HORMONE RHYTHMS--METABOLIC SIGNIFICANCE IN DEPRESSION

这是一份为期5年的修订续订申请，期限为18-22年，至 重度抑郁症患者HPA轴过度活动的继续研究。我们的 基于我们和其他人的数据的假设是，这是一个中心 神经系统(CNS)荷尔蒙和自主神经驱动的HPA过度活动， 这反映在ACTH对CRH治疗的反应减少(次级 皮质醇负反馈)，肾上腺肥大，可能还有肾上腺 对ACTH给药也有高反应性。我们进一步假设 中枢神经系统胆碱能机制是推动 百帕轴线。为了阐明荷尔蒙成分，我们计划在中枢神经系统水平上 为了继续测试我们的假设，即HPA轴的响应度为低- 严重抑郁症患者的剂量胆碱能挑战将比 单独匹配的正常对照组。在脑下垂体水平，使用 抑制皮质醇合成，我们计划验证我们的假设 即，缺乏皮质醇的负反馈，脑下垂体会更 患者对CRH的反应性明显高于对照组。在肾上腺水平， 我们计划再进行一项低剂量的ACTH/1-24刺激研究，以测试我们的 假设肾上腺的敏感度在 病人。此外，在细胞膜水平上，我们计划继续 皮质醇对心脏结构影响的量效关系初步研究 模型细胞膜、红细胞和淋巴细胞膜的排序， 作为对组织对皮质醇不敏感这一假设的检验 皮质醇增多症缺乏库欣金特征的原因 忧郁症。激素测定包括血浆ACTH/1-39、ACTH/1-24 (免疫反应ACTH)，皮质醇，加上一些胆碱能激素中的GH 刺激性研究和hCRH、甲孕酮、11-脱氧皮质酮和11- 脱氧皮质醇在甲孕酮研究中的应用。 我们进一步假设抑郁症的HPA轴多动是 依赖于国家，在治疗之后，激素措施将 以始终如一的方式回归正常。因此，所有的患者都在接受 对他们的治疗进行了追踪，并正在进行第二次研究 他们的病情正在缓解中，停药至少一个月。 这里提出的研究应该增加HPA轴的证据 过度活动是由于中枢神经系统刺激CRH产生增加所致， 这种增加与脑内胆碱能神经传递有关。 中枢神经系统。这些发现将进一步推动中枢神经系统的研究 重度抑郁症患者HPA轴活动的神经递质调节， 应力状态和其他导致HPA轴增加的条件 活动。

This is a 5-year revised renewal application, for Periods 18-22, to continue studies of HPA axis hyperactivity in major depression. Our hypothesis, based on our and others' data, is that this is a central nervous system (CNS) hormonal- and autonomic-driven HPA hyperactivity, as reflected in a reduced ACTH response to CRH administration (secondary to cortisol negative feedback), adrenal hypertrophy, and possibly adrenal hyperresponsivity to ACTH administration as well. We further hypothesize that CNS cholinergic mechanisms are one important factor that drives the HPA axis. To elucidate the hormonal component, at the CNS level we plan to continue testing our hypothesis that HPA axis responsiveness to low- dose cholinergic challenge will be greater in major depressives than in individually matched normal controls. At the pituitary level, using metyrapone blockade of cortisol synthesis, we plan to test our hypothesis that, lacking cortisol negative feedback, the pituitary will be more responsive to CRH in patients than in controls. At the adrenal level, we plan one additional low-dose ACTH/1-24 stimulation study to test our hypothesis that the sensitivity of the adrenal gland is greater in patients. Additionally at the cell-membrane level, we plan to continue pilot studies of the dose-response effect of cortisol on the structural ordering of model cell membranes and RBC and lymphocyte plasma membranes, as a test of the hypothesis that tissue insensitivity to cortisol may underlie the lack of Cushingoid features in hypercortisolemic depressives. hormone measures include plasma ACTH/1-39, ACTH/1-24 (immunoreactive ACTH), and cortisol, plus GH in some cholinergic stimulation studies and hCRH, metyrapone, 11-deoxycorticosterone, and 11- deoxycortisol in the metyrapone studies. We further hypothesize that HPA axis hyperactivity in depression is state-dependent, and that following treatment, the hormone measures will return to normal in a consistent manner. Thus, all patients are being tracked through their treatment and are being studied a second time when they are in remission and off medication for at least one month. The studies proposed herein should add to the evidence that HPA axis hyperactivity results from increased CNS stimulation of CRH production, and that this increase is related to cholinergic neurotransmission in the CNS. The findings should give further impetus to the study of CNS neurotransmitter regulation of HPA axis activity in major depression, stress states, and other conditions leading to increased HPA axis activity.