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: 10012699
• 负责人: Carlos Zarate
• 金额: $ 455.84万
• 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/10012699
• 关键词: Acute; Amygdaloid structure; Anisotropy; Anterior; Antidepressive Agents; Area; Arginine; Behavioral; Biochemical; Biological; Biological Availability; Biological Markers; Bipolar Depression; Bipolar Disorder; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; Brief Psychiatric Rating Scale; Cessation of life; Chronic; Clinical; Complex; Cross-Over Studies; Cross-Over Trials; Data; Data Analyses; Depressed mood; Diffusion Magnetic Resonance Imaging; Dose; Double-Blind Method; Drug Interactions; Electroencephalography; Electrophysiology (science); Emotional; Enrollment; Equilibrium; Exhibits; Family; Fatigue; Feeling suicidal; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic; Glutamates; Hippocampus (Brain); Hour; Image; Impairment; Individual; Infusion procedures; Insula of Reil; Intravenous; Ketamine; Kynurenine; Left; Life; MRI Scans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetoencephalography; Major Depressive Disorder; Manic; Measures; Medial; Medical; Mental Depression; MicroRNAs; Modality; Montgomery and Asberg depression rating scale; Mood Disorders; Multimodal Imaging; N-Methylaspartate; Neurobiology; Neuropsychology; Outcome Measure; Participant; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Placebos; Plasma; Protocols documentation; Proxy; Psychophysiology; Psychotherapy; Randomized; Recording of previous events; Recurrence; Relapse; Resistance; Rest; Signal Transduction; Sleep; Slow-Wave Sleep; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Time; antidepressant effect; base; blood oxygen level dependent; cingulate cortex; depressive symptoms; imaging study; impression; indexing; interest; metabolomics; multimodality; neural correlate; neuroimaging; pleasure; potential biomarker; premature; primary outcome; relating to nervous system; response; secondary outcome; spectroscopic imaging; standard care; standard of care; treatment response; treatment-resistant depression

Our results indicate 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 antianhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with standard of care treatments occur at 6-8 weeks instead of hours. Study: (Biomarkers of rapid response in major depressive disorder): protocols 04-M-0222 (NCT00088699) and 17-M-0060 (NCT03065335). OBJECTIVE: To identify 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 (magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), 3) To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes. Secondary Outcome Measures: To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e., slow wave sleep EEG activity) are associated with better antidepressant response to 0.5 mg/kg Time Frame: baseline and post-drug To demonstrate enhanced efficacy, as measured by the MADRS, of IV ketamine 0.5 mg/kg in participants with major depressive disorder (MDD) using a psychophysiological technique (i.e. NPU-threat test). Time Frame: baseline and post-drug To identify baseline peripheral measures associated with response to the administration of ketamine 0.5 mg/kg, as potential biomarkers of acute (24 hour) treatment response. Time Frame: baseline and post-drug Results in the past year: 1. Multimodal imaging reveals a complex pattern of dysfunction in corticolimbic pathways in major depressive disorder: While numerous studies have investigated the neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting-state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses. 2. Effects of ketamine on brain activity during emotional processing: differential findings in depressed versus healthy control participants: Experimental tasks involving emotional processing can be used during functional magnetic resonance imaging scanning to investigate ketamine's effects on brain function in MDD. A total of 33 individuals with treatment-resistant MDD and 24 healthy control participants (HCs) took part in this double-blind, placebo-controlled crossover study. Participants received ketamine and placebo infusions 2 weeks apart, and functional magnetic resonance imaging scans were conducted at baseline and 2 days after each infusion. Blood oxygen level-dependent signal was measured during an emotional processing task. A group-by-drug interaction was observed in several brain regions, including a right frontal cluster extending into the anterior cingulate cortex and insula. Participants with MDD had greater activity than HCs after placebo infusion but showed lower activity after ketamine infusion, which was similar to the activity in HCs after placebo. The main results indicate that ketamine had differential effects on brain activity in participants with MDD versus HCs. The pattern of activation in participants with MDD after ketamine infusion resembled the activation in HCs after placebo infusion, suggesting a normalization of function during emotional processing. The findings contribute to a better understanding of ketamine's actions in the brain. 3. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Ketamine's mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine's mechanism of action from studies of healthy controls alone. 4. Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects. The metabolomic profile of these subjects was characterized at multiple time points in MDD and healthy controls, treatment and placebo in both groups and the corresponding response to ketamine treatment. Ketamine response resulted in more pronounced effects in the kynurenine pathway and the arginine pathway at 4 h post-infusion, where a larger decrease in circulating kynurenine levels and a larger increase in the bioavailability of arginine were observed in responders to ketamine treatment.

