Grover Sandeep, Kasudhan Kripa Shanker, Murali Naveen, Patil Amol N, Pattanaik Smita, Chakrabarti Subho, Avasthi Ajit
Department of Psychiatry, PGIMER, Chandigarh, India.
Department of Pharmacology, PGIMER, Chandigarh, India.
Asian J Psychiatr. 2022 Jan;67:102939. doi: 10.1016/j.ajp.2021.102939. Epub 2021 Nov 24.
To study the association of clozapine pharmacometabolomics and clozapine response in Asian patients with treatment-resistant schizophrenia (TRS).
A cross-sectional study was performed on 50 consecutive TRS patients following up in psychiatry department of the tertiary care hospital. Demographic details, response assessment, were collected on the case record form. A blood sample was also collected for trough concentration assessment of drug and its metabolites. Clozapine (CLZ) the parent drug and its two major metabolites - Clozapine N oxide (CNO) and N-Desmethyl clozapine (N-DSMC) levels were assessed using a high-performance liquid chromatography method. Clozapine responders and nonresponders patients were classified based upon Andreasen criteria.
The average trough concentration of CNO, N-DSMC, and CLZ were 123 ± 76.04, 171.93 ± 93.24, 229.27 ± 124.25 ng/ml, respectively. The two patient subgroups did not differ for CLZ, CNO, and N-DSMC concentrations statistically. However, clozapine nonresponse was associated with a higher CLZ/N-DSMC ratio (p = 0.03) and clozapine dose (p = 0.01). The receiver operator characteristic curve showed that the cut-off CLZ/N-DSMC ratio of 1.54 with a sensitivity of 85% and a positive predictive value of 84% for identifying nonresponders.
CLZ/N-DSMC ratio and clozapine dose were identified as significant variables for future dose optimization algorithms. Pharmacometabolomics-guided clozapine therapy has the potential to revolutionize TRS management.
研究亚洲难治性精神分裂症（TRS）患者中氯氮平药物代谢组学与氯氮平反应之间的关联。
对一家三级护理医院精神科连续随访的50例TRS患者进行了一项横断面研究。在病例记录表上收集了人口统计学细节、反应评估。还采集了一份血样用于评估药物及其代谢物的谷浓度。使用高效液相色谱法评估母药氯氮平（CLZ）及其两种主要代谢物——氯氮平N氧化物（CNO）和N - 去甲基氯氮平（N - DSMC）的水平。根据安德烈亚森标准对氯氮平反应者和无反应者患者进行分类。
CNO、N - DSMC和CLZ的平均谷浓度分别为123±76.04、171.93±93.24、229.27±124.25 ng/ml。两个患者亚组在CLZ、CNO和N - DSMC浓度方面无统计学差异。然而，氯氮平无反应与较高的CLZ/N - DSMC比值（p = 0.03）和氯氮平剂量（p = 0.01）相关。受试者工作特征曲线显示，CLZ/N - DSMC比值的截断值为1.54时，识别无反应者的灵敏度为85%，阳性预测值为84%。
CLZ/N - DSMC比值和氯氮平剂量被确定为未来剂量优化算法的重要变量。药物代谢组学指导的氯氮平治疗有可能彻底改变TRS的管理。
