The Neurobiology Of Major Depression

重度抑郁症与任何年龄的死亡率和心血管疾病增加一倍有关，与吸烟和其他导致健康不良的风险因素无关。我们首次报道，患有重度抑郁症的患者有过早的骨量减少和骨质疏松，即使在绝经前的女性中也是如此。我们已经在阐明与这两个过程相关的病理生理机制方面取得了重大进展。 我们的研究确定了代谢、内分泌、止血、炎症和自主神经过程网络中的失调，这些过程独立地和协同地促成了过早的冠状动脉疾病。其中一些符合世界卫生组织(WHO)关于代谢综合征的标准，包括胰岛素抵抗及其后果，包括高血压和血脂异常。除了这些异常，我们还发现了胰岛素抵抗的其他序列，如炎症、凝血和交感神经系统的激活。具体地说，我们发现：在一大组匹配良好的重度抑郁症患者中，存在代谢胰岛素抵抗、高胰岛素血症和高血糖。 临床神经内分泌科在两个基本领域取得了重大进展，这两个领域与报告的重度抑郁症患者过早死亡有关。我们首先确定了自主神经、内分泌、代谢和止血异常的相互关联的网络，这些异常独立地和协同地促进动脉粥样硬化。其中一些异常与世界卫生组织指定的代谢或胰岛素抵抗综合征相对应，代谢、内分泌异常导致动脉和小血管损伤。 我们已经确定了抑郁症患者的改变，包括：1)胰岛素抵抗；2)高胰岛素血症；3)高血糖；4)瘦体重减轻和肥胖增加；以及(5)血脂异常。我们还发现，我们的患者的因子显著增加，这是一种由高胰岛素水平刺激的凝血因子。因为胰岛素还刺激促炎细胞因子IL-6的分泌，所以我们全天候连续测量这种化合物。IL-6水平全天候高度升高，并在许多小时内超过2.9pg/ml的临界值，这预示着冠状动脉疾病风险的增加。我们还发现，我们的患者的CRP水平升高，心脏病的相对风险至少增加了3倍。针对代谢综合征，有许多潜在有用的干预措施，提高了对严重抑郁症进行诊断和治疗的紧迫性。 除了代谢综合征的组成部分，我们还发现，患有严重抑郁症的非药物患者的血压和脉搏显著增加，血浆和脑脊液NE水平全天候显著升高(连续30小时每小时评估一次)。这些患者的血浆肾上腺素也有明显的全天候升高。经电休克治疗后，上述指标恢复到正常水平。事实上，这些化合物的水平在夜间和清晨最高，这表明我们的发现与这种疾病的有意识的痛苦无关。我们还发现，抑郁程度较轻的无药物治疗的抑郁症患者在休息时以及对心理和药物应激源的反应中，整体去甲肾上腺素外溢显著增加。 我们曾报道，在患有严重抑郁症的绝经前妇女中，超过20%的人有骨量减少，6%的人符合骨质疏松的标准，这使得她们面临更大的骨折风险。考虑到重度抑郁症在女性中的发生率，这些数据结果预测，近36万绝经前妇女患有与重度抑郁症有关的骨质疏松症。骨质疏松症是一种沉默的情况，在骨折发生后变得明显。我们还表明，患有严重抑郁症和骨质疏松症的绝经前妇女对阿仑膦酸盐有良好的反应，阿仑膦酸盐是一种抑制骨吸收的化合物。这种非常安全的化合物的广泛使用加强了及早识别和治疗严重抑郁症的过早骨丢失的重要性。

Major depression is associated with a doubling of mortality and cardiovascular disease at any age, independent of smoking and other risk factors for poor health. We first reported that patients with major depression have premature osteopenia and osteoporosis that was marked even in premenopausal women. We have made significant strides in elucidating pathophysiological mechanisms of relevance to both processes. Our studies have identified dysregulations in a network of metabolic, endocrine, hemostatic, inflammatory, and autonomic processes that independently and synergistically contribute to premature coronary artery disease. Some of these correspond to those specified in the World Health Organization's (WHO) criteria for the Metabolic Syndrome, consisting of insulin resistance and its sequella, including hypertension and dyslipidemia. In addition to these abnormalities we have also identified other sequella of insulin resistance such as increased inflammation, coagulation, and activation of the sympathetic nervous system. Specifically, we have found: Metabolic - insulin resistance, hyperinsulinemia, and hyperglycemia in a large group of well matched patients with major depression. The Clinical Neuroendocrinology Branch has made major advances in two fundamental areas of relevance to the premature mortality reported in patients with major depression. We have first identified an interrelated network of autonomic, endocrine, metabolic, and hemostatic abnormalities that independently and synergistically promote atherosclerosis. Several of these abnormalities correspond to what the WHO has designated, the Metabolic, or Insulin Resistance Syndrome, a cluster of metabolic, endocrine, abnormalities that induce arterial and small blood vessel damage. We have identified alterations in patients with major depression that include: 1) insulin resistance; 2) hyperinsulinemia; 3) hyperglycemia; 4) loss of lean body mass and increased adiposity; and (5) dyslipidemia. We also found that our patients have significant increases in factor VIII, a coagulation factor stimulated by high insulin levels. Because insulin also stimulates the secretion of the proinflammatory cytokine IL-6, we measured this compound serially around the clock. The levels of IL-6 are highly elevated around the clock, and for many hours exceed the 2.9 pg/ml cutoff that is predictive of increased risk for coronary artery disease. We also found that our patients have increased levels of CRP, shown to increase the relative risk of heart disease by a factor of at least 3. There are many potentially useful interventions for the metabolic syndrome, heightening the urgency of making the diagnosis and instituting treatment for major depressive illness. In addition to components of the metabolic syndrome, we have also found that drug-free patients with severe melancholic depression have significant increases in blood pressure and pulse rate, as well as significant around-the-clock elevations of plasma and CSF NE levels (assessed hourly for thirty continuous hours). These patients also had significant around-the-clock elevations in plasma epinephrine. These parameters returned to normal levels after electroconvulsive treatment. The fact that the levels of these compounds were highest at night and early in the morning, indicate that our findings are independent of the conscious distress of the disorder. We also found that less severely depressed drug free patients with melancholic depression had significant increases in total body norepinephrine spillover at rest and in response to psychological and pharmacological stressors. We have reported that over 20% of premenopausal women with major depression have osteopenia, 6% meet criteria for osteoporosis, rendering them at greater risk for fracture. Given the incidence of major depression in women, these data results predict that almost 360,000 premenopausal women have osteoporosis related to major depression. Osteoporosis is a silent condition and becomes manifest after a fracture has occurred. We have also shown that premenopausal women with major depression and osteoporosis respond well to alendronate, a compound that inhibits bone resorption. The widespread availability of this very safe compound heightens the importance of identifying and treating the premature bone loss of major depression early.