Tryptophan Metabolism, Genes, and Major Depression

描述(申请人提供)：5-羟色胺是一种单胺能神经递质，与多种精神疾病有关，特别是抑郁症。中枢5-羟色胺神经元是三环类抗抑郁药和选择性5-羟色胺再摄取抑制剂(SSRI)的主要靶点。色氨酸羟化酶(TPH)是5-羟色胺生物合成的第一步限速酶。色氨酸的代谢始于肝脏，并导致犬尿氨酸的形成。这些化合物的浓度和其他代谢途径的成分可以通过代谢组学进行分析，代谢组学是一种新的生物技术，它应用先进的质谱学技术来表征整个代谢途径。然后可以为一个人或一组人确定由此产生的“代谢特征”。最近，我们小组报告了人类色氨酸羟基酶-2基因(TPH2)的特定单核苷酸多态(C1463G)与抑郁症风险增加以及抗抑郁药物无效风险增加之间的关联。这项应用将检查以下具体目标：1)确定抑郁症患者与对照组色氨酸代谢中关键底物的水平。2)利用代谢组学技术研究色氨酸代谢及其他代谢途径。3)收集先导数据，以检测具有和不具有TPH2基因C1463G多态的抑郁症患者色氨酸合成和代谢中的关键底物水平。我们将招募40名抑郁症患者和20名从未患抑郁症的对照组。患者将符合单相重度抑郁症的标准，并将从三个地点招募，以确保广泛的严重性和先前接触抗抑郁药物：电休克治疗计划、门诊情绪障碍诊所和普通内科诊所。一旦抑郁症诊断成立，排除了其他精神疾病，受试者就会抽血。我们的目标是获得10名携带TPH-2 C1463G突变的受试者。将对患者和对照组之间的代谢特征进行统计分析，并根据抑郁组中的严重程度进行分析。还将获得携带TPH-2 C1463突变的抑郁症受试者的飞行员数据，并将其与抑郁症受试者和对照组进行比较。这项研究的结果将有助于为未来使用遗传学和代谢组学技术的治疗研究提供信息。

DESCRIPTION (provided by applicant): Serotonin is a monoaminergic neurotransmitter involved in a wide variety psychiatric disorders, particularly depression. Central serotonin neurons are the primary targets for tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Tryptophan hydroxylase (TPH) is the first-step and rate-limiting enzyme in serotonin biosynthesis. The metabolism of tryptophan initiates in the liver and leads to formation of kynurenine. The concentrations of these compounds and constituents of other metabolic pathways can be analyzed through metabolomics, a new biotechnology that applies advanced mass spectrometry techniques to characterize entire metabolic pathways. The resultant "metabolic signature" can then be determined for an individual or group of individuals. Recently, our group reported an association between a specific single nucleotide polymorphism (C1463G) in the human tryptophan hydroxylase-2 gene (TPH2) and increased risk of depression, and increased risk of refractoriness to antidepressant medications. This application will examine the following specific aims: 1) determine levels of key substrates in tryptophan metabolism in depressed patients versus controls. 2) To use metabolomic technology to examine tryptophan metabolism and other metabolic pathways. 3) To gather pilot data to examine levels of key substrates in tryptophan synthesis and metabolism among depressed patients with and without C1463G polymorphisms in TPH2. We will recruit 40 depressed patients and 20 never-depressed controls. Patients will meet criteria for unipolar major depression and will be recruited from three sites to ensure broad ranges of severity and prior exposure to antidepressants: the electroconvulsive therapy program, an outpatient mood disorders clinic, and a general internal medicine clinic. Once depression diagnoses are established and other psychiatric disorders are ruled out, subjects will have blood drawn. We will aim to get 10 subjects with the TPH-2 C1463G mutation. Metabolic signatures will be statistically analyzed between patients and controls and by severity within the depressed group. Pilot data on depressed subjects with the TPH-2 C1463 mutation will also be obtained and compared with ofher depressed subjects and controls. Results from this study will help inform future treatment studies using genetics and metabolomic technology.