Arranz M J, de Leon J
Clinical Neuropharmocology, Division of Psychological Medicine, Institute of Psychiatry - King's College, London, UK.
Mol Psychiatry. 2007 Aug;12(8):707-47. doi: 10.1038/sj.mp.4002009. Epub 2007 Jun 5.
The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and -141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (-759-T/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.
过去十年间，抗精神病药物的药物遗传学研究取得了一定进展，开发出了用于确定患者代谢状态的基因检测方法，并首次尝试实现抗精神病药物治疗的个性化。最显著的成果是发现药物代谢多态性（主要存在于细胞色素P450基因中）与药物代谢率及副作用的变化之间存在关联。基因检测确定为CYP2D6慢代谢者（PMs）状态的患者可能需要较低剂量的抗精神病药物。相反，CYP2D6超快代谢者（UMs）则需要增加药物剂量才能获得治疗效果。此外，多巴胺和5-羟色胺受体基因的多态性也多次被发现与反应表型相关，这可能反映了大多数抗精神病药物对这些受体具有较强的亲和力。特别是，有重要证据表明多巴胺2受体（D2）多态性（Taq I和-141-C Ins/Del）以及多巴胺3受体（D3）多态性（Ser9Gly）与抗精神病药物反应及药物诱发的迟发性运动障碍有关。此外，越来越多的证据表明5-HT2C多态性（-759-T/C）对抗精神病药物引起的体重增加有影响。将这一知识应用于临床实践的进程正在缓慢推进，通过CYP基因分型对个体药物代谢率进行预处理测定引领了该领域的发展。通过帮助调整治疗剂量和减少不良反应，确定患者的代谢状态有望带来临床益处。用于抗精神病药物反应预处理预测的基因检测虽然仍处于起步阶段，但对选择和改进抗精神病药物治疗具有明显意义。这些进展可被视为成功，但将药物遗传学和药物基因组学研究应用于精神科临床实践的目标仍远未实现。在能够将个性化治疗概念应用于精神药物治疗之前，还需要进一步开发基因检测方法。本综述旨在总结该领域过去十年研究的关键发现。将对药物代谢状态、总体反应及药物诱发副作用的基因预测的现有知识进行综述，并探讨未来的药物基因组学和表观遗传学研究。
