IL-2 Neuropsychiatric Symptoms: Mechanisms, Prevention

D.越来越多的数据表明细胞因子与包括癌症在内的多种医学疾病患者的行为改变的发展有关；患有内科疾病的患者患抑郁症的比率比一般人群高5-10倍。医学疾病患者的抑郁症与治疗依从性降低、生活质量受损以及在一些研究中发病率和死亡率增加有关。研究神经生物学和细胞因子诱导的抑郁症治疗的模型系统需要开发新的策略来帮助诊断和管理医学疾病中的抑郁症。其中一个模型系统涉及到接受细胞因子白介素-2的患者。这种T细胞因子被用于治疗癌症患者，并导致严重的行为改变，包括情绪抑郁、快感缺乏、厌食症、疲劳、认知功能障碍（尤其是记忆障碍）、睡眠改变和精神病，这些症状与许多重度抑郁症的症状重叠。此外，IL-2有效激活下丘脑-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（如ll -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。70例IV期恶性黑色素瘤患者（年龄18 - 75岁）将在静脉注射（IV） IL-2治疗前和治疗期间进行研究[720,000单位/kg Q8小时X 5天（1周期）每3周X 4周期]。在静脉注射IL-2治疗前两周，患者将进入一项随机双盲治疗试验，比较抗抑郁药帕罗西汀与安慰剂治疗的14周。我们将确定帕罗西汀是否会：a)减少IL-2相关的神经精神症状，b)减少IL-2相关的ACTH和皮质醇升高，增加糖皮质激素敏感性，c)预防IL-2诱导的血清素代谢下降，表现为血浆色氨酸和5HT降低，血浆kyneurine升高，d)改善IL-2耐受剂量。我们还将在IL-2治疗之前和期间将特定的神经精神症状（包括记忆障碍和精神病）与HPA轴和免疫功能联系起来，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不同机制提供见解。

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.