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

晚年抑郁症认知控制系统的烟碱调节

• 批准号: 10225310
• 负责人: Warren D Taylor
• 金额: $ 92.74万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-29 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225310
• 关键词: Affect; Agonist; Anterior; Antidepressive Agents; Attention; Blinded; Blood; Brain region; Clinical; Cognitive deficits; Conflict (Psychology); Data; Depressed mood; Detection; Dose; Elderly; Emotional; Episodic memory; Executive Dysfunction; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Image; Individual; Left; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mediating; Mental Depression; Mental disorders; Moods; Negative Finding; Neurobehavioral Manifestations; Neuropsychological Tests; Nicotine; Nicotinic Receptors; Outcome; Patient Self-Report; Performance; Pharmacotherapy; Phase; Placebos; Process; Randomized; Randomized Controlled Trials; Reaction Time; Research; Selective Serotonin Reuptake Inhibitor; Severities; Short-Term Memory; Specificity; Stimulus; Symptoms; System; Task Performances; Testing; Therapeutic; Thinking; Validation; Work; acetylcholine receptor agonist; affective disturbance; base; blood oxygenation level dependent response; clinical effect; cognitive benefits; cognitive control; cognitive enhancement; cognitive performance; cognitive testing; depressive symptoms; disability; emotion dysregulation; emotion regulation; geriatric depression; improved; innovation; mood symptom; network dysfunction; nicotine exposure; nicotine patch; open label; pilot trial; relating to nervous system; response; secondary outcome; targeted imaging; trait

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.

项目摘要：认知控制的缺陷是晚期抑郁症的核心特征，两者都贡献 情绪失调和抑制无关信息，冲突检测和工作的问题 记忆。这些定义在临床上被视为执行功能障碍，与对 抗抑郁药和更高水平的残疾。认知控制网络（CCN）功能障碍的改善 可能会受益于情绪和认知表现，但是当前的药物治疗没有改善CCN LLD中的缺陷。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增强 CCN功能，并在晚期抑郁症中显着改善情绪和认知表现。目标 该R61 / R33建议首先确定透皮尼古丁是否会增强CCN神经活动 在情感反应抑制任务（情感障碍任务）中，依赖曝光的方式。如果我们 通过证明依赖暴露的CCN目标参与来满足我们的GO标准，然后我们将进行 R33飞行员随机对照试验至：1）确定目标参与与临床之间的关系 改进; 2）检查尼古丁对CCN的影响的特异性； 3）获得初步 TDN临床作用的证据。这项研究线的长期目标是确定烟碱是否是否 乙酰胆碱受体激动剂增强了CCN功能，并为晚期患者提供临床益处 沮丧。在我们的飞行员数据的支持下，该项目的理由是它将阐明是否广泛的烟碱 乙酰胆碱受体激动剂增强了CCN活性，如果是的，则该机制会积极影响 临床症状。负面的发现将改善我们对广泛活跃的神经影响的理解 烟碱受体激动剂以及针对CCN是否具有治疗益处。我们对R61的方法 阶段是在36名患有重度抑郁症的老年人中检查dransdermal Nicotine斑块 通过在fMRI期间通过情感stroop任务在fMRI期间测量的12周内增强CCN活性 尼古丁和尼古丁代谢物水平。如果我们通过证明依赖暴露目标达到GO标准 参与，我们将继续进行R33 Pilot临床增强试验。七十二个沮丧的长老 稳定的SSRI或SNRI单一疗法将随机分为13周活跃的透皮尼古丁或安慰剂 补丁，在基线和试验结束时完成MRI和认知测试。剂量将由 尼古丁血液水平以及基于暴露与目标参与之间的关系，如 R61阶段。该提案具有重要意义和创新性，因为目前的药物疗法没有改善CCN 功能或改善晚期抑郁症的认知定义。透皮尼古丁具有作用机理 这与当前的抗抑郁药不同，有可能使其成为重要的增强剂。如果我们 假设正确 确定的研究，可能适用于以CCN功能障碍为特征的其他精神疾病。