Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect

快速谷氨酸调节剂

• 批准号: 8342152
• 负责人: Carlos Zarate
• 金额: $ 230.52万
• 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/8342152
• 关键词: Acute; Address; Age; Amino Acid Neurotransmitters; Anterolateral; Antidepressive Agents; Anxiety; Behavioral; Biochemical; Biological Markers; Bipolar Depression; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Brief Psychiatric Rating Scale; Chronic; Clinical; Clinical Research; DSM-IV; Data; Diagnosis; Dorsal; Dose; Double-Blind Method; Electroencephalography; Emergency Situation; Family; Feeling suicidal; Functional disorder; Future; Genetic; Glutamates; Glutamine; Hour; Image; Impairment; Infusion procedures; Intervention; Intravenous; Intravenous infusion procedures; Investigation; Ketamine; Life; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetoencephalography; Major Depressive Disorder; Manic; Medical; Mental Depression; MicroRNAs; Montgomery and Asberg depression rating scale; Mood Disorders; Moods; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Outcome Measure; Participant; Patients; Physical Function; Physiological; Placebos; Play; Positron-Emission Tomography; Prefrontal Cortex; Protocols documentation; Protons; Public Health; Randomized; Recording of previous events; Recruitment Activity; Relapse; Reporting; Research; Research Design; Resistance; Resolution; Riluzole; Role; Sleep; Slow-Wave Sleep; Social Functioning; Spectrum Analysis; Suicide; Surrogate Markers; Symptoms; Synapses; System; Testing; Unipolar Depression; depressive symptoms; gamma-Aminobutyric Acid; impression; improved; inhibitor/antagonist; instrument; metabolomics; neurophysiology; neuropsychological; open label; preclinical study; pressure; prevent; primary outcome; response; secondary outcome

Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. The current protocol consists of 3 primary studies designed to address 3 major questions: Study 1 (Rapid improvement research in unipolar depression) OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. 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. There is now an ongoing study with subunit selective NMDA antagonists (NR2A and NR2B). Study 2 (Rapid improvement research in bipolar depression) Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? The efficacy component of the study is completed and the data are being analyzed. The study remains open for active recruitment as more subjects are required to complete the neurophysiological (MEG, PSG, PET substudies) in search of biomarkers of response. Study 3 (Rapid and sustained improvement research in unipolar depression) Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine? Patients ages 18 to 65 years with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine are then randomized to receive in a double-blind study with either riluzole or placebo to determine if the rapid response obtained can be sustained. The study is still actively recruiting study participants. The results from this study are not yet available because the study has not yet been completed. Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, and 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression. Other 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), and 3) to test other glutamatergic modulators in mood disorders that target NR2A and NR2B. Results in the past year: 1) Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg). Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. 2) Rapid antidepressant effects in treatment-resistant 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. 3) Acute changes in mood and sleep slow waves induced by a single infusion of an NMDA antagonist in Treatment-Resistant Major Depression We examined the possible link between slow waves, sensitive markers of sleep pressure, and NMDA channel blockade as a biomarker of response to ketamine. The effects of a single ketamine infusion followed by double-blind administration of either placebo or riluzole on sleep EEG and mood were studied in 30 patients with treatment-resistant MDD. Montgomery-sberg Depression Rating Scale (MADRS) scores decreased significantly (30%) and rapidly following ketamine infusion. Compared to baseline, SWA significantly increased during the first NREM sleep episode after ketamine infusion. Furthermore, the occurrence of high amplitude waves significantly increased during the first NREM sleep episode, consistent with a net increase in synaptic efficacy. Mood effects correlated with the effects on high amplitude slow waves, consistent with an association between behavioral changes and changes at the synaptic level. Taken together, the results suggest that strengthening of cortico-cortical connections, reflected by increased SWA and slow wave amplitude, may be the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. 4) An investigation of Amino Acid Neurotransmitters as potential predictors of clinical improvement to ketamine in depression Dysfunction of amino acid neurotransmitter systems plays a major role in the pathophysiology of major depressive disorder (MDD). Accumulating evidence shows that the NMDA antagonist ketamine produces a rapid antidepressant response in patients with treatment-resistant MDD. We herein applied proton magnetic resonance spectroscopy (1H-MRS) to investigate whether prefrontal levels of GABA, glutamate (Glu) and the ratio Glx/Glutamate (a surrogate marker of glutamine) correlate with the decrease in depressive symptoms after a single intravenous infusion of ketamine in patients with MDD. Pretreatment Glx/Glutamate ratio in the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PF)was negatively correlated with clinical improvement in depressive symptoms (rs(11) = -0.572, p < 0.05). Pretreatment glutamate levels in the VM-PF were positively correlated with improvement in anxiety symptoms (rs(11) = 0.569, p < 0.05). The findings suggest an association between lower Glx/Glutamate ratio and greater clinical improvement by ketamine treatment. Since glutamine is mainly contained in glia, the decreased glutamine found in this study may reflect the reduction in glial cells found in the same regions in post mortem studies of MDD and suggests that glial integrity may be associated with antidepressant responsiveness to ketamine.

