Tryptophan Depletion: A Phenotypic Marker for Depression

色氨酸耗竭：抑郁症的表型标志

• 批准号: 6981999
• 负责人: FRANCISCO A MORENO
• 金额: $ 46.45万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6981999
• 关键词: anxiety; behavioral /social science research tag; clinical research; depression; disease /disorder etiology; gene expression; genetic markers; genetic polymorphism; genetic promoter element; genetic susceptibility; genotype; human genetic material tag; human subject; interview; longitudinal human study; mood disorders; pathologic process; phenotype; polymerase chain reaction; serotonin; tryptophan

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.

描述（由申请人提供）：本研究的研究目的是提高我们对重度抑郁症及其病理生理学的理解，提高我们预测未来发作的能力，并识别易导致重度情绪障碍的易感基因。我们希望通过利用候选基因方法来研究几种单胺相关基因型标记与色氨酸（TRP）耗竭的抑郁反应之间的关系，从而实现这些目标。TRP耗竭范式是一种广泛使用的研究方法，安全有效地促进了我们对各种研究模型和受试者群体中血清素神经传递的生理效应的理解。具体来说，神经递质耗竭范式已经被提出作为主要情感性障碍的表型，基于它们在被认为有抑郁风险的受试者中（如抑郁症缓解者和具有多代情感性障碍家族史的受试者）诱导短暂和可逆抑郁反应的能力，但在健康对照中却没有。我们建议研究一个新的表型定义，因为“抑郁症”是一个高度异质性的条件。这一点，加上缺乏对该病的客观生物学测量，限制了该领域的进展。本研究将对100名重度抑郁症患者进行TRP消耗测试，这些患者目前处于缓解期，并且至少有三个月没有使用药物。TRP消耗包括两个为期3天的双盲、对照、交叉设计（主动消耗和对照）。第一天摄入不含色氨酸的15种氨基酸饮料或补充色氨酸的16种氨基酸饮料。临床和自评抑郁、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中性氨基酸的血液样本将在测试前、测试中和测试后获得。在随访的一年中，将对受试者进行重度抑郁症复发的前瞻性监测。TRP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。基于聚合酶链反应的基因分型将进行，以研究与单胺功能相关的几个候选基因多态性。基因分型将在亚利桑那大学进行。一个精心实施的程序来保护人类受试者，以保障参与者的安全。提出了令人信服的试点数据，以支持研究的可行性和提出的假设的有效性。