IL-2 Neuropsychiatric Symptoms: Mechanisms, Prevention

IL-2 神经精神症状：机制、预防

基本信息

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
项目类别：
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

项目摘要

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. 越来越多的数据表明细胞因子与患有包括癌症在内的多种疾病的患者发生行为改变有关；患有内科疾病的患者的抑郁症发病率比普通人群高 5-10 倍。医学疾病患者的抑郁症与治疗依从性降低、生活质量受损有关，并且在一些研究中，发病率和死亡率增加。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，以开发新的策略来帮助诊断和管理医学疾病患者的抑郁症。其中一种模型系统涉及接受细胞因子白介素 (IL)-2 治疗的患者。这种 T 细胞因子用于治疗癌症患者，会导致严重的行为改变，包括情绪低落、快感缺乏、厌食、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（例如 IL-6）的释放。我们计划表征接受 IL-2 治疗恶性黑色素瘤的患者的神经精神、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 名 IV 期恶性黑色素瘤患者（年龄 18 至 75 岁）将在静脉 (IV) IL-2 治疗之前和治疗期间进行研究 [720,000 单位/kg Q8 小时 X 5 天（1 个周期）每 3 周 X 4 个周期]。在 IV IL-2 治疗前两周，患者将参加一项随机、双盲治疗试验，比较抗抑郁药帕罗西汀与安慰剂的 14 周治疗。我们将确定帕罗西汀是否会：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 诱导的血清素代谢下降（如所表明的）通过降低血浆色氨酸和 5HT 以及增加血浆犬神经氨酸，以及 d) 提高耐受的 IL-2 剂量数量。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。