The Neurobiology Of Major Depression

事实上，没有确凿的数据来阐明抑郁症中的过早死亡、冠状动脉疾病或骨质疏松症的病理生理学。当然，这首先是患者生存和生活质量的问题。关于病理生理机制的令人信服的数据也将有助于在一般医学界正式确立重性抑郁症为全身性疾病。反过来，这将引起医学界对抑郁症患者全身异常的监测，并制定有效的预防干预措施，以减轻这些全身异常。为这项任务做出贡献可以帮助强调诊断和治疗抑郁症的紧迫性，减少抑郁症的耻辱感，并使保险公司像治疗任何其他系统性疾病一样治疗抑郁症。 我们已经确定了一个新兴的代谢综合征的年轻，瘦缓解患者的严重抑郁症，以及过早的骨质疏松症，并在确定的重要介质，可能会导致过早死亡和全身表现失调。 我们发现，与47名BMI匹配的对照组相比，缓解的、年轻的、消瘦的重度抑郁症患者存在胰岛素抵抗，血浆胰岛素、葡萄糖和甘油三酯水平升高，以及其他严重的胰岛素抵抗和高胰岛素血症后遗症。胰岛素会产生许多不良反应，这些反应在急性应激时是适应性的，但在持续应激时是不适应的。胰岛素刺激促炎细胞因子如IL-6、促凝血化合物如因子VIII、抗纤维蛋白溶解化合物如PAI-1的分泌，并激活交感神经系统。我们已经发现增加的昼夜血浆IL-6水平，和增加的早晨水平的因子VIII和PAI-1水平，和明确的交感神经激活指数（后者在抑郁症患者）。IL-6和NE均促进骨质疏松症和冠状动脉疾病，这是令人感兴趣的。我们的一个必然目标是确定共同的病理生理特征，参与过早骨质疏松症和冠状动脉疾病。这项工作也可以扩展代谢综合征的概念，作为一种综合征，包括上述代谢异常以及病理性骨丢失。 我们发现血浆IL-6水平持续升高有几个含义。IL-6具有多效性作用，并且其本身引起胰岛素抵抗、炎症增加、凝血增加和纤维蛋白溶解减少。IL-6在动脉粥样硬化（其具有强烈的炎症成分）和骨质疏松症中都是非常重要的因子。健康个体的血浆IL-6水平是随后冠状动脉疾病的最佳预测因子，其预测价值超过C反应蛋白（CRP）。IL-6水平也可预测骨质疏松症，IL-6是骨吸收的最有效诱导剂之一。在绝经后时期，这种情况的重要机制之一是雌激素介导的IL-6释放抑制的丧失。 我们还发现，一组非介导性抑郁症患者的神经源性抑郁症有高，周围的时钟中枢和外周高分泌NE，以及血浆肾上腺素和皮质醇分泌。当他们抑郁时，他们的血压和脉搏率也会增加;所有这些都可以通过集中治疗（ECT）来逆转。CSF NE、血浆NE和血浆皮质醇在整个24小时内一起上升和下降，并且在EEG记录的睡眠期间进行性上升，在清晨达到峰值，这是猝死和心肌梗死发生率最高的时间。血浆EPI水平在这一点上也非常高，在我们以前的研究中血浆IL-6水平也是如此。中枢NE激活和外周血浆NE、EPI和皮质醇的高分泌都是心脏毒性的，并且它们在24小时内一起上升和下降可能具有特别不利的影响。此外，慢性心力衰竭合并抑郁症患者的发病率和死亡率也会翻倍。NE水平不高于我们的抑郁症患者是慢性心力衰竭随后死亡率和发病率的最佳预测因子。这一发现提供了一种机制，当抑郁症叠加在另一种系统性疾病上时，它会产生有害的影响。 我们首先发现，患有抑郁症的绝经前妇女骨质减少和骨质疏松症的患病率显著增加。与3 - 4%的一般绝经前人群相比，我们发现20 - 25%的抑郁症患者骨质减少或骨质疏松症。从我们的数据推断，我们估计有超过40万名绝经前抑郁症妇女因抑郁症而出现骨质减少或骨质疏松症。不幸的是，骨质疏松症在发生骨折之前是一种无声的疾病。然而，这是一种高度可治疗的疾病，突出表明需要早期发现。绝经前妇女骨质减少和骨质疏松症的发病率高得惊人，是一个重大的公共卫生危害。 总之，抑郁症会增加过早死亡率、冠心病和骨质疏松症。我们的小组进行临床和转化研究的计划，以确定这些现象的病理生理学。

There are virtually no incontrovertible data elucidating the pathophysiology of the premature mortality, coronary artery disease, or osteoporosis seen in major depression. This is, of course, first and foremost an issue of patient survival and quality of life. Compelling data regarding pathophysiolgical mechanisms will also help formally establish major depression as a systemic disease in the general medical community. This, in turn, will elicit the surveillance of the medical community for systemic abnormalities in depressed patients, and the institution of effective preventive interventions to mitigate these systemic abnormalities. Contributing to this task could help highlight the urgency of diagnosing and treating depression, reduce the stigma of depression, and make it imperative for insurance companies to treat depression like any other systemic disease. We have identified an emerging metabolic syndrome in young, lean remitted patients with major depression, as well as premature osteoporosis, and are well on the way to ascertaining dysregulations among important mediators that could lead to the premature death and to both systemic manifestations. We found that compared to 47 BMI matched controls, remitted, young, lean patients with a major depressive illness had insulin resistance, increased plasma insulin, glucose, and triglyceride levels, as well as other serious sequella of insulin resistance and hyperinsulinism. Insulin exerts many adverse effects that are adaptive during acute stress but maladaptive when sustained. Insulin stimulates the secretion of proinflammatory cytokines such as IL-6, procoagulant compounds such as factor VIII, antifibrinolytic compounds such as PAI-1, and activates the sympathetic nervous system. We have found increased around-the-clock plasma IL-6 levels, and increased morning levels of factor VIII and PAI-1 levels, and unequivocal indices of sympathetic