Glutamatergic Mediators of Antidepressant Response in Major Depression

描述（由申请人提供）：这是一个K23指导的以患者为导向的研究职业发展奖的申请，题为“谷氨酸介导的抗抑郁反应在严重抑郁症”。候选人具有情绪障碍临床管理和临床试验方法培训的背景，目前是姆克林医院生物精神病学实验室转化神经科学研究的副主任。当前提案旨在使候选人获得使用磁共振波谱（MRS）作为体内神经成像工具的经验和培训，以与临床试验一起连续使用，以测量与治疗相关的神经化学变化。在这样做的过程中，候选人希望能够确定对情绪障碍的标准和新型治疗的治疗反应的介质，并更好地了解这些治疗的作用机制。通过拟议的研究，与导师和顾问的互动，以及教学课程，候选人旨在获得专业培训和经验：1）先进的临床试验方法和生物统计学; 2）MRS技术及其在临床精神病学研究中的应用; 3）神经化学的原则;和4）负责任的研究行为。暴露于姆克林的大型神经科学研究社区，以及接触姆克林的大量临床人群和无限制地进入姆克林脑成像中心，为候选人提供了开展这项工作的理想环境。该培训将促进候选人发展成为独立的临床研究者，使用MRS阐明情绪障碍治疗的作用机制，重点是识别治疗反应的潜在神经化学生物标志物。 这项研究使用一种新的MRS技术，J-分辨质子MRS，来测量西酞普兰治疗后抑郁症患者大脑谷氨酸和谷氨酰胺水平的急性和慢性变化，同时评估抑郁症状，通过21项汉密尔顿抑郁评定量表（HAM-D）测量。具体而言，候选人建议用西酞普兰20-60 mg每日治疗25名抑郁的MDD患者，持续6周。在研究过程中，候选人将在以下时间点进行总共4次MRS扫描：1）基线; 2）治疗第3天; 3）治疗第7天; 4）治疗第6周。在研究过程中每周进行一次临床评估。主要目的是检验西酞普兰治疗与前扣带皮层（ACC）中谷氨酰胺/谷氨酸盐比值（Gln/Glu）从基线至治疗第3天升高相关的假设，谷氨酰胺/谷氨酸盐比值是一种谷氨酸能神经递质活性指数。次要目的是检验西酞普兰治疗与ACC中Gln/Glu比值从基线至治疗第7天增加相关的假设。探索性目的将调查：1）西酞普兰治疗是否与ACC中的Gln/Glu比率从基线至治疗第6周无变化相关; 2）ACC中的Gln/Glu比率从基线至第3天的变化是否与第6周抑郁症状的改善正相关; 3）ACC中Gln/Glu比率从基线到第7天的变化与第6周抑郁症状的改善正相关;和4）基线时的Gln/Glu比率与第6周时抑郁症状的改善正相关。在这样做的过程中，候选人希望确定西酞普兰治疗后可能介导临床反应的多巴胺能活性的早期变化。 抑郁症是一种常见的，经常使人衰弱的疾病。尽管如此，很大一部分MDD患者对目前可用的治疗没有反应，许多其他患者必须忍受多次药物试验才能确定有效的治疗方法。拟议的项目将具有重大意义，原因有几个。 首先，它将进一步阐明选择性5-羟色胺再摄取抑制剂（SSRIs）的作用机制，也许还有其他标准的抗抑郁药物，促进新的MDD治疗的未来发展。其次，如果Gln/Glu比值的早期变化显示出介导临床反应，则该证据将支持进一步研究Gln/Glu比值作为生物标志物，其可预测对西酞普兰的治疗反应，以及可能的其他抗抑郁治疗。考虑到目前对现有抗抑郁药进行充分试验所需的时间，以及经常需要多次试验才能获得应答，找到一种能够在MDD治疗早期预测临床应答的生物标志物将是一个重大进展。第三，这项研究可能会提供更多的见解，在情绪障碍，扩大科学知识的病理生理学和潜在的治疗抑郁症的作用。

DESCRIPTION (provided by applicant): This is an application for a K23 Mentored Patient-Oriented Research Career Development Award entitled "Glutamatergic Mediators of Antidepressant Response in Major Depression". The candidate has a background in the clinical management of mood disorders and training in clinical trial methodology and is currently the Associate Director for Translational Neuroscience Research in the Biological Psychiatry Laboratory at McLean Hospital. The current proposal is designed to enable the candidate to gain experience and training in the use of magnetic resonance spectroscopy (MRS) as an in vivo neuroimaging tool to be used adjunctively with clinical trials to measure neurochemical changes associated with treatment. In doing so, the candidate hopes to be able to identify mediators of treatment response to standard and novel treatments for mood disorders and to better understand the mechanisms of action of these treatments. Through the proposed research, interactions with mentors and consultants, and didactic coursework, the candidate seeks to obtain specialized training and experience in: 1) advanced clinical trial methodology and biostatistics; 2) MRS techniques and their applications to clinical psychiatric research; 3) principles of neurochemistry; and 4) the responsible conduct of research. Exposure to the large neuroscience research community at McLean as well as access to a large clinical population at McLean and unlimited access to the McLean Brain Imaging Center provides the candidate with the ideal environment to carry out this work. This training will foster the candidate's development into an independent clinical investigator using MRS to elucidate the mechanism of action of mood disorder treatments with a focus on the