| RATIONALES:Depression is a common mental disorder that presents mainly with depressed mood, accompanied by loss of interest or pleasure, disturbed sleep or appetite and physical discomfort. At the same time, depressive symptoms can mimic other disorders and often coexisting conditions can confound an accurate diagnosis. Making matters worse, current clinical diagnosis methods of depression rely solely on the clinician’s subjective identification of symptomatic clusters and scales (HAMD and CGI), which may lead to the inaccuracy of clinical diagnosis as the lack of objective index.Numerous of clinical studies and previous works of my group indicate that Xiaoyaosan (XYS) has obvious antidepressant activity. And compared to Western medicine, XYS has more advantages, such as little side effects, multi-component and multi-target treatment characteristics, which is the ideal antidepressant drug. However, some problems were found through analysis of relevant literatures, such as lack of standardized dosage and treatment course of XYS in clinic. The efficacy evaluation of XYS also has some problem, such as lack of efficacy evaluation criteria of XYS, the evaluation method of antidepressant efficacy was single, antidepressant mechanism of XYS is not very clear. But also there is no objective evaluation system which can evaluate the antidepressant effect of the prescription.Metabonomics adopts ’top-down’ strategy to reflect the metabolic changes of a complete system caused by interventions dynamicly and continuously. Its property was consistent with the holistic thinking of TCM, also it can reflect the therapeutic characteristics of Chinese medical formulae.Aim of the study:(1) The study was to evaluate the efficacy of XYS in the treatment of depression. The best antidepressant dose of XYS (a daily dose of 370g crude drugs) was screened through the previous works of my laboratory. (2) The study was to investigate potential diagnostic biomarkers for depression using 1H-NMR-based metabonomics approach. (3) The aim of study was also to evaluate the clinical effect of XYS and antidepressant mechanism of XYS using a metabonomics approach.Material and methods:(1) 60 depression outpatients (18-65 years) were previously recruited as the treatment group,60 healthy people as the control group. Patients were evaluated at screening, baseline and 2,4,6 and 8 weeks, measured by the HAMD and the CGI scale. SPSS 17.0 was performed for data analysis. (2) Fasting venous blood samples were collected before treatment and at the last day after the final treatment. Morning urine samples were collected at 0,2,4,6 and 8 weeks during the treatment period.1H-NMR-based metabonomics techniques and multivariate statistical method were used to analyze the plasma and urine metabolites of depressed patients before and after treatment. NMR data were reduced to integral regions of equal width using MestRenova software. After data preprocessing, multivariate statistical analysis (PCA, PLS-DA and OPLS-DA) was performed to process the acquired NMR data using SIMCA-P. Score plot was to compare the classification of different groups, loading plot was performed to obtain the biomarkers. Then the study was to determine whether XYS was possible to influence the metabolic profile of depressed patients and to interpret the antidepressant mechanism.Results:62 patients were included into the group, four patients failed to complete the treatment.(1)Based on the reduction rate of HAMD scores after 8 weeks treatment,38 cases were cured,14 cases were significantly improved,4 cases were improved, and 2 cases were invalid. The significant efficiency was 90%. The HAMD and CGI scores were significantly decreased after 2 weeks of treatment (P<0.01).(2) PLS-DA was used for analyzing the NMR spectra data, the depressed patients were clearly separated from controls. Among all the different variables selected from the PLS-DA model based on the loading plot and the p-values from the t-test (p<0.05),12 metabolites were finally identified as potential biomarkers. As compared to healthy controls, the depressed patients were characterized by significant lower level of amino acids (leucine, isoleucine, valine, alanine, and glutamate), significant lower levels of other metabolites (β-hydroxybutyrate, pyruvate, citrate, creatinine, TMAO) and significant higher level of lactate, NAG. The changes in these endogenous metabolites also suggested that related biochemical pathway perturbation was induced by depresson. The level of 11 potential biomarkers was significantly reversed under the treatment of XYS. XYS displays an obvious anti-depression effect by adjusting the amino acid metabolism, energy metabolism, ketone bodies and other metabolic pathways.(3) The metabolic patterns of depressed patients after 2 weeks XYS treatment can’t separate from the patients before treatment, indicating that the efficacy of XYS is not obvious and need a continuous medication.8 metabolites were identified as potential biomarkers for the XYS treatment. Creatinine, taurine, xanthine,2-oxoglutarate were significant increased after XYS treatment for 8 weeks when compare with before treatment; Moreover, citrate, alanine, lactate and dimethylamine were significant decreased after XYS treatment for 8 weeks. Creatinine, lactate, taurine, xanthine, citrate, alanine and dimethylamine also have found the same change trend after XYS treatment for 4 or 6 weeks (p<0.05). After XYS treatment for 2 weeks, only creatinine level significant increased (p<0.05) and dimethylamine, lactate level significant decrease (p<0.05) when compare with week 0. Reference to relevant literature, these data indicated that therapeutic effects of XYS may base on energy metabolism, gut microbes, xanthine metabolism and taurine metabolism.Conclusions:(1) XYS has exact antidepressant effect for mild to moderate depression patient, through the analysis of HAMD and TCM Syndrome scale from two aspects of Chinese and western medicine.(2)12 metabolites were finally identified as potential biomarkers though the 1H-NMR-based metabonomics analysis.(3)XYS has obvious antidepressant activity through the analysis of’H-NMR-based metabonomics and preliminary explained the antidepressant mechanism of XYS.(4)The result demonstrated that 1H-NMR based metabonomics is a powerful tool in finding potential biomarkers for clinical diagnosis of depression and therapeutic evaluation of XYS in clinic. |
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