Key factors underpinning neuroimmune-metabolic-oxidative (NIMETOX) major depression in outpatients: paraoxonase 1 activity, reverse cholesterol transport, increased atherogenicity, protein oxidation, and differently expressed cytokine networks.

Abstract Background Major depressive disorder (MDD) is associated with neuro-immune – metabolic – oxidative (NIMETOX) pathways. Aims To examine the connections among NIMETOX pathways in outpatient MDD (OMDD) with and without metabolic syndrome (MetS); and to determine the prevalence of NIMETOX aberrations in a cohort of OMDD patients. Methods We included 67 healthy controls and 66 OMDD patients and we assessed various NIMETOX pathways. Results We successfully identified a subgroup of individuals with aberrations in NIMETOX pathways, including diminished lecithin-cholesterol acyltransferase (LCAT), paraoxonase 1 (PON1) activity, and reverse cholesterol transport (RCT) activities, and elevated atherogenicity, differentially expressed immune networks, and advanced oxidation protein products (AOPP). A large part of the variance (around 44%) in atherogenicity indices was associated with AOPP, fasting blood glucose (FBG), PON1 activity, and immune activation. LCAT activity was positively correlated with PON1 activity and negatively with FBG, AOPP and immune activation. RCT was positively related with the PON1 R/R 192 genotype and negatively with FBG and immune activation. A larger part of the variance in the overall severity of OMDD (50.4%), suicidal behaviors (27.7%), and neuroticism (42.1%) was positively associated with adverse childhood experiences and NIMETOX pathways, including AOPP, immune-related neurotoxicity, FBG, insulin, and atherogenicity, and inversely with immune-related neuroprotection. Conclusions Many OMDD patients (78.8%) show aberrations in NIMETOX pathways. The features of OMDD, including severity of illness, neuroticism, and suicidal behaviors, are caused by intertwined NIMETOX pathways that may exert additional effects depending on whether MetS is present or not.