Pro-Inflammatory Cytokine Glucocorticoid Resistance in Major Depressive Disorder

描述（由申请人提供）：重度抑郁症（MDD）是一个全球性的公共卫生问题，造成大量的残疾、死亡率、成本和医疗并发症。社会心理压力源与重度抑郁症和抑郁症状的发病、严重程度和病程有关。根据抑郁的应激致敏或点燃模型，应激与抑郁的关联是动态的，较显著的应激源触发初始抑郁发作，较不显著的应激源能够触发后续抑郁发作。虽然已经提出了应激致敏的几种病理生理机制，包括免疫（“抑郁的细胞因子模型”）和激素对心理应激源的反应的改变，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），可能是应激和抑郁关联的基础。因此，本研究的目的是通过检测50名患有抑郁症和50名从未患有抑郁症的绝经前妇女对急性心理应激源的细胞因子反应和促炎细胞因子GCR的体外测量，来检验抑郁症应激致敏模型的生理学解释。这项拟议的研究探讨了抑郁症女性，尤其是那些复发性抑郁症女性：1)表现出更高的基础血浆促炎细胞因子水平（即II-1b， II-6, TNF-a），在体外有丝分裂原刺激下产生更多的促炎细胞因子，在特里尔社会压力测试中，促炎细胞因子的反应模式比从未抑郁过的对照组更夸张，2)表现出更高的基础体外淋巴细胞促炎细胞因子GCR水平。本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个月后抑郁症诊断可能性的预后指标。提出的研究旨在提高当前对重度抑郁症（MDD）病理生理学的理解。这项研究的结果可能会导致新的行为和/或药理学（例如，抗细胞因子和/或抗炎药）抗抑郁治疗复发性抑郁症。这种治疗方法不仅对原发性重度抑郁症患者有益，还可以扩展到那些伴有炎症过程的合并症患者（如心血管疾病、冠心病、风湿性关节炎、多发性硬化症）。

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).