Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events in pediatric and adolescent epilepsy: a prospective, double-blind, randomized, placebo-controlled trial.

Background: Levetiracetam commonly causes neuropsychiatric adverse events (NPAEs) in pediatric patients, including irritability and aggression. This study evaluated pyridoxine supplementation for reducing levetiracetam-related NPAEs in children and adolescents with epilepsy.

Methods: We conducted a prospective, double-blind, randomized, placebo-controlled trial at Phramongkutklao Hospital, Thailand (January-June 2024). Participants aged 1-18 years with levetiracetam-related NPAEs were randomly assigned in a 1:1 ratio to receive either pyridoxine (10 mg/kg/day, maximum 200 mg) or placebo for 8 weeks. The primary outcome was change in behavioral symptoms using a validated 30-item questionnaire (score range 30-90). Secondary outcomes included treatment adherence, time to behavioral improvement, and adverse events. Sample size (n = 102) was calculated to detect a 20 % difference in behavioral improvement with 80 % power.

Results: 102 patients were randomized (pyridoxine n = 51, placebo n = 51). Baseline characteristics-including age, sex, seizure type, and number of concomitant ASMs-were comparable between groups. The mean age was 9.2 vs 8.3 years (p = 0.363), and 52.9 % vs 51.0 % were female in the pyridoxine and placebo groups, respectively. Most participants (56.9 %) were on dual therapy, with a median of two ASMs in both groups (p = 0.94). Both groups showed significant behavioral improvement over 8 weeks: the pyridoxine group from 14.79 ± 6.87 to 11.54 ± 6.22 (p < 0.001); placebo group from 15.65 ± 8.26 to 10.47 ± 8.22 (p < 0.001). No significant between-group difference existed at week 8 (p = 0.468). However, multivariate analysis of behavioral change scores from baseline to week 8 revealed significantly greater improvement in the pyridoxine group (adjusted OR = 2.31, 95 % CI: 1.15-4.63, p = 0.020). No serious adverse events occurred in either group.

Conclusion: While pyridoxine did not significantly reduce behavioral scores compared to placebo at the study endpoint, the greater improvement in change scores over time suggests potential benefit in mitigating levetiracetam-associated NPAEs. Pyridoxine may serve as safe adjunctive therapy for patients who have behavioral side effects while maintaining seizure control. Further investigation in larger multicenter trials with extended follow-up is required before recommending pyridoxine for routine clinical use.