Psychological stress-associated ceramide and diacylglyceride lipotoxicity as contributors to first-episode depression pathophysiology: A neuroimmune-metabolic-oxidative stress (NIMETOX) perspective.
BACKGROUND Aberrations in neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways are implicated in major depressive disorder (MDD). First-episode simple dysmood disorder (FE-SDMD) without metabolic syndrome offers a unique model to investigate early lipid alterations using a systems biology approach. METHODS Plasma samples were collected from 88 university students (44 FE-SDMD, 44 healthy controls). Participants underwent psychiatric assessments, including adverse childhood experiences (ACEs), negative life events (NLEs), depression, anxiety, suicidal behaviors, and insomnia. Untargeted lipid profiling was performed using LC-QTOF-MS, while indices of oxidative and nitrosative stress (ONS) and lecithin-cholesterol acyltransferase (LCAT) activity were assessed. Data was analyzed using machine learning approaches with recursive feature elimination and cross-validation. RESULTS FE-SDMD was characterized by increased ceramides (CER), diacylglycerides (DAG), triacylglycerides (TG), sphingomyelins (SM), bis-monoacylglycerol phosphates (BMP), cholestone, and fatty-acyl amino acids (FAAA). DAG, CER, and BMP were the strongest predictors of depression severity and physiosomatic symptoms, whereas cholestone, CER, and SM predicted suicidal behaviors. These lipid modules, together with lowered LCAT and increased ONS, explained substantial variance in depression severity (46.4%), physiosomatic symptoms (42.4%), cognitive-affective symptoms (37.9%), suicidal behaviors (30.1%), insomnia (32%), and anxiety (19.5%). ACEs and NLEs were strongly associated with CER (p < 0.001), DAG (p < 0.01), and cholestone (p < 0.01), revealing coordinated lipidomic networks within a systems biology framework. CONCLUSION Early-stage MDD is characterized by lipid dysregulations, which are linked to psychosocial stress exposure, oxidative stress and attenuated reverse cholesterol transport. These lipid modules identify biologically functional pathways associated with early disease and may inform the development of future therapeutic strategies.