Predictors and Targets of Response to Cytokine Antagonism in Depression

抑郁症细胞因子拮抗反应的预测因素和目标

• 批准号: 8489793
• 负责人: ANDREW H MILLER
• 金额: $ 7.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489793
• 关键词: Acute; Adult; Anhedonia; Anti-Cytokine Therapy; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Basal Ganglia; Behavioral; Biological Assay; Blood specimen; Chronic; Clinical; Clinical Trials; Crohn' s disease; Data; Depressed mood; Disease; Double-Blind Method; Economic Burden; Exhibits; Fatigue; Funding; Future; Hamilton Rating Scale for Depression; Health Care Costs; Hour; Hydrocortisone; Immune; Immune Targeting; Individual; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Kynurenine; Link; Major Depressive Disorder; Measures; Mental Depression; Monoclonal Antibodies; Morbidity - disease rate; Necrosis; Neurobiology; Neurocognitive; Neuropsychological Tests; Pathway interactions; Patients; Pharmaceutical Preparations; Placebo Control; Placebo Effect; Placebos; Plasma; Polysomnography; Proteins; Public Health; Randomized; Research; Resistance; Sampling; Sleep; Slow-Wave Sleep; Speed; Symptoms; Testing; Therapy Clinical Trials; Time; Tryptophan; Tumor Necrosis Factor-alpha; Ulcerative Colitis; United States National Institutes of Health; base; brain behavior; cytokine; depressive symptoms; design; disability; double-blind placebo controlled trial; hypothalamic-pituitary-adrenal axis; inflammatory marker; infliximab; mortality; neurocognitive test; patient population; peripheral blood; public health relevance; response; treatment effect; treatment response; treatment trial; tumor; week trial

DESCRIPTION (provided by applicant): This project is designed to identify the predictors and targets of response to cytokine antagonism in patients with treatment resistant depression (TRD). The long term objectives are to develop personalized strategies to treat patient populations and symptom domains based on defined pathophysiologic mechanisms related to inflammation. The results of the proposed research will help inform which pathophysiologic domains and therefore which patient populations are most likely to respond to anti-inflammatory strategies including cytokine antagonism in future studies. Up to one third of the ~20 million U.S. adults with major depression are unable to respond to conventional antidepressant therapy, leading to prolonged disability, increased morbidity and mortality and significant economic burden. One pathophysiologic pathway that may contribute to TRD is inflammation. Increased inflammatory markers predict treatment non-response, and clinical factors linked with treatment resistance are associated with increased inflammation. In addition, inflammatory cytokines can sabotage and circumvent mechanisms of action of conventional antidepressant medications. A recently completed NIH-funded, double-blind, placebo-controlled trial (n=60) conducted by our group has shown that 3 infusions of the potent anti-cytokine therapy infliximab (5mg/kg) led to a greater antidepressant response than placebo in TRD patients with high baseline inflammation as reflected by a plasma high sensitivity c-reactive protein >5mg/L (n=22, representing 37% of the sample). Infliximab is a monoclonal antibody that targets the inflammatory cytokine, tumor necrosis factor (TNF)-alpha, which has been shown to be reliably elevated in patients with major depression. As part of the trial, we gathered extensive additional data and samples (which were not part of the original NIH study) including measures of multiple symptom domains, neurocognitive testing, polysomnography, and serial blood samples that can be assayed for kynurenine (KYN) pathway activation and diurnal hypothalamic-pituitary-adrenal (HPA) axis activity. This additional data was collected at baseline, 24 hrs after the first infusion and at Wek 8 of the 12 week trial. In the current study, we propose to assay and analyze these samples and data and use the results to elucidate the pathophysiologic domains that predict and respond to successful infliximab treatment, which represented 50% of infliximab-treated patients (n=15). Based on previous studies of the impact of cytokines on the brain and behavior, we hypothesize that basal ganglia function, sleep, KYN pathway activation and HPA axis activity will be relevant pathophysiologic domains that will predict and respond to acute (within 24 hrs) and chronic administration of infliximab. To test these hypotheses, symptom data, neuropsychological testing, polysomnography and peripheral blood measures of plasma tryptophan, KYN and cortisol will be compared in infliximab vs. placebo responders and non-responders. These data will provide important clues regarding relevant predictors and targets of response to cytokine antagonism and will inform the design of future immune-based therapeutic trials.

描述（由申请人提供）：该项目旨在确定耐药抑郁症患者（TRD）患者对细胞因子拮抗作用的预测因子和靶标。长期目标是制定个性化策略，以基于与炎症有关的定义病理生理机制来治疗患者人群和症状领域。拟议研究的结果将有助于告知哪些病理生理领域，因此哪些患者人群最有可能对包括细胞因子拮抗作用在未来的研究中的抗炎策略做出反应。美国大约2000万份的三分之一 患有严重抑郁症的成年人无法应对常规的抗抑郁药疗法，导致残疾长期，发病率和死亡率增加以及经济负担重大。一种可能导致TRD的病理生理途径是炎症。炎症标志物的增加预测了治疗无反应，与治疗耐药性有关的临床因素与炎症增加有关。此外，炎症细胞因子可能会破坏和规避常规抗抑郁药的作用机理。最近完成的NIH资助的，双盲的，安慰剂对照试验（N = 60）由我们的小组进行的一项有效的抗周期性疗法施加量（5mg/kg）的3次输注导致高基线炎症的抗抑郁病患者的抗抑郁反应更大，因为帕斯玛高度均具有pld炎症的高度症状，因为帕斯玛高度co; （n = 22，代表样本的37％）。英夫利昔单抗是一种靶向炎症细胞因子，肿瘤坏死因子（TNF） - α的单克隆抗体，在重度抑郁症患者中已显示出可靠的升高。作为该试验的一部分，我们收集了广泛的其他数据和样本（不是原始NIH研究的一部分），包括多个症状结构域，神经认知测试，综合仪表术和可以分析Kynurenarine（Kyn）途径活化和二炎下丘脑下腹膜下型肌张力型 - AD型 - HPAA）的衡量标准。该额外的数据是在第一次输注后24小时和12周试验中的WEK 8时收集的。在当前的研究中，我们建议分析和分析这些样品和数据，并使用结果来阐明预测和反应成功的英夫利昔单抗治疗的病理生理结构域，这代表了英夫利昔单抗治疗的患者的50％（n = 15）。基于对细胞因子对大脑和行为的影响的先前研究，我们假设基底神经节功能，睡眠，Kyn途径激活和HPA轴活动将是相关的病理生理结构域，可以预测和响应急性（在24小时内）和griveiximab的慢性给药。为了测试这些假设，将在英夫利昔单抗与安慰剂响应者和非反应者中比较血浆色氨酸，Kyn和皮质醇的血浆色氨酸，Kyn和皮质醇的多个心理学测试和外周血测量。这些数据将提供有关相关预测因子和对细胞因子拮抗作用的反应目标的重要线索，并将为未来基于免疫的治疗试验的设计提供信息。