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.

The authors have declared no competing interest.

This work was supported by the Ratchadapiseksompotch Fund, Graduate Affairs, Faculty of Medicine, Chulalongkorn University (Grant number GA64/21), a grant from CU Graduate School Thesis Grant, and Chulalongkorn University Graduate Scholarship to Commemorate the 72nd Anniversary of His Majesty King Bhumibol Adulyadej to KJ; the Thailand Science research, and Innovation Fund Chulalongkorn University (HEA663000016), and a Sompoch Endowment Fund (Faculty of Medicine) MDCU (RA66/016) to MM, and Grant No BG-RRP-2.004-0007-C01, Strategic Research and Innovation Program for the Development of MU - PLOVDIV - (SRIPD-MUP), Creation of a network of research higher schools, National plan for recovery and sustainability, European Union - NextGenerationEU.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The research project (#445/63) was approved by the Institutional Review Board of Chulalongkorn University's institutional ethics board. All patients and controls gave written informed consent prior to participation in the study.

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