activation (the latter in patients with melancholic depression). It is of interest that both IL-6 and NE promote osteoporosis and coronary artery disease. One of our corollary goals is to identify common pathophysiolgical features that are involved in both premature osteoporosis and coronary artery disease. This work could also extend concepts of the metabolic syndrome as a syndrome that includes both the metabolic abnormalities cited above as well as pathologic bone loss. Our finding of continuous elevations of plasma IL-6 levels has several implications. IL-6 has pleotropic effects and itself causes insulin resistance, increased inflammation, increased clotting, and decreased fibrinolysis. IL-6 is implicated as a highly significant factor in both atherosclerosis, which has a strong inflammatory component, as well and osteoporosis. Plasma IL-6 levels in healthy individuals are the best predictor of subsequent coronary artery disease, exceeding C-reactive protein (CRP) in its predictive value. IL-6 levels also predict osteoporosis, and IL-6 is among the most potent inducer of bone resorption. In the post-menopausal period, one of the important mechanisms posited for this condition is the loss of estrogen-mediated suppression of IL-6 release. We also found that a group of unmediated depressed patients with melancholic depression had high, around-the-clock central and peripheral hypersecretion of NE, as well as of plasma epinephrine, and cortisol secretion. While depressed, they also had increased blood pressure and pulse rates; all were reversible by a centrally directed treatment, ECT. CSF NE, plasma NE, and plasma cortisol rose and fell together throughout the 24 hour period, and rose progressively during EEG-documented sleep, peaking in the early morning, the time of the highest incidence of sudden death and myocardial infarction. Plasma EPI levels were also very high at this point, as were plasma IL-6 levels in our former study. Central NE activatiion and peripheral hypersecretion of plasma NE, EPI, and cortisol are all cardiotoxic, and their rising and falling together throughout the 24 hour period could have a particularly adverse effects. In addition, patients with chronic heart failure complicated by depression have a doubling of morbidity and mortality. NE levels no higher than in our depressed patients were the best predictor of subsequent mortality and morbidity in chronic heart failure. This finding provides a mechanism for the deleterious effect of depression when superimposed upon another systemic disease. We first found that premenopausal women with major depression have a marked increase in the prevalence of osteopenia and osteoporosis. Compared to 3-4% of the general premenopausal population, we found a 20-25% of osteopenia or osteoporosis in our depressed patients. Extrapolating from our data, we estimate that over 400,000 premenopausal women with major depression have osteopenia or osteoporosis as a consequence of their depression. Unfortunately osteoporosis is a silent disease until a fracture occurs. It is, however, a highly treatable illness, highlighting the need for early detection. The incidence of osteopenia and osteoporosis in premenopausal women is alarmingly high, and a significant public health hazard. In summary, depression increases premature mortality, coronary artery disease, and osteoporosis. Our group conducting a program of clinical and translational research to ascertain the pathophysiology of these phenomena.