Effects of comorbid anxiety disorders on the HPA axis profile of depression

描述（由申请人提供）：情绪和焦虑障碍合并症在精神科人群中很常见。抑郁症的临床病程和对抑郁症治疗的反应在存在共病性焦虑症时更差。我们之前使用应激源激活HPA轴的数据表明，与正常受试者和单纯重度抑郁症（MDD）相比，患有重度抑郁症和社交焦虑障碍（SAD）的受试者的ACTH应激反应性增加。对遭受童年虐待和重度抑郁症的女性的研究发现，对同样的压力源，即TSST，也有类似的夸张反应。这些数据表明，早发性焦虑症和创伤可能表现出类似的压力反应性增加。其他人的研究表明，早期创伤和重度抑郁症会导致对地塞米松的敏感性增加，这与传统抑郁症患者的观察结果相反。在本提案中，我们将评估是否HPA轴对TSST的反应性增加在共病心境和焦虑障碍中也伴随着基础活性的增加，正如ACTH对美吡酮（纯粹的“内分泌”挑战）的反应所评估的那样。此外，我们将评估同一受试者对地塞米松负反馈的反应，以确定应激反应的增加是否与抑制系统的失败有关，还是这两种现象是独立的。我们将检查创伤时间（成人与儿童），以确定创伤后应激障碍和重度抑郁症患者是否观察到不同的HPA轴失调模式取决于创伤暴露时间。我们还将通过比较共病MDD + PTSD组和共病MDD +早发性SAD组的结果来检验创伤的特异性。我们假设所有共病性焦虑症都会导致对TSST的过度应激反应，但早期创伤或早发性SAD的重度抑郁症会表现出正常的PM驱动（通过美西拉酮评估）和对地塞米松的过度反馈。我们进一步假设，仅继发于成人创伤后应激障碍的重度抑郁症会表现出对地塞米松的基础驱力增加和负反馈减少，这是典型的重度抑郁症模式。最后，我们假设纯粹的MDD会表现出增加的metyrapone反应，对地塞米松不敏感和对TTST的正常反应。这些数据将进一步加深我们对创伤对下丘脑轴应激反应和反馈的影响和时间的理解。暴露于一种类型的压力源，即创伤，可以导致PTSD，但关于PTSD是否有任何特征性的应激激素变化仍然存在争议。公共卫生相关性：本提案将探讨第一次创伤的时间，即童年与成人，是否会导致晚上应激激素基础分泌的不同后果，以及对地塞米松（一种类似于皮质醇的合成化合物）反馈敏感性的变化。我们还将探讨创伤的时间是否会改变应激激素对公开演讲挑战的反应。

DESCRIPTION (provided by applicant): Comorbid mood and anxiety disorders are a frequent occurrence in psychiatric populations. The clinical course of depression and response to treatment of depression is worse in the presence of a comorbid anxiety disorder. Our previous data using a stressor to activate the HPA axis, demonstrated that ACTH stress reactivity was increased in subjects with comorbid major depression and social anxiety disorder (SAD) compared to normal subjects, and pure major depression (MDD). Studies of women with childhood abuse and MDD found a similar exaggerated response to the same stressor, the TSST. These data suggest that early onset anxiety disorders and trauma may show similar increased stress reactivity. Studies by others suggest that early trauma and MDD leads to increased sensitivity to dexamethasone, the opposite of what is observed in traditional depressed patients. In this proposal we will evaluate whether increased reactivity of the HPA axis to the TSST in comorbid mood and anxiety disorders is also accompanied by increased basal activity, as assessed by the ACTH response to metyrapone, a purely "endocrine" challenge. In addition we will evaluate the response to dexamethasone negative feedback in the same subjects to determine if increased stress reactivity is linked to failure of the inhibitory systems or whether these two phenomena are independent. We will examine if timing of trauma (adult vs. childhood) to determine if different patterns of HPA axis dysregulation are observed in patients with PTSD and MDD dependent upon the time of trauma exposure. We will also examine the specificity of trauma by comparing the results in the comorbid MDD plus PTSD groups to a comorbid MDD plus early onset SAD group. We hypothesize that all comorbid anxiety disorders will lead to exaggerated stress response to the TSST but that MDD with early trauma or early onset SAD will show normal PM drive (as assessed by metyrapone) and exaggerated feedback to dexamethasone. We further hypothesize that MDD with PTSD secondary to adult trauma only will show increased basal drive and decreased negative feedback to dexamethasone, the classic MDD pattern. Finally, we hypothesize that pure MDD will show increased metyrapone response, insensitivity to dexamethasone and a normal response to the TTST. These data will further our understanding of the effects and timing of trauma on the HPA axis stress reactivity and feedback. Exposure to one type of stressor, a trauma, can lead to PTSD but controversy still exists as to whether there are any characteristic stress hormone changes with PTSD. PUBLIC HEALTH RELEVANCE: This proposal will explore if timing of first trauma, i.e. childhood versus adult, leads to different consequences on basal secretion of stress hormones in the evening and to changes in feedback sensitivity to dexamethasone, a synthetic compound similar to cortisol. We will also explore if timing of trauma changes the stress hormone response to a public speaking challenge.