Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect

快速谷氨酸调节剂

• 批准号: 8939983
• 负责人: Carlos Zarate
• 金额: $ 287.48万
• 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/8939983
• 关键词: Adverse effects; Amyotrophic Lateral Sclerosis; Antidepressive Agents; Biochemical; Biological Markers; Bipolar Depression; Bipolar Disorder; Blood; Body mass index; Brain-Derived Neurotrophic Factor; Brief Psychiatric Rating Scale; Chronic; Clinical; Complex; Dose; Electroencephalography; Family; Family history of; Feeling suicidal; First Degree Relative; Genetic; Glutamates; Hippocampus (Brain); Hour; Image; Impairment; Intravenous; Ketamine; Life; Lithium; Lysophosphatidylcholines; Magnetic Resonance Imaging; Magnetoencephalography; Major Depressive Disorder; Manic; Measurement; Mediating; Medical; Mental Depression; MicroRNAs; Mitochondria; Montgomery and Asberg depression rating scale; N-Methylaspartate; NMDA receptor antagonist; Nerve; Outcome Measure; Patients; Pattern; Physical Function; Pilot Projects; Placebos; Plasma; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Proteins; Protocols documentation; Randomized; Recording of previous events; Relapse; Relative (related person); Reporting; Research; Resistance; Riluzole; Risk; SNAP receptor; Second Messenger Systems; Serine; Sleep; Social Functioning; Spectrum Analysis; Statistical Models; Suicide attempt; Synapsin I; Synaptic Membranes; Synaptic Vesicles; Synaptosomes; System; Trauma; alcohol use disorder; calmodulin-dependent protein kinase II; collected works; depressive symptoms; impression; metabolomics; neuropsychological; presynaptic; primary outcome; relating to nervous system; response; second messenger; secondary outcome; synaptotagmin I; syntaxin 1A; treatment-resistant depression; valproate

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 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. 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) Riluzole, a glutamatergic modulator used for the treatment for amyotrophic lateral sclerosis (ALS) likely lacks antidepressant efficacy in ketamine non-responders. Subjects who were treated with ketamine non-responders were randomized to riluzole or placebo. There was no difference in response rates over the course of 4 weeks. 2) D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression. Baseline D-serine plasma concentrations were significantly lower in ketamine responders (3.02&#8201;&#8201;0.21 &#956;M) than in ketamine non-responders (4.68&#8201;&#8201;0.81 &#956;M), p&#8201;<&#8201;0.001. A significant relationship between baseline D-serine plasma concentrations and percent change in depression scores at 230 minutes was found. Baseline D-serine explaining 60 % of the variance in (R,S)-ketamine response. Measurement of blood D-serine could serve as a biomarker predicting rapid antidepressant response. 3) Clinical predictors of ketamine response in treatment-resistant major depression. We found that higher body mass index correlated with greater improvement in depression scores at 230 minutes (P = .004) and at day 1 (P = .001), but not at day 7 (P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater improvement in depressive symptoms at day 1 (P = .014) and day 7 (P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized &#946; = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of depression scores percent change variance at 230 minutes, day 1, and day 7, respectively. 4) A pilot study of plasma metabolomic patterns for patients treated with ketamine for bipolar depression. We found evidence of a response-related difference in mitochondrial networks. The metabolomic patterns were significantly different between the patients maintained on lithium and those maintained on valproate, irrespective of response to ketamine. In the patients maintained on lithium, 18 biomarkers were identified. In responders, lysophosphatidylethanolamines (4) and lysophosphatidylcholines (9) were increased relative to non-responders. 5) Dissociative side effects of ketamine mediate its antidepressants effects. We would a significant correlation between increased dissociative side effects at 40 min and percent improvement with ketamine in depressive symptoms at 230min. 6) Ketamine treatment in patients with treatment-resistant depression was not associated with greater risk of switches into mania or dissociative side effects in those subjects with a history of trauma or post-traumatic stress disorder. 7) Ketamine regulates the presynaptic release machinery in the hippocampus. A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr(286)-phosphorylated &#945;CaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine.

