Major depressive disorder, neuroticism, suicidal behaviors, and depression severity are all associated with neurotoxic immune networks and their intricate interactions with metabolic syndrome.

Abstract Background Major depressive disorder (MDD) is considered to be a neuroimmune disorder. However, there are no data regarding the association between comprehensive immune profiles and their interactions with the metabolic syndrome (MetS) in predicting neuroticism, suicidal behaviors, and severity of outpatient MDD (OMDD). Methods We assayed 48 serum cytokines, chemokines, and growth factors using a multiplex assay in 67 healthy controls and 66 OMDD patients. Around 50% of the OMDD and control participants had a diagnosis of MetS. Results Ten differentially expressed proteins (DEPs) were upregulated in OMDD (i.e., CXCL12, TNFB, PDGF, CCL11, IL9, IL4, CCL5, CCL2, CCL4, IL1RN), indicating an immune, defense and stress response. Six DEPs were downregulated (VEGFA, IL12, CCL3, CSF1, IL1B, NGF), indicating lowered neurogenesis and regulation of neuron death. Significant interactions between OMDD and MetS caused a) substantial increases in TNF signaling, and upregulation of IL4, IL17, TNF, TNFB, CCL2, CCL5, PDGF, IL1RN; and b) downregulation of VEGFA and FGF. A large part of the variance in neuroticism (26.6%), suicidal behaviors (23.6%), and the MDD phenome (31.4%) was predicted by immunological data and interactions between MetS and CCL5, TNFB or VEGFA. Discussion OMDD is characterized by an immunoneurotoxic profile which partly explains neuroticism, suicidal behaviors, and the phenome’s severity. Lowered IL-10 and increased neurotoxicity are characteristics of OMDD and other depression phenotypes, including severe first-episode inpatient MDD. The presence of MetS in OMDD considerably exacerbates immunoneurotoxicity. Consequently, immune studies in MDD should always be performed in subjects with and without MetS.