Blood and urinary metabolomic evidence validating traditional Chinese medicine diagnostic classification of major depressive disorder

Lan-Ying Liu, Hong-Jian Zhang, Li-Yuan Luo, Jin-Bao Pu, Wei-Qing Liang, Chun-Qin Zhu, Ya-Ping Li, Pei-Rong Wang, Yuan-Yuan Zhang, Chun-Yu Yang, Zhang-Jin Zhang, Lan-Ying Liu, Hong-Jian Zhang, Li-Yuan Luo, Jin-Bao Pu, Wei-Qing Liang, Chun-Qin Zhu, Ya-Ping Li, Pei-Rong Wang, Yuan-Yuan Zhang, Chun-Yu Yang, Zhang-Jin Zhang

Abstract

Background: Major depressive disorder (MDD) is a highly heterogeneous disease. Further classification may characterize its heterogeneity. The purpose of this study was to examine whether metabolomic variables could differentiate traditional Chinese medicine (TCM) diagnostic subtypes of MDD.

Methods: Fifty medication-free patients who were experiencing a recurrent depressive episode 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) was used to examine serum and urinary metabolomic profiles.

Results: Twenty-eight metabolites were identified for good separations between TCM subtypes and healthy controls in serum samples. Both TCM subtypes had similar profiles in proteinogenic branched-chain amino acids (BCAAs) (valine, leucine, and isoleucine) 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 biosynthesis of monoamine and amino acid neurotransmitters, including phenylalanine, 3-hydroxybutric acid, o-tyrosine, glycine, l-tryptophan, and N-acetyl-l-aspartic acid. Threonic acid, methionine, stearic acid, and isobutyric acid are differentially associated with the two subtypes.

Conclusions: While both TCM subtypes are associated with aberrant BCAA and energy metabolism, the LQS subtype may represent an MDD subpopulation characterized by abnormalities in the biosynthesis of monoamine and amino acid neurotransmitters and closer associations with stress-related pathophysiology. The metabolites differentially associated with the two subtypes are promising biomarkers for predicting TCM subtype-specific antidepressant response [registered at http://www.clinicaltrials.gov (NCT02346682) on January 27, 2015].

Keywords: Classification; Major depressive disorder; Metabolomics; Traditional Chinese medicine.

Figures

Fig. 1
Fig. 1
Representative tongue pictures taken from a healthy volunteer (a), depressed patients with Liver Qi Stagnation (b) and Heart Spleen Deficiency (c) subtypes
Fig. 2
Fig. 2
Flowchart of screening and recruitment. LQS Liver Qi Stagnation, HSD Heart and Spleen Deficiency
Fig. 3
Fig. 3
Clustering analysis of serum (a, b, c) and urine (d, e, f) metabolomic profiles. OPLS-DA models were built in patients with Liver Qi Stagnation (LQS) and Heart and Spleen Deficiency (HSD) subtypes of MDD and healthy controls (HC). Acceptable criteria for the models were defined as all R2X, R2Y, and Q2 values of ≥ 0.5. Comparisons were conducted between HC and LQS (a, d), HC and HSD (b, e), and LQS and HSD (c, f)
Fig. 4
Fig. 4
Heat maps generated from hierarchical Pearson clustering show metabolites in serum samples obtained from Liver Qi Stagnation (LQS) and Heart and Spleen Deficiency (HSD) subtypes of MDD and healthy controls (HC)
Fig. 5
Fig. 5
Heat maps generated from hierarchical Pearson clustering show metabolites in urine samples obtained from Liver Qi Stagnation (LQS) and Heart and Spleen Deficiency (HSD) subtypes of MDD and healthy controls (HC)
Fig. 6
Fig. 6
Correlation network analysis of 28 differential metabolites among Liver Qi Stagnation (LQS) and Heart and Spleen Deficiency (HSD) subtypes of MDD versus healthy controls. Green and red lines with ovals indicates negative and positive correlation, respectively. The ovals with half green and half red colors indicate mixed correlations. The oval size represents p value compared with healthy controls. Isobutyric acid (dark brown oral) has a significant difference between the two subtypes. B blood samples, U urine samples
Fig. 7
Fig. 7
Biochemical pathway analysis shows biological impacts in differentiating Liver Qi Stagnation (LQS, a) and Heart and Spleen Deficiency (HSD, b) subtypes of MDD from healthy controls. X- and Y-axis indicates the magnitude of the impact and p value compared with healthy controls, respectively. Aminoacyl-tRNA biosynthesis and valine, leucine and isoleucine biosynthesis pathways are most closely associated with the two subtypes. The HSD subtype was additionally associated with valine, leucine and isoleucine degradation
Fig. 8
Fig. 8
Receiver operating curve (ROC) analysis show the optimal serum metabolite panels that well differentiate Liver Qi Stagnation (LQS, a) and Heart and Spleen Deficiency (HSD, b) subtype from healthy controls

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