Response to inflammatory challenge in major depressive disorder

项目总结 大约每7个人中就有1人在一生中经历过严重抑郁障碍(MDD)，但只有1人 3通过目前的治疗达到缓解。MDD是第二大残疾来源，并造成经济损失 每年2000亿美元。MDD是一种非常不同的疾病，它会影响一个人处理事件的方式 “让你感觉良好”(正价)，“什么让你感觉不好”(负价)，以及大脑是如何 处理与身体相关的信息(内感)。一些人提出，炎症在 在以C反应蛋白(CRP)升高为临床特征的抑郁症的子集中起作用。这 该提案旨在更好地了解MDD炎症性亚型背后的生物学过程 通过检测低C反应蛋白(≤1 mg/m L)和高C反应蛋白(≥3 mg/m L)抑郁个体的亚组。在……里面 特别是，免疫系统的实验操作将被用来对比临床、免疫、 高、低C反应蛋白抑郁受试者的神经功能。具体来说，低C反应蛋白(n=44)和高C反应蛋白(n=44) C反应蛋白(n=44)组将被分成内毒素(0.8 ng/kg)或生理盐水组，以诱导 一过性炎症反应。在此期间将进行连续抽血，以量化 使用几种炎症标志物的炎症反应。同时，受试者将完成临床 并在内毒素治疗前和治疗后进行MRI扫描，以测量暂时性炎症反应 影响大脑对预期奖赏和内感的处理。对于本项目的第二阶段，所有科目将 在他们完成短暂性炎症反应后，接受10周的行为疗法(BT 扰动和临床结果将被测量。该项目有两个主要目标(重点放在1-3年级和 4-5)：(1)描述有炎症和无炎症的抑郁症患者在临床、免疫和 在基线和内毒素作用下的神经功能，以及(2)测试这些变化是否可以预测 Bt治疗结果。主要假设如下：(1)相对于低C反应蛋白组，高C反应蛋白组 将显示基线(A)非享乐症状增加，(B)IL-6和TNF增加，(C) 腹侧纹状体在正价加工期间的活动，以及(D)在 内毒素中感觉间的处理以及这些表型指标的不成比例的变化 与安慰剂条件相比。(2)这些基线差异和内毒素引起的变化的程度将 预测：(A)在BT治疗过程中抑郁评分的变化以及在BT治疗后的反应和缓解率 英国电信。这项研究具有创新性，因为这是一组 抑郁的人。它的影响力也很大，因为我们需要通过 哪种炎症导致高C反应蛋白个体的抑郁，以便(1)促进 新的药物或行为疗法，以及(2)识别预测性生物标记物。

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.