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）：累积数据表明，先天免疫炎症反应的激活可能有助于大抑郁症的发展。抑郁症的医学健康患者表现出炎症介质的血浆浓度升高，包括先天免疫系统的细胞因子，以及对动物和人类的先天免疫细胞因子给药会引起与重大抑郁症重叠的行为改变。此外，先天免疫反应的细胞因子与与抑郁症的病理生理有关的途径相互作用。对靶向抑郁症治疗的免疫系统的兴趣不断增加，集中在肿瘤坏死因子（TNF）-Alpha上。在严重抑郁症患者中，已经发现TNF-α的血浆浓度升高，并且已知TNF-Alpha会激活改变HPA轴功能，单胺代谢和突触可塑性的信号传导途径。所有这些都是与严重抑郁症发展有关的病理生理领域。此外，具有TNF-Alpha受体基因的实验动物敲除抗抑郁剂样表型，并且已显示传统抗抑郁药（即单胺再摄取抑制剂）的功效部分与对TNF的影响有关。最后，已显示TNF-Alpha活性的拮抗作用可改善自身免疫性疾病患者的抑郁症状。拟议工作的长期目标是使用TNF-Alpha拮抗剂检验抑郁症的细胞因子假设。在当前的项目中，我们计划测量抑郁症患者对TNF-Alpha拮抗剂英夫利昔单抗单一输注的行为反应。鉴于TNF-Alpha拮抗作用的潜在健康风险，拟议的研究将集中于具有耐药性抑郁症（TRD）的医学健康患者和先天免疫反应激活的证据。 TRD是一个普遍且重要的公共卫生问题，在发病率和死亡率方面造成了令人衰弱的后果。有趣的是，TRD患者似乎也比治疗反应敏感的患者更有可能证明先天免疫系统激活。我们假设1）1）英夫利昔单抗输注将减少TRD患者的抑郁症状和炎症标记增加的抑郁症状； 2）抑郁症的降低将与英夫利昔单抗诱导的TNF-α活性和其他先天免疫炎症反应的下游元素的降低相关。为了检验这些假设，有60名无TRD的无抗抑郁药将以双盲方式随机分配给英夫利昔单抗与盐水的单一输注。受试者将在基线时进行定期的神经行为，免疫和安全评估，并在英夫利昔单抗输注后的第1、2、4、6和8周进行。拟议的翻译研究将为TNF-Alpha在抑郁症中的作用提供新的见解，并有助于定义潜在的生物标志物来预测或监测抗TNF-Alpha疗法的成功。Major抑郁症是全球总体健康负担的第四个主要原因。在高达30％的抑郁症患者中，当前可用的疗法无反应是疾病人类和经济成本的主要因素。该应用建议将阻止细胞因子肿瘤坏死因子（TNF）-Alpha的新型治疗策略评估，以作为对治疗抑郁症的干预措施，基于数据表明，过度活跃的免疫系统反应，包括过度释放细胞因子（例如TNF-Alpha），可能有助于该障碍的病理生理学。