Relationships of depression and antidepressant use with epigenetic age acceleration and all-cause mortality among postmenopausal women

We investigated relations of depressive symptoms, antidepressant use, and epigenetic age acceleration with all-cause mortality risk among postmenopausal women. Data were analyzed from &le;1,900 participants in the Women's Health Initiative study testing four-way decomposition models. After a median 20.4y follow-up, 1,161 deaths occurred. Approximately 11% had elevated depressive symptoms (EDS⁺), 7% were taking antidepressant medication at baseline (ANTIDEP⁺), while 16.5% fell into either category (EDS_ANTIDEP⁺). Baseline ANTIDEP⁺, longitudinal transition into ANTIDEP⁺ and accelerated epigenetic aging directly predicted increased mortality risk. GrimAge DNA methylation age acceleration (AgeAccelGrim) partially mediated total effects of baseline ANTIDEP⁺ and EDS_ANTIDEP⁺ on all-cause mortality risk in socio-demographic factors-adjusted models (Pure Indirect Effect &gt;0, <em>P</em> &lt; 0.05; Total Effect &gt;0, <em>P</em> &lt; 0.05). Thus, higher AgeAccelGrim partially explained the relationship between antidepressant use and increased all-cause mortality risk, though only prior to controlling for lifestyle and health-related factors. Antidepressant use and epigenetic age acceleration independently predicted increased all-cause mortality risk. Further studies are needed in varying populations.