THE NEUROBIOLOGY OF MAJOR DEPRESSION

我们研究单相抑郁症的神经生物学。我们的目标是 了解这种疾病的基本病理生理机制， 发展更好的诊断和治疗手段，并阐明 其长期躯体后果的机制。我们利用各种方法 从脉动激素分泌的数学模型， 分子生物学下丘脑-垂体-肾上腺轴的评估 功能（HPA）通过每二十分钟采样超过九天揭示 我们迄今为止研究的所有非典型抑郁症患者都显示， 定性（复杂性降低）和定量（脉冲群减少 质量和振幅）的HPA功能异常，从而验证了我们的 亚群应激系统病理抑制假说 抑郁症患者。 我们已经开发了一种促肾上腺皮质激素释放激素拮抗剂， 口服活性，并通过血脑屏障，并已证实 其安全性、生物活性和标记适用性（碘化） 用于SPECT研究。我们发现这种拮抗剂可以阻断 表达和发展的条件性恐惧在大鼠和施加 在非人类灵长类动物中的长期抗焦虑作用。 瘦素向大脑发出营养状况的信号。我们发现血浆 瘦素是以脉冲方式分泌的，其昼夜节律 与HPA轴方向相反。因为瘦素抑制HPA轴 这一发现暗示瘦素在中枢神经系统的紧张性抑制中起作用， HPA轴，并建议它可能是食欲和HPA之间的联系 抑郁症的轴紊乱。我们还首次证明了瘦素 在人体内分泌与血浆LH和雌二醇分泌同步， 表明瘦素在肥胖中的生理和可能的病理生理作用， 人类生殖我们的数据显示，40%的绝经前妇女， 过去或现在的抑郁症显示骨矿物质显著减少 密度使其易于断裂。考虑到 9-12%的频率单相抑郁症的妇女，这是一个问题， 重大公共卫生问题。

We study the neurobiology of unipolar depression. Our goals are to understand fundamental pathophysiological mechanisms in this disorder, develop improved means for its diagnosis and treatment, and elucidate the mechanisms of its long-term somatic consequences. We utilize methods ranging from mathematical modeling of pulsatile hormonal secretion to molecular biology. Assessment of hypothalamic-pituitary-adrenal axis function (HPA) via every twenty-minute sampling over nine days revealed that all of our patients with atypical depression studied to date show qualitative (loss of complexity) and quantitative (decreased pulse burst mass and amplitude) abnormalities in HPA function, thus validating our hypothesis of pathological suppression of the stress system in a subgroup of depressed patients. We have developed a corticotropin releasing hormone antagonist that is orally active and that crosses the blood brain barrier, and have confirmed its safety, biological activity, and suitability for labeling (iodination) for SPECT studies. We showed that this antagonist blocks both the expression and development of conditioned fear in the rat and exerts long-term anxiolytic effects in non-human primates. Leptin signals nutritional status to the brain. We found that plasma leptin is secreted in a pulsatile fashion, and that its circadian rhythm is inverse to that of the HPA axis. Because leptin inhibits the HPA axis centrally, this finding implicates leptin in the tonic inhibition of the HPA axis and suggests that it may be a link between appetitive and HPA axis disturbances in depression. We also first showed that leptin secretion is synchronous with plasma LH and estradiol secretion in humans, indicating a physiologic and possibly pathophysiologic role for leptin in human reproduction. Our data show that 40% of premenopausal women with past or current depression show significant decrements in bone mineral density that render them susceptible to fracture. In the light of the 9-12% frequency of unipolar depression among women, this is a matter of significant public health concern.