Safety of Second Generation Antipsychotics for Adult Depression

第二代抗精神病药治疗成人抑郁症的安全性

• 批准号: 8875778
• 负责人: Tobias Gerhard
• 金额: $ 19.38万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875778
• 关键词: Acute myocardial infarction; Address; Adjuvant; Adult; Adverse effects; Affect; Age; American; Antidepressive Agents; Antipsychotic Agents; Area; Cardiovascular Diseases; Cessation of life; Characteristics; Clinical; Data; Data Files; Dementia; Diagnosis; Disease remission; Dose; Economics; Elderly; Emotional; Epidemiology; FDA approved; Generations; Health; Health Policy; Healthcare; Heterogeneity; Incidence; Individual; Major Depressive Disorder; Medicaid; Mental Depression; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Office Visits; Outcome Measure; Outpatients; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacological Treatment; Physicians; Pneumonia; Population; Population Study; Premature Mortality; Prevalence; Public Health; Randomized Clinical Trials; Randomized Controlled Trials; Registries; Residual state; Resources; Risk; Safety; Sample Size; Scoring Method; Sequential Treatment; Serious Adverse Event; Severities; Severity of illness; Stroke; Subgroup; Thromboembolism; Treatment Step; Venous; Visit; active comparator; age group; alternative treatment; base; cardiovascular risk factor; cohort; comparative; depressed patient; depressive symptoms; design; experience; falls; follow-up; improved; inclusion criteria; indexing; instrument; meetings; mortality; non-psychotic depression; older patient; personalized medicine; preference; prospective; psychotic depression; response; safety study; sudden cardiac death; treatment effect; treatment-resistant depression

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.

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，抑郁症的管理是一个中央卫生保健挑战。对初始抗抑郁药治疗的反应不足是常见的，超过一半的抑郁症患者需要多个连续的治疗步骤来缓解抑郁症状。尽管疗效有限，但第二代抗精神病药（SGAs）增强抗抑郁药是治疗难治性抑郁症最受支持和增长最快的药理学治疗替代方案。每年约有200万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几种严重的SGA相关不良反应，最引人注目的是老年痴呆患者的死亡风险增加>50%，这引发了关于SGA在抑郁症中的安全性的关键问题，因为尚不清楚这些风险是否以及在多大程度上推广到接受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福尔斯不足以检测出与痴呆症中观察到的死亡风险相当的抑郁症死亡风险。因此，迫切需要观察性研究来评估SGA增强治疗成人抑郁症的安全性。 使用最近可用的近10年的国家医疗补助数据（2001-2010），本研究在约80，000名非老年抑郁症和抗抑郁药单药治疗反应不完全的成年人中进行，是第一次系统地检查SGA增强的真实世界安全性。拟议的推理分析将通过对抑郁症增强治疗的流行病学进行严格检查来了解（目标1）。所有推断分析将采用活性对照药物初始队列设计，并使用经验证的结局指标。我们将比较开始新一次SGA强化治疗的患者和开始抗抑郁药强化治疗的患者之间罕见但严重的不良事件（全因死亡、心源性猝死、急性心肌梗死、卒中、2型糖尿病、肺炎、静脉血栓栓塞）的发生率（目标2a）。在这一级别的评估之后，我们将检查个体SGA增强策略的安全性（目标2b）。最后，为了促进个性化治疗，我们将按年龄组和基线心血管风险检查治疗效果异质性（目标3）。将通过设计（初始队列、活性对照组、仔细限制研究人群）和分析（使用倾向评分方法调整大量人口统计学、临床和地理特征）最大限度地降低偏倚。将在定量敏感性分析和工具变量分析中检查潜在残留混杂。 结果将有助于为临床、监管和医疗保健提供信息 改善难治性抑郁症管理的政策努力，支持或反驳大规模前瞻性安全性研究的必要性。

项目成果

Mortality risk of antipsychotic augmentation for adult depression.

• DOI: 10.1371/journal.pone.0239206
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gerhard T;Stroup TS;Correll CU;Setoguchi S;Strom BL;Huang C;Tan Z;Crystal S;Olfson M
• 通讯作者: Olfson M