THE NEUROBIOLOGY OF MAJOR DEPRESSION

我们研究重度抑郁症的神经生物学。构成重度抑郁症核心情感和认知症状的基本中枢神经系统病理生理变化也在导致重度抑郁症患者在任何年龄的预期死亡率是预期死亡率的两倍（与自杀无关）的事实中发挥了作用。此外，重度抑郁症患者早发缺血性心脏病和骨质疏松症的发病率明显增加。我们的工作包括设计和执行研究，以阐明基本的中枢神经系统机制，有助于情感和认知症状的严重抑郁症，以及他们的长期医疗后果。作为一个必然的结果，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在NIH纵向研究的100个家庭中进行了20多年。在60个家庭中，母亲被诊断患有重度抑郁症，两个孩子年龄在2到4岁之间。 该人群是未来几年前瞻性研究的理想人群。在过去的一年里，我们已经开始阐明骨密度显著降低的病理生理学，我们首次通过前髂嵴活检描述了重度抑郁症患者的骨密度显著降低。到目前为止，我们注意到骨转换降低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密切匹配）的瘦体重显着减少，这与骨密度相关。我们还发现，抑郁症患者的脑脊液NE水平显示出深刻的，昼夜不停的增加，NE和皮质醇增多症相互加强，这些缺陷与中央CRH系统的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，CRHplays在恒河猴的行为，自主神经，代谢和内分泌应激反应的滋补作用。这些研究预示着将该化合物引入人类受试者中进行研究。

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.