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，造成相当大的残疾、死亡率、成本和医疗并发症。社会心理压力与MDD和抑郁症状的发作、严重程度和病程有关。根据抑郁症的应激致敏或点燃模型，应激和抑郁症的关联是动态的，更显著的应激源触发最初的抑郁发作，而不太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致敏的病理生理学机制，包括免疫（“抑郁症的细胞因子模型”）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），可能是应激和抑郁症关联的基础。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和促炎细胞因子GCR在50名目前抑郁和50名从未抑郁的绝经前妇女中的体外测量来测试抑郁症的应激致敏模型的生理学解释。拟议的研究解决了抑郁症女性，特别是复发性抑郁症女性是否：1）表现出更高的促炎细胞因子基础血浆水平（即，II-1b，II-6，TNF-α），对体外促分裂原刺激的更大促炎细胞因子产生，以及对Trier社会应激试验的更夸张的促炎细胞因子应答模式，和2）比从未抑郁的对照组表现出更高水平的基础体外淋巴细胞促炎细胞因子GCR。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。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。本研究的结果可能导致新的行为和/或药理学（例如，抗细胞因子和/或抗炎剂）用于复发性抑郁症的抗抑郁治疗。这样的治疗不仅有益于患有原发性MDD的个体，而且还可以扩展到患有涉及炎症过程的共病医学疾病的个体（例如，心血管疾病、冠心病、类风湿性关节炎、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).