The Neurobiology Of Major Depression

几乎没有无可辩驳的数据来阐明抑郁症中出现的过早死亡、冠状动脉疾病或骨质疏松的病理生理学。当然，这首先是病人生存和生活质量的问题。有关病理生理学机制的令人信服的数据也将有助于在普通医学界将严重抑郁症正式确立为一种系统性疾病。这反过来将促使医学界对抑郁症患者的系统性异常进行监测，并制定有效的预防性干预措施来减轻这些系统性异常。为这项任务做出贡献可能有助于突出诊断和治疗抑郁症的紧迫性，减少抑郁症的耻辱，并使保险公司将抑郁症视为任何其他系统性疾病一样势在必行。 我们已经在年轻、消瘦缓解期的重度抑郁症和早发性骨质疏松症患者中发现了一种新出现的代谢综合征，并正在很好地确定可能导致过早死亡和两种全身表现的重要介质之间的失调。 我们发现，与47名体重指数匹配的对照组相比，患有严重抑郁症的缓解、年轻、消瘦的患者存在胰岛素抵抗，血浆胰岛素、血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。胰岛素会产生许多不良反应，在急性应激时是适应的，但在持续时是不适应的。胰岛素刺激促炎细胞因子的分泌，如IL-6，促凝剂化合物，如第八因子，抗纤溶化合物，如PAI-1，并激活交感神经系统。我们发现全天候血浆IL-6水平升高，早晨因子VIII和PAI-1水平升高，交感神经激活的明确指数(后者在忧郁症患者中)。有趣的是，IL-6和NE都促进骨质疏松症和冠状动脉疾病。我们的推论目标之一是确定与早产儿骨质疏松症和冠状动脉疾病相关的共同病理生理学特征。这项工作还可以将代谢综合征的概念扩展为一种综合征，包括上述代谢异常和病理性骨丢失。 我们对血浆IL-6水平持续升高的发现有几点启示。IL-6具有多效性，其本身会引起胰岛素抵抗，增加炎症，增加凝血，减少纤溶。IL-6被认为是动脉粥样硬化和骨质疏松症的一个非常重要的因素。健康人的血浆IL-6水平是预测后续冠状动脉疾病的最佳指标，其预测价值超过C-反应蛋白(CRP)。IL-6水平也可以预测骨质疏松，而IL-6是骨吸收最有效的诱导剂之一。在绝经后时期，这种情况的重要机制之一是失去雌激素介导的对IL-6释放的抑制。 我们还发现一组非介导性抑郁症患者存在高水平的中枢和外周去甲肾上腺素、肾上腺素和皮质醇的高分泌。在抑郁的同时，他们的血压和脉搏也有所增加；所有这些都可以通过中央指导的ECT治疗而逆转。脑脊液中去甲肾上腺素、血浆去甲肾上腺素和皮质醇在24小时内同时上升和下降，并在EEG记录的睡眠期间逐渐上升，在凌晨达到峰值，这是猝死和心肌梗死发生率最高的时间。在这一点上，血浆EPI水平也非常高，正如我们先前研究中的血浆IL-6水平一样。中枢NE的激活和外周血浆NE、EPI和皮质醇的高分泌都是心脏毒性的，它们在24小时内的上升和下降可能会产生特别不利的影响。此外，慢性心力衰竭合并抑郁症的患者的发病率和死亡率翻了一番。在慢性心力衰竭患者中，NE水平不高于抑郁症患者是预测随后死亡率和发病率的最佳指标。这一发现为抑郁症叠加另一种系统性疾病时的有害影响提供了一种机制。 我们首次发现，患有严重抑郁症的绝经前女性骨量减少和骨质疏松症的患病率明显增加。与一般绝经前人群的3-4%相比，我们发现抑郁症患者中有20%-25%的骨量减少或骨质疏松。从我们的数据推断，我们估计有超过400,000名患有严重抑郁症的绝经前妇女由于抑郁而患有骨量减少或骨质疏松。不幸的是，骨质疏松症是一种默默无闻的疾病，直到骨折发生。然而，这是一种高度可治疗的疾病，突显了早期发现的必要性。绝经前妇女骨量减少和骨质疏松症的发生率高得惊人，是一个重大的公共健康危害。 总而言之，抑郁症会增加过早死亡率、冠状动脉疾病和骨质疏松症。我们小组正在进行一项临床和翻译研究计划，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.