Basile V S, Masellis M, McIntyre R S, Meltzer H Y, Lieberman J A, Kennedy J L
Centre for Addiction and Mental Health, Clarke Division, University of Toronto, Ontario, Canada.
J Clin Psychiatry. 2001;62 Suppl 23:45-66.
Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYPIA2); the beta3 and alpha,alpha-adrenergic receptor genes (ADRB3/ADRAIA); and tumor necrosis factor alpha (TNF-alpha). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-alpha, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing.
非典型抗精神病药物如氯氮平在治疗精神分裂症方面相较于典型抗精神病药物有显著改善，尤其是在外周锥体外系症状方面。尽管它们有诸多益处，但因出现如镇静和体重增加等不良反应，其使用受到限制。本文全面综述并讨论了与肥胖相关的途径，并将这些途径与非典型抗精神病药物作用的已知机制相结合，以确定在抗精神病药物治疗期间可能受到干扰的候选分子。本文展示了新的初步数据，旨在从基因层面剖析这些肥胖途径，并阐明这些候选分子对氯氮平所致体重增加的遗传作用。氯氮平导致体重增加的能力在个体间存在相当大的差异。已有研究表明存在氯氮平所致体重增加的遗传易感性。因此，这些候选分子的基因变异可能预测患者对氯氮平所致体重增加的易感性。针对9个候选基因中的10个基因多态性进行了该假设检验，这些基因包括5-羟色胺2C、2A和1A受体基因（HTR2C/2A/1A）；组胺H1和H2受体基因（H1R/H2R）；细胞色素P450 1A2基因（CYPIA2）；β3和α,α-肾上腺素能受体基因（ADRB3/ADRA1A）；以及肿瘤坏死因子α（TNF-α）。获取了80例完成结构化氯氮平试验的精神分裂症患者的前瞻性体重增加数据。观察到ADRB3、ADRA1A、TNF-α和HTR2C有相关趋势；然而，需要在更大的独立样本中进行重复验证。尽管精神科药物遗传学尚处于起步阶段，但未来它将有助于临床实践预测反应和副作用，如抗精神病药物所致体重增加，并尽量减少当前“试错”式的处方方法。
