Glutamatergic Modulators for Rapid and Sustained Antidepressant Effect

谷氨酸能调节剂具有快速和持续的抗抑郁作用

• 批准号: 9357286
• 负责人: Carlos Zarate
• 金额: $ 419.84万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9357286
• 关键词: Adipose tissue; Adverse effects; Antidepressive Agents; Biochemical; Biological Markers; Bipolar Depression; Bipolar Disorder; Body mass index; Brain-Derived Neurotrophic Factor; Brief Psychiatric Rating Scale; Chronic; Clinical; Clinical Trials; Data; Disease; Distress; Dose; Electroencephalography; Electrophysiology (science); Emotional; Face; Family; Fatigue; Feeling suicidal; Genetic; Glutamates; Government; Hour; Image; Individual; Industry; Inflammation; Infusion procedures; Intervention; Intravenous; Investments; Ketamine; Life; Magnetic Resonance Imaging; Magnetoencephalography; Major Depressive Disorder; Manic; Measures; Mediating; Medical; Mental Depression; Meta-Analysis; Metabolism; MicroRNAs; Montgomery and Asberg depression rating scale; Mood Disorders; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Nature; Neuronal Plasticity; Outcome Measure; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Protocols documentation; Publishing; Recording of previous events; Relapse; Reporting; Research; Risk; Role; Safety; Scopolamine; Sea Sickness; Series; Signal Transduction; Signaling Protein; Sleep; System; Time; Unipolar Depression; Work; adipokines; antidepressant effect; blood oxygenation level dependent response; bone metabolism; collected works; functional disability; imaging genetics; impression; insulin sensitivity; interest; intravenous administration; metabolomics; neural correlate; neuropsychological; primary outcome; relating to nervous system; response; secondary outcome; spectroscopic imaging; treatment response; treatment-resistant depression

This Report involves work collected under protocol 04-M-0222 (NCT00088699). Our research suggests that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. In addition, this system may be a feasible target for developing treatments that have rapid and robust efficacy in individuals who have treatment-resistant depression and suicidal thoughts. We found that the glutamatergic modulator ketamine resulted in rapid, robust and relatively sustained antidepressant, antisuicidal, and anti-anhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with existing treatments occur at 6-8 weeks instead of hours. Study: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To determine the neural correlates of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist (ketamine); onset occurred within 2 hours post-infusion and continued to remain significant for 1 week. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include these data/outcome measures: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics). Results in the past year: NMDA-independent antidepressant actions of ketamine metabolite (2R,6R)-hydroxynorketamine. In this paper published in Nature 2016, we uncover the mechanism of how ketamine produces its rapid and sustained antidepressant effect. More importantly, we find that this effect takes place through one of its metabolites, (2R,6R)-hydroxynorketamine. This metabolite does not produce the dissociative and psychomimetic side effects or risk of abuse potential that ketamine has. This discovery has resulted in a series of drugs that could be developed for treatment-resistant depression that have rapid antidepressant effects and are well tolerated. 1. The role of adipokines in the rapid antidepressant effects of ketamine. In this project, we find that adipokines, which are cell signaling proteins secreted by the adipose tissue mediate the rapid antidepressant effects of ketamine. Adipokines have a key role in metabolism (including body mass index) and directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders 2. Pre-treatment differences in BOLD response to emotional faces correlate with antidepressant response to scopolamine. Intravenous administration of scopolamine (used for sea-sickness) produces rapid antidepressant effects. Here we show that a BOLD response to emotional faces correlates with the antidepressant effects of scopolamine. This work has importance because it begins to tease how prior to treatment who might or might not respond to a particular treatment intervention before the treatment is administered. 3. Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression. In this study, we conducted a meta-analysis of efficacy, safety and time trajectories of all studies of ketamine in treatment-resistant depression. We confirmed that ketamine in multiple centers did indeed produce rapid and relatively sustained antidepressant efficacy in patients with treatment-resistant depression. This meta-analysis supports our work and findings to date with ketamine in depression. 4. Ketamine has rapid anti-fatigue effects in patients with depression. In a reanalysis of data from our ongoing studies, we demonstrate that ketamine produces rapid and relatively sustained anti-fatigue effects in patients with depression. This finding is important as it could give us clues to drugs that might produce rapid anti-fatigue effects for a variety of medical disorders and other conditions. 5. Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant. In this project, we assessed measures of suicidal thinking in subjects who participated in our ketamine studies. We demonstrate that some measures are reliable in measuring suicidal thinking and response to treatment.

