Neurobiological Predictors of Stress-Related Disorders

压力相关疾病的神经生物学预测因素

• 批准号: 6764209
• 负责人: Israel Liberzon
• 金额: $ 31.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-05 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764209
• 关键词: biomarker; cardiovascular surgery; catecholamines; clinical research; comorbidity; corticosteroid receptors; depression; dexamethasone; disease /disorder proneness /risk; human morbidity; human subject; hypercortisolism; hypothalamic pituitary adrenal axis; injury /disease stressor; longitudinal human study; neurobiology; neuroendocrine system; patient oriented research; postoperative state; posttraumatic stress disorder; preoperative state; social support network; stress

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.

描述（由申请人提供）：一般而言，与压力相关的精神疾病，特别是术后抑郁症，构成了一项重大挑战。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压力源之后出现的，而这些疾病很可能具有脆弱性因素。下丘脑-垂体-肾上腺 (HPA) 异常的独特特征在抑郁症和 PTSD 中已得到充分证实，但那些改变是预先存在的，那些是对压力/创伤的反应，以及那些是活动的组成部分病情，尚待鉴定。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个问题，并前瞻性地阐明神经内分泌对应激的反应在此过程中的作用。研究经历可预测的压力事件（例如大手术）的受试者的易感性候选标记不仅对于术后抑郁症的研究很重要，而且对于一般压力相关疾病的研究也很重要。我们的假设是，神经内分泌功能预应激改变与特定病前危险因素相一致的患者术后抑郁会发生。我们的初步研究结果表明，腹部大手术构成了一种可预测的压力事件，导致术后患者亚组出现新的抑郁症。因此，我们将检验以下假设：HPA 轴和儿茶酚胺能系统的预应激标记物将预测腹部手术可预测应激后抑郁症的发展。我们预测高皮质醇血症和夏令时非抑制将预测抑郁症。将研究一组210名因动脉瘤或闭塞性疾病而接受选择性血管内或腹主动脉手术的患者和70名接受保守治疗的主动脉疾病“对照”患者（4组）。手术患者将在术前和术后三次（3、9和18个月）进行评估，以记录术前和术后的神经内分泌功能和精神疾病发病率。将评估对照患者以确定精神异常自发发作的频率。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共病的发展。我们还将确定手术后或地塞米松反应终止神经内分泌应激反应的能力是否可以预测结果，以及这是否与应激前异常有关。识别应激前脆弱性标志物显然对我们理解应激相关功能障碍、精神疾病的病理生理学具有深远的影响。