THE NEUROBIOLOGY OF MAJOR DEPRESSION

我们研究严重抑郁症的神经生物学。作为重度抑郁症核心情感和认知症状基础的基本中枢神经系统病理生理变化，也在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)中发挥了作用。此外，重度抑郁症患者早产儿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，以阐明导致严重抑郁症的情感和认知症状及其长期医学后果的基本中枢神经系统机制。作为推论，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NIH纵向研究超过20年的100个家庭中进行的。在60个家庭中，母亲被诊断出患有严重抑郁症，两个孩子年龄在2岁到4岁之间。这一群体代表了未来几年进行前瞻性研究的理想群体。在过去的一年里，我们已经开始阐明我们首次描述的重度抑郁症患者通过对髂骨前部进行生物检查而导致骨密度显著丧失的病理生理学机制。到目前为止，我们注意到骨周转减少，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匹配)显示出与骨密度相关的瘦体重显著减少。我们还发现，抑郁症患者的脑脊液去甲肾上腺素水平全天候显著升高，去甲肾上腺素和皮质醇增多症相互促进，这些缺陷与中枢CRH系统中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CRH在恒河猴对应激的行为、自主神经、代谢和内分泌反应中发挥着紧张性作用。这些研究是将这种化合物引入人体研究的前兆。

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.