Improved methods for elucidating hormonal mechanisms in mental health studies

描述（由申请人提供）：MDD是一种常见的衰弱性疾病，超过一半的MDD诊断患者未能达到完全缓解。迫切需要新的、更有针对性的治疗模式。开发更有针对性的治疗方法需要更好地了解MDD的精神病理学。下丘脑-垂体-肾上腺（HPA或应激）轴可能是MDD中研究最广泛的生理学途径。这源于一致的发现，即许多MDD患者的HPA轴激素升高。尽管在这一轴上进行了大量的研究，但病理生理学的全貌仍然难以捉摸。这种缺乏明确性的一个原因是，现有的分析方法未能适当地表征HPA轴中生物学上重要的激素波动。该提案的目标是通过消除HPA轴和MDD研究中的数据分析障碍来改善MDD的治疗选择。 研究HPA轴是具有挑战性的，因为轴中的激素是间歇性分泌的，无法直接观察到。该轴由脉冲释放模式沿着昼夜节律调节。脉冲分泌的电流分析分别在每个个体上进行，并且组比较在模型拟合之外。这导致对脉冲释放特征的不稳定估计，特别是表征昼夜节律的能力有限，因为每个受试者上的脉冲数量很小。我们通过为患者群体开发单个模型而不是为每个患者开发单独的模型来解决这些缺点。我们使用我们的新方法更彻底地调查疾病的严重程度或分类是否与：1）脉动分泌的规律性或2）脉冲频率或脉冲大小的昼夜节律模式的变化有关。这些是当前HPA轴MDD研究中感兴趣的机制问题。 我们建立在我们现有的贝叶斯方法来建模脉动激素数据，以克服计算问题，排除了在压力系统中的激素分析的进步。我们的具体目标是：1）使用贝叶斯方法开发和评估脉动激素数据的群体模型，2）使用这些创新方法评估抑郁和非抑郁参与者之间ACTH和皮质醇分泌的差异，以及3）传播新方法并使其可用于心理健康研究人员。通过这项工作，我们将开发一个新的分析框架，研究人员可以使用它来更好地理解压力轴在精神病理学中的作用。此外，本研究还为 统计基础，从建立在表征复杂的反馈和前向回路中存在的HPA轴。最终，这项工作为精神卫生界提供了新的工具，这些工具对于开发和评估MDD和其他精神健康状况的新的神经靶向疗法至关重要。

DESCRIPTION (provided by applicant): MDD is a common debilitating condition with over half of those diagnosed with MDD failing to achieve complete remission. New, more targeted, treatment paradigms are desperately needed. The development of more targeted treatments requires a better understanding of the psychopathology of MDD. The hypothalamic- pituitary-adrenal (HPA or stress) axis is possibly the most widely studied physiology pathway in MDD. This stems from the consistent finding that HPA axis hormones are elevated in many with MDD. Despite the amount of research being performed on this axis, a complete picture of the pathophysiology remains elusive. One reason for this lack of clarity is that the existing analysis methods fail to appropriately characterize the biologically important hormonal fluctuations in the HPA axis. The goal of this proposal is to improve the treatment options in MDD by removing the data analysis barriers in studies of the HPA axis and MDD. Studying the HPA axis is challenging because the hormones in the axis are secreted intermittently in boluses (called pulses), which are not directly observable. The axis is regulated by the pulse release patterns along with circadian rhythms. Current analyses of the pulse secretion are performed separately on each individual, and group comparisons are external to the model fitting. This results in unstable estimates of the pulse release features, especially a limited ability to characterize circadian rhythms, because the number of pulses on each subject is small. We address these shortcomings by developing a single model for a population of patients rather than a separate model for each patient. We use our new methods to more thoroughly investigate whether disease severity or classification is associated with: 1) the regularity of the pulsatile secretionor 2) changes in the circadian patterns in pulse frequency or pulse size. These are current mechanistic questions of interest in MDD studies of the HPA axis. We build upon our existing Bayesian approach to modeling pulsatile hormone data to overcome the computational issues that have precluded advancements in the analysis of hormones in the stress system. Our specific aims are: 1) to develop and evaluate a population model of pulsatile hormone data using a Bayesian approach, 2) to use these innovative methods to assess how ACTH and cortisol secretion differs between depressed and non-depressed participants, and 3) to disseminate the novel methodology and make it accessible to mental health researchers. Through this work, we will develop a novel analysis framework that investigators can use to better understand the role of the stress axis in psychopathology. In addition, this research lays a statistical foundation from which to build upon to characterize the complex feedback and forward loops that exist in the HPA axis. Ultimately, the work provides the mental health community with new tools critically useful for developing and evaluating new hormonally targets therapies for MDD and other mental health conditions.