Glutamatergic Mediators of Antidepressant Response in Major Depression

描述(申请人提供)：这是一份K23指导的以患者为导向的研究职业发展奖的申请书，题为《严重抑郁症患者抗抑郁反应的谷氨酸能调节因子》。应聘者有情绪障碍临床管理和临床试验方法学培训的背景，目前是麦克莱恩医院生物精神病学实验室翻译神经科学研究的副主任。目前的建议旨在使候选人能够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，该工具将与临床试验一起使用，以衡量与治疗相关的神经化学变化。通过这样做，候选人希望能够确定治疗反应的调解人的标准和新的治疗情绪障碍的方法，并更好地了解这些治疗的作用机制。通过建议的研究，与导师和顾问的互动，以及教学课程，候选人寻求获得以下方面的专门培训和经验：1)先进的临床试验方法学和生物统计学；2)MRS技术及其在临床精神病学研究中的应用；3)神经化学原理；以及4)负责任的研究指导。与麦克莱恩大型神经科学研究社区的接触，以及麦克莱恩大量临床人群的接触，以及对麦克莱恩脑成像中心的无限制访问，为应聘者提供了开展这项工作的理想环境。这项培训将促进候选人发展成为一名独立的临床调查员，使用MRS来阐明情绪障碍治疗的作用机制，重点是识别潜在的治疗反应的神经化学生物标志物。这项拟议的研究使用了一种新的磁共振波谱技术--J-分辨质子磁共振波谱技术，用于测量西酞普兰治疗后患有严重抑郁障碍(MDD)的抑郁症患者大脑中谷氨酸和谷氨酰胺水平的急性和慢性变化，同时用21个条目的汉密尔顿抑郁评定量表(HAM-D)来评估抑郁症状。具体来说，候选人建议用西酞普兰每天20-60 mg治疗25名抑郁的MDD患者，为期6周。在研究过程中，候选人将在以下时间进行总共4次MRS扫描：1)基线；2)治疗第3天；3)治疗第7天；以及4)治疗6周。临床评估将在研究过程中每周进行一次。主要目的是验证这样一个假设，即从基线到治疗第3天，西酞普兰治疗与前扣带回(ACC)谷氨酰胺/谷氨酸比率(Gln/Glu)的增加有关，谷氨酰胺/谷氨酸是谷氨酸能神经递质活性的指标。第二个目的是验证这一假设，即从基线到治疗第7天，西酞普兰治疗与ACC中Gln/Glu比率的增加有关。探索性目的将调查：1)西酞普兰治疗是否与从基线到治疗6周时ACC中的Gln/Glu比率没有变化有关；2)从基线到第3天ACC中Gln/Glu比率的变化与第6周抑郁症状的改善呈正相关；3)从基线到第7天ACC中Gln/Glu比率的变化与第6周抑郁症状的改善呈正相关；4)基线时的谷氨酰胺/谷氨酸比率与第6周抑郁症状的改善呈正相关。通过这样做，候选人希望确定西酞普兰治疗后谷氨酸能活动的早期变化，这可能是临床反应的中介。MDD是一种常见的、经常使人虚弱的疾病。尽管如此，相当一部分MDD患者对目前可用的治疗没有反应，其他许多人必须忍受多次药物试验才能确定有效的治疗方法。由于几个原因，拟议的项目将具有重大意义。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，可能还有其他标准的抗抑郁药物，促进未来MDD新疗法的发展。其次，如果Gln/Glu比率的早期变化被证明是临床反应的中介，这一证据将支持进一步研究Gln/Glu比率作为一个生物标记物，可能预测西酞普兰的治疗反应，也许还有其他抗抑郁药物治疗。考虑到目前对现有抗抑郁药物进行充分试验所需的时间，以及经常需要多次试验才能达到疗效，找到一种能够预测MDD治疗早期临床反应的生物标记物将是一个重大进展。第三，这项研究可能会为谷氨酸能功能障碍在情绪障碍中的作用提供更多的见解，扩大对MDD的病理生理学和潜在治疗的科学知识。

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.