Predictors and Targets of Response to Cytokine Antagonism in Depression

描述（申请人提供）：该项目旨在确定难治性抑郁症（TRD）患者对细胞因子拮抗作用反应的预测因素和靶点。长期目标是根据定义的炎症相关病理生理机制，制定个性化策略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学领域，因此哪些患者人群最有可能在未来的研究中对抗炎策略（包括细胞因子拮抗作用）做出反应。两千万美元中的三分之一。 患有严重抑郁症的成年人无法对常规抗抑郁剂治疗作出反应，导致长期残疾、发病率和死亡率增加以及严重的经济负担。一种可能导致TRD的病理生理学途径是炎症。增加的炎症标志物预测治疗无应答，与治疗抵抗相关的临床因素与增加的炎症相关。此外，炎性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NIH资助的双盲安慰剂对照试验（n=60）显示，在具有高基线炎症的TRD患者中，输注3次强效抗细胞因子治疗英夫利西单抗（5 mg/kg）导致比安慰剂更大的抗抑郁反应，这反映在血浆高敏C反应蛋白> 5 mg/L（n=22，占样本的37%）。英夫利西单抗是一种单克隆抗体，靶向炎症细胞因子，肿瘤坏死因子（TNF）-α，已被证明是可靠的升高，在患者的抑郁症。作为试验的一部分，我们收集了大量额外的数据和样本（不属于原始NIH研究的一部分），包括多个症状领域的测量，神经认知测试，多导睡眠图和系列血液样本，可以分析犬尿氨酸（KYN）通路激活和昼夜下丘脑-垂体-肾上腺（HPA）轴活动。这些额外数据是在基线、首次输注后24小时和12周试验的第8周收集的。在目前的研究中，我们建议测定和分析这些样本和数据，并使用结果来阐明预测和响应成功英夫利昔单抗治疗的病理生理学领域，这代表了50%的英夫利昔单抗治疗患者（n=15）。基于先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轴活动将是预测和响应英夫利西单抗急性（24小时内）和慢性给药的相关病理生理学领域。为了检验这些假设，将比较英夫利西单抗与安慰剂应答者和非应答者的症状数据、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。这些数据将提供重要的线索，相关的预测因子和细胞因子拮抗作用的反应目标，并将告知未来的免疫为基础的治疗试验的设计。

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.