The Neurobiology Of Major Depression

世界卫生组织将重度抑郁症列为全球第四大致残原因。这不仅反映了抑郁症的精神痛苦，也反映了对身体疾病的易感性，这些疾病使患者在任何年龄的死亡率都翻了一番。我们报告了超过10%的患有严重抑郁症的绝经前妇女患有骨质疏松症，另有15%患有骨量减少。这两种情况都会增加骨折的风险。我们在一项更大的研究中重复了这一发现，该研究包括73名患有严重抑郁症的绝经前女性和73名分别与每个患者的年龄、吸烟史、身高和体重相匹配的对照组。鉴于重度抑郁症在普通人群中的发病率，我们的两项研究都预测，今天美国有超过35万名绝经前妇女患有继发于重度抑郁症的未被认识的骨质疏松症。骨质疏松症通常是一种沉默的疾病，直到第一次临床事件，所以这些患者中的许多人直到骨折后才能被诊断出来。我们目前已经开展了阿仑膦酸盐的双盲安慰剂对照试验，这是一种双膦酸盐，能够逆转骨丢失，每年产生2-3%的骨密度增加，足以非常显著地降低骨折风险。在73名患者和对照组中每隔一小时测量一次的荷尔蒙样本中，我们发现那些失去骨质的人血浆皮质醇水平升高，并且与血浆皮质醇水平和骨质丢失的程度呈正相关。 除了早产性骨质疏松症外，患有重度抑郁症的患者早发冠状动脉疾病的几率增加了一倍。我们推测，由于抑郁症的神经内分泌环境，抑郁症患者容易出现胰岛素抵抗，这种情况对增加冠状动脉疾病的发生率有显著影响。在一组62名患有严重抑郁症的女性中，62名对照在性别、年龄和体重指数方面匹配。我们发现，患有严重抑郁症的患者确实存在胰岛素抵抗。我们还发现，我们的抑郁症患者的血糖和血浆胰岛素水平显著较高，后者是对他们的胰岛素抵抗的代偿反应。高胰岛素水平是高致病性的。胰岛素刺激交感神经系统，促进炎症介质的复发，释放增加凝血的凝血因子，以及释放抑制纤溶的化合物。事实上，我们发现患有重度抑郁症的患者第VIII因子显著增加，已知这会显著增加与临床相关的血栓形成的发生率。 我们还发现，患有极度严重抑郁症的非药物患者基础血压和脉搏增加，血浆和脑脊液NE显著持续增加，持续30小时留置静脉和腰椎引流管。这些异常在电休克治疗他们的抑郁症后消失了。我们发现，在无药物治疗的抑郁症患者中，抑郁程度较轻的患者在基线和对心理和生理应激源的反应中，全身去甲肾上腺素和脉搏显著增加。 总而言之，我们的抑郁症患者似乎并不是由过量的皮质醇和去甲肾上腺素引起的综合症，这些综合症显著降低了骨密度，促进了胰岛素抵抗(及其狂风)：凝血和抗纤溶因子增加。这种不利的神经内分泌和自主神经环境具有高度的临床相关性：早产性骨质疏松症和骨量减少；高血压和交感神经流出大幅增加；胰岛素抵抗和体内平衡介质的病理变化。我们工作的目标是找到更好的方法来早期发现、治疗或预防抑郁症的早发性骨质疏松症和冠状动脉疾病。

World Health Organization has named major depression as the fourth overall cause of disability worldwide. This reflects not only the mental anguish of depression, but also susceptibility to physical illnesses that double the patients' mortality at any age. We reported that over 10% of premenopausal women with major depression have osteoporosis, and another 15% have osteopenia. Both conditions increase the risk of fracture. We have replicated this finding in a larger study that included 73 premenopausal women with major depression and 73 individually controls matched individually to each patient for age, smoking history, height, and weight. Given the incidence of major depression in the general population, both of our studies predict that over 350,000 premenopausal women in the United States today have unrecognized osteoporosis secondary to major depression. Osteoporosis is generally a silent disease until the first clinical event so that many of these patients will not be diagnosed until after a fracture. We have currently instituted double blind, placebo controlled trial of alendronate, a bisphosphonate capable of reversing bone loss and of producing a 2-3% increase in bone density per year, enough t very significantly reduce the risk of fracture. In hormonal samples measured every one hour for 24 hours in each of our 73 patients and controls, we found that those who had lost bone had increased plasma levels of cortisol, and that there was a positive correlation with plasma cortisol levels and the magnitude of bone loss. In addition to premature osteoporosis, patients with major depression have a doubling of the rate of premature coronary artery disease. We postulated that because of the neuroendocrine milieu of major depression, patients with depressive disorder would be prone to insulin resistance, a condition that has a pronounced effect on increasing the rate of coronary artery disease. In a group of 62 women with major depression an 62 controls matched for gender, age, and body mass index. We found that patients with major depression were indeed insulin resistance. We also found that our patients with depressive illness had significantly higher levels of plasma glucose and plasma insulin, the latter as a compensatory response to their insulin resistance. High insulin levels are highly pathogenic. Insulin stimulates the sympathetic nervous system, the relapse of proinflammatory mediator, the release of clotting factors that increase coagulation, and the release of compounds that inhibit fibrinolysis. Indeed we found that patients with major depression have a significant increase in factor VIII, known to significantly increase the incidence of clinically-relevant thrombosis. We also found that drug free patients with extremely severe melancholic depression have increased basal blood pressures and pulse rates, and significant, continuous increases in plasma and CSF NE measured hourly for 30 hour via indwelling venous and lumbar drains. These abnormalities resolved after electroconvulsive treatment of their depressions. We found that a less severely depressed group of drug free patients with melancholic depression had significant increases n total body norepinephrine and pulse rates at baseline and in response to psychological an physiological stressors. Taken together, our depressed patients seem t have a syndrome driven by excess cortisol and norepinephrine that significantly reduces bone mineral density and promotes insulin resistance (and its squall): increased clotting and antifibrinolytic factors. This adverse neuroendocrine and autonomic milieu in thus highly clinically relevant: premature osteoporosis and osteopenia; hypertension and profound increases in sympathetic outflow; insulin resistance and pathological changes in homeostatic mediators. The goal of our work is to find improved means for the early detection, treatment, or prevention of the premature osteoporosis and coronary artery disease of depressive illness.