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: 8641432
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641432
• 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）：该项目旨在确定治疗抵抗性抑郁症（TRD）患者对细胞因子拮抗反应的预测因素和目标。长期目标是根据与炎症相关的明确病理生理机制制定个性化策略来治疗患者群体和症状领域。拟议研究的结果将有助于了解哪些病理生理领域以及哪些患者群体最有可能在未来的研究中对包括细胞因子拮抗在内的抗炎策略产生反应。高达约 2000 万美国人的三分之一 患有重度抑郁症的成年人无法对传统的抗抑郁治疗产生反应，导致长期残疾、发病率和死亡率增加以及沉重的经济负担。可能导致 TRD 的一种病理生理途径是炎症。炎症标志物的增加预示着治疗无反应，而与治疗抵抗相关的临床因素与炎症的增加有关。此外，炎症细胞因子可以破坏和规避传统抗抑郁药物的作用机制。我们小组最近完成的一项由 NIH 资助的双盲安慰剂对照试验 (n=60) 表明，3 次输注强效抗细胞因子疗法英夫利昔单抗 (5mg/kg) 比安慰剂产生更好的抗抑郁反应血浆高敏 C 反应蛋白 >5mg/L 反映的高基线炎症的 TRD 患者（n=22，代表样本的 37%）。英夫利昔单抗是一种单克隆抗体，针对炎症细胞因子肿瘤坏死因子 (TNF)-α，已证明该因子在重度抑郁症患者中确实会升高。作为试验的一部分，我们收集了广泛的额外数据和样本（不属于最初的 NIH 研究的一部分），包括多个症状领域的测量、神经认知测试、多导睡眠图和可用于检测犬尿氨酸 (KYN) 通路的系列血液样本激活和每日下丘脑-垂体-肾上腺 (HPA) 轴活动。这些额外数据是在基线、第一次输注后 24 小时以及 12 周试验的第 8 周收集的。在当前的研究中，我们建议对这些样本和数据进行测定和分析，并利用结果来阐明预测英夫利昔单抗治疗成功并对其做出反应的病理生理学领域，该领域占英夫利昔单抗治疗患者的 50% (n=15)。根据之前关于细胞因子对大脑和行为影响的研究，我们假设基底神经节功能、睡眠、KYN 通路激活和 HPA 轴活动将是预测和应对急性（24 小时内）和慢性疾病的相关病理生理学领域。英夫利昔单抗的给药。为了检验这些假设，将英夫利昔单抗与安慰剂应答者和无应答者的症状数据、神经心理学测试、多导睡眠图和血浆色氨酸、KYN 和皮质醇的外周血测量进行比较。这些数据将提供有关细胞因子拮抗反应的相关预测因素和目标的重要线索，并将为未来基于免疫的治疗试验的设计提供信息。