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Proton Pump Inhibitor Use and Incident Epilepsy in the UK Biobank: Evidence From Pharmacovigilance and Multi‐Omics Analyses

Year: 2026

Type: article

Abstract: AIMS: Proton pump inhibitors (PPIs) are widely used, but their association with incident epilepsy remains uncertain. We examined this association in the UK Biobank and integrated evidence from pharmacovigilance and multi-omics. METHODS: We included 492,858 UK Biobank participants without epilepsy at baseline. Cox models, age- and sex-stratified analyses, active-comparator analyses against H2RA users, propensity score matching, competing-risk models, and sensitivity analyses were performed. FAERS disproportionality, Olink proteomics, and NMR metabolomics provided supportive evidence. RESULTS: Baseline PPI use was associated with incident epilepsy after full adjustment (HR 1.43, 95% CI 1.29-1.59) and in the PPI-H2RA propensity score-matched analysis (HR 1.41, 95% CI 1.03-1.94). In the GP-linked subset, requiring an ASM prescription within 365 days after diagnosis yielded HR 1.47 (95% CI 1.07-2.02). FAERS showed a PPI-epilepsy reporting signal (ROR 1.70, 95% CI 1.61-1.79). Proteomic and metabolomic analyses identified immune-inflammatory and metabolic associations. CONCLUSION: Baseline PPI use was associated with incident epilepsy in the UK Biobank. Active-comparator, outcome-definition, and prescription-supported analyses supported the primary association. Pharmacovigilance and molecular findings provided complementary evidence but did not establish causality.

Source: CNS Neuroscience & Therapeutics

DOI: 10.1002/cns.71223