Mediation of the Association Between Vascular Risk Factors and Depressive Symptoms by C-Reactive Protein.

Background: This study examined whether C-reactive protein (CRP), a marker of low-grade systemic inflammation, mediates the association between vascular risk factor (VRF) burden and depressive symptoms. Methods: We drew on the prospective design of the UK Biobank to include participants with longitudinal data on VRF burden, CRP, and depressive symptoms. Total, direct, and indirect effects were estimated using regression-based mediation models while controlling for confounding by sociodemographic factors, baseline CRP, and baseline depression. Sensitivity analyses probed the robustness of results to unmeasured confounding. Results: We analyzed data from 10,470 participants from the UK Biobank (mean age = 56.75 years at baseline). Net of covariates, VRFs at baseline were associated with higher depressive symptoms at follow-up (total effect = 0.099; 95% CI, 0.002-0.163). CRP mediated this association (indirect effect = 0.010; 95% CI, 0.004-0.017), accounting for 10.0% (95% CI, 0.3%-30.0%) of the total effect of VRF burden on depressive symptoms. Exploratory analyses suggested that the total and indirect effects pertained to somatic depressive symptoms (tiredness and appetite). Conclusions: These results suggest that inflammation-promoting effects of VRFs may contribute to depressive symptoms in mid- and later life. However, the mediating pathway via CRP explains only a small part of the association between VRFs and depression after accounting for important covariates and may pertain to specific depressive symptoms. Future studies leveraging similar longitudinal designs are needed to further disentangle the time-varying effects between VRFs, inflammation, and certain depressive symptoms while addressing important confounders.