HPA axis dysregulation and phenomenology of depression

描述(由申请者提供)：NIMH指导的以患者为导向的研究职业发展奖申请的目的是支持我的职业目标，成为一名专门研究抑郁症的神经生物学机制和临床特征之间关系的独立研究员。我之前的培训侧重于情绪障碍的现象学和治疗研究。研究表明，HPA调节失调影响抑郁症的表现，与忧郁和非典型症状有关。更好地了解这些差异背后的机制可能会导致抑郁症治疗的新靶点，并有助于解释神经内分泌研究之间的差异，这些研究通常包括关于抑郁亚型的不同样本。为此，我提出了一项培训计划，其中包括获得抑郁症HPA调节障碍的神经生物学方面的专业知识，整合生物和临床数据的研究的统计设计和分析，以及人类研究伦理。该研究计划包括评估健康志愿者和抑郁症患者的HPA活动和急性应激反应，因为它们与忧郁和非典型症状维度有关。假设抑郁症患者HPA轴活性升高与忧郁症患者过度觉醒和食欲减退有关，而非典型抑郁症患者HPA轴活性低下与疲劳和吞噬功能亢进有关。此外，HPA活性增加和抑郁症状被假设与对Trier社会压力测试(TSST)的更大反应相关，而HPA活性低和非典型症状被假设与对TSST的压力反应减少相关。这些假说将通过收集抑郁症患者在三种不同条件下的24小时尿游离皮质醇和血浆皮质醇和ACTH水平来验证：早晚一小时的连续收集；用于评估中枢HPA驱动的神经内分泌挑战(DEX/CRH测试)；以及对TSST的响应。这项研究将在两个富有成效的研究环境中进行，即辛辛那提大学系的生物精神病学和躁郁症和精神障碍研究项目。精神病学专家。拟议的培训和研究计划将促进我作为上述领域的独立研究人员的发展，并增加我们对与抑郁亚型相关的症状特征相关的神经生物学的理解。

DESCRIPTION (provided by applicant): The aim of this NIMH Mentored Patient-Oriented Research Career Development Award application is to support my career objective to become an independent investigator specializing in the relationship between neurobiological mechanisms and clinical features of depression. My previous training focuses on phenomenological and treatment studies in mood disorders. Studies suggest that HPA dysregulation influences the presentation of depression related to melancholic and atypical symptom dimensions. A better understanding of the mechanisms underlying these differences could lead to novel targets for the treatment of depression, and help to explain variability among neuroendocrine studies that typically included heterogeneous samples with regard to depressive subtypes. Toward this end, I have proposed a training plan that includes obtaining expertise in the neurobiology of HPA dysregnlation in depression, statistical design and analysis of studies integrating biological and clinical data, and human research ethics. The research plan includes assessing HPA activity and measures of acute stress responses in healthy volunteers and depressed patients as they relate to melancholic and atypical symptom dimensions. The hypothesis is that elevated HPA axis activity in depression is associated with hyperarousal and anorexia in melancholia, whereas low HPA activity is linked with fatigue and hyperphagia in atypical depression. Moreover, increased HPA activity and melancholic symptoms are hypothesized to correlate with greater response to the Trier Social Stress Test (TSST), whereas low HPA activity and atypical symptoms are hypothesized to correlate with a decreased stress response to the TSST. These hypotheses will be tested by collection of 24-hour urinary free cortisol, and plasma cortisol and ACTH levels in depressed patients in three separate conditions: one-hour serial collections in the morning and evening; after a neuroendocrine challenge used to assess central HPA drive (DEX/CRH test); and in response to the TSST. This study will be conducted in two highly productive research settings, the Biological Psychiatry and Bipolar and Psychotic Disorder Research Programs of the University of Cincinnati Dept. of Psychiatry. The proposed training and research plans will foster my development as an independent researcher in the areas described above, and increase our understanding of the neurobiology related to the symptom profiles associated with depressive subtypes.