Stressed, Sick, and Sad: A Transdiagnostic Investigation of the Translation of Stress into Depression through Neuroendoimmune Disruptions

Depression is a prevalent and disabling form of psychopathology that is frequently precipitated by experiences of stress. Disruptions in stress-sensitive biological systems, notably the immune system and hypothalamic-pituitary-adrenal axis, are strongly implicated in depression, and disturbances in these systems could reflect potential pathways through which experiences of stress are translated into depression. These systems, broadly subsumed within the neuroendoimmune system, may be highly responsive to stress and cognitive abilities related to stress management. To characterize the links between stress and depression and the potential influence of immune activity, the present study investigated the following: (1) the associations among perceived stress (across different time periods of life), proinflammatory immune markers, and depressive symptoms; (2) whether neuroendoimmune activity mediates the relationship between perceived stress and depressive symptoms; and (3) whether perceived stress and immune activity mediate the relationship between cognitive control and depressive symptoms. Fifty-nine medically healthy adult females with varying levels of depression participated in the study. Participants provided dimensional ratings of their depression symptoms and perceived life stress, and they completed a neuropsychological test of cognitive control. Plasma biomarkers of stress, including pro-inflammatory cytokines, C-reactive protein, and free cortisol, were assayed following a fasted morning blood draw. Consistent with hypotheses, both greater perceived stress and higher concentrations of the proinflammatory immune marker, interleukin-6 (IL-6), were associated with greater depressive symptoms. Although levels of IL-6 alone did not significantly mediate the relationship between perceived stress and depressive symptoms, when considered together, elevated concentrations of IL-6 and lower free cortisol mediated the relationship between severity of childhood stress and current depressive symptoms. Contrary to expectations, cognitive control was not significantly associated with stress, immune markers, or depression. The findings are interpreted in the context of a potentially long-term reduction in glucocorticoid tone triggered by early life stress that curbs cortisol output, produces chronic low-grade immune activation, and leads to depression vulnerability later in life. Overall, the study provides new insights into potential pathways among stress, the neuroendoimmune system, and depression, shedding light on how early life stress may be translated into depression in adulthood.Ph.D