Neural response to inflammatory challenge in major depressive disorder

重度抑郁症对炎症挑战的神经反应

基本信息

批准号：
10612922
负责人：
Jonathan Savitz
金额：
$ 64.15万
依托单位：
LAUREATE INSTITUTE FOR BRAIN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-14 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612922
关键词：
Acute Affect Anhedonia Attention Behavior Biological Blood Brain Characteristics Chronic Clinical Clinical assessments Color Communication Data Depressed mood Development Diagnosis Double-Blind Method Emotions Failure Functional Magnetic Resonance Imaging Heart Homeostasis Hour Human Immune Immune system Immunologics Immunotherapy In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infusion procedures Insula of Reil Interleukin-6 Interoception Intervention Knowledge Lipopolysaccharides MRI Scans Major Depressive Disorder Measures Mediating Medicine Mental Depression Mood Disorders Moods Outcome Participant Pathogenesis Pathway interactions Patients Pattern Persons Placebo Control Placebos Process Psychometrics Public Health Randomized Recovery Recurrence Research Rest Risk Role Saline Sex Differences Signal Transduction Sleep Stimulus Stomach Subgroup Symptoms System Testing Time Treatment Failure Visit cingulate cortex clinical predictors cytokine depressed patient depressive behavior depressive symptoms early life stress experimental study follow-up hemodynamics in vivo inflammatory marker innovation monocyte neural neural circuit patient population patient subsets placebo controlled study pleasure primary outcome programs psychologic recurrent depression response safety assessment sex symptomatology

项目摘要

PROJECT SUMMARY: Chronic inflammation likely underlies the pathogenesis of major depressive disorder (MDD) in a significant number of cases but we do not understand why these individuals get stuck in an inflammatory state. We hypothesize that this subgroup of depressed patients has a defective homeostatic or regulatory response to inflammatory stimuli such that appropriate, acute inflammatory responses fail to resolve, leading to chronic inflammation which increases the risk for (a) developing depression, (b) its recurrence, and (c) treatment failure. To test this hypothesis, we propose challenging the immune system of both MDD subjects and healthy controls (HC) with an inflammatory stimulus (lipopolysaccharide, LPS) to induce a homeostatic response. Specifically, 90 MDD and 90 HC participants will be randomized (2:1) to LPS (0.8ng/kg) or saline. Serial blood draws will be obtained to quantify the pattern of inflammatory response using several inflammatory markers. At the same time, participants will complete clinical ratings and undergo a pre- and post-LPS MRI scan to measure how the transient inflammatory response affects the brain processing of interoceptive (bodily- relevant) stimuli. Participants will also return one day and one week after LPS/saline infusion to complete identical psychometric measures and blood draws. The MDD group, only, will also complete psychological assessments once per month for 6 months in order to determine whether the acute response to LPS predicts the clinical course of MDD. The main hypotheses are that: (1) relative to HC, the MDD group will show a greater acute increase in inflammatory mediators but a blunted acute response of the neural circuitry mediating interoceptive processes (insula and cingulate cortex) in the LPS vs. placebo condition. For the acute outcomes we focus on the changes that occur at the peak of the inflammatory response, i.e. 2 hours post-infusion. (2). Within the MDD group, LPS-associated changes in interoceptive processing and functional connectivity will be correlated with the strength of the acute pro-inflammatory response. (3) These acute effects will be more salient in MDD participants with chronic inflammation (baseline CRP ³3mg/L). That is, relative to the low inflammation MDD group (CRP £1mg/L), the high inflammation MDD group will display a blunted hemodynamic response of the insula and cingulate during internally-focused attention. In exploratory analyses we will also examine whether there is a sex by diagnosis interaction effect on inflammatory and insular response to LPS and whether the acute effects of LPS will relate to depressive symptoms over the 6-month follow-up. This research is innovative and highly impactful because it will open up a new program of research that will allow us to draw strong conclusions about the biological mechanisms underlying the failure to resolve inflammation-related depressive behavior. This knowledge can ultimately be used to develop new brain or immune-based treatments to jump-start the neural circuitry normally engaged by inflammatory stimuli, and to target these interventions at specific patient populations.

