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

项目摘要：认知控制缺陷是晚年抑郁症的核心特征，两者都有贡献 情绪失调和抑制无关信息、冲突检测和工作方面的问题 记忆。这些缺陷的临床特征是执行功能障碍，与对 抗抑郁药物和更高水平的残疾。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，但目前没有药物疗法改善CCN LLD中的赤字。在我们的实验数据的支持下，我们提出尼古丁乙酰胆碱受体激动剂可以增强 CCN发挥作用，从而改善老年抑郁症患者的情绪和认知表现。目标是 R61/R33的建议之一是首先确定尼古丁透皮是否增强CCN神经活动。 在情绪反应抑制任务(情绪Stroop任务)中依赖于暴露的方式。如果我们 通过演示依赖于曝光的CCN目标接洽来满足我们的GO标准，然后我们将进行 R33先导随机对照试验：1)确定目标参与和临床之间的关系 改进；2)检测尼古丁透皮吸收对CCN影响的特异性；3)初步获得 TDN临床疗效的证据。这一系列研究的长期目标是确定尼古丁 乙酰胆碱受体激动剂增强CCN功能，为晚年患者提供临床益处 抑郁症。在我们试点数据的支持下，该项目的基本原理是它将阐明广泛的尼古丁 乙酰胆碱受体激动剂增强CCN活性，如果是这样，这一机制是否对 临床症状。否定的发现将提高我们对广泛活跃的神经影响的理解。 尼古丁受体激动剂以及靶向CCN是否具有治疗益处。我们对R61的方法 阶段是检查36名患有严重抑郁障碍的老年人是否有经皮尼古丁贴片 在使用情绪Stroop任务的fMRI中测量时，在12周内增强CCN活性 尼古丁和尼古丁代谢物水平。如果我们通过展示曝光依赖的目标来满足GO标准 参与后，我们将继续进行R33试点临床增强试验。72名抑郁的老年人 稳定的SSRI或SNRI单一疗法将随机接受13周的活性尼古丁透皮吸收或安慰剂治疗 贴片，在基线和试验结束时完成核磁共振和认知测试。剂量将由以下人员指导 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期。这一建议具有重大意义和创新意义，因为目前没有药物疗法可以改善CCN 功能或改善晚年抑郁症的认知缺陷。尼古丁透皮有一种作用机制 这与目前的抗抑郁药不同，有可能使其成为重要的增强剂。如果我们的 假设是正确的，因为补丁可以在商业上买到，这种方法可能会迅速进入 权威性研究，并可能适用于以CCN功能障碍为特征的其他精神障碍。

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.