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Table of Contents
Year : 2020  |  Volume : 6  |  Issue : 2  |  Page : 171-179

Research progress on antidepressant therapeutic biomarkers of Xiaoyaosan

Modern Research Center for Traditional Chinese Medicine; Shanxi Key Laboratory of Active constituents Research and Utilization of TCM, Shanxi University, Taiyuan, China

Date of Submission19-Dec-2020
Date of Acceptance19-Jan-2020
Date of Web Publication30-May-2020

Correspondence Address:
Prof. Jun-Sheng Tian
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Xiaodian, Taiyuan 030006
Prof. Xue-Mei Qin
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Xiaodian, Taiyuan 030006
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjtcm.wjtcm_16_20

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Depression is one of the most prevalent and serious mental disorders with a significant burden of disease. Xiaoyaosan (XYS), a well-known Chinese formula, has been widely used in the treatment of depression. Both clinical studies and animal experiments have indicated that XYS has an obvious antidepressant activity. How to select objective pharmacodynamic markers for traditional Chinese medicine (TCM) treatments based on clinical metabolites, linking pathogenic genes, and drug targets, is a bottleneck problem in the modernization of TCM. To address this issue, we sorted out clinical metabonomics experiments of XYS in treating depression, constructed a metabolic profile of therapeutic biomarkers, and deduced metabolic biomarker-protein interactions networks. The therapeutic biomarkers found for XYS were involved in neurotransmitter synthesis, energy metabolism, and gut microbial metabolism. This study aims to provide a scientific basis for the clinical diagnosis of depression and evaluate the efficacy of XYS in its treatment.

Keywords: Depression, efficacy evaluation, metabonomics, therapeutic biomarkers, xiaoyaosan

How to cite this article:
Gao Y, Zhao YX, Xu T, Tian JS, Qin XM. Research progress on antidepressant therapeutic biomarkers of Xiaoyaosan. World J Tradit Chin Med 2020;6:171-9

How to cite this URL:
Gao Y, Zhao YX, Xu T, Tian JS, Qin XM. Research progress on antidepressant therapeutic biomarkers of Xiaoyaosan. World J Tradit Chin Med [serial online] 2020 [cited 2023 Dec 1];6:171-9. Available from: https://www.wjtcm.net/text.asp?2020/6/2/171/285411

  Introduction Top

Depression is one of the most prevalent and serious mental disorders. With a lifetime prevalence of 20%, it is characterized by high disease burden and excess mortality.[1],[2] In recent years, the number of patients suffering from depression has increased rapidly. From 1990 to 2016, depression was the fifth-leading cause of years lived with disability worldwide, contributing with a total of 34.1 million years lived with disability.[3] At the same time, depression often coexists with other conditions that mask the symptoms, hindering its diagnosis. Due to the lack of objective standards, the diagnosis of depression currently relies solely on the clinician's subjective judgment according to the type and severity of symptoms.[4] Increasing evidences show that the treatment of depression by traditional Chinese medicine (TCM) has drawn ever increasing attention worldwide due to its high therapeutic performance, low toxicity, and few side effects.[5]

Xiaoyaosan (XYS) decoction, one of the most famous traditional Chinese formulas in the treatment of depression, was described in the Taiping Huimin Heji Jufang during the Song Dynasty (960–1127 A.D.) [Figure 1]. XYS is also officially registered in the Chinese Pharmacopoeia as having some positive effects in the body, including soothing the liver, strengthening the spleen, and nourishing blood.[6] Up to now, increasing clinical evidences show that that XYS has a therapeutic influence on depression.[7] In our previous experiments, we used XYS according to the traditional method, each dose included Radix Bupleuri (60 g), Radix Angelicae Sinensis (60 g), Poria (60 g), Radix Paeoniae Alba (60 g), Rhizoma Atractylodis Macrocephalae (60 g), Radix Glycyrrhizae (30 g), Herba Menthae (20 g), and Rhizoma Zingiberis Recens (20 g), to search for biochemical and behavioral changes in the subjects of the study. Results showed that XYS had a noticeable antidepressant activity.[8] XYS has also shown an obvious superiority in the treatment of depression when combined with syndrome differentiation and an individualized treatment.[9] However, the lack of an objective pharmacodynamic evaluation system that includes both the symptoms and the effects of the tested compound has become challenging. At present, the evaluation of the efficacy of XYS relies on the presentation of symptoms and on rating scale scores, leading to a limited sensitivity. Therefore, the development of a sensitive and specific approach that can provide a relatively objective index for the evaluation of the antidepressant effects of XYS is crucial.
Figure 1: Traditional Chinese medicine prescription Xiaoyaosan. The Xiaoyaosan prescription consists of eight herbs, (1) Radix Bupleuri (Bupleurum chinenseDC.), (2) Radix Angelicae Sinensis (Angelica sinensis [Oliv.] Diel), (3) Radix Paeoniae Alba (Paeonia lactiflora Pall.), (4) Rhizoma Atractylodis Macrocephalae (Atractylodes macrocephala Koidz.), (5) Poria (Poria cocos [Schw.] Wolf), (6) Rhizoma Zingiberis Recens (Zingiber officinale Rosc.), (7) Herba Menthae (Mentha haplocalyx Briq.) and (8) Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch.)

