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

In this study, we aimed to investigate the associations between the recurrence of illness (ROI) and biomarkers related to an activated immune network, immune-linked neurotoxicity (INT), and a combined INT and atherogenicity index (METAMMUNE). The study involved 67 healthy controls and 66 outpatient MDD (OMDD) participants. We utilized a Multiplex method to measure 48 cytokines and examined INT and METAMMUNE composite scores in association with different ROI indices. Our findings revealed that a ROI index was successfully created by extracting a validated principal component, from the physician-rated or self-declared number of depressive episodes, the frequency of lifetime suicidal ideation and attempts. ROI was significantly associated with INT and METAMMUNE indices, neuroticism, lifetime and current suicidal behaviors, and the phenome. Our analysis also revealed that a significant portion 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. The results indicate that increasing ROI indicates heightened immune-metabolic abnormalities, increased risk of suicidal behaviors, and elevated severity of lifetime and current phenome features.