest CNB dose possible and potential cognitive side effects appears advisable, which requires the implementation of cognitive monitoring in standard care where possible.