Antipsychotic Drug Interactions and Short‐Term Mortality Risk in People With Dementia: A National Cohort Study

Antipsychotics are often prescribed in the management of behaviors and psychological symptoms of dementia. While the potential harms of antipsychotic use in people with dementia have been established, little is known about the risk associated with antipsychotic drug-drug interactions (DDIs). This study aims to examine the patterns of antipsychotic DDIs and their association with 90-day mortality among people with dementia using antipsychotics. This retrospective cohort study utilized Australian nationwide linked 2021 Census and Pharmaceutical Benefits Scheme data. People with dementia aged ≥ 65 years who initiated a single antipsychotic (risperidone, quetiapine, aripiprazole, haloperidol, or olanzapine) between August 2021 and July 2022 were included. Antipsychotic DDIs were defined by Micromedex® Drug-Reax, and were stratified by number, severity, and pharmacological mechanism. Mortality risk was assessed using modified Poisson regression and confounding was addressed with overlapped weighting. Among 9064 incident antipsychotic users, 6913 (76.3%) were exposed to ≥ 1 DDI, with the majority of them classed as "major" severity (n = 6709). Nervous system drugs were the most commonly interacting agents. When compared to those without antipsychotic interactions, those with ≥ 1 DDI had a 43% increased risk of 90-day mortality (adjusted relative risk [aRR]: 1.43; 95% confidence interval [CI]: 1.22-1.69), while those with ≥ 2 DDIs had an 80% increased risk (aRR: 1.80; 95% CI: 1.49-2.17). Overall, antipsychotic DDIs are common among older adults with dementia and are associated with increased risk of 90-day mortality. As such, medication review and regular monitoring is important when initiating antipsychotics in this vulnerable population.