Cytokine-CRH Interactions in IFN-alfa-Induced Depression

描述（由申请人提供）：越来越多的人认为抑郁症是一种全球性的健康负担，在医疗疾病的背景下，抑郁症尤其具有破坏性。事实上，抑郁症增加了一系列医学疾病的发病率并加速了死亡率。关于抑郁症的病理生理学在医学疾病的最新概念的发展集中在免疫激活/炎症和相关的促炎细胞因子的释放的潜在作用。促炎细胞因子诱导与重性抑郁症重叠的疾病症状，并诱导中枢神经系统（CNS）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。该R 01申请（PI的第一次R 01申请）的长期目标是进一步了解麻黄碱诱导的CRH在医学疾病中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有效地诱导促炎细胞因子，并导致30-50%的患者出现抑郁症状，这取决于剂量。在动物中，IFN-α刺激CNS内CRH的产生和释放，并且阻断CNS CRH减弱IFN-α诱导的疾病行为。我们的初步数据表明，在CRH介导的神经内分泌通路中表现出对第一剂IFN-α反应过度的患者在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通路的敏感化有关，表明压力敏感性与细胞因子治疗期间发生抑郁症的风险之间存在潜在联系。我们假设：a）对免疫激发反应表现出CRH高活性的患者也会对心理应激反应表现出高活性，和B）对两种类型的应激反应的高活性将与IFN-α诱导的抑郁症的发展相关。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将表现出对免疫和心理压力的CRH反应性增加。为了检验这些假设，将评价50名接受IFN-α/利巴韦林治疗HCV的受试者对免疫激发（第一剂IFN-α）和实验室心理应激（特里尔社会应激试验）的神经内分泌反应。将在基线和IFN-α/利巴韦林治疗12周期间评价抑郁症状。所有评估将在研究期间随机分配至延迟IFN-α的25例HCV+患者（HCV+对照）中平行进行。这些研究的结果将为CRH作为医学疾病中抑郁症的潜在脆弱性因素提供重要的新数据，并将为开发这些患者抑郁症的新治疗策略奠定基础。

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.