项目摘要：慢性炎症可能是主要抑郁症的发病机理的基础（MDD）在大量案件中，但我们不明白为什么这些人被困在一个炎症状态。我们假设这个抑郁症患者亚组的体内平衡或对炎症刺激的调节反应，使得适当的急性炎症反应无法解决，导致慢性炎症增加（a）抑郁症的风险，（b）复发，以及（c）治疗失败。为了检验这一假设，我们提出了两个MDD受试者的免疫系统的挑战和健康对照（HC），具有炎症刺激（脂多糖，LPS），以诱导体内平衡回复。具体而言，将有90个MDD和90 HC参与者被随机分配给LPS（0.8ng/kg）或盐水。将获得串行血液抽血，以量化使用几种炎症的炎症反应模式标记。同时，参与者将完成临床评级并接受LPS前和LPS MRI 扫描以测量瞬时炎症反应如何影响互感的大脑加工（身体相关）刺激。参与者还将在LPS/Saline Infusion后一天又一周返回完成相同的心理计量测量和血液抽血。仅MDD组也将完成心理每月一次评估6个月，以确定对LPS的急性反应是否预测 MDD的临床过程。主要假设是：（1）相对于HC，MDD组将显示炎症介质的急性增加，但神经回路的急性反应钝化 LPS与安慰剂条件中的互感过程（绝缘和扣带皮层）。急性结果我们专注于炎症反应峰值的变化，即输注后2小时。（2）。在MDD组中，与LPS相关的互感处理和功能连接性的变化将是与急性促炎反应的强度相关。（3）这些急性影响将更多 MDD参与者的慢性感染（基线CRP ′3mg/L）的显着性。也就是说炎症MDD组（CRP£1mg/L），高炎症MDD组将显示出钝的在内部关注期间，绝缘体的血液动力学反应和扣带。在探索性分析中我们还将检查是否通过诊断互动对炎症和孤立性有性别对LP的反应以及LPS的急性影响是否与6个月的抑郁症状有关后续。这项研究具有创新性和高度影响力，因为它将开辟一项新的研究计划这将使我们能够就无法解决的生物学机制得出有力的结论与炎症有关的抑郁行为。这些知识最终可用于发展新的大脑或基于免疫治疗，以开始通常由炎症刺激参与的神经回路，并这些干预措施针对特定的患者人群。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute administration of ibuprofen increases serum concentration of the neuroprotective kynurenine pathway metabolite, kynurenic acid: a pilot randomized, placebo-controlled, crossover study.

DOI：
10.1007/s00213-022-06263-w
发表时间：
2022-12
期刊：
PSYCHOPHARMACOLOGY
影响因子：
3.4
作者：
Savitz, Jonathan;Ford, Bart N.;Kuplicki, Rayus;Khalsa, Sahib;Teague, T. Kent;Paulus, Martin P.
通讯作者：
Paulus, Martin P.

Herpesviruses and neuropsychiatric disorders: overlooked adversaries or innocent bystanders?

疱疹病毒和神经精神疾病：被忽视的对手还是无辜的旁观者？

DOI：
10.1038/s41386-023-01674-5
发表时间：
2024
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Zheng,Haixia;Savitz,Jonathan
通讯作者：
Savitz,Jonathan

Association between cytomegalovirus infection, reduced gray matter volume, and resting-state functional hypoconnectivity in major depressive disorder: a replication and extension.

DOI：
10.1038/s41398-021-01558-6
发表时间：
2021-09-07
期刊：
Translational psychiatry
影响因子：
6.8
作者：
Zheng H;Ford BN;Kuplicki R;Burrows K;Hunt PW;Bodurka J;Kent Teague T;Irwin MR;Yolken RH;Paulus MP;Savitz J
通讯作者：
Savitz J

Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples.

巨细胞病毒抗体与死后大脑样本中的情绪障碍、自杀、神经炎症标志物和小胶质细胞激活有关。

DOI：
10.1038/s41380-023-02162-4
发表时间：
2023
期刊：
Molecular psychiatry
影响因子：
11
作者：
Zheng,Haixia;Webster,MareeJ;Weickert,CynthiaShannon;Beasley,ClareL;Paulus,MartinP;Yolken,RobertH;Savitz,Jonathan
通讯作者：
Savitz,Jonathan

C-Reactive protein and the kynurenic acid to quinolinic acid ratio are independently associated with white matter integrity in major depressive disorder.

C反应蛋白和犬尿酸与喹啉酸的比例与重度抑郁症的白质完整性独立相关。