Slow Wave Induction by Propofol to Eliminate Depression (SWIPED) Trial

摘要 老年人的难治性抑郁症（TRD）是残疾的主要原因， 自杀和痴呆认知问题和睡眠障碍是常见的，有助于复发， 长期效果不佳。慢波睡眠中断是抑郁症和认知功能障碍的联系， 老年人缺乏针对这一核心病理生理学的新方法。我们的机械工程， 丙泊酚慢波诱导消除抑郁症（SWIPED）试验旨在阐明 老年人TRD、睡眠障碍和认知障碍之间的关系。通过个性化 针对脑电图（EEG）模式的输注，我们的目标是系统表征 丙泊酚诱发的EEG慢波、慢波睡眠增强和认知功能之间的关系 结果。通过对异丙酚的再利用，这一创新的提议将确定脑电图慢波是否 是新型抗抑郁药的可行治疗靶点。该项目包括两项临床试验 （1期和2期）老年TRD患者。在第一阶段，我们将招募15名个人接受剂量探索 丙泊酚输注，然后以确定诱导慢波的剂量进行第二次输注。这一阶段将 建立丙泊酚在输注过程中诱导慢波并增强慢波睡眠（SWS）， 输液后的睡眠时间然后，在第二阶段，我们将随机分配60名患者多次输注异丙酚 在诱导慢波的剂量下，或者在不诱导慢波的阈下剂量下，我们将 检查输注后SWS以及执行功能、警觉性和 抑郁症状这一阶段将测试SWS的增强是否会导致认知功能的改善。 功能和情绪。这项工作将加强我们对导致情绪不佳的核心缺陷的理解， 阿尔茨海默病和相关痴呆症风险人群的认知能力。随着老龄化的加剧 人口，我们希望为未来的精准医学提供可翻译的生物标志物和方法， 长期目标是改善TRD患者的公共健康和生活质量。

ABSTRACT Treatment Resistant Depression (TRD) in older adults is a leading cause of disability, excess mortality from suicide, and dementia. Cognitive problems and sleep disturbances are common, contributing to recurrence and poor long-term outcomes. Disrupted slow wave sleep is at the nexus of depression and cognitive dysfunction in older adults. Novel approaches to target this core pathophysiology are lacking. Our mechanistic project, Slow Wave Induction by Propofol to Eliminate Depression (SWIPED) Trial, is designed to elucidate the relationships between TRD, sleep disturbances, and cognitive impairments in older adults. Through personalized infusions targeting electroencephalographic (EEG) patterns, we aim for a systematic characterization of the relationships between the propofol-induced EEG slow waves, enhancement of slow wave sleep, and cognitive outcomes. Through the repurposing of propofol, this innovative proposal will establish whether EEG slow waves are a viable therapeutic target for novel antidepressant approaches. The project consists of two clinical trials (Phase 1 and Phase 2) in older adults with TRD. In Phase 1 we will enroll 15 individuals to receive a dose-finding propofol infusion, and then a second infusion at the dose determined to induce slow waves. This phase will establish that propofol both induces slow waves during the infusion and enhances slow wave sleep (SWS) on nights of sleep post-infusion. Then, in Phase 2 we will randomize 60 individuals to multiple infusions of propofol at either a dose that induces slow waves, or a subthreshold dose that does not induce slow waves, and we will examine short and long-term changes in post-infusion SWS as well as executive function, alertness, and depressive symptoms. This phase will test whether enhancement of SWS leads to improvements in cognitive function and mood. This work will enhance our understanding of core deficits contributing to poor mood and cognition in a population at risk for Alzheimer's disease and related dementias. With the rise in the aging population, we hope to provide translatable biomarkers and approaches for future precision medicine, with a long-term goal of improving public health and quality of life for those afflicted with TRD.