Reduced Systemic Homeostatic and Endothelial Protective Capacity in Adolescent Major Depression: Associations with Early-Life Adversity and Clinical Phenotypes

Background: Major depressive disorder (MDD) is a heterogeneous condition characterized by neuro-immune-metabolic-oxidative stress (NIMETOX) pathways. A systems-biology approach may help elucidate how these interconnected NIMETOX disturbances relate to early-life adversity and multidimensional clinical phenomes in adolescent MDD. Objectives: This study aimed to define the peripheral metabolic, vascular, and acute-phase, oxidative, and lipid biomarker profiles of adolescent MDD and to investigate associations with ACEs and clinical phenotypes. Methods: This cross-sectional study recruited 80 adolescents with MDD and 53 matched healthy controls and assessed C-peptide and insulin, vascular tone markers, the acute-phase inflammatory axis, oxidative stress, and lipid profiles. Results: MDD adolescents exhibited significant reductions in C-peptide, NO, ApoE, ApoA1, HDL-C, albumin, and transferrin, together with increased ApoB/ApoA1 ratio. These biomarkers correlated significantly with family dysfunction, childhood trauma, bullying exposure, and maladaptive parenting. These biomarkers and stressors accounted for 46.2% to 61.2% of the variance in psychological resilience, and major affective, physiosomatic, self-injurious, suicidal, and self-regulation phenomes. ACEs and bullying exposure, together with relevant socio-demographic data, explained 10.5% to 28.4% of the variance in selected metabolic, vascular, and acute-phase biomarkers. Multivariable classification models showed adequate discrimination between MDD and healthy controls, achieving up to 88.5% classification accuracy and an AUC of 0.948. Conclusion: Adolescent MDD is characterized by coordinated reductions in negative acute-phase proteins, metabolic and lipoprotein protective factors, and endothelial NO, without overt CRP-defined inflammation or conventional dyslipidemia. These findings support a systems-biology model of impaired peripheral homeostatic protection associated with developmental adversity and multidimensional depressive phenomes.