Pro-Inflammatory Cytokine Glucocorticoid Resistance in Major Depressive Disorder

描述(由申请人提供)：严重抑郁障碍(MDD)是一个世界性的公共卫生问题，导致相当大的残疾、死亡率、费用和医疗合并症。心理社会应激源与MDD和抑郁症状的发病、严重程度和病程有关。根据抑郁的压力敏感化或点燃模型，压力和抑郁的关联是动态的，较显著的应激源触发最初的抑郁发作，而较不显著的应激源能够触发随后的抑郁发作。虽然已经提出了几种应激敏化的病理生理学机制，包括免疫变化(“抑郁症的细胞因子模型”)和激素对心理应激源的反应，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)，可能是应激和抑郁联系的基础。因此，这项拟议的研究的目的是通过检测50名目前患有抑郁症和50名从未抑郁的绝经前女性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，来测试抑郁应激敏化模型的生理学解释。这项拟议的研究旨在探讨抑郁症妇女，特别是那些反复抑郁的妇女：1)与从未抑郁的对照组相比，抑郁症妇女的基础血浆促炎细胞因子(即II-1b、II-6、TNF-a)水平更高，体外有丝分裂原刺激反应的促炎细胞因子产生更多，以及Trier社会应激试验中更夸张的促炎细胞因子反应模式；2)与从未抑郁的对照组相比，体外淋巴细胞基础促炎症细胞因子GCR水平更高。这项研究还将探讨体外淋巴细胞促炎症细胞因子GCR是否是12个月后抑郁症女性诊断为抑郁症的可能性的预后指标。这项拟议的研究旨在提高目前对严重抑郁障碍(MDD)的病理生理学的理解。这项研究的结果可能导致新的行为学和/或药理学(例如，抗细胞因子和/或抗炎药)抗抑郁药物治疗复发性抑郁症。这种治疗不仅使患有原发MDD的个人受益，还可能扩展到那些患有涉及炎症过程的并存内科疾病(例如，心血管疾病、冠心病、类风湿性关节炎、多发性硬化症)的人。

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).