最近的临床前和临床研究表明，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）在耐药的重度抑郁症中有效。氯胺酮导致快速，健壮和相对持续的抗抑郁作用。对氯胺酮的反应发生在2小时内，大约持续了1周。当前协议由3项主要研究组成，旨在解决3个主要问题： 研究1（单极抑郁症的快速改善研究） 目的：确定在患有严重抑郁症的受试者的N-甲基-D-天冬氨酸受体处的拮抗剂是否可以通过拮抗剂来快速抗抑郁作用。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。现在正在进行一项针对亚基选择性NMDA拮抗剂（NR2A和NR2B）的研究。 研究2（双相抑郁症的快速改善研究） NMDA拮抗剂氯胺酮在耐药性双极抑郁症患者中是否会产生快速的抗抑郁作用？研究的疗效组成部分已经完成，并且正在分析数据。这项研究仍然可以进行主动招募，因为需要越来越多的受试者才能完成神经生理学（MEG，PSG，PET替代）以寻找反应的生物标志物。 研究3（单极抑郁症的快速和持续改进研究） Riluzole（谷氨酸释放的一种抑制剂）是否可以防止对抗治疗剂抑郁症患者的复发，他们对单一静脉内剂量的氯胺酮迅速反应？随后对单次静脉内剂量的氯胺酮或安慰剂进行随机反应的耐药性重大（单极）抑郁症患者对单个静脉内剂量的耐药性迅速反应，以riluzole或安慰剂进行随机反应，以确定是否可以持续获得快速反应。该研究仍在积极招募研究参与者。这项研究的结果尚未获得，因为该研究尚未完成。 这些研究的主要假设是：1）在具有治疗耐药性重大（单极）抑郁症的患者中可以实现快速反应（相同或第二天），2）可以在治疗抑郁症患者中得以快速反应（相同或第二天）的快速反应（相同或第二天）。 Other 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）和3）在靶向NR2A和NR2B的情绪障碍中测试其他谷氨酸能调节剂。 过去一年的结果： 1）单次注入N-甲基-D-天冬氨酸拮抗剂后，自杀意念的快速分辨率在耐药的重度抑郁症患者中。 自杀念头是医疗紧急情况，尤其是在严重的情况下。关于可以解决此问题的药理干预措施的研究很少。据报道，氯胺酮是一种N-甲基-D-D-甲虫的拮抗剂，在数小时内具有抗抑郁作用。我们检查了一种氯胺酮对具有治疗耐药性抑郁症（MDD）受试者自杀意念的影响。 DSM-IV诊断的MDD的33名受试者接受了单个标签输注氯胺酮（0.5 mg/kg）。 SSI以及其他评级工具的自杀分量值在40分钟内显着下降。这些减少在灌注后的前4小时保持显着（p <.001）。在氯胺酮输注后40分钟内，在MDD的背景下，自杀构想在灌注后长达4个小时。由于潜在的对公共卫生的影响，因此有必要对氯胺酮进行自杀意念的未来研究。 2）在耐治疗的躁郁症抑郁症中快速抗抑郁作用。 在具有耐药性躁郁症抑郁症的患者中，由单个静脉内剂量的N-甲基-D-天冬氨酸拮抗剂产生了鲁棒和快速的抗抑郁作用。 3）在耐药的大抑郁症中，单个输注NMDA拮抗剂引起了情绪和睡眠慢波的急性变化 我们研究了慢波，敏感的睡眠压力标记和NMDA通道阻滞之间的可能联系，作为对氯胺酮反应的生物标志物。在30例耐药MDD患者中，研究了单个氯胺酮输注的影响，然后对安慰剂或riluzole双盲施用对睡眠脑电图和情绪进行了研究。蒙哥马利 - 塞伯格抑郁量表（MADRS）得分显着降低（30％），氯胺酮输注后迅速下降。与基线相比，在氯胺酮输注后的第一次NREM睡眠发作中，SWA显着增加。此外，在第一次NREM睡眠发作中，高振幅波的发生显着增加，这与突触功效的净增加一致。情绪效应与对高振幅慢波的影响相关，这与行为变化与突触水平变化之间的关联一致。综上所述，结果表明，通过增加的SWA和慢波幅度反映的皮质皮质连接的加强可能是NMDA拮抗剂快速抗抑郁作用的生理机制。 4）对氨基酸神经递质的研究，作为抑郁症氯胺酮临床改善的潜在预测指标 氨基酸神经递质系统的功能障碍在主要抑郁症（MDD）的病理生理学中起主要作用。积累的证据表明，NMDA拮抗剂氯胺酮在耐药MDD患者中会产生快速的抗抑郁反应。我们在此应用质子磁共振光谱（1H-MR）来研究GABA，谷氨酸（GLU）的前额叶水平和比率GLX/谷氨酸（谷氨酰胺的替代标记）是否与单次静脉内注入酮的乳酸患者的抑郁症状降低相关。 背侧/背侧前外侧前额叶皮层（DM/DA -PF）的预处理GLX/谷氨酸比与抑郁症状的临床改善（RS（11）= -0.572，P <0.05）有关。 VM-PF中的预处理谷氨酸水平与焦虑症状的改善呈正相关（rs（11）= 0.569，p <0.05）。研究结果表明，较低的GLX/谷氨酸比率与氯胺酮治疗的临床改善之间存在关联。由于谷氨酰胺主要包含在神经胶质中，因此在本研究中发现的谷氨酰胺降低可能反映了MDD验尸研究中同一区域发现的胶质细胞的降低，并表明神经胶质完整性可能与抗抑郁药对氯胺酮的反应性有关。