THE NEUROBIOLOGY OF MAJOR DEPRESSION

我们研究重度抑郁症的神经生物学。中枢神经系统的基本病理生理变化是严重抑郁症的核心情感和认知症状的基础，也是严重抑郁症患者在任何年龄段的预期死亡率（独立于自杀）高出两倍的原因之一。此外，重度抑郁症患者发生过早缺血性心脏病和骨质疏松症的几率明显增加。我们的工作包括设计和实施研究，以阐明中枢神经系统的基本机制，这些机制导致了重度抑郁症的情感和认知症状，以及它们的长期医学后果。因此，我们的目标是开发更好的方法来诊断、治疗和预防抑郁症的心理和医学成分。我们的临床研究主要是在美国国立卫生研究院纵向研究了20多年的100个家庭中进行的。在60个家庭中，母亲进入研究时被诊断患有严重抑郁症，两个孩子的年龄在2到4岁之间。这一人群代表了未来几年前瞻性研究的理想群体。在过去的一年里，我们已经开始阐明骨矿物质密度的显著损失的病理生理学，我们首先通过髂前嵴的生物检查描述了重度抑郁症患者。到目前为止，我们注意到骨转换减少和骨矿化率显著降低。我们还发现，重度抑郁症患者（在身高、体重和性别方面与志愿者非常接近）的瘦体重显著下降，这与骨密度有关。我们还发现，忧郁性抑郁症患者脑脊液NE水平持续升高，NE与高皮质醇症相互加强，这些缺陷与中枢CRH系统特定成分的缺陷密切相关。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，我们已经证明了crh在恒河猴对应激的行为、自主神经、代谢和内分泌反应中起着滋补作用。这些研究是将该化合物引入人体研究的先兆。

We study the neurobiology of major depression. The fundamental central nervous system pathophysiological changes that underlie the core affective and cognitive symptoms of major depression also play a role in the fact that patients with major depression have twice the expected death rate at any age, independent of suicide. In addition, patients with major depression show a marked increase in the incidence of premature ischemic heart disease and osteoporosis. Our work consists of designing and performing studies to elucidate fundamental central nervous system mechanisms that contribute both to the affective and cognitive symptoms of major depression as well as their long-term medical consequences. As a corollary, our goal is to develop improved means for the diagnosis, treatment,, and prevention of the psychological and medical components of depressive disorders. Our clinical studies proceed predominantly in a group of 100 families studied longitudinally at the NIH for over twenty years. In 60 families the mother entered the study with a diagnosis of major depression and two children between the ages of 2 and 4. This population represents an ideal group for prospective studies in the years to come. In the past year, we have begun to elucidate the pathophysiology of the significant loss of bone mineral density we first described in patients with major depression via biospy of the anterior iliac crest. To date, we note decreased bone turnover and a marked decrease in the bone mineralization rate. We have also found that patients with major depression (matched closely with volunteers with respect to height, weight, and gender) show a significant decrement in lean body mass that correlates with bone mineral density. We have also found that patients with melancholic depression show profound, around-the-clock increases in CSF NE levels, that NE and the hypercortisolism mutually reinforce one another, and that these defects are closely related to defects in specific components of the central CRH system. We have developed and deployed a non-peptide CRH type 1 receptor antagonist. Utilizing this compound, we have demonstrated that CRHplays a tonic role in the behavioral, autonomic, metabolic, and endocrine responses to stress in rhesus macaques. These studies are premonitory to introducing this compound for study in human subjects.