The Neurobiology Of Major Depression

CNE的主要目标是研究严重抑郁症的长期医学后果，确定其病理生理机制，并开发改进的诊断和治疗方法。我们研究两种主要疾病，冠状动脉疾病和骨质疏松症，并尽可能集中在这两种疾病常见的内分泌介质上。我们恢复了NIMH纵向家庭研究，这项研究始于1979年，包括68名患有严重抑郁症的年轻母亲，她们的两个2-6岁的孩子，以及一组匹配的对照组(超过400名受试者，90%我们已经重新登记)。这些对象是无与伦比的资源，是研究抑郁症的长期医学后果的理想对象。这些母亲现在都是中年，这是表现出早产性骨质疏松症和冠状动脉疾病的理想年龄。这些孩子现在是年轻人，已经大到可以开始出现圣痕，这表明他们对早产儿心脏病和骨质疏松症的易感性增加。超过一半的孩子已经患上了抑郁症。我们要强调的是，这群人是整个NIMH的资源。在过去一年的研究中，我们发现抑郁症患者的血浆和脑脊液去甲肾上腺素水平全天候增加，这些去甲肾上腺素在ECT后可以分解。我们还发现，这些患者在抑郁时是高血压，康复后血压正常，与正常的NE功能恢复有关。此外，我们还发现，中度抑郁的抑郁症患者在休息和应对应激刺激时，全身去甲肾上腺素外溢显著增加。我们还发现了胰岛素敏感度显著降低、生长激素缺乏和全身肥胖增加的证据，这与他们骨密度的显著下降有关。我们已经开发并部署了一种非肽CRH 1型受体拮抗剂。利用这种化合物，我们已经证明CRH在猕猴和大鼠对应激的行为、自主神经、代谢和内分泌反应中发挥紧张性作用，在条件性恐惧、外周炎症和应激性溃疡的易感性的发展和表达中发挥作用。

The principal goal of the CNE is to study the long term medical consequences of major depression, to determine their pathophysiological mechanisms, and to develop improved means for their diagnosis and treatment. We study two main illnesses, coronary artery disease and osteoporosis, and, insofar as possible, focus on endocrine mediators that are common to the two illnesses. We have restored the NIMH Longitudinal Family Study, a study begun in 1979 consisting of 68 young mothers with major depression, two of their children between the ages of 2-6, and a group of matched controls (more than 400 subjects 90% of whom we have re-enrolled). These subjects represent an incomparable resource and are ideal for studying long-term medical consequences of depression. The mothers are now middle aged, an ideal age for demonstrating premature osteoporosis and coronary artery disease. The children are now young adults, and are old enough to begin showing stigmata suggestive of enhanced susceptibility to premature heart disease and osteoporosis. More than half of the children have already developed depression. We would like to emphasize that this cohort is a resource for the entire NIMH. In our studies this past year, we have found that patients with melancholic depression have increased around-the-clock levels of plasma and CSF norepinephrine that resolve after ECT. We also found that these patients were hypertensive while depressed and normotensive after recovery, in association with restoration of normal NE function. In addition, we found that moderately depressed outpatients with melancholic depression have significant increase in total body NE spillover at rest and in response to stressful stimuli. We have also found evidence of significant, interrelated decrements in insulin sensitivity, growth hormone deficiency, and increases in total body adiposity that correlates with their significant losses of bone mineral density. We have developed and deployed a non-peptide CRH type 1 receptor antagonist. Utilizing this compound, we have demonstrated that CRH plays a tonic role in the behavioral, autonomic, metabolic, and endocrine responses to stress in rhesus macaques, and in the rat, in the development as well as the expression of conditioned fear, peripheral inflammation, and susceptibility to stress ulcer.