Increased Oxidation Susceptibility of HDL Particles as a Mechanistic Signature of Major Depressive Disorder

Abstract Background Major depressive disorder (MDD) involves disturbances in neuroimmune–metabolic and oxidative stress (NIMETOX) pathways. However, oxidized HDL (OxHDL) and oxidized LDL (OxLDL) have not been examined together. Methods Serum OxHDL, OxLDL, and a panel of oxidative, antioxidant, and acute phase inflammatory (API) biomarkers were measured in 125 Chinese MDD patients and 40 healthy controls using ELISA and spectrophotometry. Results MDD patients showed increased OxHDL, reduced OxLDL, and markedly lowered antioxidant defenses, while classical lipid peroxidation markers remained unchanged. These alterations were independent of metabolic syndrome. The acute phase response was closely linked to reductions in HDL-related antioxidants and OxLDL. A combined biomarker model including the HDL/OxHDL ratio, apolipoprotein (ApoA)1, OxHDL, OxLDL, lipid hydroperoxides, and API index achieved an area under the ROC curve of 0.915 (SE=0.023) and a cross-validated sensitivity of 83.1% with 84.6% specificity. The variance in overall severity of depression, physiosomatic symptoms and recurrence of illness was to a large extent explained by oxidative/antioxidant biomarkers. The top-most important biomarkers were OxHDL/OxLDL (increased) and antioxidant (decreased) levels. Conclusion Increased OxHDL is a key component of MDD, indicating structural and dysfunctional HDL particles and oxidative damage to its major structural protein (ApoA1). HDL particles rather than LDL particles and other lipids are the most vulnerable sites to be attacked by oxidative stress and inflammatory processes in MDD. These data support the view that increased oxidative damage to HDL particles is a key process in MDD. Preventing HDL particle oxidation is a major new drug target in MDD.