A nested case-control study finds an association.

Although epilepsy and Parkinson’s disease (PD) have a known association, the contributory role of antileptic agents has not been examined previously. In this nested case-control study, researchers studied the risk for PD with exposure to carbamazepine, lamotrigine, levetiracetam and sodium valproate in 500,000 longitudinally enrolled participants in the UK Biobank, 45% of whom had linked data on primary care prescriptions. The final study cohort contained 1433 individuals with PD diagnosis based on Hospital Episode Statistics (HES) code (mean age, 71 years; 61% male; 98% white) and 8598 controls matched for age, sex, race and ethnicity, and socioeconomic status.

Individuals receiving antiepileptic prescriptions were at increased odds of developing PD. On an individual drug level, the association between sodium valproate and incident PD was most robust, even after adjusting for an epilepsy diagnosis. Levetiracetam had a moderate association with PD, followed by lamotrigine. The strength of association did not alter even after excluding prescriptions that were issued one, two and five years before PD diagnosis, thus minimising the possibility of the association reflecting drug-induced parkinsonism. There was also a trend for a greater number of prescription issues and multiple antiepileptic drugs to be associated with a greater risk of disease.

Comment: This study shows a higher incidence of PD after chronic exposure to drugs used to manage epilepsy. Antiepileptic drugs have the potential to interfere with dopamine pathways. Some drugs, such as sodium valproate, also downregulate the sensitivity of dopamine receptors. The study findings are important as the clinicians prescribing antiepileptic drugs can now caution patients, especially older white men, about the potential long-term risk. With these study findings, researchers should consider diving deeper to understand the pathogenic connection between these drugs and PD.

Aparna Wagle Shukla

Dr. Wagle Shukla reports receiving consultant fees from Merz, Jazz and Acadia, manufacturers of antiepileptic drugs.

Belete D, et al. Association between antiepileptic drugs and incident Parkinson disease in the UK Biobank. JAMA Neurol 2023; 80: 183-187.