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）：越来越多地被认为是全球比例的健康负担，在医学疾病的背景下，抑郁症尤其是毁灭性的。实际上，抑郁症会增加发病率，并加快各种医疗疾病的死亡率。关于医学疾病中抑郁症的病理生理学的最新概念发展集中在免疫激活/炎症的潜在作用以及促炎细胞因子的相关释放上。促炎细胞因子会引起与重度抑郁症重叠的疾病症状，并诱导中枢神经系统（CNS）皮质激素释放激素（CRH）的产生和释放，这被认为是抑郁症的关键介体。该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在医学疾病中抑郁症发展中的潜在作用。作为模型系统，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-Alpha有效诱导促炎细胞因子，并导致30-50％的患者抑郁症状，具体取决于剂量。在动物中，IFN-Alpha刺激了CNS内CRH的产生和释放，CNS CRH会减弱IFN-Alpha诱导疾病行为。我们的初步数据表明，在IFN-Alpha疗法期间，响应第一剂IFN-Alpha响应于首次剂量IFN-Alpha而在CRH介导的神经内分泌途径中表现出多动症的患者增加了抑郁症的风险。我们还表明，早期的生命压力（EL）与CRH途径的敏感性有关，表明应力敏感性与在细胞因子治疗期间抑郁症的风险之间存在潜在的联系。我们假设a）a）表现出对免疫挑战的CRH过度活性的患者也将表现出对心理压力源的反应性多动，而b）对两种压力源的过度活跃将与IFN-Alpha诱导的抑郁症的发展有关。此外，我们预计具有ELS病史，当前的生活压力和/或抑郁症家族史的患者将表明CRH对免疫学和心理压力源的反应性增加。为了检验这些假设，将评估50名接受IFN-Alpha/Ribavirin的HCV的受试者，以对神经内分泌对免疫挑战的反应（IFN-Alpha的首次剂量）和实验室心理压力（Trier社会压力测试）的反应。抑郁症状将在基线和IFN-Alpha/Ibavirin治疗的12周期间评估。在研究期间，将在25个HCV+患者中并行进行所有评估（HCV+对照）。这些研究的结果将为CRH提供重要的新数据，作为医学疾病中抑郁症的潜在脆弱性因素，并将为这些患者的抑郁症制定新颖的治疗策略建立基础。