The Neurobiology Of Major Depression

世界卫生组织将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增加一倍。我们曾报道，超过10%的绝经前抑郁症妇女患有骨质疏松症，另有15%的妇女骨质减少。这两种情况都会增加骨折的风险。我们在一项更大规模的研究中重复了这一发现，该研究包括73名绝经前抑郁症女性和73名对照组，这些对照组分别与每个患者的年龄、吸烟史、身高和体重相匹配。考虑到一般人群中重度抑郁症的发病率，我们的两项研究都预测，今天美国有超过35万绝经前妇女患有继发于重度抑郁症的未识别的骨质疏松症。骨质疏松症通常是一种沉默的疾病，直到第一次临床事件，使许多这些患者将不会被诊断，直到骨折后。我们目前已经建立了阿仑膦酸钠的双盲、安慰剂对照试验，阿仑膦酸钠是一种双磷酸盐，能够逆转骨丢失，每年使骨密度增加2-3%，足以显著降低骨折风险。在我们的73名患者和对照组中，每隔一小时测量一次激素样本，持续24小时，我们发现那些骨质流失的人血浆皮质醇水平升高，并且血浆皮质醇水平与骨质流失的程度呈正相关。 除了过早的骨质疏松症，患有严重抑郁症的患者患早发性冠状动脉疾病的几率也会增加一倍。我们假设，由于重度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病率有明显影响。在一组62名患有重度抑郁症的女性和62名性别、年龄和体重指数相匹配的对照组中。我们发现抑郁症患者确实存在胰岛素抵抗。我们还发现，抑郁症患者的血糖和血浆胰岛素水平显著升高，后者是对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、促炎介质的复发、增加凝血的凝血因子的释放以及抑制纤维蛋白溶解的化合物的释放。事实上，我们发现，抑郁症患者的凝血因子VIII显著增加，已知会显著增加临床相关血栓形成的发生率。 我们还发现，无药物的极重度抑郁症患者的基础血压和脉率增加，通过留置静脉和腰椎引流每小时测量血浆和CSF NE显著持续增加30小时。这些异常解决后，电休克治疗抑郁症。我们发现，一个不太严重的抑郁组的药物自由抑郁症患者有显着增加全身去甲肾上腺素和脉搏率在基线和心理和生理应激源的反应。 总之，我们的抑郁症患者似乎没有一种由过量的皮质醇和去甲肾上腺素驱动的综合征，这种综合征显著降低了骨密度，促进了胰岛素抵抗（及其风暴）：增加了凝血和抗纤维蛋白溶解因子。因此，这种不良的神经内分泌和自主神经环境与临床高度相关：过早骨质疏松和骨质减少;高血压和交感神经流出量的显著增加;胰岛素抵抗和稳态介质的病理变化。我们工作的目标是找到早期发现、治疗或预防过早骨质疏松症和抑郁性冠状动脉疾病的改进方法。

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.