BOSTON — What are the psychiatric and behavioral side effects (PBSEs) of antiseizure medications (ASMs) in adults with epilepsy?
That was the question addressed in a recent study in which researchers from the Bruce W. Carter VAMC in Miami joined colleagues from Harvard Medical School and Mass General Brigham sought to “provide actionable guidance for medication selection, monitoring and switching.”
The study team performed a narrative review of PubMed, Embase, Web of Science, Cochrane Library and regulatory documents from Jan. 1, 1990, to Sept. 30, 2025. Included were randomized trials, observational cohorts, pharmacovigilance databases and mechanistic studies reporting PBSEs. The researchers extracted data on PBSE frequency, discontinuation rates, risk factors and putative mechanisms and qualitatively integrated the information. They also introduced and applied a pragmatic PBSE-based classification that grouped ASMs into Very Low, Low, Moderate, High and Very High behavioral-risk tiers to help guide clinical decision-making.
Results published in the Journal of Neurology indicated that, across 28 ASMs, PBSE burden spanned more than an order of magnitude under a composite risk-tiering method.1
Findings included that:
- Levetiracetam, perampanel, felbamate and stiripentol clustered at the upper end of the risk spectrum, with irritability and aggression dominating the clinical picture.
- Carbamazepine, ethosuximide, lacosamide, oxcarbazepine, phenytoin, pregabalin and primidone exhibited the lowest behavioral liability and, in some cases, mood-stabilizing properties.
“Polytherapy, rapid titration, higher doses, pre-existing psychiatric illness, intellectual disability, and social deprivation were associated with higher risk,” the authors explained.“Mechanisms leading to PBSEs converged on excessive AMPA-receptor modulation (including selective antagonism), broad GABAergic potentiation, folate depletion, NMDA antagonism, and pharmacokinetic interactions.”
The study team concluded that PBSEs often can be anticipated, mitigated and frequently reversed. “A risk-stratified prescribing strategy-monotherapy first, enzyme-neutral or mood-friendly medications for vulnerable patients, folate supplementation for inducers, and early switch from offending agents-can safeguard mental health without compromising seizure control,” the researchers added.
- Lyndon S, Dworetzky BA, Baslet G. Psychiatric and behavioural side effects of antiseizure medications in epilepsy. J Neurol. 2025 Dec 23;273(1):45. doi: 10.1007/s00415-025-13591-2. PMID: 41432787.