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

描述(申请人提供)：共病情绪和焦虑症是一种常见的精神疾病人群。合并焦虑症时，抑郁症的临床病程和对抑郁症的治疗反应更差。我们以前使用应激源激活HPA轴的数据表明，与正常和单纯重度抑郁症(MDD)相比，重度抑郁症和社交焦虑症(SAD)并存的受试者ACTH应激反应增强。对患有儿童期虐待和MDD的女性的研究发现，对相同的压力源TSST也有类似的夸大反应。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增强。其他人的研究表明，早期创伤和MDD导致对地塞米松的敏感性增加，这与在传统抑郁症患者中观察到的情况相反。在这项建议中，我们将评估在共病的情绪和焦虑障碍中，HPA轴对TSST的反应性增加是否也伴随着基础活动的增加，正如ACTH对美曲酮的反应所评估的那样，这是一种纯粹的“内分泌”挑战。此外，我们将评估同一受试者对地塞米松负反馈的反应，以确定压力反应性增加是否与抑制系统的故障有关，或者这两种现象是否独立。我们将检查创伤的时间(成人和儿童)，以确定是否根据创伤暴露的时间在PTSD和MDD患者中观察到不同的HPA轴失调模式。我们还将通过比较MDD合并创伤后应激障碍组和MDD合并早发性SAD组的结果来检验创伤的特异性。我们假设，所有共病的焦虑症都会导致对TSST的夸大应激反应，但早期创伤或早期SAD的MDD将表现出正常的PM驱动力(由美替拉酮评估)和对地塞米松的夸大反馈。我们进一步假设，只有在成人创伤后继发创伤后应激障碍的MDD患者，才会表现出对地塞米松的基本驱动力增加和负反馈减少，地塞米松是典型的MDD模式。最后，我们假设单纯的MDD将表现出更强的甲孕酮反应，对地塞米松不敏感，对TTST的反应正常。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机的理解。暴露于一种类型的应激源，即创伤，可能会导致创伤后应激障碍，但对于创伤后应激障碍是否存在任何特有的应激激素变化，仍存在争议。公共卫生相关性：这项提案将探索首次创伤的时机，即儿童和成人，是否会导致晚上应激激素基础分泌的不同后果，以及对地塞米松的反馈敏感性的变化，地塞米松是一种类似皮质醇的合成化合物。我们还将探索创伤的时机是否会改变压力荷尔蒙对公开演讲的反应。

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.