Social isolation, loneliness, and the onset and progression of depression and anxiety: The mediating role of peripheral immune biomarkers.

Social isolation and loneliness are increasingly recognized as key social determinants of mental health. This study aimed to investigate their roles in the onset and progression of depression and anxiety. In this cohort study, we included 445,678 participants free of depression or anxiety at baseline. Social isolation and loneliness were assessed using validated questionnaires, and mental health outcomes were ascertained through hospital records. Multistate Markov models estimated associations of social isolation and loneliness with transitions from baseline to incident depression or anxiety and subsequently to comorbidity. Exploratory mediation analyses examined the role of peripheral immune biomarkers, and exploratory partial correlation analyses investigated associations with brain structural volumes. Participants had a mean (SD) age of 56.6 (8.1) years, and 208,845 (46.9%) were male. Both social isolation and loneliness were linked to higher risks of depression, anxiety, and progression to comorbidity, with loneliness showing consistently stronger associations. Loneliness more than doubled the risk of first-onset depression (HR, 2.10; 95% CI, 1.99-2.23). Mediation analyses indicated that C-reactive protein, white blood cell count, neutrophils, and platelets partially explained a small proportion of these associations. Exploratory correlation analyses identified modest associations between social isolation, loneliness, and brain structures. These findings suggest that social isolation and loneliness contribute not only to the onset of depression and anxiety but also to their progression toward comorbidity. Interventions targeting subjective loneliness and objective social isolation may help reduce the burden. Peripheral immune biomarkers and brain structural alterations may warrant future investigation as potential biological correlates of these associations.