Antidepressant use and Parkinson's disease risk: Overall protective effect with drug‐specific variation

ABSTRACT Background Antidepressants can cause extrapyramidal side effects, but their impact on Parkinson's disease (PD) risk remains unclear. Aims We aimed to investigate the association between genetic liability to antidepressant use and PD. Methods We examined the causal effect of antidepressant use on PD using Mendelian randomisation (MR) analysis. We further performed multivariable MR (MVMR) analysis to determine the independent effect of genetic liability to antidepressant use on PD by accounting for the effect of major depressive disorder (MDD) on PD. The United States Food and Drug Administration Adverse Event Reporting System (FAERS) database (2004 Q1–2024 Q2, 53.4 million event‐level records) was mined to assess associations between 13 antidepressants and PD. Colocalisation analyses identified shared genetic variants between genetic liability to antidepressant use and PD. Results MR analyses demonstrated that genetic liability to antidepressant use was inversely associated with PD (odds ratio [OR]: 0.74, p ‐false discovery rate (FDR) = 0.016), whereas MDD itself showed no causal association (OR: 1.01, p ‐FDR = 0.934). MVMR confirmed that the inverse association between genetic liability to antidepressant use and PD was independent of genetic liability to MDD (OR: 0.69, p ‐FDR = 0.018). Colocalisation highlighted LHFPL3 , KMT2E and SRPK2 at the chromosome 7q22.3 locus as shared genetic components. Furthermore, real‐world FAERS data revealed that although most antidepressants (10/13) showed no significant disproportionate reporting for PD, clomipramine and mirtazapine were associated with increased reporting odds, whereas duloxetine exhibited a significant inverse reporting signal. Conclusions Genetic and observational evidence together support an inverse association between antidepressant use and PD. Given varying individual drug profiles, agents such as duloxetine warrant further prospective evaluation.