Cytokine Induced Depression

在医学疾病中，抑郁症的发生率是普通人群的5-10倍，对治疗依从性、生活质量、发病率和死亡率都有重大影响。在医学疾病中抑郁症概念化的新进展集中在免疫激活/炎症和相关的促炎细胞因子释放的潜在作用上。已发现促炎细胞因子可影响神经生物学功能，并诱发与重度抑郁症有重叠特征的抑郁综合征。这项工作的长期目标是进一步了解这种细胞因子诱导的抑郁症的病理生理学和治疗，因为它与医学疾病中的抑郁症有关。为了实现这一目标，我们计划建立一个细胞因子诱导抑郁症的动物模型，使用给予细胞因子干扰素(IFN) α的恒河猴。IFN α是促炎细胞因子（尤其是白细胞介素6）的有效诱导剂，根据剂量不同，可导致30-50%的患者出现抑郁症状。此外，IFN α激活促肾上腺皮质激素释放因子（CRF）途径，并已被证明导致单胺消耗

Depression in the medically ill occurs 5-10 times more often than depression in the general population and has 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 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 pathophysiology and treatment of this cytokine-induced depression as it relates to depression in the medically ill. To accomplish this goal, we plan to develop an animal model of cytokine-induced depression using rhesus monkeys administered the cytokine, interferon (IFN) alpha. IFN alpha is a potent inducer of proinflammatory cytokines (especially interleukin 6) and leads to depressive symptoms in 30-50% of patients depending on dose. In addition, IFN alpha activates corticotropin releasing factor (CRF) pathways and has been shown to lead to monoamine depletion in laboratory animals (including rhesus monkeys). In addition, IFN alpha has been shown to alter fronto-striatal neurocircuitry in humans and induce REM sleep changes (decreased REM latency, increased REM percentage) consistent with depression in both humans and rhesus animals. Thus, IFN alpha treatment provides a unique model system to further understand the pathophysiology and treatment of cytokine-induced mood disorders. The specific aims of the proposed work are 1) to characterize neuroendocrine, monoamine, immune and behavioral responses of rhesus monkeys to IFN alpha and 2) to examine the therapeutic efficacy (capacity to reverse IFN alpha-induced neuroendocrine, monoamine, immune and behavioral changes) of pharmacologic compounds that antagonize activation of the cytokine network (NK-1 antagonists), antagonize CRF, or increase the activity of neurotransmission in monoamine neurocircuits. Relevant techniques to be used to accomplish these aims will include repeated blood and CSF sampling, telemetric polysomnography, microPET, and behavioral analysis of fear potentiated startle and social interactions. Results from these studies will identify novel targets as well as pharmacologic strategies for treatment of mood disorders in the medically ill.