UCLA

Increases in pro-inflammatory cytokines, the immunological response to pathogens, have been observed in close to one third of patients with major depression. Further, interpersonal stressors, the most potent and well-established risk for depression, have also been found to elicit pro-inflammatory cytokines. Thus, inflammation may represent a biological response to stress that heightens the risk of depression. A better understanding of the relationships among stress, depression and inflammation has the potential to shed light on the cycle of stress and depression, as well as the increased prevalence of inflammatory illness in depressed patients, which is of growing concern in our aging population.

This dissertation sought to confirm that among young, healthy adults, depressive symptoms tend to develop before, and contribute to elevations in pro-inflammatory cytokines, and to determine whether functional variation in immunological genes would create susceptibility to depression and inflammation in response to stress, and/or create susceptibility to inflammation following an elevation in depressive symptoms. The dissertation explored these questions in a pair of longitudinal cohort studies, the first of which followed Australian youth with a high prevalence of familial risk for depression from ages 15 to 20, and included assessments of depressive symptoms, stress exposure and genotypic information for a trio of immunological genes. Exposure to interpersonal stress was moderated by variation at IL6 and IL1β, so that -174C allele carriers at IL6, and -511C carriers at IL1β had greater depressive symptoms in response to stress, while neither of these genotypes affected the prediction of depressive symptoms from exposure to non-interpersonal stressors, such as finances and work. TNF genotype was not a moderator of either type of stress exposure.

In the second dissertation study, the prediction of growth in depressive symptoms and C-reactive protein (CRP) from childhood stress exposure, and potential moderation of these paths by IL6 genotype, was examined in 4,276 participants in the Coronary Artery Risk Development Study of Young Adults. Stress exposure in the childhood home was predictive of depressive symptoms at age 30, which were in turn associated with slight, but significant growth in CRP between age 32 and age 50. African Americans in this sample showed a unique moderating effect of IL6 genotype, so that the relationship between stress and CRP was significant among G allele carriers, but not among African American CC homozygotes, or among Caucasians, regardless of genotype. Taken together, the two dissertation studies suggest that genetic variation at IL6 may contribute to increases in depressive symptoms and CRP following interpersonal stress exposure. Further, although a strong relationship from stress exposure to depression was observed in both study populations, a direct relationship between stress and CRP was not found. Instead, stress led to depression which in turn predicted CRP, and this effect was more pronounced in Caucasians.