HORMONE RHYTHMS--METABOLIC SIGNIFICANCE IN DEPRESSION

这是一份为期5年的修订后的续期申请，适用于第18-22期， 继续研究重度抑郁症的HPA轴亢进。 我们 根据我们和其他人的数据，假设这是一个中心的 神经系统（CNS）激素和激素驱动的HPA活动过度， 这反映在对CRH给药的ACTH反应降低（继发性 皮质醇负反馈），肾上腺肥大，可能肾上腺 对促肾上腺皮质激素的高反应性。 我们进一步假设 中枢神经系统胆碱能机制是驱动 HPA轴。 为了阐明激素成分，在中枢神经系统水平，我们计划 继续测试我们的假设，HPA轴对低- 重度抑郁症患者的胆碱能激发剂量将大于重度抑郁症患者。 单独匹配的正常对照。 在脑垂体水平， 甲吡酮阻断皮质醇合成，我们计划测试我们的假设 如果没有皮质醇的负反馈，脑垂体会更 对CRH的反应性。 在肾上腺水平， 我们计划进行一项额外的低剂量ACTH/1-24刺激研究， 假设肾上腺的敏感性更大， 患者 此外，在细胞膜水平，我们计划继续 皮质醇的剂量反应效应的初步研究 模型细胞膜和RBC及淋巴细胞质膜的排序， 作为对组织对皮质醇不敏感性可能 皮质机能亢进症患者缺乏库欣样特征的基础 抑郁症患者 激素测量包括血浆ACTH/1-39、ACTH/1-24 （免疫反应性ACTH）和皮质醇，加上GH在一些胆碱能 刺激研究和hCRH、甲吡酮、11-脱氧皮质酮和11- 去氧皮质醇在甲吡酮研究中的作用 我们进一步假设，抑郁症的HPA轴过度活跃， 状态依赖性，以及随后治疗，激素措施将 以一种始终如一的方式恢复正常。 因此，所有患者均 通过他们的治疗跟踪，并正在进行第二次研究时， 他们的病情已得到缓解，至少有一个月没有服药。 本文提出的研究应增加证据表明，HPA轴 活动过度是由于CRH产生的CNS刺激增加， 这种增加与大脑中的胆碱能神经传递有关， CNS。 这一发现将进一步推动中枢神经系统的研究 抑郁症HPA轴活动的神经递质调节， 应力状态和导致HPA轴增加的其他条件 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.