Plasma Lipidomic Features of Adolescent Major Depressive Disorder and Lipid Changes After Fluoxetine Treatment

BACKGROUND: Major depressive disorder (MDD) in adolescents is a major public health concern, yet objective biological markers and treatment-related metabolic changes remain insufficiently understood. This study aimed to characterize plasma lipidomic alterations in adolescent MDD and explore lipid changes associated with fluoxetine treatment. METHODS: This study enrolled 75 adolescents with MDD and 75 matched healthy controls (HCs). Among the adolescents with MDD, 44 had paired baseline and week-8 plasma samples available and were included in the longitudinal analysis. Plasma lipidomic profiles were analyzed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). RESULTS: A total of 865 lipid species were detected. Compared with HCs, adolescents with MDD showed distinct plasma lipidomic profiles, with 82 differentially abundant lipid species identified, primarily involving triglycerides, lysophospholipids, free fatty acids, membrane phospholipids, and sphingolipids. Among the machine-learning models, logistic regression showed the highest discriminative performance, with a pooled out-of-fold AUC of 0.85 (95% CI, 0.79-0.91). Longitudinal analysis identified 21 lipid species meeting the differential criteria following fluoxetine treatment, mainly involving triglycerides and bile acid-related metabolites. Integrative pathway and target analyses suggested that fluoxetine-associated lipid changes may involve neurotransmitter signaling, inflammatory lipid metabolism, PI3K-Akt signaling, and nuclear receptor-related pathways. CONCLUSION: This study characterizes alterations in plasma lipid metabolism in adolescent MDD and the lipidomic changes following fluoxetine treatment, providing new lipidomic evidence for candidate lipid signatures and potential treatment-associated biological pathways. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05814640. Registered 20 February 2023, https://clinicaltrials.gov/study/NCT05814640.