Recent antipsychotics use associated with elevated risk of Parkinson's disease

Introduction: Parkinson's disease is a neurodegenerative disease affecting motor and cognitive function that has a major impact on society. Epidemiological evidence has suggested that the incidence of PD may be increasing; however, the underlying etiology is unclear. Here, we investigated the role of increasingly used antipsychotics in the diagnosis of PD. Methods: We harnessed Merative Marketscan insurance claims databases to conduct a case-control study of 65,275 new cases of PD and 652,364 age-, sex-, and time-matched controls. We estimated associations between exposure and duration of use for antipsychotics adjusted for important confounders using fixed effects logistic regression. We performed sensitivity analyses stratified by the level of D2 receptor inhibition to assess dose-response relationships; a lagged exposure analysis to address confounding by indication; analysis assessing exposure of other psychiatric medications without significant D2 inhibition (bupropion, trazodone, and Z-drugs); analysis assessing exposure of non-psychiatric medications with significant (metoclopramide) or no D2 inhibition (ondansetron). Results: We found cases with PD had elevated odds of antipsychotic exposure. Longer durations of exposure and greater affinity for the D2 receptor were associated with greater associations with PD. There was a dose-response relationship between D2 inhibition activity and increased odds of PD for a similar duration of exposure. There was a dose response relationship between duration of metoclopramide and the odds of PD; however, there was no such relationship between the non-D2 inhibiting control medications. The association between exposure to an antipsychotic and increased odds of PD was present even when the first exposure was 10 years prior to the PD diagnosis date. Conclusion: If these results are causal, antipsychotic use may explain up to 2.4% of all cases of PD. Given the increasing rate of use of these medications, and the concurrent increasing age-adjusted incidence of PD, there is an urgent need for further investigation into this association and greater awareness of the potential risks of these medications in older adults.