Response to inflammatory challenge in major depressive disorder

项目摘要 大约七分之一的人在他们的一生中经历过重度抑郁症（MDD），但只有一分之一的人 3例在当前治疗下达到缓解。MDD是残疾的第二大来源，并花费经济 每年2000亿美元MDD是一种非常异质性的疾病，它影响一个人如何处理事件--“什么 “让你感觉良好”（正效价），“什么让你感觉不好”（负效价），以及大脑如何 处理身体相关信息（内感受）。有些人认为炎症是 在临床上以C-反应蛋白（CRP）升高为特征的抑郁症亚群中的作用。这 一项提案旨在更好地了解MDD炎症亚型的生物学过程 通过检测低CRP（≤ 1 mg/mL）和高CRP（≥ 3 mg/mL）抑郁个体亚组。在 特别地，免疫系统的实验操作将用于对比临床，免疫， CRP高低对抑郁症患者神经功能的影响。具体而言，低CRP（n=44）和高CRP（n=44） CRP（n=44）组将被分成接受内毒素（0.8ng/kg）或盐水以诱导 短暂的炎症反应。在此期间将获得连续抽血，以量化 使用几种炎症标志物的炎症反应。与此同时，受试者将完成临床 并进行内毒素前后的MRI扫描，以测量短暂的炎症反应是如何发生的。 影响大脑对预期奖赏和内感受的处理。对于本项目的第2阶段，所有受试者将 在完成短暂的炎症反应后，接受10周的行为治疗（BT）。 将测量扰动和临床结果。该项目有两个主要目标（侧重于1-3年， （4-5）：（1）描述有炎症和无炎症的抑郁症患者在临床、免疫和 在基线和内毒素下的神经功能，和（2）测试这些变化是否预示着 BT治疗结果。主要假设为：（1）相对于低CRP组，高CRP组 将显示基线（a）快感缺乏症状增加，（B）IL-6和TNF增加，（c） 腹侧纹状体活动在积极的效价处理，和（d）减少岛皮质活动期间， 内感受性加工以及内毒素中这些表型指标的不成比例变化 vs.安慰剂条件。(2)这些基线差异的程度和内毒素诱导的变化将 预测：（a）BT过程中抑郁评分的变化以及BT后的反应和缓解率 BT.这项研究是创新的，因为它是一组炎症扰动实验中的第一个。 抑郁的人。这也是非常有影响力的，因为我们需要通过 炎症导致高CRP个体的抑郁，以（1）促进 新的药理学或行为疗法，以及（2）鉴定预测性生物标志物。

PROJECT SUMMARY About 1 out of 7 individuals experience Major Depressive Disorder (MDD) during their life time but only 1 out of 3 achieve remission with current treatment. MDD is the 2nd largest source of disability and costs the economy $200 billion annually. MDD is a very heterogeneous disorder that affects how one processes events - ‘what makes you feel good’ (positive valence), ‘what makes you feel bad’ (negative valence), and how the brain processes body-relevant information (interoception). Some have proposed that inflammation plays a central role in a subset of depression that is characterized clinically by an increase in c-reactive protein (CRP). This proposal seeks to better understand the biological processes that underlie the inflammatory subtype of MDD by examining subgroups of depressed individuals with low CRP (≤1mg/mL), and high CRP (≥3mg/mL). In particular, an experimental manipulation of the immune system will be used to contrast the clinical, immune, and neural function of depressed subjects with high and low CRP. Specifically, the low CRP (n=44) and high CRP (n=44) groups will be divided to receive either endotoxin (0.8 ng/kg) or saline in order to induce a transient inflammatory response. Serial blood draws will be obtained during this time to quantify the pattern of inflammatory response using several inflammatory markers. At the same time, subjects will complete clinical ratings and undergo a pre- and post-endotoxin MRI scan to measure how the transient inflammatory response affects brain processing of anticipatory reward and interoception. For Phase 2 of this project, all subjects will undergo 10 weeks of behavioral therapy (BT) after they have completed the transient inflammatory perturbation and clinical outcomes will be measured. This project has two main goals (focused on year 1-3 and 4-5): (1) to delineate how the depressed people with and without inflammation differ in clinical, immune, and neural function both at baseline and under endotoxin, and (2) to test whether these changes are predictive of BT treatment outcome. The main hypotheses are that: (1) relative to the low CRP group, the high CRP group will show baseline (a) increases in anhedonic symptoms, (b) increases in IL-6 and TNF, (c) decreases in ventral striatal activity during positive valence processing, and (d) decreases in insular cortex activity during interoceptive processing as well as disproportionate changes in these phenotypic measures in the endotoxin vs. placebo condition. (2) The degree of these baseline differences and endotoxin-induced changes will predict: (a) changes in depression scores over the course of the BT and response and remission rates after BT. This research is innovative because it is the first inflammatory perturbation experiment in a group of depressed individuals. It is also highly impactful because we need to understand the mechanisms through which inflammation leads to depression in high CRP individuals in order to (1) facilitate the development of new pharmacological or behavioral therapies, and (2) identify predictive biomarkers.