Safety of Second Generation Antipsychotics for Adult Depression

描述（由申请人提供）：每年有超过1500万成年美国人符合重度抑郁症的标准，抑郁症的管理是医疗保健的核心挑战。最初的抗抑郁治疗反应不足是很常见的，超过一半的抑郁症患者需要多个顺序治疗步骤才能达到抑郁症状的缓解。尽管疗效适中，抗抑郁药与第二代抗精神病药物（SGAs）的结合是治疗难治性抑郁症最受支持和发展最快的药物治疗选择。每年大约有200万的成人抑郁症门诊就诊包括SGA。然而，在其他临床人群中发现了一些与SGA相关的严重不良反应，最引人注目的是老年痴呆患者的死亡风险增加了50%，这引发了关于SGA治疗抑郁症安全性的关键问题，因为尚不清楚这些风险是否以及在多大程度上适用于接受SGA增强治疗抑郁症的非老年人。不幸的是，SGAs治疗抑郁症的随机临床试验的综合经验远远不足以发现抑郁症的死亡率风险与在痴呆症中观察到的死亡率风险相当。因此，迫切需要进行观察性研究来评估SGA增强治疗成人抑郁症的安全性。利用最近10年的全国医疗补助数据（2001-2010），本研究对大约80,000名非老年抑郁症患者进行了研究，这些患者对抗抑郁药单一疗法的反应不完全，这是第一次系统地检查SGA增强的现实安全性。所提出的推断分析将通过对抑郁症强化治疗的流行病学的严格检查来获得信息（目的1）。所有的推理分析将采用主动比较者初始队列设计，并使用经过验证的结果测量。我们将比较开始新的SGA增强和开始抗抑郁药物增强的患者之间罕见但严重的不良事件（全因死亡率、心源性猝死、急性心肌梗死、中风、2型糖尿病、肺炎、静脉血栓栓塞）的发生率（Aim 2a）。在此分级评估之后，我们将检查单个SGA增强策略的安全性（Aim 2b）。最后，为了促进个性化治疗，我们将根据年龄组和基线心血管风险来检查治疗效果的异质性（目的3）。通过设计（初始队列、有效比较组、仔细限制研究人群）和分析（使用倾向评分方法对大量人口统计学、临床和地理特征进行调整），将偏倚最小化。潜在的残留混淆将在定量敏感性分析和工具变量分析中进行检查。研究结果将有助于临床、监管和卫生保健

DESCRIPTION (provided by applicant): With more than 15 million adult Americans meeting criteria for major depressive disorder each year, the management of depression is a central health care challenge. Inadequate response to initial antidepressant treatment is common and more than half of depressed patients require multiple sequential treatment steps to achieve remission of depressive symptoms. Despite modest efficacy, augmentation of antidepressants with second-generation antipsychotics (SGAs) is the most strongly supported and fastest growing pharmacological treatment alternative for treatment-resistant depression. Each year approximately 2 million outpatient visits for adult depression include a SGA. Yet the discovery of several serious SGA-associated adverse effects in other clinical populations, most strikingly a >50% increase in mortality risk in elderly dementia patients, raises critical questions about the safety of SGAs in depression as it is not known whether and to what extent these risks generalize to non-elderly adults who receive SGA augmentation for depression. Unfortunately, the combined experience of randomized clinical trials of SGAs for depression falls far short of sufficient power to detect a mortality risk in depression comparable to that observed in dementia. As a result, there is an urgent need for observational research to assess the safety of SGA augmentation in the treatment of adult depression. Using the most recent available 10 years of near national Medicaid data (2001-2010), the present study in approximately 80,000 non-elderly adults with depression and incomplete response to antidepressant monotherapy is the first to systematically examine the real-world safety of SGA augmentation. The proposed inferential analyses will be informed by a rigorous examination of the epidemiology of augmentation treatments in depression (Aim 1). All inferential analyses will employ an active comparator inception cohort design and use validated outcome measures. We will compare the incidence of rare, but serious, adverse events (all-cause mortality, sudden cardiac death, acute myocardial infarction, stroke, type 2 diabetes, pneumonia, venous thromboembolism) between patients initiating new episodes of SGA augmentation and those initiating antidepressant augmentation (Aim 2a). Following this class-level assessment, we will examine the safety of individual SGA augmentation strategies (Aim 2b). Finally, to facilitate personalized treatment, we will examine treatment effect heterogeneity by age group and baseline cardiovascular risk (Aim 3). Bias will be minimized by design (inception cohort, active comparator groups, careful restriction of the study population) and in the analysis (adjustment for a large number of demographic, clinical, and geographic characteristics using propensity score methods). Potential residual confounding will be examined in quantitative sensitivity analysis and instrumental variable analysis. The results will help inform clinical, regulatory, and health care policy efforts to improve the management of treatment-resistant depression and support or refute the need for large-scale prospective safety studies.