Statin use and depression in older adults: a target trial emulation with implication for prevention and long-term management

BACKGROUND: Late-life depression is one of the most common mental disorders, with limited response to antidepressant therapy. Statins, widely used for CVD, may influence depression risk through pleiotropic effects, though evidence remains inconclusive. This study evaluated the association between statin use and depression in older adults, assessing both prevention and management, effect modification by low-grade inflammation, and polygenic risk score (PGS), and statin safety. METHODS: We used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and its extended follow up, aged ≥70 years (≥65 years for US minorities) followed for a median of 8.4 years. We investigated whether statin use was associated with a lower risk of depressive symptom occurrence (prevention) and improved existing depression (long-term management). To address these distinct research questions, two analytic cohorts were defined at time zero (T0): individuals without depression and those with pre-existing depression, respectively. We emulated trial using a prespecified protocol and inverse probability treatment weighting were used to address confounding. RESULTS: The study included 17,231 participants without and 3478 with depression at time zero. Statin use was associated with a lower risk of depression (RR, 0.80; 95% CI, 0.76-0.84), irrespective of statin lipophilicity among those without depression at T0. Preventive associations strengthened with higher PGS, depression severity, and treatment duration. No significant association was observed in existing depression cohort; while protective association was observed in higher PGS (RR 0.84, 95% CI 0.73-0.95). No evidence of long-term statin hepatic safety concerns was observed. Findings were robust across sensitivity analyses. CONCLUSIONS: Statin use was associated with a lower risk of depressive symptoms among those without depression at T0, but not among those with existing depression regardless of lipophilicity. Associations were stronger among individuals with higher genetic susceptibility to depression but showed no evidence of modification low-grade inflammation. Residual confounding cannot be excluded, and confirmation in future RCTs is warranted.