Psychiatric Outcomes of Antiseizure Medications in Newly Diagnosed Focal Onset Epilepsy: From the Human Epilepsy Project Cohort Study.

Authors

Hamada Hamid Altalib, Poojith Nuthalapati, Zhiyuan Zhang, Margaret T Gopaul, Andres M Kanner, Barry E Gidal, as the HEP Investigators

Published in

Neurology. Clinical practice. Volume 16. Issue 5. Pages e200645. Epub Aug 10, 2026.

Abstract

Psychiatric comorbidities are highly prevalent in people with epilepsy, which adversely affect treatment outcomes. The proper choice of antiseizure medication (ASM) is therefore crucial because different ASMs have varying psychiatric safety profiles. This study investigates the psychiatric tolerability of commonly used ASMs in people with newly diagnosed focal epilepsy.
This post hoc analysis included participants from the Human Epilepsy Project, an international, multicenter prospective cohort. Of 357 participants aged ≥12 years enrolled within 4 months of treatment initiation for focal epilepsy, those receiving levetiracetam, lamotrigine, or sodium channel blockers (SCBs, including carbamazepine, oxcarbazepine, and phenytoin) monotherapy who completed the Mini International Neuropsychiatric Interview at enrollment were included. Median doses at discontinuation for each treatment group were reported.
Of 357 patients, 214 (60%) received levetiracetam, 69 (19%) lamotrigine, and 74 (21%) other SCBs. Treatment groups differed significantly by sex (p = 0.028) and education level (p = 0.001). During the 2-year follow-up, levetiracetam and other SCBs had a significantly higher risk of withdrawal because of psychiatric adverse events compared with lamotrigine (p = 0.001 and p = 0.024, respectively). Most withdrawals occurred early. Multivariable Cox regression showed a higher withdrawal risk for levetiracetam vs lamotrigine (adjusted HR 2.76; 95% CI 1.51-5.04; p ≤ 0.001) and for other SCBs vs lamotrigine (adjusted HR 2.25; 95% CI 1.13-4.47; p = 0.021). Discontinuation doses were substantially lower than maintenance doses across all groups (p < 0.001 for levetiracetam and lamotrigine; p = 0.0022 for other SCBs). Among patients without baseline depression or anxiety (n = 232), discontinuation occurred in 40% of those receiving levetiracetam, 40% receiving other SCBs, and 19% receiving lamotrigine. Consistent with the overall cohort, levetiracetam was associated with a higher risk of discontinuation (OR 2.40 [1.18-5.20], p = 0.020) compared with lamotrigine.
People who were newly diagnosed with focal epilepsy on ASM monotherapy showed that levetiracetam was associated with approximately 2.8-fold risk of treatment withdrawal compared with lamotrigine because of psychiatric adverse events. Our analysis also demonstrated a better psychiatric tolerability profile for lamotrigine compared with other SCBs. Most discontinuations occurred at significantly lower doses than maintenance therapy, suggesting either failure to reach therapeutic dosing or dose tapering before discontinuation.

PMID:
42574692
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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