IL-2 Neuropsychiatric Symptoms: Mechanisms, Prevention

IL-2 神经精神症状：机制、预防

• 批准号: 7171908
• 负责人: DOMINIQUE L. MUSSELMAN
• 金额: $ 30.08万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-25 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7171908
• 关键词: Adherence; Affect; Age; Anhedonia; Anorexia; Antidepressive Agents; Behavioral; Biological Models; Cancer Etiology; Cancer Patient; Corticotropin; Cytokine Signaling; Data; Depressed mood; Development; Dexamethasone; Diagnosis; Dose; Double-Blind Method; Exhibits; Fatigue; Functional disorder; General Population; Glucocorticoids; Hormones; Hour; Hydrocortisone; Immune; Immune system; Impaired cognition; Interferon Type II; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-6; Intravenous; Lilium; Major Depressive Disorder; Measures; Medical; Memory impairment; Mental Depression; Metabolism; Mood Disorders; Morbidity - disease rate; NF-AT; NF-kappa B; Nature; Neurobiology; Neuropsychological Tests; Neurosecretory Systems; Numbers; Paroxetine; Pathway interactions; Patients; Placebo Control; Placebos; Plasma; Prevention; Proteins; Psychotic Disorders; Quality of life; Randomized; Range; Rate; Research Personnel; Serotonin; Severities; Signal Pathway; Sleep; Staging; Symptoms; T-Cell Activation; T-Lymphocyte; Time; Tryptophan; Tumor Necrosis Factor-alpha; Week; cognitive function; computerized; cytokine; cytokine therapy; day; design; hypothalamic-pituitary-adrenal axis; immune function; improved; in vivo; insight; melanoma; mortality; neurochemistry; neuropsychiatry; nuclear factors of activated T-cells; prevent; programs; response; therapy development; treatment trial; trial comparing

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.

描述（由申请人提供）：D。增加数据暗示细胞因子在包括癌症在内的各种医学疾病患者的行为改变的发展中；患有医疗疾病的患者的抑郁症发生率是普通人群的5-10倍。医学疾病中的抑郁症与治疗依从性降低有关，生活质量受损以及在几项研究中增加了发病率和死亡率。需要研究细胞因子引起的抑郁症的神经生物学和治疗的模型系统，以制定新的策略来帮助诊断和管理医学疾病的抑郁症。这样的模型系统涉及接受细胞因子白介素（IL）-2的患者。该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，包括情绪低落，Anhedonia，厌食症，疲劳，认知功能障碍（尤其是记忆力障碍），睡眠和精神病的改变，症状，与许多严重抑郁症重叠的症状。此外，IL-2有效地激活下丘脑 - 垂体肾上腺（HPA）轴并改变神经逆转录膜代谢，同时激活与情绪障碍有关的其他细胞因子（例如，例如，例如，6）。我们计划表征正在接受IL-2治疗恶性黑色素瘤的患者的神经精神病，神经内分泌和免疫变化，并评估抗抑郁药是否可以防止这些变化。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（年龄18至75岁）的患者[720,000单位/kg Q8小时x 5天（1个周期）每3周x 4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，比较与抗抑郁药帕罗西汀（抗过安慰剂）的14周治疗。 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)改善耐受的IL-2剂量的数量。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轴和免疫功能相关联，并确定帕罗西汀对这些关系的影响。这些研究将提供有关细胞因子疗法期间症状发育和治疗反应的差异机制的见解。