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Metabonomics is an omics technology developed after genomics and proteomics, which can simultaneously analyze multiple metabolites in body fluids. The development of the metabonomics technology provides possibilities for the prediction and early diagnosis of depression. Compared with traditional diagnostic approaches and conventional clinical biomarkers, metabonomics technology shows potential advantages, both in sensitivity and specificity, because of its simultaneous assessment of multiple metabolites. Therefore, metabonomics has integrity and objectivity as main advantages and set up a scientific bridge between Chinese and Western medicine. It is useful for the discovery or diagnosis of diseases and for evaluating the efficacy of TCM formulas.[10]

In recent years, some scholars have used metabonomics techniques to conduct a comprehensive and systematic study of metabolite changes in depression, to provide a theoretical basis for the pathogenesis of this disorder.[11],[12] Increasing evidence has shown that differential metabolites related to XYS antidepressant effects are found in both the plasma [8],[12] and urine.[13],[14] Considering the differences between species, animal experimental results and clinical research results may not be very different. Therefore, we based our research on XYS and its antidepressant effects in the clinic regarding potential biomarkers.

In this article, we focused on clinical metabonomics experiments of XYS in treating depression, summarized those biomarkers identified for this metabolic therapy, and deduced metabolic biomarker-protein interaction networks (BPINs). We found that the therapeutic biomarkers of the XYS antidepressant treatment were involved in neurotransmitter synthesis, energy metabolism, and gut microbial metabolism. This study aims to provide a scientific basis for the clinical diagnosis of depression and evaluate the efficacy of XYS in the treatment of this condition.

  The Metabolic Therapeutic Biomarkers of the Xiaoyaosan Antidepressant Treatment Top

Metabonomics promises to be a useful tool for biomarker discovery in the clinical practice. Specific methods employed in the study of metabonomics include nuclear magnetic resonance, gas chromatography-mass spectrometry, and liquid chromatography-mass spectrometry. As metabonomics can be applied in the evaluation of the therapeutic effects of XYS in depressed individuals, we have taken the results from several experiments and identified and summarized those potential biomarkers of XYS antidepressant treatments.

In the plasma, a total of 32 biomarkers related to the antidepressant efficacy of XYS were screened, including amino acids (alanine, valine, and leucine), organic acids (lactate and oxalic acid), amines (trimethylamine oxide, glutamine, and ceramide), fatty acids (stearic acid), lipids (sphingolipids), acyl carnitines (carnitine C10:4 and carnitine C14:2), glucose, and choline [Table 1].
Table 1: Study on plasma biomarkers and related metabolic pathways in patients with depression by metabolomics

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In the urine, a total of 11 biomarkers related to the antidepressant efficacy of XYS were screened, including amino acids and their derivatives (tyrosine, alanine, phenylalanine, and hippuric acid), organic acids (citrate, lactate, xanthate acid, taurine, and α-ketoglutaric acid), amines (dimethylamine), and creatinine [Table 2].
Table 2: Study on urine biomarkers and related metabolic pathways in patients with depression by metabolomics

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According to the results of the receiver operating characteristic curve, the area under the corresponding curve of lactate, trimethylamine, phenylalanine, oxalic acid, and stearic acid in the plasma is > 0.7, implying that they can be used as efficacy biomarkers of the antidepressant XYS. Noteworthy, according to the results of a dynamic analysis, after the ingestion of XYS for 2 weeks, in a patient with depression, lactate, creatinine, dimethylamine, phenylalanine, alanine, tyrosine, citric acid, and hippuric acid provoked a callback phenomenon in the urine. However, after 8 weeks of taking the drug, these metabolites were back again at normal levels and could be used as biomarkers for the XYS antidepressant treatment.

