Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect

快速谷氨酸调节剂

• 批准号: 8556954
• 负责人: Carlos Zarate
• 金额: $ 254.33万
• 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/8556954
• 关键词: Address; Adverse effects; Alleles; Animals; Antidepressive Agents; Biochemical; Biological Markers; Bipolar Depression; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Brief Psychiatric Rating Scale; Chemosensitization; Chronic; Clinical; Diagnostic; Disease; Dose; Electroencephalography; Exhibits; Family; Feeling suicidal; Generations; Genetic; Glutamates; Hour; Image; Impairment; Infusion procedures; Intravenous; Ketamine; Legal patent; Life; Magnetic Resonance Imaging; Magnetoencephalography; Major Depressive Disorder; Manic; Measures; Medical; Mental Depression; Metabolism; MicroRNAs; Montgomery and Asberg depression rating scale; N-Methylaspartate; NMDA receptor antagonist; Outcome Measure; Patients; Physical Function; Positron-Emission Tomography; Protocols documentation; Recording of previous events; Relapse; Relative (related person); Research; Research Design; Resistance; Sleep; Slow-Wave Sleep; Social Functioning; Spectrum Analysis; Stimulus; Symptoms; Synapses; Synaptic plasticity; System; depressive symptoms; impression; meetings; metabolomics; neuropsychological; primary outcome; relating to nervous system; response; secondary outcome; somatosensory; valylvaline

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).

我们的研究表明，多巴胺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）导致快速，稳健和相对持续的抗抑郁和抗自杀作用。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。当前方案包括旨在解决3个主要问题的研究： 研究1：（重性抑郁症快速反应的生物标志物）。 目的：探讨重度抑郁症受试者对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，单次静脉注射N-甲基-D-天冬氨酸拮抗剂可产生强大而快速的抗抑郁作用;在输注后2小时内起效，并持续显著性1周。 研究2：双相抑郁症快速反应的生物标志物。 目的：探讨重度抑郁症受试者对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，单次静脉注射N-甲基-D-天冬氨酸拮抗剂可产生强大而快速的抗抑郁作用;在输注后2小时内起效，并持续显著性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，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： 1)难治性双相抑郁症的快速抗抑郁作用 我们重复了我们以前在双相抑郁症中使用氯胺酮的发现。在难治性双相抑郁症患者中，单次静脉注射N-甲基-D-天冬氨酸拮抗剂可产生强大而快速的抗抑郁作用。此外，我们发现在1小时内快速抗自杀作用。 2)睡眠标志物是对氯胺酮反应的预测因子 脑电图（EEG）睡眠慢波活动（SWA; EEG功率在0.6和4 Hz之间）已被提出作为中枢突触可塑性的标志。睡眠慢波的产生减少-抑郁症睡眠的核心特征-表明疾病的潜在可塑性变化。我们发现，基线时的Delta睡眠比率（DSR），SWA的一种测量方法，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。 我们认为在重度抑郁症患者中，携带瓦尔/瓦尔BDNF等位基因的MDD患者比携带BDNF Met的患者更容易表现出对氯胺酮的抗抑郁反应。 4)突触增强对于氯胺酮的快速抗抑郁反应至关重要 我们在20例难治性抑郁症患者中使用脑磁图记录，发现氯胺酮（反应者）输注后230分钟抑郁症状明显改善的患者表现出皮质兴奋性增加。具体来说，我们发现，刺激诱发的体感皮层反应增加后，氯胺酮输注，相对于治疗前的反应，但不是在治疗无反应。 5)氯胺酮代谢物在其反应和副作用方面很重要（专利申请） 在氯胺酮的代谢和处置方面观察到诊断差异（双相抑郁症与重度抑郁症）。（2S，5S; 2 R，5 R）-HNK代谢产物的浓度与双相抑郁症对氯胺酮的无反应有关。氯胺酮的一些羟基化代谢产物与精神病和分离症状（氯胺酮的副作用）相关。