Nucifora Frederick C, Mihaljevic Marina, Lee Brian J, Sawa Akira
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Clinic for Psychiatry, Clinical Center of Serbia, Belgrade, Serbia.
Neurotherapeutics. 2017 Jul;14(3):750-761. doi: 10.1007/s13311-017-0552-9.
Schizophrenia is a devastating illness that affects up to 1% of the population; it is characterized by a combination of positive symptoms, negative symptoms, and cognitive impairment. Currently, treatment consists of one class of medications known as antipsychotics, which include typical (first-generation) and atypical (second-generation) agents. Unfortunately, antipsychotic medications have limited efficacy, with up to a third of patients lacking a full response. Clozapine, the first atypical antipsychotic developed, is the only medication shown to be superior to all other antipsychotics. However, owing to several life-threatening side effects and required enrollment in a registry with routine blood monitoring, clozapine is greatly underutilized in the US. Developing a medication as efficacious as clozapine with limited side effects would likely become the first-line therapy for schizophrenia and related disorders. In this review, we discuss the history of clozapine, landmark studies, and its clinical advantages and disadvantages. We further discuss the hypotheses for clozapine's superior efficacy based on neuroreceptor binding, and the limitations of a receptor-based approach to antipsychotic development. We highlight some of the advances from pharmacogenetic studies on clozapine and then focus on studies of clozapine using unbiased approaches such as pharmacogenomics and gene expression profiling. Finally, we examine how these approaches could provide insights into clozapine's mechanism of action and side-effect profile, and lead to novel and improved therapeutics.
精神分裂症是一种严重的疾病，影响着多达1%的人口；其特征是存在阳性症状、阴性症状和认知障碍的组合。目前，治疗方法包括一类称为抗精神病药物的药物，其中包括典型（第一代）和非典型（第二代）药物。不幸的是，抗精神病药物的疗效有限，多达三分之一的患者没有完全缓解。氯氮平是开发的第一种非典型抗精神病药物，是唯一一种被证明优于所有其他抗精神病药物的药物。然而，由于几种危及生命的副作用以及需要登记并进行常规血液监测，氯氮平在美国的使用率极低。开发一种与氯氮平疗效相当但副作用有限的药物可能会成为精神分裂症及相关疾病的一线治疗方法。在这篇综述中，我们讨论了氯氮平的历史、标志性研究及其临床优缺点。我们进一步讨论了基于神经受体结合的氯氮平疗效卓越的假说，以及基于受体的抗精神病药物开发方法的局限性。我们强调了氯氮平药物遗传学研究的一些进展，然后重点关注使用药物基因组学和基因表达谱分析等无偏倚方法对氯氮平的研究。最后，我们研究这些方法如何能够深入了解氯氮平的作用机制和副作用特征，并带来新的和改进的治疗方法。
