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，并确定易患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的关联以及色氨酸（TRP）消耗作为新定义的表型的抑郁反应来实现这些目标。 TRP 消耗范式是一种广泛使用的研究方法，它安全有效地有助于我们更好地了解血清素神经传递在各种研究模型和受试者群体中的生理效应。具体来说，神经递质耗竭范式已被提议作为主要情感障碍的表型，因为它们能够在被认为有抑郁风险的受试者（例如缓解性抑郁症患者和具有多代情感障碍家族史的受试者）中诱导短暂且可逆的抑郁反应，但是不在健康对照范围内。我们建议研究一个新的表型定义，因为“抑郁症”是一种高度异质性的病症。再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 名有重度抑郁症病史但目前处于缓解状态且至少三个月未服用药物的受试者进行 TRP 消耗测试。 TRP 消耗涉及双盲、受控、交叉设计中的两个为期 3 天的疗程（主动消耗和控制）。第一天饮用不含 TRP 的 15 种氨基酸饮料或补充 TRP 的 16 种氨基酸饮料。在测试之前、期间和之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 TRP 和大中性氨基酸的血液样本。在接下来的一年中，将前瞻性地监测受试者的重度抑郁复发情况。 TRP 消耗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性。基因分型将在亚利桑那大学进行。已制定周密实施的保护人类受试者的程序，以保障参与者的安全。提供了令人信服的试点数据来支持所提出假设的研究可行性和有效性。