Objective:

To evaluate whether pyridoxine supplementation reduces levetiracetam discontinuation and improves behavioral tolerability in adult patients.

Background:

Levetiracetam (LEV) is a widely prescribed anti-seizure medication, but up to 13% of patients experience psychiatric and behavioral adverse effects (BAEs) leading to early discontinuation. Pyridoxine (vitamin B6) has been proposed as a potential adjunct to reduce LEV-related irritability and improve tolerability, though evidence in adults remains limited.

Design/Methods:

We conducted a 10-year retrospective cohort study of adults initiated on LEV monotherapy across the OSF healthcare system (2014–2024). Patients were divided into two groups: those who received concurrent pyridoxine (B6 group) and those who did not (No B6 group). Patients with psychiatric comorbidities or polytherapy were excluded. Primary outcome was LEV discontinuation or dose reduction due to adverse effects. Secondary outcomes included persistence on therapy ≥30 days and documentation of behavioral improvement. Group comparisons were performed using chi-square and t-tests.

Results:

A total of 269 patients met inclusion criteria (147 No B6, 122 B6). Mean age was 52.2 years, 55% were female, and focal epilepsy was the most common diagnosis (20.4%). Patients receiving pyridoxine were more likely to remain on LEV for ≥30 days compared with those without B6 (87.7% vs. 75.5%, p = 0.017). Trends toward longer persistence were observed at other duration thresholds (<2 weeks: 11.5% vs. 20.4%, p = 0.07). No significant demographic or epilepsy-type differences were identified between groups. Pyridoxine supplementation was well tolerated, and no adverse reactions were reported.

Conclusions:

Pyridoxine co-administration was associated with improved LEV persistence and a lower rate of early discontinuation. These findings support the potential role of B6 in mitigating LEV-induced behavioral side effects and improving medication tolerability in adults. Prospective studies are warranted to confirm these results.