氯氮平治疗抗NMDAR脑炎合并精神障碍患者代谢组学研究

Metabonomics of Clozapine in Treatment of Anti-NMDAR Encephalitis with Mental Disorder

目的:探讨抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎合并精神障碍患者经氯氮平治疗前后血清、尿液中代谢产物状况。方法:纳入18例抗NMDAR脑炎合并精神障碍患者(患者组)和18例健康对照者(对照组),患者经氯氮平治疗直至临床症状消失。采用阳性和阴性症状量表(PANSS)、改良Rankin量表(mRS)、临床疗效总评量表(CGI)分别评估患者精神状况、神经功能和药物疗效。采集血清和尿液进行超高效液相色谱串联质谱(UPLC-MS/MS)检测,采用代谢组学技术结合多元统计方法分析各组血清和尿液中内源性代谢产物的变化及其规律,通过受试者操作特征(ROC)曲线探讨生物标志物在临床诊断的可靠性及氯氮平的疗效。结果:患者组治疗后与治疗前相比PANSS评分、m RS评分和CGI评分明显降低(P<0.05)。代谢组学分析结果表明,患者组的血清和尿液中分别鉴定到11种和9种差异代谢物,经ROC曲线分析发现患者组谷氨酰胺、牛磺酸、γ-氨基丁酸对该病的诊断具有一定的准确性;患者用药前后的血清和尿液中分别鉴定到7种和6种差异代谢产物,经ROC曲线分析得牛磺酸和甘氨酸可作为与氯氮平药物疗效相关代谢物。结论:抗NMDAR脑炎合并精神障碍患者中,谷氨酰胺、牛磺酸、γ-氨基丁酸可能可作为疾病诊断的候选生物标志物,患者经药物治疗后,牛磺酸和甘氨酸可能可作为评判药物效果的候选生物标志物。

Objective:To investigate differences of metabolites in serum and urine between patients with both anti-N-methyl-D-aspartic acid receptor(NMDAR)encephalitis and mental disorder before and after clozapine treatment.Methods:Total 18 patients with anti-NMDAR encephalitis and mental disorder(patients group)and18 healthy individuals(control group)were enrolled.Patients were treated with clozapine until clinical symptoms disappeared.The Positive and Negative Syndrome Scale(PANSS),modified Rankin Scale(mRS),and Clinical Global Impression(CGI)scale were used to evaluate mental status,neurological function,and drug efficacy in patients.Ultra performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS)was used to analyze metabolites in serum and urine.Changes in and patterns of endogenous metabolites in the serum and urine of both groups were analyzed by metabonomics technology combined with multivariate statistical methods.The receiver operating characteristic(ROC)curve was used to further explore the reliability of biomarkers in clinical diagnosis and the therapeutic effect of clozapine in patients.Results:PANSS score,mRS score,and CGI score of the patients group were significantly lower after treatment than that before treatment(P<0.05).The results of metabonomic analysis showed that 11 and 9 different metabolites were identified in the serum and urine of patients group,respectively.The ROC curve analysis of serum and urine data showed that glutamine,taurine,and gamma-aminobutyric acid(GABA)provided certain accuracy in diagnosis.Seven different metabolites and 6different metabolites were identified in the serum and urine of patients before and after treatment,respectively.The ROC curve showed that taurine and glycine could be used as metabolites related to the efficacy of clozapine.Conclusion:Glutamine,taurine,and GABA can be used as candidate biomarkers for diagnosis in patients with anti-NMDAR encephalitis combined with mental disorder.Taurine and glycine can be used as candidate biomarkers to evaluate drug efficacy after treatment.