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

摘要 老年人的难治性抑郁(TRD)是导致残疾的主要原因， 自杀和痴呆症。认知问题和睡眠障碍是常见的，导致复发和 长期结果不佳。慢波睡眠障碍是抑郁症和认知功能障碍的结合点 上了年纪的人。缺乏针对这一核心病理生理学的新方法。我们的机械项目， 异丙酚慢波诱导消除抑郁(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(EEG)模式的输液，我们的目标是系统地描述 异丙酚诱发的脑电慢波、慢波睡眠增强与认知功能的关系 结果。通过改变异丙酚的用途，这项创新的建议将确定脑电慢波 是抗抑郁药物新方法的一个可行的治疗靶点。该项目包括两项临床试验。 (1期和2期)对患有TRD的老年人。在第一阶段，我们将招募15名个人接受剂量发现 输注异丙酚，然后按确定的剂量再次输注，以诱发慢波。这一阶段将 确定异丙酚在输注过程中既能诱导慢波，又能增强慢波睡眠 输液后的夜间睡眠。然后，在第二阶段，我们将随机选择60名患者进行多次异丙酚输注 无论是诱发慢波的剂量，还是不诱发慢波的亚阈值剂量，我们都会 检查输液后SWS的短期和长期变化以及执行功能、警觉性和 抑郁症状。这一阶段将测试SWS的增强是否会改善认知 功能和情绪。这项工作将增强我们对导致情绪不佳和核心缺陷的理解 阿尔茨海默病和相关痴呆高危人群的认知能力。随着老龄化的加剧 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，具有 改善TRD患者的公共健康和生活质量的长期目标。

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.