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

描述（由申请人提供）：共病的情绪和焦虑障碍是一个经常发生在精神病人群。抑郁症的临床病程和对抑郁症治疗的反应在存在共病焦虑障碍的情况下更差。我们以前的数据使用的应激激活HPA轴，表明ACTH应激反应增加的主题共病的抑郁症和社交焦虑障碍（SAD）相比，正常人，和纯抑郁症（MDD）。对儿童虐待和MDD的女性的研究发现，对相同的压力源TSST有类似的夸大反应。这些数据表明，早发性焦虑症和创伤可能表现出类似的应激反应性增加。其他研究表明，早期创伤和MDD导致对地塞米松的敏感性增加，与传统抑郁症患者中观察到的情况相反。在这个建议中，我们将评估是否增加HPA轴的TSST共病情绪和焦虑症的反应性也伴随着增加的基础活动，评估促肾上腺皮质激素对甲吡酮，一个纯粹的“内分泌”的挑战。此外，我们还将评估相同受试者对地塞米松负反馈的反应，以确定应激反应性增加是否与抑制系统的失败有关，或者这两种现象是否是独立的。我们将检查创伤的时间（成人与儿童），以确定是否在PTSD和MDD患者中观察到不同模式的HPA轴失调，这取决于创伤暴露的时间。我们还将通过比较共病MDD + PTSD组与共病MDD+早发SAD组的结果来检查创伤的特异性。我们假设所有共病焦虑症都会导致对TSST的过度应激反应，但伴有早期创伤或早发SAD的MDD会显示正常的PM驱动（通过甲吡酮评估）和对地塞米松的过度反馈。我们进一步假设，伴有PTSD的MDD仅继发于成人创伤，将表现出基础驱动增加和对地塞米松的负反馈减少，这是典型的MDD模式。最后，我们假设纯MDD将显示甲吡酮反应增加，对地塞米松不敏感，对TTST反应正常。这些数据将进一步加深我们对创伤对HPA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，创伤，可以导致创伤后应激障碍，但仍然存在争议，是否有任何特征性的压力激素变化与创伤后应激障碍。公共卫生相关性：这项提案将探讨是否第一次创伤的时间，即儿童与成人，导致不同的后果基础分泌的压力激素在晚上和变化的反馈敏感性地塞米松，合成化合物类似皮质醇。我们还将探讨创伤的时间是否会改变对公开演讲挑战的应激激素反应。

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.