J Clin Psychopharmacol. 2018 Jun;38(3):193-199. doi: 10.1097/JCP.0000000000000885.
Clozapine impairs gastrointestinal motility owing to its anticholinergic and antiserotonergic properties. This commonly leads to constipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic receptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms during clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT).
Blood samples from 176 clozapine-treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholinergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single-nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS).
No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was associated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining variables (permuted P = 0.014). Generalized linear univariate model analysis performed on the opiate-induced constipation-associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002).
Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility.
氯氮平因其抗胆碱能和抗血清素特性而损害胃肠道动力。这通常导致便秘，并可能导致更严重的并发症，如肠梗阻和缺血。本研究旨在确定编码毒蕈碱和血清素受体（CHRM2、CHRM3、HTR2、HTR3、HTR4 和 HTR7）的基因中的遗传变异是否可以解释氯氮平治疗期间便秘和抗胆碱能症状的发生率变化。本分析还包括与阿片类药物引起的便秘相关的基因（TPH1、OPRM1、ABCB1 和 COMT）。
对 176 名接受氯氮平治疗的芬兰白人精神分裂症患者的血液样本进行基因分型。使用利物浦大学神经阻滞剂副作用评分量表自我报告问卷评估便秘和抗胆碱能症状。总共检测到 192 个单核苷酸多态性（SNP）并分组以制定加权遗传风险评分（GRS）。
未观察到单个 SNP 或 GRS 与便秘或泻药使用之间存在显著关联。CHRM2、CHRM3、HTR3C、HTR7、ABCB1、OPRM1 和 TPH1 中 19 个 SNP 的 GRS 与普遍线性单变量模型中的抗胆碱能症状相关，体重指数、氯氮平单药治疗和 GRS 作为解释变量（置换 P = 0.014）。对阿片类药物引起的便秘相关 SNP 进行的普遍线性单变量模型分析和单个 CHRM3 SNP 揭示了抗胆碱能症状与 8 个 SNP 评分之间的关联（调整后 P = 0.038，置换后 P = 0.002）。
两个 GRS 能够预测接受氯氮平治疗的患者发生抗胆碱能症状的风险，并且可能增加胃肠道动力不足的风险。
