Metabolomic Signatures Linking Depressive Symptoms to Atherosclerotic Cardiovascular Disease Comorbidity: Evidence from the UK Biobank

Depression and cardiovascular disease (CVD) frequently co-occur and exacerbate each other's clinical outcomes, potentially through shared immune or metabolic dysregulation. This study used tripartite network analysis to examine interactions among depressive symptoms, metabolic biomarkers, and CVD, aiming to identify mediating metabolic pathways. Using UK Biobank data (N = 35 711; 56% female; mean age 64), NMR-based plasma metabolites, PHQ-9 depressive symptoms, and ICD-10 atherosclerotic CVD were analyzed. A tripartite network (symptom-metabolite-CVD) was constructed using partial correlation analyses to identify metabolites shared between depression and CVD. These metabolites were then subsequently entered in a longitudinal mediation analysis, spanning 6 years, to quantify metabolite-mediated associations between depressive symptoms and incident CVD. Models progressively adjusted for: (1) age and sex; (2) socioeconomic status, lifestyle factors, and antidepressant use; and (3) BMI. Analyses were repeated using PHQ-9 total scores as the exposure. The initial unadjusted network analysis identified 11 shared metabolic markers. Longitudinal mediation revealed six symptom-metabolite-CVD pathways, whereas only one metabolite-mediated pathway emerged using total PHQ-9 scores. After full adjustment, four pathways remained significant: alpha-1-glycoprotein acetyls (AGP) mediated associations involving appetite changes and fatigue (both p < .001), and monounsaturated fatty acids (MUFAs) mediated associations involving appetite changes and sleep disturbances (both p < .05). AGP (an inflammatory acute-phase protein) and MUFAs link energy-related depressive symptoms (appetite changes, fatigue, sleep disturbances) to CVD. This symptom-level approach enhances precision in identifying shared biological mechanisms underlying the co-morbidity between depression and CVD, potentially informing novel avenues for tailored prevention and treatment strategies.