In the above studies, we found that the trends of the biomarkers detected by different methods were the same. Besides, we summarized the metabolic therapeutic biomarkers involved and constructed the metabolic pathway maps of the antidepressant XYS. Combined with the analysis of the existing biochemical knowledge, the following three different mechanisms of energy metabolism, neurotransmitter synthesis, and gut microbial metabolism were obtained.

  Energy Metabolism of the Antidepressant Xiaoyaosan Top

Among energy metabolism biomarkers, citrate, lactate, and glucose should be mentioned. Besides, the biological pathways involved in energy metabolism are the tricarboxylic acid (TCA) cycle and the pyruvate, the glyoxylic acid and dicarboxylate, and the fatty acid metabolic pathways.

The tricarboxylic acid cycle

Citrate is related to energy metabolism and is one of the important intermediates in the TCA cycle. Compared with the healthy control group, the level of citrate in the plasma of patients with depression was decreased, resulting in low-energy availability. Reduced activity due to a lack of energy is one of the common symptoms of depression.[15] Oxalic acid, metabolized either by acetaldehyde acid or ascorbic acid, is an important intermediate in the transformation of malic acid into formic acid. In the TCA cycle, the regeneration of oxaloacetate is achieved by the dehydrogenation oxidation of malic acid. Therefore, a significant increase in oxalic acid levels in the plasma of patients with depression suggests that this disorder may inhibit the TCA cycle.

In addition, the level of oxaloacetate in the plasma of patients with depression receded to normal levels during XYS treatment, suggesting that XYS may increase energy availability and thus the activity of patients with depression by regulating the TCA cycle.

Pyruvate metabolism

Compared with the healthy control group, a decrease in glucose and lipid levels in depressive patients, together with an increase of lactic acid levels, under anaerobic conditions once again indicated that depression leaded to a diminishment in patients' energy. In contrast, in patients treated with XYS, lactic acid in plasma reached normal levels, indicating that XYS could improve depressive symptoms of patients by regulating their metabolic capacity.[16]

Glyoxylic acid and dicarboxylate metabolism

As previously mentioned, oxalic acid, synthesized by either glyoxylic acid or ascorbic acid metabolisms, is an important intermediate for the conversion of malic acid into formic acid. In the TCA cycle, the recycling of oxaloacetate is achieved by the oxidation of malic acid by malate dehydrogenase. The high levels of oxalic acid observed in depressive patients suggest that depression may inhibit the TCA cycle and reduce energy availability, leading to a diminishment in the physical activity of individuals.[17] Interestingly, the levels of oxaloacetate in the plasma of patients with depression treated with XYS were within the normal limits, suggesting that XYS could provoke and increase in the physical activity of patients with depression by regulating the metabolism of glyoxylic acid and dicarboxylates.

Fatty acid metabolism

Fatty acids are an important source of energy production and storage in the human body. Acetyl-CoA, produced by the oxidation of β-fatty acids, can be used to produce adenosine triphosphate in the TCA cycle and can also be converted into ketone bodies for storage in the kidneys and liver.[18] The concentration of stearic acid in the plasma of patients with depression, compared to nondepressed individuals, was significantly increased, which might lead to a certain degree of blockage of fatty acid transport and of inhibition of the TCA cycle, ultimately affecting the entire energy metabolism process. However, the plasma level of stearic acid reached normal concentrations in patients with depression treated with XYS, showing that XYS could play an antidepressant role by regulating fatty acid metabolism.

