Department of Neuroscience, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Neuropsychopharmacology. 2010 May;35(6):1315-24. doi: 10.1038/npp.2009.235. Epub 2010 Jan 27.
Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21+/-4.51 vs 4.33+/-3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.
抗精神病药引起的体重增加已成为治疗非典型抗精神病药物患者的严重并发症。大麻素受体 1 (CNR1) 在中枢下丘脑区域表达，并与食欲和饱腹感有关，也在外周表达。CNR1 的拮抗剂（利莫那班）已被证明能有效减轻肥胖患者的体重，这表明 CNR1 可能在抗精神病药引起的体重增加中起重要作用。对接受慢性精神分裂症治疗（氯氮平、奥氮平、氟哌啶醇或利培酮）的 183 例患者的 20 个标签 SNP 进行了分析，以评估 14 周内抗精神病药引起的体重增加。在接受氯氮平或奥氮平治疗的欧洲血统患者中，rs806378 多态性与体重增加呈显著相关。T 等位基因携带者（CT+TT）比 CC 携带者（2.76%，p=0.008，FDR q 值=0.12）体重增加更多。这意味着携带 T 等位基因的患者比 CC 纯合子基因型的患者体重增加约 2.2 公斤（CC 与 CT+TT，2.21+/-4.51 与 4.33+/-3.89 公斤；p=0.022）。这在等位基因分析中得到了反映（C 与 T 等位基因，3.84 与 5.83%，p=0.035）。我们进行了电泳迁移率变动分析，结果表明 T 等位基因的存在为芳香烃受体转运蛋白（ARNT）创造了一个结合位点，ARNT 是基本螺旋-环-螺旋/Per-Arnt-Sim 蛋白家族的成员。在这项研究中，我们提供了证据表明 CNR1 基因可能与慢性精神分裂症患者抗精神病药引起的体重增加有关。然而，这些观察结果是在相对较小的患者人群中得出的；因此，这些结果需要在更大的样本集中得到复制。