我们的结果表明，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。与护理标准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）：方案04-M-0222（NCT00088699）和17-m-0060（NCT03065333）。 目的：确定对主要抑郁症受试者中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药对氯胺酮反应的相关性，包括这些数据/结果指标：临床（例如，家族史），成像（磁性共鸣/分光镜）（磁性成像），电子物理学的绘制学效果，磁性成像（磁性共鸣）神经心理学和生物化学（例如遗传学，microRNA，BDNF，代谢组学），3）表现出了通过酮症0.5 mg/kg与40分钟相比，通过神经药物动力学成像（FMRI+EEG和MEG）进行了更强的神经药效效应（FMRI+EEG和MEG）。 次要结局指标：为了确定突触可塑性的增加，使用电生理措施响应TMS并与睡眠有关（即慢波睡眠脑电图）与更好的抗抑郁药对0.5 mg/kg的抗抑郁反应有关 通过通过心理生理技术（即NPU威胁性测试），通过MADRS衡量的iV氯胺酮0.5 mg/kg的静脉注射氯胺酮（即MDD）（即NPU-Wisteat检测）的疗效增强。时间范围：基线和毒品后 确定与氯胺酮0.5 mg/kg的反应有关的基线外围测量，是急性（24小时）治疗反应的潜在生物标志物。时间范围：基线和毒品后 过去一年的结果： 1。多模式成像揭示了主要抑郁症中皮质唇途径中功能障碍的复杂模式：虽然许多研究研究了MDD的神经生物学相关性，但大多数研究仅使用了单个神经影像学方式。特别是，扩散张量成像（DTI）研究未能产生均匀的结果。在这种情况下，检查关键区域并使用来自多种神经影像模式的信息可以更好地表征MDD脑中潜在的异常。这项研究分析了30名MDD参与者和26名健康参与者的数据，他们接受了DTI，磁共振光谱（MRS），静止状态功能磁共振成像（fMRI）和磁脑摄影（MEG）。将左右杏仁核以及与左右海马和thalamus连接连接的，连接下扣带回皮层（SGACC）以及左右杏仁核的区域。在所研究的区域中观察到减少的分数各向异性（FA）。在连接SGACC和右杏仁核的区域，MDD与健康参与者之间的内侧前谷氨酸浓度和FA之间的相关性显着差异。健康的参与者表现出很强的相关性，但MDD参与者没有这种关系。在同一道中，在MDD参与者中，FA与随后对氯胺酮输注的抗抑郁反应之间观察到相关性。这项研究是第一个结合MRS，DTI，fMRI和MEG数据以获得MDD和抗抑郁反应的多模式指数的研究，并可能为将来的分析奠定基础。 2。氯胺酮对情绪处理过程中大脑活动的影响：抑郁症与健康对照参与者的差异发现：在功能磁共振成像扫描中，可以使用涉及情绪处理的实验任务，以研究氯胺酮对MDD中大脑功能的影响。共有33名具有耐药MDD的人和24名健康对照参与者（HCS）参加了这项双盲，安慰剂对照的跨界研究。参与者相隔2周接受了氯胺酮和安慰剂输注，并在基线和每次输注后2天进行功能性磁共振成像扫描。在情绪处理任务中测量了血氧水平依赖性信号。在几个大脑区域中观察到了逐批相互作用，包括右侧额叶簇延伸到前扣带回皮层和岛菌中。安慰剂输注后，患有MDD的参与者的活性大于HCS，但在氯胺酮输注后表现出较低的活性，这与安慰剂后HC的活性相似。主要结果表明，氯胺酮对MDD与HCS参与者的脑活动有不同的影响。氯胺酮输注后MDD参与者的激活模式类似于安慰剂输注后HCS的激活，这表明情绪处理过程中功能的归一化。这些发现有助于更好地理解氯胺酮在大脑中的作用。 3。氯胺酮在抑郁和健康的受试者中具有不同的电生理和行为影响。氯胺酮的作用机制是使用磁脑电图（MEG）的伽马功率评估的，这是35名具有重大抑郁症（MDD）的未经测验受试者的稳态平衡的衡量标准，并在双重抑郁症（MDD）和25个健康对照组中进行了双度，安慰剂控制的，随机的，随机的，随机的，随机的，随机的交叉验试验。 MDD受试者显示出抑郁症状的显着改善，健康对照受试者表现出适中但在氯胺酮给药后长达1天的抑郁症状显着增加。两组均表现出氯胺酮后静息伽马功率的增加。在MDD受试者中，γ功率与抗抑郁作用的大小无关。然而，发现基线伽马功率可以减轻酮后伽马能力和抗抑郁反应之间的关系。具体而言，较高的酮后γ功率与基线伽马较低的MDD受试者的反应更好，并且在MDD受试者的基线γ较高的MDD受试者的关系中。在涉及与MDD病理生理学有关的网络中涉及的多个地区观察到了这种关系。这一发现表明基于稳态失调方向的生物亚型，并且对仅通过对健康对照的研究来推断氯胺酮的作用机理具有重要意义。 4。对主要抑郁症和健康对照受试者的氯胺酮和安慰剂跨界试验的血浆代谢组分析。这些受试者的代谢组学特征在MDD的多个时间点以及两组中的健康对照，治疗和安慰剂以及对氯胺酮治疗的相应反应中进行了表征。氯胺酮反应在诱发后4小时后在kynurenine途径和精氨酸途径中产生更明显的作用，其中循环中的雌激素水平的降低较大，而在酮胺治疗的反应者中观察到精氨酸的生物利用氨酸的增加。