Neural Mechanisms of Monoaminergic Engagement in Late-Life Depression Treatment Response (NEMO)

在这个竞争性的更新（11年级）中，我们的R 01使用fMRI研究晚年抑郁症（LLD）药物治疗 （R 01 MH 076079），主要目的是表征与初始 药物暴露（12小时攻毒）。我们的初步数据表明，这些最初的功能磁共振成像变化反映了 单胺能参与，无论单胺能类别（肾上腺素能或去甲肾上腺素能），并预测 后期治疗反应。在拟议的研究中，我们测试了一个神经系统水平的模型，在LLD的反应是 通过急性药理学诱导的认知和情感大规模网络变化介导。 老年人的抑郁症通常会导致残疾，并且通常对一线治疗有抵抗力，需要更多治疗 延长治疗试验比年轻的成年人，主要是由于其异质性的病理生理学（例如， 血管和退行性脑变化）。目前，几乎没有神经生物学数据来指导改变或 增加抗抑郁药物因此，人们更加注重根据具体情况调整治疗方法， 优化2015年NIMH战略计划草案（战略3.2）中所述的成果。虽然抗抑郁药 临床反应可能需要长达8周，最近的研究表明，生理变化，如测量 药理学功能磁共振成像（phMRI）是在24小时内开始一个新的单胺能抗抑郁药1。为 在这个建议中，我们重点讨论了三个主要的认知和情感网络（CAN）：默认模式网络 (DMN)显著性网络（SN）和执行控制网络（ECN）。该模型表明， 单胺能参与导致核心CAN变化，这些变化随后与整体相关 临床反应以及特定症状群的反应，如阴性偏倚、躯体化/ 焦虑和认知控制。当个体处于静止状态时， 在执行任务时也会有选择地参与。我们先前的工作表明，药物治疗-无论类型的 抗抑郁药使用-从事这些特定的网络在休息和在标准的认知和情感 任务鉴于脑血管疾病在LLD治疗反应中的作用，我们还将探讨 血管负荷对CAN参与和治疗之间的拟议关联的调节作用 反应我们将招募100名患有LLD的老年人，他们将随机接受以下治疗： 非常特异的5-羟色胺再摄取抑制剂（依他普仑）或去甲肾上腺素再摄取抑制剂 （左旋米那西泮）。间隔一天的一对fMRI扫描将用于测量与药物相关的FC 滴定我们建议使用非常早期（治疗开始后12小时）的治疗生物标志物 这将大大减少药物变化之间的等待时间。 此外，我们的研究将进一步加深我们对急性神经系统变化的理解， 单胺能抗抑郁药;这种机制的知识对于指导LLD治疗 研究，并作为LLD治疗研究的参与目标。

In this competing renewal (Year 11) of our R01 using fMRI to study late-life depression (LLD) pharmacotherapy (R01MH076079), the primary aim is to characterize functional connectivity changes associated with initial medication exposure (12-hour challenge). Our preliminary data suggests that these initial fMRI changes reflect monoaminergic engagement, regardless of monoaminergic class (serotonergic or noradrenergic), and predict later treatment response. In the proposed study we test a neural systems level model that response in LLD is mediated by acute pharmacologically-induced changes in cognitive and affective large scale network. Depression in older adults is frequently disabling and is often resistant to first-line treatments, requiring more prolonged treatment trials than in younger adults, mainly due to its heterogeneous pathophysiology (e.g. vascular and degenerative brain changes). Currently, there is little neurobiological data to guide changing or augmenting antidepressant medications. Thus, there has been a heightened focus on tailoring treatment to optimize outcome as described in the 2015 NIMH draft strategic plan (strategy 3.2). While antidepressant clinical response may take up to 8 weeks, recent studies suggest that physiologic changes, as measured with pharmacologic fMRI (phMRI) are seen within 24 hours of starting a new monoaminergic antidepressant1. For this proposal, we focus on three major Cognitive and Affective Networks (CAN): the Default Mode Network (DMN), the Salience Network (SN) and the Executive Control Network (ECN). The proposed model suggests that monoaminergic engagement leads to core CAN changes, changes that subsequently are related to overall clinical response as well as response in specific symptom clusters such as negative bias, somatizations/ anxiety and cognitive control. The same networks that are functionally connected while individuals are at rest, are also selectively engaged during tasks. Our prior work shows that pharmacotherapy – regardless of type of antidepressant used - engages these specific networks at rest and during standard cognitive and affective tasks. Given the role of cerebrovascular disease in LLD treatment response, we will also explore the moderating role of vascular burden on the proposed association between CAN engagement and treatment response. We will recruit 100 older adults with LLD who will be randomized to receive treatment with either a very specific serotonin reuptake inhibitor (escitalopram) or a norepinephrine reuptake inhibitor (levomilnacipram). A pair of fMRI scans one day apart will be used to measure FC associated with medication titration. We propose to use a very early (12 hours after initiation of treatment) biomarker of treatment response, which, when validated, would decrease substantially the waiting time between medication changes. Additionally, our study will further our understanding of the acute neural system changes associated with monoaminergic antidepressants; this knowledge of mechanism is essential for both guiding LLD treatment research, and serving as an engagement target in LLD treatment research.