In addition, fatty acids are the most abundant energy reservoirs in the body. They” supply energy through β-oxidation processes that occur in both the mitochondria and peroxisomes. During fatty acylcarnitine oxidation, long chain fatty acids are transferred from the cytoplasm to the mitochondria. Their accumulation leads to the destruction of the mitochondrial membrane, which in turn affects the body's energy supply, resulting in a lack of energy. Compared with the healthy control group, the content of acylcarnitine (carnitine C14:2 and carnitine C10:4) in the plasma of patients with depression was increased, but showed a normal level in patients treated with XYS. These results indicate that XYS could improve the symptoms of reduced physical activity in patients with depression by increasing β-oxidation of fatty acids.

  Neurotransmitter Biomarkers of the Antidepressant Xiaoyaosan Top

Main neurotransmitter biomarkers include proline, leucine, valine, and glutamine. The biological pathways involved in their biosynthesis are the valine, leucine and isoleucine pathway and the tyrosine, taurine and hypotaurine, the arginine and proline, the cysteine and methionine, the glycerol phospholipid, and the sphingolipid metabolic routes.[19]

Biosynthesis of valine, leucine, and isoleucine

Leucine and valine are branched-chain amino acids (BCAAs) bearing aliphatic side chains. The concentration of BCAAs is significantly lower in patients with depression than in healthy controls. It is known that a decreased BCAA concentration can interfere with the release of 5-hydroxytryptamine (5-HT) in the brain and lead to central fatigue, which is an common symptom of depression.[11] As amino acid donors, BCAAs can rapidly cross the blood-brain barrier to synthesize glutamic acid in the brain. Decreases in plasma levels of leucine, together with an abnormal synthesis of 5-HT and glutamic acid lead to a depressive behavior.

Tyrosine metabolism

Tyrosine is an essential aromatic amino acid that easily passes through the blood-brain barrier. It is a precursor of neurotransmitters, such as adrenaline, norepinephrine, and dopamine, in the brain. These neurotransmitters are closely related to the sympathetic nervous system of the human body. At the same time, tyrosine is also a precursor of hormones, thyroxine, and melanin. A higher tyrosine supplementation is needed under stress conditions; whereas, tyrosine supplementation can prevent depletion of norepinephrine in patients with depression.[20] Besides, phenylalanine is the precursor of tyrosine synthesis, as well as the precursor of catecholamines, such as tyramine, dopamine, adrenaline, and norepinephrine. Thus, tyrosine and phenylalanine are closely related to neurotransmitters, and directly or indirectly participate in their synthesis.[21],[22]

As expected, both tyrosine and phenylalanine play an important role in maintaining the levels of neurotransmitters. We found that patients with depression had abnormal levels of tyrosine, phenylalanine, and hippuric acid, which affected the synthesis of neurotransmitters to a certain extent. Moreover, it was determined that XYS can adjust the body levels of tyrosine and phenylalanine, leading to a significant improvement in life quality.

Hippuric acid, also known as benzoylglycine, is mainly a detoxification metabolite synthesized from benzoic acid in the liver and excreted through the urine by glomerular filtration. There are several sources of benzoic acid in the body; one of them is phenylalanine catabolism. Benzoic acid and glycine conjugate to form hippuric acid.[23] Therefore, hippuric acid is important in the metabolism of the body. Our results showed that the level of hippuric acid was significantly adjusted toward normal levels in patients treated with XYS, indicating that the metabolism of glycine and hippuric acid had a certain correlation with depression. These results suggest that XYS may play an important role in the regulation of neurotransmitters and the normal function of the nervous system.

Taurine and hypotaurine metabolism

Taurine, a sulfur-containing amino acid, is widely found in the brain, heart, gallbladder, and kidney. It has a variety of biological functions; it may act as a neurotransmitter, a stabilizer in cell membranes, and a promoter of calcium and sodium transport. The earliest and most significant symptom of taurine deficiency is depression, manifested by a sleeping disorder, exhaustion, and weight loss. Alanine, glutamic acid, and pantothenic acid can inhibit the metabolism of taurine to varying degrees. In contrast, Vitamin A and Vitamin B6 can promote the synthesis of taurine.[24]

Taurine was found to be almost insufficient in all patients with depression.[25] Besides, patients with depression had high levels of alanine in their urine and relatively low levels of taurine. However, the total content of alanine decreased in the urine of patients treated with XYS, while the level of taurine increased significantly. These results indicate that XYS may inhibit alanine synthesis, promote taurine synthesis, and regulate energy metabolism and neurotransmission.

