Drug Interactions Involving Second-generation Antipsychotic Agents Leading to Sudden Cardiac Arrest

精神分裂症影响约1.1%的人口，或约350万美国人。预期寿命 精神分裂症患者的平均寿命比一般人群短10-25年， 几十年心脏骤停（SCA）和室性心律失常（VA），占本研究中所有死亡的8-10%。 在精神分裂症患者中，精神分裂症的发病率是非精神分裂症患者的三倍。最明显的风险 精神分裂症患者SCA/VA的一个因素是抗精神病药物的使用，并且这种风险是剂量依赖性的。 第二代抗精神病药（SGAs）是精神分裂症最常见的治疗方法，也用于治疗精神分裂症。 其他常见的精神健康状况，包括双相情感障碍、重度抑郁症和精神病/激越 与痴呆症有关。目前美国成人使用抗精神病药物的患病率为1.6%，即380万成人。一 最近的荟萃分析发现，几种广泛使用的SGAs与SCA/VA的风险升高有关。考虑到高 精神分裂症和其他精神健康状况患者中多种药物的流行率， 对于服用SGAs的人的药物相互作用，临床医生迫切需要基于证据的指导， 不会增加服用特定SGAs的人患SCA/VA的风险。不幸的是，几乎所有关于 涉及SGA的潜在DDI的健康影响来自1）自发报告的药物不良事件， 由于其轶事性质，或来自2）血清药代动力学研究，提供的因果关系证据有限 SGAs的浓度，其中包括少数受试者，不检查健康终点。更严格的管理 识别和阐明药物相互作用将有助于识别真正增加SCA/VA风险的药物-药物对， 以及改善向精神分裂症患者和其他精神健康状况患者提供药物治疗的安全性。 为了解决这些关键的知识差距，哪些药物应该和不应该在接受治疗的人中避免， 常用的第二代抗精神病药物，我们将进行高通量药物流行病学 筛查，以确定可能增加服用常用药物的患者的院外SCA/VA发生率的药物 第二代抗精神病药物然后，在两个独立的验证群体中，我们将进行假设- 驱动病原学药物流行病学研究，以证实或反驳高优先级的潜在药物相互作用，以及 阐明与特定药物对相关的患者院外SCA/VA风险增加的因素。的 这项研究的结果将为药物相互作用汇编的编辑提供有效的、可操作的证据， 他们警告临床医生真正危险的药物组合。同样重要的是，这项研究将使临床医生能够 减轻了关于实际上可以安全施用的药物组合的不必要和繁重的警报。我们 进一步建议通过我们正在进行的一系列 网络研讨会，通讯和视频，我们为我们建立的利益相关者编辑和药物管理者群体制作 互动简编和计算机化决策支持系统。

Schizophrenia affects approximately 1.1% of the population, or approximately 3.5 million Americans. The life expectancy of persons with schizophrenia is 10-25 years less than that of the general population, and has not improved in recent decades. Sudden cardiac arrest (SCA) and ventricular arrhythmia (VA), which account for 8-10% of all deaths in this population, is three times as common among those with than without schizophrenia. The most clearly established risk factor for SCA/VA in persons with schizophrenia is the use of antipsychotic agents, and this risk is dose-dependent. Second-generation antipsychotic agents (SGAs) are the most common treatment for schizophrenia, and are also used for other common mental health conditions including bipolar disorder, major depressive disorder, and psychosis/agitation associated with dementia. The prevalence of current antipsychotic drug use in US adults is 1.6%, or 3.8 million adults. A recent meta-analysis found that several widely used SGAs are associated with an elevated risk of SCA/VA. Given the high prevalence of polypharmacy in persons with schizophrenia and other mental health conditions, and the high potential for drug interactions in persons taking SGAs, clinicians badly need evidence-based guidance on which drugs do and do not increase the risk of SCA/VA in persons taking specific SGAs. Unfortunately, almost all available evidence about the health effects of potential DDIs involving SGAs comes from either 1) spontaneously reported adverse drug events, which provide limited evidence for causation because of their anecdotal nature, or from 2) pharmacokinetic studies of serum concentrations of SGAs, which include few subjects and do not examine health end-points. A more rigorous approach to identifying and elucidating drug interactions will help to identify drug-drug pairs that truly increase the risk of SCA/VA, and improve the safety of pharmacotherapy provided to persons with schizophrenia and other mental health conditions. To address these critical knowledge gaps about which drugs should and should not be avoided in persons receiving commonly used second generation antipsychotic drugs, we will perform high-throughput pharmacoepidemiology screening to identify drugs that may increase the rate of out-of-hospital SCA/VA in persons taking commonly used second-generation antipsychotic agents. Then, in two independent validation populations, we will conduct hypothesis- driven etiologic pharmacoepidemiology studies to either confirm or refute high-priority potential drug interactions, and elucidate factors that place patients at increased risk of out-of-hospital SCA/VA associated with specific drug pairs. The results of this research will provide drug interaction compendia editors with valid, actionable evidence that will allow them to warn clinicians about truly risky drug combinations. Of equal importance, this research will allow clinicians to be relieved of unnecessary and burdensome alerts about drug combinations that can actually be administered safely. We further propose to enhance the impact of our research by disseminating key findings through our ongoing series of webinars, newsletters, and videos that we produce for our established stakeholder group of editors and curators of drug interaction compendia and computerized decision support systems.