The Spectrum of Uncommon Adverse Effects in Patients Treated With Levetiracetam

Levetiracetam is a commonly prescribed broad-spectrum antiseizure medication (ASM) known for its effectiveness and favourable pharmacokinetic profile, leading to its widespread adoption as first-line therapy for focal and generalized epilepsy worldwide. While its well-known side effects are documented, a range of unusual and serious psychiatric and physical side adverse drug reactions (ADRs) is becoming more recognized but less measured.

To present 15 patients who experienced unusual adverse effects linked to levetiracetam, examining demographic patterns, dose relationships, and management outcomes in a real-world clinical setting.

We reviewed 15 consecutive cases from Mahatma Gandhi Medical College and Research Institute (MGMCRI) hospital in Puducherry, India, where an unusual adverse effect occurred during levetiracetam monotherapy or combination therapy between 2020 and 2024. We collected and analysed data on patient demographics, levetiracetam dose, descriptions of adverse effects, and concomitant ASMs. We also retrospectively applied a standardized causality assessment (Naranjo ADR probability scale). Data analysis was performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA) Results: The mean age of the cohort was 43.1 years (standard deviation [SD] ± 19.6 years), with a male predominance (9/15, 60%). The mean dose of levetiracetam before patients reported experiencing adverse effects was 1400 mg/day (SD ± 450 mg/day; range: 500-2000 mg/day). The mean time from levetiracetam initiation or dose adjustment to adverse effect onset was 30 days (range: 7-90 days), providing a clinically useful window for heightened monitoring. Neuropsychiatric adverse effects predominated (12/15, 80%), including behavioural dysregulation (hypersexuality, over-spirituality, akathisia), mood disorders (severe depression, suicidal tendency, mania), anxiety-related symptoms (claustrophobia, insomnia), and cognitive disturbances. Non-neuropsychiatric adverse effects (3/15, 20%) included excessive bleeding, difficulty in urination, and weight gain. Naranjo scale scores ranged from 5 to 8, indicating probable causality in all cases. The most common management approach involved medication adjustment - either levetiracetam dose reduction or switching to lacosamide, sodium valproate, or brivaracetam - with adverse effects resolving approximately three to four months after therapeutic modification, often with adjunctive psychiatric intervention.

Early recognition of these uncommon neuropsychiatric and non-neuropsychiatric adverse effects, beyond the standard somnolence or irritability, is critical for patient safety and medication adherence. Recognition of these neurological adverse effects and appropriate therapy changes will help ensure patient safety, satisfaction with drug therapy, and adherence to the prescribed regimen. Clinicians should maintain heightened vigilance for atypical presentations following levetiracetam initiation. Further research should be conducted to determine the true incidence and risk factors associated with these distressing adverse effects, as the limitations of this retrospective review do not support definitive conclusions regarding these relationships.