The recurrence of illness (ROI) index is a key factor in major depression that indicates increasing immune-linked neurotoxicity and vulnerability to suicidal behaviors

Background The first author of this paper introduced new precision nomothetic models for a major depressive episode (MDD) which incorporate quantitative scores that measure recurrence of illness (ROI). Objective To explore the connections between ROI and biomarkers related to an activated immune network, immune-linked neurotoxicity (INT), and a combined INT and atherogenicity index (METAMMUNE). Methods The study involved 67 healthy controls and 66 outpatient MDD (OMDD) participants. We utilized a Multiplex method to measure 48 cytokines, and developed INT and METAMMUNE composite scores. The measurements included triglycerides, free cholesterol, LDL and HDL-cholesterol, apolipoprotein (Apo)A1 and ApoB. Results A ROI index was successfully created by extracting a validated principal component, from the number of physician-rated depressive episodes, the frequency of lifetime suicidal ideation and attempts. Adverse childhood experiences accounted for 20-22% of the variance in ROI. The latter was significantly associated with INT and METAMMUNE indices, neuroticism, lifetime and current suicidal behaviors, and the phenome (p<0.001). Our analysis revealed that a significant portion (55.1%) of the variance in the OMDD phenome, which includes current suicidal behaviors, anxiety, and depression, can be accounted for by the regression on INT, ROI, and emotional neglect and abuse. A validated latent construct was successfully extracted from the three ROI components, INT and METAMMUNE indices. Conclusions ROI and associated immune-metabolic biomarkers are indicators of a shared underlying concept, specifically a ROI-neuroimmune-metabolic pathway phenotype. ROI is a crucial indicator of the rising immune-metabolic abnormalities and heightened susceptibility to suicidal tendencies and recurrence of illness.