Neurobiological and Behavioral Effects of Cytokine Antagonism in Major Depression

细胞因子拮抗剂对重度抑郁症的神经生物学和行为影响

• 批准号: 7546540
• 负责人: Charles Raison
• 金额: $ 20.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546540
• 关键词: Acute-Phase Proteins; Animals; Anti-Cytokine Therapy; Antidepressive Agents; Autoimmune Diseases; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Biological Markers; C-reactive protein; DNA Binding; Data; Development; Disease; Dopamine; Double-Blind Method; Elements; Enzyme-Linked Immunosorbent Assay; Evaluation; Exhibits; Exposure to; Failure; Flow Cytometry; Functional disorder; Goals; Health; Human; Immune; Immune response; Immune system; Immunologics; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Infusion procedures; Interleukin 6 Receptor; Interleukin-1; Interleukin-1 beta; Interleukin-6; Interleukins; Intervention; Knock-out; Laboratory Animals; Lipopolysaccharides; Major Depressive Disorder; Measurement; Measures; Metabolism; Modality; Monitor; Moods; Morbidity - disease rate; Nature; Neurobiology; Neurotransmitters; Nuclear; Pathway interactions; Patients; Phenotype; Plasma; Population; Procedures; Process; Production; Protein C; Public Health; Randomized; Receptor Gene; Reporting; Resistance; Risk; Role; Safety; Saline; Schedule; Serotonin; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Symptoms; Synaptic plasticity; Testing; Time; Translational Research; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; anakinra; base; behavior measurement; chimeric antibody; cytokine; depressed; depression; depressive symptoms; economic cost; exhaust; human TNFRSF1A protein; hypothalamic-pituitary-adrenal axis; improved; in vivo; indexing; inflammatory marker; infliximab; inhibitor/antagonist; insight; interest; monoamine; monocyte; mortality; neurobehavioral; novel; novel therapeutics; response; reuptake; success; tumor necrosis factor alpha receptor

DESCRIPTION (provided by applicant): Accumulating data suggest that activation of the innate immune inflammatory response may contribute to the development of major depression. Medically healthy patients with depression exhibit increased plasma concentrations of inflammatory mediators including cytokines of the innate immune system, and administration of innate immune cytokines to animals and humans induces behavioral alterations that overlap with major depression. In addition, cytokines of the innate immune response interact with pathways implicated in the pathophysiology of depression. Increasing interest in targeting the immune system for the treatment of depression has focused on tumor necrosis factor (TNF)-alpha. Plasma concentrations of TNF-alpha have been found to be elevated in patients with major depression, and TNF-alpha is known to activate signaling pathways that alter HPA axis function, monoamine metabolism and synaptic plasticity; all of which are pathophysiologic domains relevant to the development of major depression. Furthermore, laboratory animals with the TNF-alpha receptor gene knocked out exhibit an antidepressant-like phenotype, and the efficacy of traditional antidepressants (i.e. monoamine reuptake inhibitors) has been shown to be related in part to effects on TNF. Finally, antagonism of TNF-alpha activity has been shown to improve depressive symptoms in patients with autoimmune disorders. The long-term goal of the proposed work is to test the cytokine hypothesis of depression using a TNF-alpha antagonist. In the current project, we plan to measure the behavioral response of depressed patients to a single infusion of the TNF-alpha antagonist, infliximab. Given the potential health risks of TNF-alpha antagonism, the proposed study will focus on medically healthy patients with both treatment resistant depression (TRD) and evidence of activation of the innate immune response. TRD is a common and significant public health concern with debilitating consequences in terms of both morbidity and mortality. Interestingly, patients with TRD also appear to be more likely than treatment responsive patients to demonstrate innate immune system activation. We hypothesize that 1) infliximab infusion will decrease depressive symptoms in patients with TRD and increased markers of inflammation and 2) that decreases in depression will correlate with infliximab-induced decreases in TNF-alpha activity and other downstream elements of the innate immune inflammatory response. To test these hypotheses, sixty antidepressant-free subjects with TRD will be randomized in double-blind fashion to a single infusion of infliximab versus saline. Subjects will undergo regular neurobehavioral, immunologic and safety assessments at baseline and at weeks 1, 2, 4, 6 and 8 following infliximab infusion. The proposed translational research will provide novel insights into the role of TNF-alpha in depression and will help define potential biomarkers that predict or monitor success of anti-TNF-alpha therapy.Major depression is the fourth leading cause of overall health burden in the world. Non-response to currently available therapies in up to 30% of depressed patients is a primary contributor to the human and economic cost of the disease. This application proposes to evaluate the novel therapeutic strategy of blocking the cytokine tumor necrosis factor (TNF)-alpha as an intervention for treatment-resistant depression, based on data suggesting that overactive immune system responses, including excessive release of cytokines like TNF- alpha, may contribute to the pathophysiology of the disorder.

