IL-2 Neuropsychiatric Symptoms: Mechanisms, Prevention

描述（由申请人提供）：D。越来越多的数据表明，细胞因子参与了包括癌症在内的各种医学疾病患者的行为改变;患有医学疾病的患者表现出比普通人群高5-10倍的抑郁率。医学疾病中的抑郁症与治疗依从性降低、生活质量受损有关，在一些研究中，还与发病率和死亡率增加有关。需要研究神经生物学和治疗尼古丁诱导的抑郁症的模型系统来开发新的策略，以帮助诊断和管理医学疾病中的抑郁症。一种这样的模型系统涉及接受细胞因子白细胞介素（IL）-2的患者。这种T细胞细胞因子用于治疗癌症患者，并引起深刻的行为改变，包括抑郁情绪，快感缺乏，厌食，疲劳，认知功能障碍（特别是记忆障碍），睡眠改变和精神病，与许多重度抑郁症重叠的症状。此外，IL-2有效地激活下丘脑-垂体肾上腺（HPA）轴并改变神经递质代谢，同时激活与情绪障碍有关的其他细胞因子（例如IL-6）的释放。我们计划描述接受IL-2治疗的恶性黑色素瘤患者的神经精神、神经内分泌和免疫变化，并评估抗抑郁药是否可以预防这些变化。将在静脉内（IV）IL-2治疗之前和期间研究70例IV期恶性黑色素瘤患者（年龄为18至75岁）[720，000单位/kg Q8小时X 5天（1个周期），每3周一次X 4个周期]。在IV IL-2治疗前两周，患者将进入一项随机、双盲治疗试验，比较用抗抑郁药帕罗西汀与安慰剂治疗14周。我们将确定帕罗西汀是否将：a）减轻IL-2相关的神经精神症状，B）减少IL-2相关的ACTH和皮质醇增加并增加糖皮质激素敏感性，c）预防IL-2诱导的5-羟色胺代谢降低，如血浆色氨酸和5-HT减少和血浆犬脑啡肽增加所表现的，和d）改善耐受的IL-2剂量数。我们还将特定的神经精神症状（包括记忆障碍和精神病）与HPA轴和免疫功能在IL-2治疗之前和期间相关联，并确定帕罗西汀对这些关系的影响。这些研究将为细胞因子治疗期间症状发展和治疗反应的差异机制提供见解。

DESCRIPTION (provided by applicant): D. Increasing data implicate cytokines in the development of behavioral alterations in patients with a wide range of medical illnesses including cancer; patients with medical illnesses exhibit rates of depression 5-10 times higher than the general population. Depression in the medically ill is associated with reduced treatment adherence, impaired quality of life, and in several studies, increased morbidity and mortality. Model systems to study the neurobiology and treatment of cytokine-induced depression are needed to develop new strategies to help diagnose and manage depression in the medically ill. One such model system involves patients receiving the cytokine interleukin (IL)-2. This T cell cytokine is used to treat patients with cancer and causes profound behavioral alterations including depressed mood, anhedonia, anorexia, fatigue, cognitive dysfunction (especially memory impairment), altered sleep and psychosis, symptoms that overlap with many of those of major depression. In addition, IL-2 potently activates the hypothalamic-pituitary adrenal (HPA) axis and alter neuretransmitter metabolism, while activating the release of other cytokines (e.g.lL-6) that have been implicated in mood disorders. We plan to characterize neuropsychiatric, neuroendocrine and immune changes in patients undergoing IL-2 treatment for malignant melanoma and evaluate whether an antidepressant can prevent these changes. 70 patients with Stage IV malignant melanoma (ages of 18 to 75 years old) will be studied before and during intravenous (IV) IL-2 treatment [720,000 units/kg Q8 hours X 5 days (1 cycle) every 3 weeks X 4 cycles]. Two weeks prior to IV IL-2 therapy, patients will enter a randomized, double-blind treatment trial comparing 14 weeks of treatment with the antidepressant paroxetine, versus placebo. We will determine whether paroxetine will: a) diminish IL-2-associated neuropsychiatric symptoms, b) reduce IL-2-associated increases in ACTH and cortisol and increase glucocorticoid sensitivity, c) prevent IL-2-induced decreases in serotonin metabolism as manifested by decreased plasma tryptophan and 5HT and increased plasma kyneurinine, and d) improve the number of IL-2 doses tolerated. We will also correlate specific neuropsychiatric symptoms (including memory impairment and psychosis) with HPA axis and immune function both prior to, and during, IL-2 therapy, and determine the impact of paroxetine on these relationships. These studies will provide insights into differential mechanisms of symptom development and treatment response during cytokine therapies.