Pro-Inflammatory Cytokine Glucocorticoid Resistance in Major Depressive Disorder

重度抑郁症中的促炎细胞因子糖皮质激素抵抗

• 批准号: 7678568
• 负责人: HEATHER M BURKE
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678568
• 关键词: Acute; Address; Adrenal Glands; Age; Anti-Inflammatory Agents; Behavioral; Biological; Cardiovascular Diseases; Chronic Disease; Comorbidity; Coronary heart disease; Dexamethasone; Diagnosis; Endocrine; Exhibits; Female; Functional disorder; Glucocorticoids; High Prevalence; Hormonal; Hypothalamic structure; Immune; Immune response; In Vitro; Individual; Inflammatory; Inflammatory Response Pathway; Interleukin-6; Kindling (Neurology); Lead; Link; Lipopolysaccharides; Lymphocyte; Major Depressive Disorder; Measures; Medical; Mitogens; Modeling; Multiple Sclerosis; Participant; Pattern; Persons; Physiological; Pituitary Gland; Plasma; Premenopause; Process; Production; Public Health; Recovery; Recurrence; Research Personnel; Resistance; Rheumatoid Arthritis; Severities; Stress; Telephone; Testing; Time; Trier Social Stress Test; Woman; base; biological adaptation to stress; cost; cytokine; depressed; depression; depressive symptoms; design; disability; follow-up; improved; in vivo; mortality; novel; prognostic; prognostic indicator; prospective; psychological stressor; psychosocial; recurrent depression; research study; response; stressor

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a worldwide public health problem, responsible for considerable disability, mortality, cost, and medical comorbidity. Psychosocial stressors have been linked with the onset, severity, and course of MDD and depressive symptoms. According to the stress-sensitization or kindling model of depression, the stress and depression association is dynamic, with more significant stressors triggering initial depressive episodes, and less significant stressors capable of triggering subsequent depressive episodes. While several pathophysiological mechanisms of stress sensitization have been proposed, including alterations in immune ("the cytokine model of depression") and hormonal responses to psychological stressors, it is possible that endocrine-immune interactions, specifically pro-inflammatory cytokine glucocorticoid resistance (GCR), underlie the stress and depression association. Thus, the purpose of this proposed study is to test a physiological explanation for the stress sensitization model of depression by examining cytokine responses to an acute psychological stressor and in vitro measures of pro-inflammatory cytokine GCR in 50 currently depressed and 50 never-depressed pre-menopausal women. The proposed study addresses whether depressed women, and particularly those with recurrent depression: 1) exhibit higher basal plasma levels of pro-inflammatory cytokines (i.e., II-1b, II-6, TNF-a), greater pro-inflammatory cytokine production in response to in vitro mitogen stimulation, and a more exaggerated pattern of pro-inflammatory cytokine responses to a Trier Social Stress Test than never-depressed controls, and 2) exhibit higher levels of basal in vitro lymphocyte pro-inflammatory cytokine GCR than never-depressed controls. This study will also address whether in vitro lymphocyte pro-inflammatory cytokine GCR is a prognostic indicator of likelihood of depression diagnosis 12 months later in depressed women. The proposed research study is designed to improve current understanding of the pathophysiology of major depressive disorder (MDD). Results of this study may lead to novel behavioral and/or pharmacological (e.g., anti-cytokine and/or anti-inflammatory agents) anti-depressant treatments for recurrent depression. Such treatments would not only benefit individuals with primary MDD, but may also extend to those with comorbid medical illnesses involving inflammatory processes (e.g., cardiovascular disease, coronary heart disease, rheumatoid arthritis, multiple sclerosis).

描述（由申请人提供）：重度抑郁症 (MDD) 是一个世界性的公共卫生问题，造成相当大的残疾、死亡率、费用和医疗合并症。社会心理压力源与重度抑郁症和抑郁症状的发生、严重程度和病程有关。根据抑郁症的压力敏化或点燃模型，压力和抑郁的关联是动态的，较大的压力源会引发最初的抑郁发作，而较不显着的压力源则能够引发随后的抑郁发作。虽然已经提出了几种压力敏化的病理生理学机制，包括免疫的改变（“抑郁的细胞因子模型”）和对心理压力源的激素反应，但内分泌-免疫相互作用，特别是促炎细胞因子糖皮质激素抵抗（GCR），可能是压力和抑郁关联的基础。因此，本研究的目的是通过检查细胞因子对急性心理应激源的反应以及 50 名当前抑郁症和 50 名从未抑郁的绝经前女性的促炎细胞因子 GCR 的体外测量，来测试抑郁症压力敏化模型的生理学解释。拟议的研究探讨了抑郁女性，尤其是复发性抑郁女性是否：1）与从未抑郁的对照组相比，促炎细胞因子（即 II-1b、II-6、TNF-a）的基础血浆水平更高，体外促炎细胞因子刺激产生更多的促炎细胞因子，对特里尔社会压力测试的促炎细胞因子反应模式更夸张， 2) 与从未抑郁的对照组相比，体外基础淋巴细胞促炎细胞因子 GCR 的水平更高。这项研究还将探讨体外淋巴细胞促炎细胞因子 GCR 是否是抑郁症女性 12 个月后诊断抑郁症可能性的预后指标。拟议的研究旨在提高目前对重度抑郁症（MDD）病理生理学的理解。这项研究的结果可能会导致针对复发性抑郁症的新型行为和/或药理学（例如抗细胞因子和/或抗炎药）抗抑郁治疗。此类治疗不仅有益于患有原发性 MDD 的个体，而且还可能适用于那些患有涉及炎症过程的共存疾病（例如心血管疾病、冠心病、类风湿性关节炎、多发性硬化症）的患者。