描述（由申请人提供）：积累的数据表明先天免疫炎症反应的激活可能导致重度抑郁症的发生。医学上健康的抑郁症患者表现出炎症介质（包括先天免疫系统细胞因子）血浆浓度升高，对动物和人类施用先天免疫细胞因子会诱导与重度抑郁症重叠的行为改变。此外，先天免疫反应的细胞因子与抑郁症病理生理学中涉及的途径相互作用。人们越来越关注免疫系统治疗抑郁症，重点关注肿瘤坏死因子 (TNF)-α。研究发现，重度抑郁症患者的血浆 TNF-α 浓度升高，并且已知 TNF-α 可以激活改变 HPA 轴功能、单胺代谢和突触可塑性的信号通路；所有这些都是与重度抑郁症的发展相关的病理生理学领域。此外，TNF-α受体基因被敲除的实验动物表现出类似抗抑郁药的表型，并且传统抗抑郁药（即单胺再摄取抑制剂）的功效已被证明部分与对TNF的影响有关。最后，TNF-α 活性的拮抗作用已被证明可以改善自身免疫性疾病患者的抑郁症状。这项工作的长期目标是使用 TNF-α 拮抗剂来测试抑郁症的细胞因子假说。在当前的项目中，我们计划测量抑郁症患者对单次注射 TNF-α 拮抗剂英夫利昔单抗的行为反应。考虑到 TNF-α 拮抗剂的潜在健康风险，拟议的研究将重点关注患有治疗抵抗性抑郁症 (TRD) 和先天免疫反应激活证据的医学健康患者。 TRD 是一种常见且重要的公共卫生问题，会导致发病率和死亡率下降。有趣的是，TRD 患者似乎比治疗有反应的患者更有可能表现出先天免疫系统激活。我们假设 1) 英夫利昔单抗输注将减少 TRD 患者的抑郁症状并增加炎症标志物，2) 抑郁症的减少将与英夫利昔单抗诱导的 TNF-α 活性和先天免疫炎症反应其他下游因素的降低相关。为了检验这些假设，60 名未服用抗抑郁药物的 TRD 受试者将以双盲方式随机分配，分别接受英夫利昔单抗与生理盐水的单次输注。受试者将在基线以及英夫利昔单抗输注后第 1、2、4、6 和 8 周定期接受神经行为、免疫学和安全性评估。拟议的转化研究将为 TNF-α 在抑郁症中的作用提供新的见解，并将有助于定义预测或监测抗 TNF-α 治疗成功的潜在生物标志物。重度抑郁症是世界上总体健康负担的第四大原因。多达 30% 的抑郁症患者对目前可用的疗法没有反应，这是造成该疾病造成的人员和经济损失的主要原因。本申请旨在评估阻断细胞因子肿瘤坏死因子 (TNF)-α 作为治疗难治性抑郁症干预措施的新治疗策略，数据表明过度活跃的免疫系统反应，包括细胞因子如 TNF-α 的过度释放，可能会导致该疾病的病理生理学。