Neural response to inflammatory challenge in major depressive disorder

重度抑郁症对炎症挑战的神经反应

• 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
• 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

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.

慢性炎症可能是抑郁症发病机制的基础 (MDD)在相当多的情况下，但我们不明白为什么这些人会陷入困境， 炎症状态我们假设这一亚组的抑郁症患者有一个缺陷的稳态或 对炎性刺激的调节反应，使得适当的急性炎性反应未能消退， 导致慢性炎症，其增加（a）发展成抑郁症，（B）其复发，和 (c)治疗失败。为了验证这一假设，我们建议挑战两个MDD受试者的免疫系统 和健康对照（HC），用炎症刺激物（脂多糖，LPS）诱导体内平衡， 反应具体来说，90名MDD和90名HC参与者将被随机（2：1）分配至LPS（0.8ng/kg）或盐水组。 将获得连续抽血，以使用几种炎性细胞因子来量化炎性反应的模式。 标记。同时，参与者将完成临床评级，并接受LPS前后的MRI检查 扫描以测量瞬时炎症反应如何影响内感受性（身体- 相关）刺激。参与者还将在LPS/盐水输注后一天和一周返回，以完成 相同的心理测量和抽血MDD组，只有，也将完成心理 每月评估一次，持续6个月，以确定对LPS的急性反应是否预示 MDD的临床过程。主要假设是：（1）相对于HC，MDD组将显示出 炎症介质的急性增加更大，但神经回路介导的急性反应迟钝， 内感受性过程（皮层和扣带皮层）在LPS与安慰剂条件。对于急性结果 我们关注的是在炎症反应的峰值，即输注后2小时发生的变化。（二）、 在MDD组中，LPS相关的内感受性处理和功能连接的变化将被评估。 与急性促炎反应的强度相关。(3)这些急性影响将更多 在伴有慢性炎症（基线CRP ≥ 3 mg/L）的MDD参与者中显著。也就是说，相对于低 炎症MDD组（CRP <1 mg/L），高炎症MDD组将表现为一个钝化的 在内部集中注意力期间，小脑和扣带回的血流动力学反应。在探索性分析中 我们还将研究性别与诊断之间是否存在相互作用， 对LPS的反应以及LPS的急性效应是否与6个月内的抑郁症状有关 随访这项研究具有创新性和高度影响力，因为它将开辟一个新的研究计划 这将使我们能够得出关于未能解决的生物机制的强有力的结论， 与炎症有关的抑郁行为。这些知识最终可以用来开发新的大脑， 基于免疫的治疗，以启动通常由炎症刺激参与的神经回路， 将这些干预措施针对特定的患者群体。

项目成果

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
• 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。

• DOI: 10.1016/j.bbi.2022.07.011
• 发表时间: 2022-10
• 期刊: Brain, behavior, and immunity