The Immune System and Depression: From Epidemiological to Clinical Evidence

Depression is a frequent mental disorder with a substantial contribution to years lived with disability worldwide. In the search for new treatment targets, the immune system's contribution to the pathogenesis of depression has received increased attention as immune activation has been associated with depression in various epidemiological and case-control studies. Epidemiological studies have shown that immune exposures such as severe infections and autoimmune disorders increase the risk of depression. Furthermore, immune system activation has been indicated in case-control studies of depression revealing higher levels of key pro-inflammatory cytokines among patients with depression than healthy controls, particularly in blood and to some extent in the cerebrospinal fluid. Moreover, brain imaging studies indicate increased microglial activity during depression, and gut microbiota studies have documented alterations of gut microbiota composition to be associated with depression. Based on findings from animal and human studies, several immune-mediated molecular mechanisms have been suggested to underlie the association between increased immunological activity and depression. However, the research is challenged by the heterogeneity of the depression diagnosis and - to some extent - the precision of currently available technology for immune biomarker quantification, particularly regarding the assessment of low-grade neuroinflammation. Nonetheless, an enhanced understanding of the complex interactions between the immune system and the brain in the context of depression could pave the way for precision medicine approaches with immune-modulating treatment as a promising additional option in the treatment of depression.