Cytokine-CRH Interactions in IFN-alfa-Induced Depression

描述(申请人提供)：越来越多的人认识到抑郁症是一种全球性的健康负担，在医学疾病的背景下，抑郁症尤其具有破坏性。事实上，抑郁症增加了一系列医疗疾病的发病率并加速了死亡率。最近关于内科疾病患者抑郁的病理生理学的概念性进展集中在免疫激活/炎症的潜在作用以及相关的促炎细胞因子的释放上。促炎性细胞因子引起与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。这一R01应用的长期目标(Pl的第一个R01应用)是为了进一步了解细胞因子诱导的CRH在内科疾病患者抑郁发展中的潜在作用。作为一个模型系统，我们建议对接受细胞因子干扰素-α(干扰素-α)治疗丙型肝炎病毒感染(HCV)的患者进行研究。根据剂量的不同，干扰素-α可有效地诱导促炎细胞因子，并在30-50%的患者中导致抑郁症状。在动物中，干扰素-α刺激中枢神经系统CRH的产生和释放，阻断中枢神经系统CRH可减轻干扰素-α诱导的疾病行为。我们的初步数据表明，在第一剂干扰素-α治疗中，CRH介导的神经内分泌通路过度活跃的患者在干扰素-α治疗期间发生抑郁的风险增加。我们还表明，早期生活应激(ELS)与CRH通路的敏化有关，这表明在细胞因子治疗期间，应激敏感性与发展为抑郁症的风险之间存在潜在的联系。我们假设，a)在免疫挑战中表现出CRH过度活跃的患者也会表现出对心理应激源的过度活跃，以及b)对这两种应激源的过度活跃都将与干扰素-α诱导的抑郁的发生有关。此外，我们预计，有ELS病史、当前生活压力和/或个人或家族抑郁症病史的患者将对免疫和心理应激源表现出更高的CRH反应性。为了验证这些假设，50名接受干扰素-α/利巴韦林治疗丙型肝炎病毒的受试者将被评估对免疫挑战(第一剂干扰素-α)和实验室心理应激源(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干扰素-α/利巴韦林治疗12周期间进行评估。所有评估将在研究期间随机推迟干扰素-α的25名丙型肝炎病毒阳性患者(丙型肝炎病毒+对照)中同时进行。这些研究的结果将为CRH作为内科疾病患者抑郁的潜在易感因素提供重要的新数据，并将为开发针对这些患者的抑郁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.