Population-level trends of Psychiatric Medication Co-Prescriptions in Persons with Epilepsy: an EPIC Cosmos Study

Persons with epilepsy (PWE) experience high rates of psychiatric comorbidity, yet the population-scale pharmacoepidemiology of psychiatric medication (PM) use alongside antiseizure medications (ASMs) has not been previously characterized. Using Epic Cosmos, a federated electronic health record network spanning >300 million patients across >2,000 hospital systems, we examined patterns of ASM and PM co-prescriptions in PWE (ICD-10 G40.x) every year between 2018-2025. PM prescriptions were similarly assessed in patients with asthma (J45.x). We found that despite the introduction of several newer ASMs, the overall prescribing landscape remained stable, with little change in the relative use of individual ASMs over time. Compared with asthma patients, PWE were more likely to receive prescriptions for opiates, antidepressant and antipsychotic medications across the age spectrum. ≤17-year-old PWE were more likely to receive ADHD/stimulant medications, whereas adults and older adults exhibited a shift toward cognitive enhancing agents. We did not observe a preponderance of PM co-prescribing with any specific ASM or ASM class. Together, these results provide a population-scale, age-specific survey of psychiatric medication co-prescriptions in epilepsy, establishing a framework to monitor surrogate markers of psychiatric comorbidity and to support pharmacovigilance of potential drug-drug interactions.