Major depression is not an inflammatory disorder: depletion of the compensatory immunoregulatory system is a hallmark of a mild depression phenotype

Abstract Background Major depression comprises two discrete subtypes, major (MDMD) and simple (SDMD) dysmood disorder. MDMD, but not SDMD, patients were identified to have highly sensitized cytokine/growth factor networks using stimulated whole blood cultures. However, no information regarding serum cytokines/chemokines/growth factors in SDMD is available. Objectives This case-control study compares 48 serum cytokines/chemokines/growth factors in academic students with SDMD (n=64) and first episode (FE)-SDMD (n=47) to those of control students (n=44) using a multiplex assay. Findings Both FE-SDMD and SDMD exhibit a notable inhibition of immune profiles, such as the compensatory immunoregulatory response system (CIRS) and alternative M2 macrophage and T helper-2 (Th-2) profiles. We observed a substantial reduction in the serum concentrations of five proteins: interleukin (IL)-4, IL-10, soluble IL-2 receptor (sIL-2R), IL-12p40, and macrophage colony-stimulating factor. A significant proportion of the variability observed in suicidal behaviors (26.7%) can be accounted for by serum IL-4, IL-10, and sIL-2R (all decreased), and CCL11 (eotaxin) and granulocyte CSF (both increased). The same biomarkers (except for IL-10), accounted for 25.5% of the variance in SDMS severity. A significant correlation exists between decreased levels of IL-4 and elevated ratings of the brooding type of rumination. Conclusions The immune profile of SDMD and FE-SDMD exhibits a significant deviation from that observed in MDMD, providing additional evidence that SDMD and MDMD represent distinct phenotypes. SDMD is characterized by the suppression of the CIRS profile, which signifies a disruption of immune homeostasis and tolerance, rather than the presence of an inflammatory response.