Tryptophan Depletion: A Phenotypic Marker for Depression

色氨酸耗竭：抑郁症的表型标志

• 批准号: 7214815
• 负责人: FRANCISCO A MORENO
• 金额: $ 36.9万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214815
• 关键词: Affect; Alleles; American; Amino Acids; Anxiety; Arizona; Biological; Blood specimen; Candidate Disease Gene; Catechols; Categories; Condition; Crossover Design; DRD4 gene; Data; Development; Disease; Disease remission; Dopamine Receptor; Dopamine-beta-monooxygenase; Double-Blind Method; Early Diagnosis; Exons; Family history of; Feasibility Studies; Functional disorder; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Hamilton Rating Scale for Depression; Heterogeneity; Individual; Ingestion; Intervention; Introns; Major Depressive Disorder; Measurement; Medical; Mental Depression; Methaqualone; Methyltransferase Gene; Mixed Function Oxygenases; Modeling; Monitor; Monoamine Oxidase A; Mood Disorders; Moods; Neurotransmitters; Neutral Amino Acids; Numbers; Participant; Pharmaceutical Preparations; Phenotype; Physiological; Plasma; Polymerase Chain Reaction; Population; Principal Investigator; Procedures; Promoter Regions; Psychiatry; Rate; Receptor Gene; Recording of previous events; Recurrence; Research; Research Methodology; Risk; Role; Safety; Score; Serotonin; Serotonin Receptor 5-HT1A; Site; Susceptibility Gene; Symptoms; Syndrome; Testing; Tryptophan; Tryptophan 5-monooxygenase; Universities; University Hospitals; base; behavior measurement; day; depressive symptoms; dopamine transporter; drinking; experience; follow-up; genetic association; human subject; improved; monoamine; neurotransmission; noradrenaline transporter; programs; response; serotonin transporter; single episode major depressive disorder; social; transcription factor; transmission process

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）：本研究的研究目标是提高我们对重性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，并确定易患重性情绪障碍的易感基因。 我们希望通过利用候选基因的方法来研究几个单胺相关的基因型标记和色氨酸（TRP）耗竭作为一个新定义的表型的抑郁反应的关联来实现这些。 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人群中5-羟色胺神经传递生理效应的理解。具体来说，神经递质耗竭范式已被提出作为主要情感障碍的表型，其基础是它们能够在被认为有抑郁症风险的受试者中诱导短暂和可逆的抑郁反应-例如缓解的抑郁症患者和具有多代情感障碍家族史的受试者-但不在健康对照中。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。沿着的是缺乏对疾病的客观生物测量，限制了该领域的进展。本研究将在100名有重度抑郁症病史但目前处于缓解期且至少三个月未服药的受试者中进行TRP耗竭测试。TRP耗竭涉及两个为期3天的疗程（主动耗竭和对照），采用双盲、对照、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。在测试之前、期间和之后，将获得抑郁、焦虑和躯体症状的临床医生和自评行为测量值，以及用于测量血浆TRP和大分子中性氨基酸的血液样本。在随访年期间，将前瞻性监测受试者的重度抑郁复发。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反应的基因分型，以研究与单胺功能相关的几种候选基因多态性。基因分型将在亚利桑那大学进行。制定了一项周密实施的人类受试者保护程序，以保障参与者的安全。令人信服的试点数据，以支持研究的可行性和有效性提出的假设。

项目成果

Association Study of Genotype by Depressive Response during Tryptophan Depletion in Subjects Recovered from Major Depression.

• DOI: 10.1159/000439114
• 发表时间: 2015-10
• 期刊: Molecular neuropsychiatry
• 作者: Moreno FA;Erickson RP;Garriock HA;Gelernter J;Mintz J;Oas-Terpstra J;Davies MA;Delgado PL
• 通讯作者: Delgado PL