Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect

我们的研究表明，谷氨酸能系统参与了抗抑郁药的作用机制。我们发现，非竞争性NMDA拮抗剂(氯胺酮)具有快速、强劲和相对持久的抗抑郁和抗自杀作用。对氯胺酮的反应在2小时内发生，持续约1周。与现有治疗类似的应答率发生在6-8周，而不是几个小时。目前的议定书包括旨在解决3个主要问题的研究： 研究1：(重度抑郁障碍快速反应的生物标志物)。 目的：研究NMDA拮抗剂氯胺酮对重度抑郁障碍患者的快速抗抑郁作用与神经功能的关系。我们发现，单次静脉注射N-甲基-D-天冬氨酸拮抗剂可以产生强劲而迅速的抗抑郁作用；在静脉注射后2小时内起效，并持续1周。 研究2：(双相抑郁快速反应的生物标志物)。 目的：研究NMDA拮抗剂氯胺酮对重度抑郁障碍患者的快速抗抑郁作用与神经功能的关系。我们发现，单次静脉注射N-甲基-D-天冬氨酸拮抗剂可以产生强劲而迅速的抗抑郁作用；在静脉注射后2小时内起效，并持续1周。 目的是1)检验氯胺酮的抗自杀作用，2)检验氯胺酮对严重抑郁障碍和双相情感障碍的抗抑郁反应的相关性，包括：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、脑电图)、神经心理学和生化(例如遗传学、微RNA、脑源性神经营养因子、代谢组学)。 过去一年的结果： 1)难治性双相抑郁的快速抗抑郁作用。 我们用氯胺酮治疗双相情感障碍，重复了我们之前的发现。在难治性双相抑郁患者中，单次静脉注射N-甲基-D-天冬氨酸拮抗剂可产生强劲而快速的抗抑郁效果。此外，我们在1小时内发现了快速的抗自杀作用。 2)睡眠标志物是氯胺酮反应的预测因子 脑电睡眠慢波活动(SWA；脑电功率在0.6-4赫兹之间)被认为是中枢突触可塑性的标志。睡眠慢波的产生减少--这是抑郁症睡眠的一个核心特征--表明了疾病潜在的可塑性变化。我们发现，基线时的增量睡眠比率(DSR)是衡量SWA的指标，与氯胺酮治疗后抑郁评分的降低呈正相关。 3)遗传学作为氯胺酮反应的预测因子(快速抗抑郁作用) 一项动物研究发现，氯胺酮的抗抑郁作用需要正常的脑源性神经营养因子(BDNF)功能。我们应该指出，在重度抑郁障碍患者中，携带Val/Val BDNF等位基因的MDD患者比携带BDNF Met的患者更有可能对氯胺酮表现出更强的抗抑郁反应。 4)突触增强是氯胺酮快速抗抑郁反应的关键 我们在20名难治性抑郁症患者中使用了脑磁图记录，发现在输注氯胺酮230分钟后抑郁症状明显改善的患者(反应者)表现出更强的皮质兴奋性。具体地说，我们发现，在输注氯胺酮后，刺激诱发的躯体感觉皮质反应增加，相对于治疗前反应者的反应，但在治疗无反应者中没有。 5)氯胺酮代谢物在其反应和副作用中起重要作用(专利申请) 在氯胺酮的代谢和处置(双相抑郁和重度抑郁障碍)方面观察到了诊断上的差异。双相抑郁患者的(2S，5S；2R，5R)-HNK代谢物浓度与氯胺酮无反应有关。氯胺酮的一些羟化代谢产物与精神病和分离症状(氯胺酮的副作用)有关。

Our research suggests that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) resulted in rapid, robust and relatively sustained antidepressant and antisuicidal 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. The current protocol consists of studies designed to address 3 major questions: Study 1: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To examine what the neural correlates are 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; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Study 2: (Biomarkers of rapid response in bipolar depression). OBJECTIVE: To examine what the neural correlates are 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; onset occurred within 2 hours postinfusion 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: 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: 1) Rapid antidepressant effects in treatment-resistant bipolar depression. We replicated our previous findings with ketamine in bipolar depression. In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist. In addition, we found rapid antisuicidal effects within 1 hour. 2) Sleep marker are a predictor of response to ketamine Electroencephalographic (EEG) sleep slow wave activity (SWA; EEG power between 0.6 and 4Hz) has been proposed as a marker of central synaptic plasticity. Decreased generation of sleep slow waves - a core feature of sleep in depression - indicates underlying plasticity changes in the disease. We found that Delta sleep ratio (DSR) at baseline, a measure of SWA, was positively correlated with reductions in depressive scores with ketamine treatment. 3) Genetics as a predictor of response to ketamine (rapid antidepressant effect) An animal study found that normal brain derived neurotrophic factor (BDNF) function is required for the antidepressant effects of ketamine. We should that in patients with major depressive disorder that MDD patients with the Val/Val BDNF allele were more likely to exhibit increased antidepressant responses to ketamine than BDNF Met carriers. 4) Synaptic potentiation is critical for the rapid antidepressant response to ketamine We used magnetoencephalographic recordings in 20 patients with treatment-resistant depression and found that patients with robust improvements in depressive symptoms 230 min after infusion of ketamine (responders) exhibited increased cortical excitability. Specifically, we found that stimulus-evoked somatosensory cortical responses increased after infusion with ketamine, relative to pretreatment responses in responders but not in treatment nonresponders. 5) Ketamines metabolites are important in its ressponse and side effects (patent filed) A diagnostic difference was observed in the metabolism and disposition of ketamine (bipolar depression versus major depressive disorder). Concentrations of (2S,5S;2R,5R)-HNK metabolites were related to nonresponse to ketamine in bipolar depression. Some hydroxylated metabolites of ketamine correlated with psychotic and dissociative symptoms (side effects of ketamine).