Arginine and proline metabolism

Glutamic acid is the most abundant fast excitatory neurotransmitter in the mammalian nervous system. Nerve impulses trigger the release of glutamate from cells, whereas, in the opposite postsynaptic cells, the N-methyl-D-aspartic acid receptor is activated. This mechanism plays an important role in synaptic plasticity. Therefore, the synthesis of glutamic acid has a great relationship with human cognitive functions (such as learning and memory).[26] In addition, urea is synthesized from the ammonia produced by glutamate deamination in the liver. The significant decrease in the urea content found in the plasma of patients with depression may be caused by a decrease in glutamic acid synthesis, which would further explain the decline in the cognitive function of patients with depression: A neurological dysfunction is mainly manifested in patients with depression. After treating depressive patients for 8 weeks with XYS, the plasma urea levels showed a significant regression toward normal levels, suggesting that XYS may improve the cognitive function of patients with depression by regulating both the arginine and proline metabolic pathways.

Cysteine and methionine metabolism

In recent years, studies have shown that serine plays a very important role in maintaining the normal function of the central nervous system (CNS). The lack of serine can cause mental disorders and depression of the CNS.[27] The decreased content of cysteine found in the plasma of individuals with depression may be due to serine deficiencies caused by an abnormal metabolism of cysteine and methionine. The plasma levels of serine in patients with depression were reversed to normal after the treatment with XYS, suggesting that XYS might exert its antidepressant effect by regulating both the metabolisms of cysteine and methionine.

Glycerol phospholipid metabolism

Hemolytic glycerophosphatidylcholine is formed by the hydrolysis of lecithin; it can promote the growth and development of the brain nerve system, an increased brain volume, and nerve conduction. In the human brain, it can be rapidly converted to acetylcholine by taking up phospholipids and choline directly from the plasma. Long-term supplementation of phospholipids can alleviate memory loss and prevent or delay the occurrence of Alzheimer's disease in human beings. It has been reported that a metabolic abnormality in the hemolytic glycerophosphatidylcholine route is related to depression and psychiatric diseases such as Parkinson's disease.[28] An elevated concentration of the hemolytic glycerophosphatidylcholine Lyso-phosphatidyl choline (LPC) 10:3 was found in the plasma of patients with depression compared with healthy controls. Besides, LPC 16:1, LPC 21:4, LPC 19:0, and LPC 18:0 concentrations were also elevated. All of them showed a significant callback after the treatment with XYS, indicating that XYS may improve depressive symptoms by regulating glycerophospholipid metabolism.[29]

Sphingolipid metabolism

Sheath lipids or sphingomyelins are a large class of lipid compounds with signal transduction functions. Sphingomyelins hydrolyze under the action of sphingomyelinase and release ceramides and sphingomyelin metabolites. Ceramides can also be synthesized by serine and palmitic acid, which are important cell signals for inducing apoptosis and can also be involved in a variety of signaling pathways.[30] Previous studies have reported that the occurrence of depression is related to a signaling pathway. In this study, compared with the healthy control group, we found that sphingomyelin and ceramide contents in the plasma of patients with depression were increased, and that there was a significant callback after the ingestion of XYS. These results show that XYS may achieve its antidepressant effect by improving sphingomyelinase metabolism.

  Gut Microbial Metabolism Biomarkers of Xiaoyaosan Antidepressant Effects Top

Loss of appetite is one of the most common symptoms in patients with depression, usually associated with gut microbial metabolism. Clinical studies have shown that metabolic disorders of the intestinal flora in patients with depression lead to changes in plasma levels of several compounds, such as trimethylamine N-oxide (TMAO) and dimethylamine oxide.[31] Choline is converted from phosphorylcholine and can be metabolized to TMAO by the intestinal flora.[32] Results suggested that, compared with the healthy control group, the decreased choline levels and the increased TMAO concentration in the plasma of patients with depression could cause a disorder in the intestinal flora of the patients.

Noteworthy, the levels of TMAO in the plasma of depressive patients showed a significant regression toward normal levels after the treatment with XYS, suggesting that XYS may play an antidepressant role by improving the metabolism of the intestinal flora and increasing the appetite of those patients with depression.

