Role of vitamin D supplementation and vitamin D receptor in drug‐resistant epilepsy: A double‐blind placebo‐controlled trial conducted in India

• Published in: Epilepsia (Copenhagen)
• Main Authors: Pattnaik, Soumya S., Sarangi, Sudhir C., Dash, Yajnaseni, Singh, Archana, Goswami, Ravinder, Singh, Surender, Khan, Maroof A., Banerjee, Jyotirmoy, Datta, Sudip K., Tripathi, Manjari
• Format: Journal Article
• Language: English
• Published: United States 14.06.2025
• Subjects: drug‐resistant epilepsy; neurotrophin‐3; vitamin D receptor; HMGB1; glial cell line–derived neurotrophic factor; vitamin D
• ISSN: 0013-9580; 1528-1167; 1528-1167
• DOI: 10.1111/epi.18492

Vitamin D has demonstrated potential anticonvulsant effects in experimental and pilot clinical studies; the results of these remain inconclusive. This study aims to investigate the efficacy and safety of adjunctive Vitamin D supplementation in reducing seizure frequency, modulating vitamin D receptor (VDR) activity, and altering the putative biomarkers of epileptogenesis in persons with drug-resistant epilepsy (DRE). This double-blind, placebo-controlled, parallel-group, adjunctive trial recruited patients from a tertiary care hospital in India. Adult persons with DRE and serum Vitamin D levels <30 ng/mL, experiencing ≥2 seizures/month, were randomized (1:1 ratio) to receive either Vitamin D (60,000 IU/week for 3 months, followed by 60 000 IU/month for the next 3 months) or a matching placebo, in addition to their ongoing antiseizure medications. The primary outcome was the percentage change in monthly seizure frequency from baseline to 6 months. Secondary outcomes included 50% responder, serum Vitamin D (25-hydroxycholecalciferol) levels, VDR protein/mRNA expression, putative biomarkers of epileptogenesis (including high-mobility group box protein 1 [HMGB1] and neurotrophin-3 [NT-3]), quality of life, and safety assessment. Of 200 participants, 99 were in the Vitamin D group and 101 were in the placebo group. No statistically significant difference was observed between the Vitamin D and placebo groups in the primary outcome of percentage change in monthly seizure frequency from baseline after 6 months of intervention (median 33.3, interquartile range [IQR] 0-57.4 vs 16.7, 0-66.7; median estimate 5.5, 95% confidence interval [CI]: -6.7 to 19.2); p = 0.36]. The 50% responder rate was similar between groups (37% vs 35%; odds ratio 1.1, 95% CI: 0.6-1.9; p = 0.68). However, Vitamin D supplementation significantly increased VDR mRNA and protein expression (p < 0.001) and decreased HMGB1 (p = 0.001) and NT-3 (p = 0.002) levels compared to placebo. The recommended serum Vitamin D level (≥30 ng/mL) was achieved in only 36% of subjects in the Vitamin D group. Safety outcomes were comparable between groups. Six months of Vitamin D supplementation at the selected dose did not significantly reduce seizures compared to placebo, potentially due to few persons with DRE achieving recommended serum Vitamin D level (≥30 ng/mL). Significant upregulation of VDR expression and reduction in putative biomarkers of epileptogenesis following Vitamin D supplementation were seen in Vitamin D group despite no corresponding decrease in seizure frequency. This suggests that Vitamin D may have underlying therapeutic effects that warrant further investigation and clinical correlation.