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段的死亡率都增加了一倍。我们报道了超过10%的绝经前重度抑郁症女性患有骨质疏松症，另有15%患有骨质减少症。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名患有重度抑郁症的绝经前妇女和73名单独对照者，这些对照者与每位患者的年龄、吸烟史、身高和体重相匹配。鉴于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未被识别的骨质疏松症，继发于重度抑郁症。骨质疏松症通常是一种沉默的疾病，直到第一次临床事件，所以许多这些患者直到骨折后才会被诊断出来。目前，我们对阿仑膦酸钠进行了双盲安慰剂对照试验，这种双膦酸盐能够逆转骨质流失，每年使骨密度增加2-3%，足以显著降低骨折的风险。在我们的73名患者和对照组中，每24小时测量一次激素样本，我们发现那些骨质流失的人血浆皮质醇水平升高，血浆皮质醇水平与骨质流失的程度呈正相关。

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.