  Biomarkers-Proteins Interactions Networks for the Xiaoyaosan Antidepressant Top

It is difficult to comprehensively understand the complexity of biological systems by one approach only. The data obtained from metabonomics are complementary to the data obtained by other omics approaches and thus aid in providing a complete picture of a living organism. Currently, omics sciences include genomics for DNA variants, transcriptomics for mRNA, proteomics for proteins, and metabolomics for metabolites.[33] Theoretically, metabolomics has an advantage over the other three omics for closely reflecting the organism activity at a functional level. Moreover, metabolic alterations are affected by direct genetic regulation and enzymatic reactions and changes in metabolites concentrations may reflect the changes in both mRNA and protein expression.[34] Noteworthy, different metabolites can be used as substrates or reactants for many different metabolic pathways. Therefore, we constructed metabolic BPINs to find the possible targets of XYS for exerting its antidepressant effects [Table 3] and [Figure 2].
Table 3: The metabolites with the HMDB ID, ChEBI ID, and KEGG ID were obtained in databases

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Figure 2: Effect of xiaoyaosan on antidepressant metabolic biomarkers-protein interactions networks. Hexagons nodes represent metabolites, yellow nodes represent xiaoyaosan antidepressant efficacy markers, and pink nodes represent other metabolites. The gray round nodes represent genes related to metabolites

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In our BPINs, the nodes either were metabonomic biomarkers or proteins, whereas the edges were the relationships between them. Interestingly, while for some biomarkers, concentrations were upregulated and for others, they were downregulated, related enzymes aggregated together and formed a giant cluster, meaning that all these biomarkers and proteins interacted directly or indirectly with each other. In total, we identified 20 potential metabonomic biomarkers linked to 176 proteins and enzymes [Table 4]. These potential biomarkers were mainly involved in energy metabolism, amino acid metabolism, gut microbial metabolism, glycerophospholipid metabolism, and sphingolipid metabolism. The pathogenesis of depression might be related to metabolic disorders in these biological processes. Metabolic BPINs were drawn using Cytoscape and used to visualize relationships between the identified metabonomic biomarkers and proteins.
Table 4: The relationship between biomarkers and protein in Xiaoyaosan antidepressant

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  Conclusions Top

In this article, at the level of metabolites, we systematically confirmed the curative effects of XYS. It was discovered that XYS can exert antidepressant effects by regulating neurotransmitter synthesis and energy and gut microbial metabolisms. It scientifically shows how XYS improves fatigue and loss of appetite symptoms in depressive patients. While screening for potential metabolite therapeutic biomarkers for XYS mechanisms of action in the treatment of depression, we have provided with molecular evidence to prove the efficacy of TCM.

Until now, many metabolites and differential biomarkers related to the pathogenesis of depression and XYS therapy have been discovered through metabolomics research. Previous studies have shown that metabolomics can help to address those therapeutic biomarkers involved in the treatment of depression. These biomarkers could be used for the development of a new disease diagnostic and therapeutic evaluation technique for the optimization of depression management. Metabolic perturbations in patients with depression have been shown to be altered by XYS treatment. In addition, this review envisages the application of metabonomics in the discovery of distinctive XYS therapeutic biomarkers in the treatment of depression and in future research on this medical condition: (1) With the study of several clinical potential biomarkers we can conclude that the efficiency of XYS in the treatment of depression may be verified by specific therapeutic markers; (2) functional metabonomics has replaced traditional discovery metabolomics in the evaluation of the effects of XYS treatment on depressive patients by determining the changes provoked in several metabolite levels; (3) other new technologies need to be applied to the study of XYS antidepressant clinical efficacy markers, such as stable isotope resolved metabolomics, network pharmacology, metabolic flux analysis, and spatiotemporal metabolomics technology. Therefore, the emerging applications of metabolomics and metabonomics in the treatment of depression by XYS have great potential in clinical diagnosis and in the evaluation of the efficacy of TCM in the treatment of depression.


This research was funded by the National S and T Major Projects for “orjec New Drugs Innovation and Developmente (2017ZX09301047), the Science and Technology of Shanxi Province (No. 201701D121137 and No. 201903D321210).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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