Glutamatergic Modulators for Rapid and Sustained Antidepressant Effect

本报告涉及根据方案04-M-0222（NCT 00088699）收集的工作。 我们的研究表明，多巴胺能系统参与了快速抗抑郁反应的作用机制。此外，该系统可能是开发治疗方法的可行目标，这些治疗方法对患有难治性抑郁症和自杀想法的个体具有快速和强大的疗效。我们发现，阿片类调节剂氯胺酮可产生快速、稳健和相对持续的抗抑郁、抗自杀和抗快感缺失作用。氯胺酮的反应在2小时内发生，持续约1周。与现有治疗相比，反应率在6-8周而不是几小时内发生。 研究：（重性抑郁症快速反应的生物标志物）。 目的：目的：探讨重度抑郁症患者对NMDA拮抗剂氯胺酮的快速抗抑郁反应的神经相关性。我们发现，N-甲基-D-天冬氨酸拮抗剂（氯胺酮）单次静脉给药可产生稳健且快速的抗抑郁作用;在输注后2小时内起效，并持续显著1周。 目的是1）检查氯胺酮的抗自杀作用，和2）检查在重性抑郁症和双相情感障碍中对氯胺酮的抗抑郁反应的相关性，并包括这些数据/结果测量：临床（例如，家族史）、成像（正电子发射断层扫描PET、磁共振成像/光谱学）、电生理学（脑磁图MEG、脑电图EEG）、神经心理学和生物化学（例如，遗传学、microRNA、BDNF、代谢组学）。 过去一年的成果： 氯胺酮代谢物（2 R，6 R）-羟基去甲氯胺酮的NMDA非依赖性抗抑郁作用。在2016年发表在Nature上的这篇论文中，我们揭示了氯胺酮如何产生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（2 R，6 R）-羟基去甲氯胺酮发生的。这种代谢物不会产生氯胺酮所具有的解离和拟精神副作用或滥用风险。这一发现导致了一系列药物的开发，这些药物可以用于治疗难治性抑郁症，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。在本研究中，我们发现由脂肪组织分泌的细胞信号蛋白脂肪因子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）中起关键作用，并直接调节炎症和神经可塑性通路，还影响胰岛素敏感性、骨代谢和交感神经流出;所有这些都与情绪障碍有关 2. 治疗前BOLD对情绪面孔的反应差异与抗抑郁药对东莨菪碱的反应相关。东莨菪碱静脉注射（用于晕船）产生快速的抗抑郁作用。在这里，我们表明，一个大胆的反应，情绪化的面孔与东莨菪碱的抗抑郁作用。这项工作很重要，因为它开始梳理在治疗之前，谁可能会或可能不会对特定的治疗干预作出反应。 3. 单剂量输注氯胺酮和非氯胺酮N-甲基-D-天冬氨酸受体拮抗剂治疗单相和双相抑郁症。在这项研究中，我们对氯胺酮治疗难治性抑郁症的所有研究的疗效、安全性和时间轨迹进行了荟萃分析。我们证实，氯胺酮在多个中心确实对难治性抑郁症患者产生了快速和相对持续的抗抑郁疗效。这项荟萃分析支持了我们迄今为止关于氯胺酮治疗抑郁症的工作和发现。 4. 氯胺酮对抑郁症患者有快速抗疲劳作用。在对我们正在进行的研究数据的重新分析中，我们证明氯胺酮对抑郁症患者产生快速和相对持续的抗疲劳作用。这一发现很重要，因为它可以为我们提供可能对各种医学疾病和其他疾病产生快速抗疲劳作用的药物的线索。 5. 快速抗抑郁药临床试验中自杀意念的评估指标。在本项目中，我们评估了参与氯胺酮研究的受试者的自杀想法。我们证明，一些措施是可靠的，在衡量自杀的想法和治疗反应。

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.