Pathology and Treatment of Cytokine-Induced Depression

细胞因子引起的抑郁症的病理学和治疗

• 批准号: 6696377
• 负责人: ANDREW H MILLER
• 金额: $ 11.69万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696377
• 关键词: HIV infections; antidepressants; clinical research; comorbidity; drug adverse effect; drug screening /evaluation; functional magnetic resonance imaging; hepatitis C; human subject; human therapy evaluation; interferon alpha; major depression; neuroendocrine system; pathologic process; patient oriented research; positron emission tomography; psychoneuroimmunology

DESCRIPTION (provided by applicant): This K05 Senior Scientist Award is designed to provide the applicant protected time in order to continue ongoing research on the pathology and treatment of cytokine-induced depression. Depression in the medically ill is a significant public health concern, occurring in up to 50% of patients and having a significant impact on treatment adherence, quality of life, and morbidity and mortality. New developments in the conceptualization 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 have been found to influence neurobiologic function including neurochemistry and behavior, and induce a depressive syndrome that has overlapping features with major depression. The long-term objective of the proposed work is to further understand the pathology and treatment of this cytokine-induced depression as it relates to depression in the medically ill, including patients with HIV/AIDS. As a model system, we plan to study patients receiving the cytokine, interferon (IFN) alpha, for the treatment of hepatitis C, which afflicts approximately 4 million individuals in the US and up to 25% of patients with HIV/AIDS. IFN alpha is a potent inducer of proinflammatory cytokines (especially interleukin 6) and leads to depressive symptoms in 30-50% of patients depending on the dose. In addition, IFN alpha activates corticotropin releasing hormone pathways and has been shown to lead to monoamine depletion in laboratory animals. IFN alpha also has been shown to alter fronto-striatal neurocircuitry in humans and induce REM sleep changes (decreased REM latency, increased REM percentage); changes consistent with the neurobiology of depression. Thus, IFN alpha treatment provides a unique model system to further understand the pathology and treatment of cytokine-induced mood disorders. The specific aims of the proposed research plan are 1) To determine the neuroendocrine pathways involved in the vulnerability to and development of cytokine-induced depression, 2) To determine the neural circuitry of cytokine-induced depression using functional magnetic resonance imaging and positron emission tomography, and 3) a) To test the efficacy of antidepressants in patients receiving IFN alpha therapy for hepatitis C (including patients with HCV/HIV co-infection) and b) To test novel strategies for the treatment of cytokine-induced depressive symptoms including cytokine antagonists and dopamine agonists. Results from these studies will provide important new data on neural pathways by which cytokines induce depression and will establish a foundation for developing novel strategies to diagnose and treat depression in the medically ill. In addition to the proposed research, the applicant will develop his skills in the area of neuroimaging and will participate in training and education of pre- and postdoctoral fellows and junior faculty, as well as serving as Director of the HIV/AIDS Clinical Research Training Program.

描述（由申请人提供）：该K05高级科学家奖旨在提供受申请人保护的时间，以便继续对细胞因子引起的抑郁症的病理学和治疗进行持续研究。医学疾病的抑郁症是一个重大的公共卫生问题，最多发生在50％的患者中，并对治疗依从性，生活质量以及发病率和死亡率产生重大影响。在医学疾病中抑郁症概念化的新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。已经发现促炎细胞因子会影响神经生物学功能，包括神经化学和行为，并引起抑郁综合征，其抑郁症具有重叠的特征，并具有严重的抑郁症。拟议工作的长期目标是进一步了解这种细胞因子引起的抑郁症的病理和治疗，因为它与包括HIV/艾滋病患者在内的医学疾病有关。作为模型系统，我们计划研究接受细胞因子干扰素（IFN）alpha的患者，以治疗丙型肝炎，乙型肝炎遭受了美国约400万人的HIV/AIDS患者。 IFNα是促炎细胞因子（尤其是白介素6）的有效诱导剂，并导致30-50％的患者抑郁症状，具体取决于剂量。此外，IFN Alpha激活了肾上腺激素释放激素途径，并已证明会导致实验室动物的单胺消耗。 IFNα也已显示会改变人类的额叶神经记录，并诱导REM睡眠变化（REM潜伏期降低，REM百分比增加）；变化与抑郁症的神经生物学一致。因此，IFNα治疗提供了一个独特的模型系统，可以进一步了解细胞因子诱导的情绪障碍的病理和治疗。拟议的研究计划的具体目的是1）确定与细胞因子诱导的抑郁症的脆弱性和发育有关的神经内分泌途径，2）确定细胞因子诱导的抑郁症的神经回路，使用功能磁共振成像和正面上的抑制作用抑制抑郁症，以及对疗法的疗效（a）患者的疗效（a）患者（3）患者（3）a）a）a） HCV/HIV共感染）和b）测试了细胞因子诱导的抑郁症状（包括细胞因子拮抗剂和多巴胺激动剂）的新型策略。这些研究的结果将提供有关细胞因子诱导抑郁症的神经途径的重要新数据，并将为制定新型策略诊断和治疗医学疾病的抑郁症的基础。除拟议的研究外，申请人还将在神经影像领域发展自己的技能，并将参加培训和教育前和博士后研究员和初级教师，并担任HIV/AIDS临床研究培训计划的主任。