摘要：OBJECTIVE Major depressive disorder (MDD) is a highly heterogeneous mental illness. Further classification may help characterize its heterogeneity. The purpose of this study was to examine metabolomic and brain connectomic associations with traditional Chinese medicine (TCM) diagnostic classification of MDD. METHODS Fifty unmedicated depressed patients were classified into Liver Qi Stagnation (LQS, n=30) and Heart and Spleen Deficiency (HSD, n=20) subtypes according to TCM diagnosis. Healthy volunteers (n=28) were included as controls. Gas chromatography-mass spectrometry (GC-MS) and diffusion tensor imaging were used to detect serum and urinary metabolomic profiles and whole-brain white matter connectivity, respectively. RESULTS In metabolomic analysis, 28 metabolites were identified for good separations between TCM subtypes and healthy controls in serum and urine samples. While both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids and energy metabolism-related metabolites that were differentiated from healthy controls, the LQS subtype additionally differed from healthy controls in multiple amino acid metabolites that are involved in the biosynthesis of monoamine and amino acid neurotransmitters. Several metabolites are differentially associated with the two subtypes. In connectomic analysis, The LQS subtype showed significant differences in multiple network metrics of the angular gyrus, middle occipital gyrus, calcarine sulcus, and Heschl′ s gyrus when compared to the other two groups. The HSD subtype had markedly greater regional connectivity of the insula, parahippocampal gyrus, and posterior cingulate gyrus than the other two groups, and microstructural abnormalities of the frontal medial orbital gyrus and middle temporal pole. The insular betweenness centrality was strongly inversely correlated with the severity of depression and dichotomized the two subtypes at the optimal cutoff value with acceptable sensitivity and specificity. CONCLUSION The LQS subtype may represent an MD

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