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抗抑郁药的作用机理。我们发现非竞争性NMDA拮抗剂（氯胺酮）导致快速，健壮和相对持续的抗抑郁和抗杀菌作用。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1 ：（重度抑郁症的快速反应生物标志物）。 目的：检查神经相关性在患有严重抑郁症的受试者中对NMDA拮抗剂氯胺酮的快速抗抑郁反应。我们发现由单个静脉注射剂量的N-甲基-D-天冬氨酸拮抗剂引起的强大而快速的抗抑郁作用。灌注后2小时内发作，并继续保持1周的意义。 研究2 ：（躁郁症抑郁症快速反应的生物标志物）。 目的：检查神经相关性在患有严重抑郁症的受试者中对NMDA拮抗剂氯胺酮的快速抗抑郁反应。我们发现由单个静脉注射剂量的N-甲基-D-天冬氨酸拮抗剂引起的强大而快速的抗抑郁作用。灌注后2小时内发作，并继续保持1周的意义。 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),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： 1）Riluzole是一种用于治疗肌萎缩性侧索硬化症（ALS）治疗的谷氨酸能调节剂（ALS）可能缺乏氯胺酮非应答剂的抗抑郁疗效。用氯胺酮非反应者治疗的受试者被随机分为瑞唑或安慰剂。在4周的过程中，响应率没有差异。 2）D-丝氨酸血浆浓度是（R，S） - 酮胺抗抑郁反应的潜​​在生物标志物，对治疗抑郁症的受试者。氯胺酮响应者（3.020.21μM）的基线D-丝氨酸血浆浓度明显低于氯胺酮非反应器（4.680.81μm），p <0.001。在230分钟时，发现基线D丝丝等血浆浓度与抑郁评分的变化百分比之间存在显着关系。基线D丝氨酸解释了（R，S）酮胺反应中60％的差异。血液D丝氨酸的测量可以用作一种预测抗抑郁反应的生物标志物。 3）氯胺酮反应在耐治疗的重度抑郁症中的临床预测指标。 我们发现，较高的体重指数与230分钟（p = .004）和第1天（p = .001）时的抑郁评分的改善相关，但在第7天（p = .10）无关。一级亲戚中酒精使用障碍的家族病史与第1天（P = .014）和第7天（P <.001）的抑郁症状改善有关。仅在第7天就没有自杀企图的先前历史与更大的改善有关（标准化的β= 0.28，p = .01）。总体统计模型分别解释了230分钟，第1天和第7天的抑郁得分百分比变化的13％，23％和36％。 4）针对氯胺酮治疗双相抑制的患者的血浆代谢组模式的试验研究。 我们发现线粒体网络中与响应相关的差异的证据。在锂上维持的患者和丙戊酸酯上维持的患者之间的代谢组模式显着差异，而与氯胺酮的反应无关。在维持锂的患者中，确定了18个生物标志物。在响应者中，相对于非应答者，溶物磷脂酰乙醇胺（4）和溶血磷脂酰胆碱（9）增加。 5）氯胺酮的解离性副作用介导其抗抑郁药作用。 我们将在40分钟时增加解离性副作用与氯胺酮在230分钟处的抑郁症状之间有显着相关性。 6）耐药性抑郁症患者的氯胺酮治疗与患有创伤或创伤后应激障碍病史的受试者转向躁狂症或分离副作用无关。 7）氯胺酮调节海马中的突触前释放机械。 在氯胺酮给药1、2和4小时后，在海马突触膜中观察到了圈套复合物的积累大幅度降低。同时，我们发现突触囊泡蛋白突触I的表达有选择性降低，以及在海马突触体中突触I水平的增加，这表明了一种机制，氯胺酮通过调节nerve nerve术语中的突触小囊体数量来减少部分突触囊泡的数量。此外，氯胺酮降低了THR（286）磷酸化的αCAMKII及其与语法1A的相互作用，该酶1a将CAMKII鉴定为氯胺酮第二允许的企业介导作用的潜在目标。