identification of potential neurochemical biomarkers of treatment response. The proposed research uses a novel MRS technique, J-resolved proton MRS, to measure acute and chronic changes in brain levels of glutamate and glutamine in depressed patients with major depressive disorder (MDD) following treatment with citalopram while simultaneously assessing depressive symptoms as measured by the 21-item Hamilton Depression Rating Scale (HAM-D). Specifically, the candidate proposes to treat 25 depressed MDD patients with citalopram 20-60 mg daily for a period of 6 weeks. During the course of the study, the candidate will perform a total of 4 MRS scans occurring at: 1) baseline; 2) day 3 of treatment; 3) day 7 of treatment; and 4) week 6 of treatment. Clinical assessments will be performed weekly during the course of the study. The primary aim is to test the hypothesis that citalopram treatment is associated with an increase in the glutamine/glutamate ratio (Gln/Glu), an index of glutamatergic neurotransmitter activity, in the anterior cingulate cortex (ACC) from baseline to day 3 of treatment. The secondary aim is to test the hypothesis that citalopram treatment is associated with an increase in the Gln/Glu ratio in the ACC from baseline to day 7 of treatment. Exploratory aims will investigate whether: 1) citalopram treatment is associated with no change in the Gln/Glu ratio in the ACC from baseline to week 6 of treatment; 2) change in the Gln/Glu ratio in the ACC from baseline to day 3 is positively associated with improvement in depressive symptoms at week 6; 3) change in the Gln/Glu ratio in the ACC from baseline to day 7 is positively associated with improvement in depression symptoms at week 6; and 4) the Gln/Glu ratio at baseline is positively associated with improvement in depressive symptoms at week 6. In doing so, the candidate hopes to identify early changes in glutamatergic activity following citalopram treatment that may mediate clinical response. MDD is a common and often debilitating disorder. Despite this, a significant fraction of MDD patients do not respond to currently available treatments and many others must endure multiple medication trials before an effective treatment can be identified. The proposed project would have major significance for several reasons. First, it will further elucidate the mechanism of action of selective serotonin reuptake inhibitors (SSRIs), and perhaps other standard antidepressant medications, facilitating the future development of novel MDD treatments. Second, if early changes in the Gln/Glu ratio are shown to mediate clinical response, this evidence would support further investigation of the Gln/Glu ratio as a biomarker that may predict treatment response to citalopram, and perhaps other antidepressant treatments. Given the time presently required for an adequate trial of existing antidepressants, and the frequent need for multiple trials to achieve response, it would be a major advance to find a biomarker able to predict clinical response early in the treatment of MDD. Third, this study will likely provide additional insights into the role of glutamatergic dysfunction in mood disorders, expanding scientific knowledge of the pathophysiology and potential treatment of MDD.