Tryptophan Depletion: A Phenotypic Marker for Depression

描述(申请人提供)：这项研究的目的是提高我们对严重抑郁症及其病理生理学的了解，提高我们预测未来发作的能力，并确定易患重大情绪障碍的易感基因。我们期望通过利用候选基因方法来研究几个与单胺相关的基因标记与色氨酸(Trp)耗竭的抑郁反应之间的关系，作为一种新定义的表型。色氨酸耗竭范式是一种被广泛使用的研究方法，它安全有效地有助于我们在各种研究模型和受试者群体中更好地理解5-羟色胺神经传递的生理效应。具体地说，神经递质耗竭范式被认为是主要情感障碍的表型，基于它们在被认为有抑郁风险的受试者中诱导短暂和可逆的抑郁反应的能力--例如缓解的抑郁症患者和有多代情感障碍家族史的受试者--但在健康对照中不是。我们建议研究一种新的表型定义，因为“抑郁症”是一种高度异质性的疾病。这一点，加上缺乏对该疾病的客观生物学测量，限制了该领域的进展。本研究将对100名有严重抑郁症病史但目前处于缓解期且停药至少三个月的受试者进行色氨酸耗竭测试。Trp耗竭包括两个为期3天的疗程(主动耗尽和控制)，采用双盲、受控、交叉设计。第一天包括摄入不含Trp的15种氨基酸饮料或补充Trp的16种氨基酸饮料。在测试前、测试中和测试后，将获得临床医生和自我评估的抑郁、焦虑和躯体症状的行为测量，以及用于测量血浆色氨酸和大量中性氨基酸的血液样本。在接下来的一年中，受试者将被前瞻性地监测是否有严重的抑郁症复发。色氨酸耗竭测试将在两个地点进行：亚利桑那大学和克利夫兰大学医院/凯斯西储大学精神病学系。将进行基于聚合酶链式反应的基因分型，以研究与单胺功能相关的几个候选基因多态。基因分型将在亚利桑那大学进行。为保障参赛者的安全，制定了周到的保护人类受试者的程序。令人信服的试点数据被用来支持所提出的假设的可行性和有效性。

DESCRIPTION (provided by applicant): The research objectives of this study are to improve our understanding of major depression and its pathophysiology, improve our ability to predict future episodes, and identify susceptibility genes predisposing to major mood disorders. We expect to accomplish these by utilizing a candidate gene approach to study the association of several monoamine related genotypic markers and the depressive response to tryptophan (TRP) depletion as a newly defined phenotype. The TRP depletion paradigm is a broadly utilized research methodology that safely and effectively has contributed to our improved understanding of the physiological effects of serotonin neurotransmission in a variety of research models and subject populations. Specifically, the neurotransmitter depletion paradigms have been proposed as phenotypes for major affective disorders based on their ability to induce brief and reversible depressive responses in subjects considered at risk for depression - such as remitted depressives, and subjects with multigenerational family history of affective disorders - but not in healthy controls. We propose to study a new phenotypic definition because "depression" is a highly heterogeneous condition. This, along with the lack of objective biological measurements of the disease, has limited progress in the field. The present study will conduct TRP depletion testing in 100 subjects with history of major depression but who are currently in remission and medication-free for at least three months. TRP depletion involves two 3-day sessions (active depletion and control) in a double blind, controlled, crossover design. Day one involves the ingestion of a TRP-free 15 amino acid drink or a TRP-supplemented 16 amino acid drink. Clinician and self-rated behavioral measurements of depression, anxiety, and somatic symptoms, as well as blood samples for measurement of plasma TRP and large neutral amino acids will be obtained prior to, during, and after testing. Subjects will be monitored prospectively for major depressive recurrences during the follow-up year. TRP depletion testing will take place at two sites: The University of Arizona, and University Hospitals of Cleveland / Case Western Reserve University Departments of Psychiatry. Polymerase Chain Reaction based Genotyping will be performed in order to study several candidate gene polymorphisms relevant to monoamine function. Genotyping will take place at the University of Arizona. A thoughtfully implemented procedure for protection of human subjects is in place to safeguard participant's safety. Compelling pilot data are presented to support the study feasibility and validity of the proposed hypotheses.