Altered Serum Lipid and Amino Acid Metabolism in First-Episode Treatment-Naïve Major Depressive Disorder: A UHPLC-Q-TOF-MS Metabolomics Study

Background Major depressive disorder (MDD) is accompanied by widespread systemic metabolic perturbations. Most existing metabolomic investigations of MDD have included medicated patients, and the intrinsic serum metabolic signatures of untreated first-episode MDD remain poorly defined. Acylcarnitines, key mediators of mitochondrial fatty-acid β-oxidation, are hypothesized to link mitochondrial dysfunction with MDD pathophysiology. Methods We performed a cross-sectional case-control study enrolling 118 first-episode drug-naïve MDD patients and 56 demographically matched healthy controls (HC). Serum untargeted metabolomics was implemented using UHPLC-Q-TOF-MS. Rigorous quality-control workflows including pooled quality-control samples and ComBat batch-effect correction were applied. Multivariate statistical models (PCA, OPLS-DA) together with a three-criterion filtering framework (VIP > 1, BH-adjusted FDR < 0.05, |log₂FC| ≥ 0.585) were used to screen differential metabolites. Partial Spearman correlation was used to evaluate metabolite-clinical phenotype associations, and ROC analysis was performed to assess discriminatory performance. Results In total, 2466 metabolites passed quality-control filtering. The OPLS-DA model yielded acceptable group discrimination (R²X = 0.565, R²Y = 0.410, Q² = 0.539; permutation P < 0.001). Eighteen significantly altered metabolites, all down-regulated in MDD patients, were identified, comprising 13 lipid-derived metabolites (10 acylcarnitines and three eicosanoids) and five amino-acid derivatives. Acylcarnitine concentrations were negatively correlated with HAMD-17 total scores (ρ = −0.28 to − 0.45), anhedonia, psychomotor retardation and sleep disturbance. Eicosanoids correlated with somatic anxiety, whereas amino-acid derivatives were associated with suicidal ideation. Acylcarnitine levels displayed a monotonic decreasing trend across escalating C-SSRS suicide-risk strata (Jonckheere-Terpstra test, P < 0.05). A five-metabolite diagnostic panel achieved an AUC of 0.767 in the training dataset, with a repeated 5-fold cross-validated AUC of 0.694. No KEGG pathway survived FDR correction; fatty-acid β-oxidation obtained the highest exploratory uncorrected enrichment score. Conclusions First-episode drug-naïve MDD is characterized by global reduction of circulating serum acylcarnitines, consistent with impaired mitochondrial fatty-acid transport and β-oxidation. These metabolites correlate with core depressive symptoms and suicide risk and exhibit modest discriminatory capacity. Given the cross-sectional design and unmeasured confounders including diet and physical activity, causal inference cannot be drawn. Large-scale independent external validation is required.