该报告涉及根据协议04-M-0222（NCT00088699）收集的工作。 我们的研究表明，谷氨酸能系统参与了快速抗抑郁反应的作用机理。此外，该系统可能是开发具有耐药性抑郁症和自杀思想的个体具有快速且效率强大的治疗方法的可行目标。我们发现，谷氨酸能调节剂氯胺酮会导致快速，健壮和相对持续的抗抑郁药，抗杀虫剂和抗抗雄性作用。对氯胺酮的反应发生在2小时内，大约持续了1周。现有治疗的可比较响应率在6-8周而不是小时内发生。 研究：（重度抑郁症的快速反应生物标志物）。 目的：确定在患有重度抑郁症的受试者中对NMDA拮抗剂氯胺酮快速抗抑郁反应的神经相关性。我们发现由单个静脉注射剂量的N-甲基-D-天冬氨酸拮抗剂（氯胺酮）产生了鲁棒和快速的抗抑郁作用。灌注后2小时内发作，并继续保持1周的意义。 目的是1）检查氯胺酮的抗杀菌作用，以及2）检查主要抑郁症和双相情感障碍中抗抑郁反应的相关性，包括这些数据/结果指标：临床（例如家族史）（例如家族史），Immation（Positron Semustron Pet，磁性共生率，磁性映射），磁性图像元素（Electopraphy Immerypodictical）（Electopraphy）（Electopraphy）（Electopraphy）（Electopraphy）学（Electopraphy）学（Electopraphy Imparosementy（Electoplosementy），电子学）（电子元素）脑电图EEG），神经心理学和生化（例如遗传学，microRNA，BDNF，代谢组学）。 过去一年的结果： 氯胺酮代谢物（2R，6R） - 羟基诺甲胺的NMDA无关抗抑郁作用。在2016年在《大自然》上发表的本文中，我们发现了氯胺酮如何产生其快速和持续的抗抑郁作用的机制。更重要的是，我们发现这种作用是通过其代谢产物之一（2R，6R） - 羟基甲基氨基胺发生的。这种代谢产物不会产生氯胺酮具有的分离和心理副作用或滥用潜力的风险。这一发现导致了一系列药物，这些药物可以用于抗治疗抑郁症，这些抑郁症具有快速的抗抑郁作用，并且耐受性良好。 1。脂肪因子在氯胺酮快速抗抑郁作用中的作用。在这个项目中，我们发现脂肪因子是脂肪组织分泌的细胞信号蛋白，可介导氯胺酮的快速抗抑郁作用。脂肪因子在代谢（包括体重指数）中具有关键作用，直接调节炎症和神经塑性途径，还影响胰岛素敏感性，骨骼代谢和交感神经流出；所有这些都与情绪障碍有关 2。对情感面部反应的大胆反应的预处理差异与抗抑郁药对西侧的反应有关。静脉内施用西孢子（用于海泡）会产生快速的抗抑郁作用。在这里，我们表明，对情感面孔的大胆反应与东pol碱的抗抑郁作用相关。这项工作很重要，因为它开始逗弄在治疗之前可能会或可能对特定治疗干预措施做出反应的治疗前。 3。单极和双极抑郁症的单剂量输注氯胺酮和非酮胺N-甲基-D-天冬氨酸受体拮抗剂。在这项研究中，我们对氯胺酮在耐药性抑郁症中的所有研究的疗效，安全性和时间轨迹进行了荟萃分析。我们证实，多个中心的氯胺酮确实确实在耐药抑郁症患者中产生了快速且相对持续的抗抑郁功效。这项荟萃分析支持了我们迄今为止与氯胺酮在抑郁症中的工作和发现。 4。氯胺酮在抑郁症患者中具有快速的抗毒液作用。在对我们正在进行的研究中的数据进行重新分析时，我们证明氯胺酮在抑郁症患者中会产生快速且相对持续的抗疾病作用。这一发现很重要，因为它可以为我们提供有关可能对各种医疗疾病和其他疾病产生快速抗狂热作用的药物的线索。 5。在临床试验中评估自杀意念的度量，并具有快速作用的抗抑郁药。在这个项目中，我们评估了参加我们氯胺酮研究的受试者中自杀思维的措施。我们证明，有些措施在衡量自杀思维和对治疗的反应方面是可靠的。