Are abnormalities in lipid metabolism, together with adverse childhood experiences, the silent causes of immune-linked neurotoxicity in major depression?

Background Severe or recurring major depression is associated with increased adverse childhood experiences (ACEs), heightened atherogenicity, and immune-linked neurotoxicity (INT). Nevertheless, the interconnections among these variables in outpatient of major depression (OMDD) have yet to be determined. Objectives Determine the correlations among INT, atherogenicity, and ACEs in 66 OMDD patients (of whom thirty-three had metabolic syndrome, MetS) and sixty-seven controls (31 of whom had MetS). Results The free cholesterol/reverse cholesterol transport ratio, apolipoprotein (Apo) B and E, and a comprehensive atherogenicity index were all significantly associated with increased INT in OMDD subjects without MetS. ACEs were substantially correlated with INT in patients with MetS. INT (only in MetS) and atherogenicity indices (only in people without MetS) were significantly associated with the clinical phenome features of OMDD, including the recurrence of illness (ROI, including lifetime suicidal behaviors), the lifetime phenome (neuroticism + lifetime anxiety disorders and dysthymia), and the current phenome (including current suicidal behaviors). A significant proportion of the variability (58.3%) in the lifetime + current phenome could be accounted for by INT, interactions between INT and atherogenicity (labeled "atherommune index"), ApoE, three ACE subtypes (all positively correlated), and age (inversely correlated). A single validated latent construct could be extracted from ROI, lifetime phenome, current phenome, INT, and atherommune index. 36.1% of this factor’s variance was accounted for by three ACE subtypes. Discussion We have developed a novel OMDD model, namely a pathway phenotype, labeled the "atherommune-phenome," which demonstrates that the interplay between INT and atherogenicity is essential to OMDD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement 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 BGRRP2.0040007С01 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. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes