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

精神分裂症影响着大约1.1%的人口，或者说大约350万美国人。预期寿命 精神分裂症患者的发病率比一般人群少10-25岁，而且近年来没有改善 几十年。心脏骤停(SCA)和室性心律失常(VA)，占所有死亡人数的8%-10% 在患有精神分裂症的人中，这种情况是没有精神分裂症的人的三倍。最明确确立的风险 精神分裂症患者SCA/VA的危险因素是使用抗精神病药物，并且这种风险是剂量依赖的。 第二代抗精神病药物(SGA)是精神分裂症最常见的治疗方法，也用于 其他常见的精神健康状况，包括双相情感障碍、严重抑郁障碍和精神病/激越。 与痴呆症有关。目前美国成年人中使用抗精神病药物的流行率为1.6%，即380万成年人。一个 最近的荟萃分析发现，几种广泛使用的SGA与SCA/VA的风险增加有关。考虑到高价 精神分裂症和其他精神健康疾病患者中多种药物的流行率，以及高潜力 对于服用SGAs的人之间的药物相互作用，临床医生迫切需要循证指导，以确定哪些药物起作用，哪些药物起作用 不会增加服用特定SGA的人患SCA/VA的风险。不幸的是，几乎所有可用的证据都表明 涉及SGAs的潜在DDIS对健康的影响来自1)自发报告的不良药物事件，即 提供的病因证据有限，因为它们的轶事性质，或来自2)血清药代动力学研究 包括少数受试者且不检查健康终点的SGA浓度。一种更严格的方法 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， 并提高为精神分裂症和其他精神健康疾病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，哪些药物应该避免，哪些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 筛查可能增加服用常用药人群院外SCA/VA比率的药物 第二代抗精神病药物。然后，在两个独立的验证总体中，我们将进行假设- 推动病因学药物流行病学研究，以确认或驳斥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使患者面临院外SCA/VA风险增加的因素。这个 这项研究的结果将为药物相互作用纲要的编辑提供有效的、可操作的证据，使 提醒临床医生注意真正有风险的药物组合。同样重要的是，这项研究将使临床医生能够 消除了关于实际上可以安全使用的药物组合的不必要和繁琐的警报。我们 进一步建议通过我们正在进行的一系列研究来传播关键发现，以增强我们研究的影响 我们为我们已建立的药物编辑和策展人利益相关者小组制作的网络研讨会、时事通讯和视频 互动纲要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.