Neurobiological and Behavioral Effects of Cytokine Antagonism in Major Depression

描述（由申请人提供）：累积的数据表明，先天免疫炎症反应的激活可能有助于重度抑郁症的发展。医学上健康的抑郁症患者表现出增加的炎症介质的血浆浓度，包括先天免疫系统的细胞因子，并且向动物和人类施用先天免疫细胞因子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。针对免疫系统治疗抑郁症的兴趣越来越多地集中在肿瘤坏死因子（TNF）-α上。已发现在患有重性抑郁症的患者中TNF-α的血浆浓度升高，并且已知TNF-α激活改变HPA轴功能、单胺代谢和突触可塑性的信号传导通路;所有这些都是与重性抑郁症的发展相关的病理生理学领域。此外，TNF-α受体基因敲除的实验室动物表现出抗抑郁药样表型，传统抗抑郁药（即单胺再摄取抑制剂）的疗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拮抗剂来检验抑郁症的细胞因子假说。在目前的项目中，我们计划测量抑郁症患者对TNF-α拮抗剂英夫利昔单抗单次输注的行为反应。考虑到TNF-α拮抗作用的潜在健康风险，拟议的研究将重点关注医学健康的患者，这些患者患有难治性抑郁症（TRD）和先天免疫应答激活的证据。TRD是一个常见的重大公共卫生问题，在发病率和死亡率方面都具有削弱性后果。有趣的是，TRD患者似乎也比治疗应答患者更有可能表现出先天免疫系统激活。我们假设：1）英夫利西单抗输注将减少TRD患者的抑郁症状，并增加炎症标志物; 2）抑郁的减少与英夫利西单抗诱导的TNF-α活性和先天免疫炎症反应的其他下游因素的降低相关。为了检验这些假设，将60例无抗抑郁药的TRD受试者以双盲方式随机分配至单次输注英夫利西单抗组和生理盐水组。受试者将在基线和英夫利西单抗输注后第1、2、4、6和8周接受定期神经行为、免疫学和安全性评估。这项转化研究将为TNF-α在抑郁症中的作用提供新的见解，并将有助于确定预测或监测抗TNF-α治疗成功的潜在生物标志物。重度抑郁症是全球第四大健康负担原因。高达30%的抑郁症患者对目前可用的治疗无反应是该疾病的人力和经济成本的主要贡献者。本申请提出评估阻断细胞因子肿瘤坏死因子（TNF）-α作为难治性抑郁症的干预的新治疗策略，其基于表明过度活跃的免疫系统应答（包括细胞因子如TNF-α的过度释放）可能促成该病症的病理生理学的数据。

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.