Tryptophan Metabolism, Genes, and Major Depression

描述（由申请人提供）：血清素是一种单胺能神经递质，与多种精神疾病，特别是抑郁症有关。中枢5 -羟色胺神经元是三环抗抑郁药和选择性5 -羟色胺再摄取抑制剂（SSRIs）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和限速酶。色氨酸的代谢开始于肝脏，并导致犬尿氨酸的形成。这些化合物和其他代谢途径成分的浓度可以通过代谢组学来分析，代谢组学是一种新的生物技术，应用先进的质谱技术来表征整个代谢途径。由此产生的“代谢特征”可以被确定为一个或一组个体。最近，我们的研究小组报道了人类色氨酸羟酶-2基因（TPH2）中特定的单核苷酸多态性（C1463G）与抑郁症风险增加以及抗抑郁药物难耐风险增加之间的关联。该应用程序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的关键底物水平。2)利用代谢组学技术检测色氨酸代谢和其他代谢途径。3)收集试点数据，检测TPH2中C1463G多态性和非C1463G多态性的抑郁症患者中色氨酸合成和代谢的关键底物水平。我们将招募40名抑郁症患者和20名未患抑郁症的对照组。患者将符合单极重性抑郁症的标准，并将从三个地点招募，以确保其严重程度和抗抑郁药物的暴露程度：电休克治疗项目、门诊情绪障碍诊所和普通内科诊所。一旦确定了抑郁症的诊断，并排除了其他精神疾病，研究对象将被抽血。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以及抑郁症组的严重程度进行统计分析。还将获得携带TPH-2 C1463突变的抑郁症患者的初步数据，并与其他抑郁症患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.