Neurobiological Predictors of Stress-Related Disorders

描述(由申请人提供)：压力相关的精神障碍，特别是术后抑郁，构成了一个主要的挑战。抑郁、焦虑和创伤后应激障碍(PTSD)通常是在手术、严重疾病、机动车事故和自然灾害等各种应激源之后发展起来的，这些障碍可能具有共同的易感性因素。在抑郁症和创伤后应激障碍中，下丘脑-垂体-肾上腺(HPA)异常的不同特征已经得到了很好的证实，但那些先前存在的变化，那些对压力/创伤的反应，以及那些作为活动性疾病的组成部分，仍有待确定。只有在可预测的应激事件之前对标记物进行前瞻性研究，才能有效地解决这一问题，并前瞻性地阐明神经内分泌反应在这一过程中的作用。研究在经历了可预测的应激事件(如大手术)的受试者中的候选易感标记，不仅对于术后抑郁的研究，而且对于一般的应激相关障碍的研究都将是重要的。我们的假设是，术后抑郁发生在具有特定发病前风险因素的应激前神经内分泌功能改变的患者中。我们的初步研究结果表明，腹部大手术构成了一种可预见的应激事件，导致术后患者亚组出现从头抑郁。因此，我们将验证HPA轴和儿茶酚胺能系统的预应激标志物将预测腹部手术后可预测的应激后抑郁障碍的发展的假设。我们预测高皮质醇血症和DST非抑制将预测抑郁症。研究对象为2LO因动脉瘤或闭塞症而行腔内或腹主动脉手术的择期手术患者和70名保守治疗的主动脉疾病对照患者(4组)。手术患者将在术前、术后三次(3、9和18mo)进行评估。记录手术前后神经内分泌功能和精神疾病的发生率。将对对照患者进行评估，以确定精神异常自发性发作的频率。通过混合模型回归，我们将检验心理和神经内分泌异常在术后抑郁中的作用，并确定特定因素(神经内分泌测量、精神症状和诊断)的稳定性以及它们是否可靠地预测术后并发疾病的发展。我们还将确定手术后终止神经内分泌应激反应的能力或对地塞米松的反应是否预测结果，以及这是否与应激前异常有关。识别应激前的脆弱性标记显然对我们理解应激相关的功能障碍，即精神疾病的病理生理学有着深远的意义。

DESCRIPTION (provided by applicant): Stress-related psychiatric disorders in general, and post-operative depression in particular, constitute a major challenge. Depression, anxiety and post-traumatic stress disorder (PTSD) often develop after various stressors like surgery, serious illnesses, motor vehicle accidents, and natural disasters, and vulnerability factors are likely shared by these disorders. Distinct profiles of hypothalamo-pituitary - adrenal (HPA) abnormalities, are well-established in depression and PTSD, but those alterations which are pre-existing, those which are a response to stress/trauma, and those which are a component of the active illness, remain to be identified. Only prospective study of markers prior to a predictable stressful event will be able to address this question effectively and clarify the role of a neuroendocrine response to stress in the this process prospectively. Studying candidate markers of susceptibility in subjects who undergo a predictable stressful event, such as major surgery, will be important not only for study of post-operative depression but also for study of stress-related disorders in general. Our hypothesis is that postoperative depression develops in patients with pre-stress alteration of neuroendocrine function in concert with specific premorbid risk factors. Our pilot findings suggest that major abdominal surgery constitutes a predictable stressful event leading to a de novo depression in a subgroup of postoperative patients. Therefore, we will test the hypothesis that pre-stress markers of HPA axis and catecholaminergic system will predict the development of depressive disorder following predictable stress of abdominal surgery. We predict that hypercortisolemia and DST non-suppression will predict depression. A cohort of 2lO patients undergoing elective endovascular or abdominal aortic operation for aneurysmal or occlusive disease and 70 "control" patients with aortic disease treated conservatively will be studied (4 groups). Surgical patients will be assessed preoperatively, and at three times postoperatively (3, 9, and 18 mo.) to document preoperative and postoperative neuroendocrine function and psychiatric morbidity. Control patients will be assessed to determine frequency of spontaneous onset of psychiatric abnormalities. Using mixed model regression, we will examine the role of psychological and neuroendocrine abnormalities in post-operative depression and determine the stability of specific factors (neuroendocrine measures, psychiatric symptoms and diagnoses) and whether they reliably predict the development of comorbid disorders postoperatively. We will also determine if the ability to terminate neuroendocrine stress response after surgery or in response to dexamethasone predicts outcome, and if this is linked to pre-stress abnormalities. Identification of pre-stress markers of vulnerability clearly has profound implications for our understanding of stress-related dysfunction, the pathophysiology of psychiatric disorders.