Nicotinic Modulation of the Cognitive Control System in Late-Life Depression

项目总结：认知控制缺陷是晚年抑郁症的核心特征， 情绪失调和抑制不相关信息、冲突检测和工作的问题 记忆临床上表现为执行功能障碍，这些缺陷与对 抗抑郁药和更高程度的残疾改善认知控制网络（CCN）功能障碍 可能有益于情绪和认知表现，但目前没有药物治疗改善CCN LLD的缺陷。在我们的试验数据的支持下，我们提出尼古丁乙酰胆碱受体激动剂可以增强 CCN功能和结果改善晚年抑郁症的情绪和认知表现客观 这项R61 / R33建议的第一个目的是首先确定经皮尼古丁是否能增强CCN神经活动， 在情绪反应抑制任务（情绪Stroop任务）中，如果我们 通过展示依赖于安全性的CCN目标参与来满足我们的Go标准，然后我们将进行 R33初步随机对照试验，以：1）确定靶点接合与临床 改进; 2）检查透皮尼古丁对CCN影响的特异性;以及3）获得初步的 TDN临床效果的证据。这一系列研究的长期目标是确定尼古丁是否 乙酰胆碱受体激动剂增强CCN功能，并为老年患者提供临床益处 萧条在我们的试验数据的支持下，该项目的基本原理是，它将阐明是否广泛的烟碱 乙酰胆碱受体激动剂增强CCN活性，如果是这样，其机制是否积极影响 临床症状。一个负面的发现将提高我们对广泛活跃的神经影响的理解。 烟碱受体激动剂以及靶向CCN是否具有治疗益处。我们的R61方法 第一阶段是检查36名患有重度抑郁症的老年人， 增强CCN活动超过12周，如在fMRI期间用情绪Stroop任务测量的，同时测量 尼古丁和尼古丁代谢物水平。如果我们通过证明依赖于确定性的目标来满足Go标准， 我们将继续进行R33试点临床增强试验。72位抑郁的老人 稳定的SSRI或SNRI单药治疗将被随机分配至13周的活性透皮尼古丁或安慰剂组 在基线和试验结束时完成MRI和认知测试。给药将遵循以下指导原则： 尼古丁血液水平，并基于暴露与目标参与之间的关系，如在 R61阶段。这一建议是重要的和创新的，因为目前没有药物治疗改善CCN 功能或改善老年抑郁症的认知缺陷。经皮尼古丁具有一种作用机制， 这与目前的抗抑郁药不同，可能使其成为一种重要的增强剂。如果我们的 假设是正确的，因为贴片是商业上可获得的，这种方法可以迅速地移动到 明确的研究，并可能适用于以CCN功能障碍为特征的其他精神疾病。

PROJECT SUMMARY: Deficits in cognitive control are core features of late-life depression, contributing both to emotion dysregulation and problems with inhibiting irrelevant information, conflict detection, and working memory. Clinically characterized as executive dysfunction, these deficits are associated with poor response to antidepressants and higher levels of disability. Improvement of cognitive control network (CCN) dysfunction may benefit both mood and cognitive performance, however no current pharmacotherapy improves CCN deficits in LLD. Supported by our pilot data, we propose that nicotine acetylcholine receptor agonists enhance CCN function and resultantly improve mood and cognitive performance in late-life depression. The objective of this R61 / R33 proposal is to first determine whether transdermal nicotine enhances CCN neural activity in an exposure-dependent fashion during an emotional response inhibition task (the emotional Stroop task). If we meet our Go Criteria by demonstrating exposure-dependent CCN target engagement, we will then conduct the R33 pilot randomized controlled trial to: 1) determine the relationship between target engagement and clinical improvement; 2) examine the specificity of transdermal nicotine’s effects on the CCN; and 3) obtain preliminary evidence of TDN’s clinical effects. The long-term goal of this line of research is to determine whether nicotinic acetylcholine receptor agonists enhance CCN function and provide clinical benefit to individuals with late-life depression. Supported by our pilot data, this project’s rationale is that it will elucidate whether broad nicotinic acetylcholine receptor agonists enhance CCN activity and if so, does that mechanism positively influence clinical symptoms. A negative finding will improve our understanding of the neural effects of broadly active nicotinic receptor agonists and whether targeting the CCN has therapeutic benefit. Our approach for the R61 phase is to examine in 36 older adults with Major Depressive Disorder whether transdermal nicotine patches enhance CCN activity over 12 weeks as measured during fMRI with the emotional Stroop task while measuring nicotine and nicotine metabolite levels. If we meet Go Criteria by demonstrating exposure-dependent target engagement, we will proceed to the R33 pilot clinical augmentation trial. Seventy-two depressed elders on stable SSRI or SNRI monotherapy will be randomized to 13 weeks of active transdermal nicotine or placebo patches, completing MRI and cognitive testing at baseline and at the trial’s end. Dosing will be guided by nicotine blood levels and based on the relationship between exposure and target engagement as observed in the R61 phase. This proposal is significant and innovative as no current pharmacotherapy improves CCN function or improves cognitive deficits in late-life depression. Transdermal nicotine has a mechanism of action that is distinct from current antidepressants, potentially making it an important augmentation agent. If our hypotheses are correct, as patches are commercially available, this approach could be rapidly moved into definitive studies and may have applicability to other psychiatric disorders characterized by CCN dysfunction.