Cytokine-CRH Interactions in IFN-alfa-Induced Depression

IFN-α 诱导的抑郁症中细胞因子-CRH 相互作用

• 批准号: 6870834
• 负责人: Charles Raison
• 金额: $ 30.98万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-13 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870834
• 关键词: adrenocorticotropic hormone; blood chemistry; chemical hypersensitivity; clinical research; corticotropin releasing factor; cortisol; cytokine; depression; disease /disorder proneness /risk; disease /therapy duration; hepatitis C; hormone regulation /control mechanism; human subject; iatrogenic disease; immunotherapy; interferon alpha; mental health epidemiology; neuropsychological tests; patient oriented research; psychological stressor; ribavirin; therapy adverse effect

DESCRIPTION (provided by applicant): Increasingly recognized as a health burden of global proportions, depression is especially devastating in the context of medical illness. Indeed, depression increases morbidity and hastens mortality across a range of medical disorders. Recent conceptual developments regarding the pathophysiology of depression in the medically ill have focused on the potential role of immune activation/inflammation and the associated release of proinflammatory cytokines. Proinflammatory cytokines induce symptoms of sickness that overlap with major depression and induce the production and release of central nervous system (CNS) corticotropin-releasing hormone (CRH), which is believed to be a key mediator of depression. The long term objective of this R01 application (the Pl's first R01 application) is to further understand the potential role of cytokine-induced CRH in the development of depression in the medically ill. As a model system, we propose to study patients receiving the cytokine, interferon-alpha (IFN-alpha) for the treatment of hepatitis C virus infection (HCV). IFN-alpha potently induces proinflammatory cytokines and leads to depressive symptoms in 30-50% of patients, depending on the dose. In animals, IFN-alpha stimulates the production and release of CRH within the CNS, and blocking CNS CRH attenuates IFN-alpha induced sickness behavior. Our preliminary data indicates that patients who demonstrate hyperactivity in CRH-mediated neuroendocrine pathways in response to a first dose of IFN-alpha have an increased risk of developing depression during IFN-alpha therapy. We have also shown that early life stress (ELS) is associated with sensitization of CRH pathways, indicating a potential link between stress sensitivity and the risk for developing depression during cytokine therapy. We hypothesize that a) patients who demonstrate CRH hyperacitvity in response to an immune challenge will also demonstrate hyperactivity in response to a psychological stressor, and b) hyperactivity to both types of stressors will be associated with the development of IFN-alpha induced depression. Moreover, we anticipate that patients with a history of ELS, current life stress and/or a personal or family history of depression will demonstrate increased CRH reactivity to immunological and psychological stressors. To test these hypotheses, 50 subjects receiving IFN-alpha/ribavirin for HCV will be evaluated for neuroendocrine responses to an immune challenge (first dose of IFN-alpha) and a laboratory psychological stressor (Trier Social Stress Test). Depressive symptoms will be evaluated at baseline and during 12 weeks of treatment with IFN-alpha/ribavirin. All assessments will be conducted in parallel in 25 HCV+ patients randomized to postpone IFN-alpha during the study period (HCV+ controls). Results from these studies will provide important new data on CRH as a potential vulnerability factor for depression in the medically ill and will establish a foundation for developing novel treatment strategies for depression in these patients.

描述（由申请人提供）：抑郁症越来越被认为是全球范围内的健康负担，在医学疾病的背景下尤其具有破坏性。事实上，抑郁症增加了一系列疾病的发病率，加速了死亡率。最近关于医学疾病中抑郁症病理生理学的概念发展集中在免疫激活/炎症和相关的促炎细胞因子释放的潜在作用上。促炎细胞因子诱导的疾病症状与重度抑郁症重叠，并诱导中枢神经系统促肾上腺皮质激素释放激素（CRH）的产生和释放，CRH被认为是抑郁症的关键介质。这项R01应用的长期目标（Pl的第一个R01应用）是进一步了解细胞因子诱导的CRH在疾病患者抑郁症发展中的潜在作用。作为一个模型系统，我们建议研究接受细胞因子干扰素- α (ifn - α)治疗丙型肝炎病毒感染（HCV）的患者。ifn - α有效诱导促炎细胞因子，并导致30-50%的患者出现抑郁症状，具体取决于剂量。在动物中，ifn - α刺激中枢神经系统内CRH的产生和释放，阻断中枢神经系统CRH可减弱ifn - α诱导的疾病行为。我们的初步数据表明，在首次剂量ifn - α治疗后表现出crh介导的神经内分泌通路过度活跃的患者在ifn - α治疗期间发生抑郁症的风险增加。我们还表明，早期生活压力（ELS）与CRH通路的敏化有关，这表明在细胞因子治疗期间，压力敏感性与患抑郁症的风险之间存在潜在联系。我们假设a)在免疫挑战下表现出CRH高活性的患者也会表现出对心理应激源的高活性，b)对两种应激源的高活性都与ifn - α诱导的抑郁症的发展有关。此外，我们预计有ELS病史、当前生活压力和/或个人或家族抑郁史的患者对免疫和心理压力源的CRH反应性会增加。为了验证这些假设，50名接受干扰素α /利巴韦林治疗HCV的受试者将被评估对免疫挑战（第一剂干扰素α）和实验室心理压力源（特里尔社会压力测试）的神经内分泌反应。抑郁症状将在基线和12周的ifn - α /利巴韦林治疗期间进行评估。所有评估将在25名HCV阳性患者（HCV阳性对照）中并行进行，这些患者在研究期间随机推迟ifn - α治疗。这些研究结果将为CRH作为医学疾病中抑郁症的潜在易感因素提供重要的新数据，并为开发新的治疗策略奠定基础。