The Neurobiology Of Major Depression

CNE的主要目标是研究严重抑郁症的长期医疗后果，确定其病理生理机制，并开发改进的诊断和治疗手段。我们研究了两种主要疾病，冠状动脉疾病和骨质疏松症，并尽可能地关注这两种疾病共同的内分泌介质。我们恢复了NIMH纵向家庭研究，这是一项始于1979年的研究，由68名患有严重抑郁症的年轻母亲，她们的两个2-6岁的孩子和一组匹配的对照（超过400名受试者，其中90%我们重新登记）组成。这些对象代表了一个无与伦比的资源，是研究抑郁症的长期医学后果的理想选择。这些母亲现在已步入中年，是出现过早骨质疏松症和冠状动脉疾病的理想年龄。这些孩子现在已经成年，并且已经足够大，可以开始显示出对过早心脏病和骨质疏松症的易感性增加的污点。超过一半的孩子已经患上了抑郁症。我们想强调的是，这个队列是整个NIMH的资源。在我们过去一年的研究中，我们发现抑郁症患者的血浆和脑脊液去甲肾上腺素的昼夜水平在ECT治疗后有所升高。我们还发现，这些患者有高血压，同时抑郁，恢复后血压正常，这与恢复正常的NE功能有关。此外，我们发现中度抑郁合并忧郁性抑郁的门诊患者在休息和应激刺激下的全身NE外溢显著增加。我们还发现了胰岛素敏感性显著下降、生长激素缺乏和全身脂肪增加与骨密度显著下降相关的证据。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在恒河猴和大鼠的应激行为、自主神经、代谢和内分泌反应中起着补药作用，在条件恐惧、外周炎症和应激性溃疡易感的发育和表达中起着补药作用。

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.