Neurobiological Predictors of Stress-Related Disorders

描述（由申请人提供）：与压力相关的精神疾病，特别是术后抑郁症，是一个主要的挑战。抑郁、焦虑和创伤后应激障碍（PTSD）通常在各种压力因素（如手术、严重疾病、机动车事故和自然灾害）后发展，而这些疾病的脆弱性因素可能是共同的。下丘脑-垂体-肾上腺（HPA）异常的不同特征在抑郁症和创伤后应激障碍中已得到证实，但那些先前存在的改变，那些是对压力/创伤的反应，以及那些是活动性疾病的组成部分，仍有待确定。只有在可预测的压力事件发生前对标记物进行前瞻性研究，才能有效地解决这个问题，并阐明神经内分泌对压力的反应在这一过程中的作用。在经历可预测的压力事件（如大手术）的受试者中研究候选易感性标记，不仅对术后抑郁症的研究很重要，而且对一般压力相关疾病的研究也很重要。我们的假设是，术后抑郁发生在神经内分泌功能的应激前改变的患者中，与特定的病前危险因素相一致。我们的初步研究结果表明，腹部大手术构成了一个可预测的压力事件，导致亚组术后患者的新生抑郁。因此，我们将检验HPA轴和儿茶酚胺能系统的预应激标志物对腹部手术可预测应激后抑郁症发展的预测假设。我们预测高皮质醇血症和DST不抑制将预测抑郁症。本研究分为4组，选取2lO例因动脉瘤性或闭塞性疾病而行择期血管内或腹主动脉手术的患者和70例保守治疗的主动脉疾病患者作为对照。术前和术后3次（3、9和18个月）评估手术患者，记录术前和术后神经内分泌功能和精神疾病。对照患者将被评估以确定自发性精神异常发作的频率。使用混合模型回归，我们将检查心理和神经内分泌异常在术后抑郁症中的作用，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合并症的发展。我们还将确定手术后或地塞米松治疗后终止神经内分泌应激反应的能力是否能预测预后，以及这是否与应激前异常有关。识别脆弱的压力前标记显然对我们理解与压力相关的功能障碍、精神疾病的病理生理学具有深远的意义。

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.