Neuropsychiatric adverse events with anti-seizure medications in patients with epilepsy: A systematic review and meta-analysis

AI Summary

ASM use in epilepsy is associated with a spectrum of neuropsychiatric adverse events, with risk varying across drug classes and individual agents.
Topiramate showed the strongest association with psychosis (OR 3.07), and levetiracetam linked to higher anxiety and suicidality in observational cohorts.
Findings limited by observational design, residual confounding, heterogeneity, and scarce dose, duration, polytherapy, and newer ASM data; monitor NPAEs in treatment selection.

Epilepsy Res. 2026 Jul 16;227:107875. doi: 10.1016/j.eplepsyres.2026.107875. Online ahead of print.

ABSTRACT

OBJECTIVE: Anti-seizure medications (ASMs) are the cornerstone of epilepsy pharmacotherapy; however, emerging evidence suggests a potential link between ASM use and neuropsychiatric adverse events (NPAEs). We aimed to synthesise observational evidence on the risk of NPAEs with ASM use in patients with epilepsy.

METHODS: Medline, Embase, and PsycINFO were searched from inception to May 2026. Primary outcomes included the occurrence of behavioural, cognitive, mood, sleep, and psychotic disorders with ASM use compared with control groups in patients with epilepsy. Where studies were sufficiently comparable, risk ratios were pooled with 95% confidence intervals using a random-effects model; otherwise, findings were summarized narratively.

RESULTS: Of 6769 retrieved citations, 18 observational studies including 5151,367 patients were identified. Memory disorders were reported in 8.7%, 3.8%, and 6.2% of participants receiving first-, second-, and third-generation ASMs, respectively. Depression was reported in 2.3%, 1.2%, and 3.0%, respectively. No statistically significant difference in psychosis risk was observed between first- and second-generation ASMs (RR 0.77; 95% CI 0.34-1.76). Second-generation ASMs had a lower point estimate for psychotic disorders compared with third-generation ASMs, but this finding was borderline and imprecise, with the unrounded confidence interval crossing the null value. Topiramate demonstrated the strongest association with psychosis risk (OR 3.07; 95% CI 2.55-3.71), and levetiracetam was notably associated with higher rates of anxiety in one cohort and higher odds of suicidality in one nested case-control study.

CONCLUSION: ASM use in patients with epilepsy is accompanied by a range of NPAEs, with risk varying across distinct types of ASMs. These findings support considering NPAEs in ASM selection and routine monitoring in patients with epilepsy. The observational nature of the included studies, residual confounding, heterogeneity in comparator groups, outcome definitions, and limited data on dose, duration, polytherapy, and newer ASMs limit the precision and generalizability of findings.

PMID:42470751 | DOI:10.1016/j.eplepsyres.2026.107875

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