Efficacy of an Antiglutamatergic Agents in Treatment-Resistant Depression

抗谷氨酸药物治疗难治性抑郁症的疗效

基本信息

批准号：
8939977
负责人：
Carlos Zarate
金额：
$ 23.96万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/8939977
关键词：
Acute Antidepressive Agents Biological Markers Bipolar Depression Bipolar Disorder Clinical Controlled Study Data Depressed mood Dose Double-Blind Method Enhancers Enrollment Family history of Functional disorder Genetic Glutamates Hour Infusion procedures Intervention Intravenous Intravenous infusion procedures Ketamine Left Major Depressive Disorder Measures Mental Depression Montgomery and Asberg depression rating scale Mood Disorders N-Methylaspartate Neurotransmitters Patients Phase Placebos Protocols documentation Randomized Recording of previous events Relapse Reporting Resistance Riluzole System Time Unipolar Depression Work alcohol use disorder collected works depressive symptoms drug development drug discovery family genetics improved inhibitor/antagonist novel open label response reuptake trafficking treatment response treatment trial treatment-resistant depression

项目摘要

This Report involves work collected under protocols 03-M-0092 (NCT00054704) and 04-M-0222 (NCT00088699). Novel targets for developing new treatments for treatment-resistant major depression are urgently needed. The glutamatergic system stands as an important to target to pursue in the developing improved treatments for mood disorders. In previous work, we found that the glutamate modulating agent riluzole (inhibitor of glutamate release, and enhancer of AMPA trafficking and glutamate reuptake) was effective in treatment-resistant unipolar and bipolar depression. These data suggest that the glutamatergic system might have a key role in the pathophysiology and treatment of depression, and that agents which modulate this neurotransmitter system, may represent a novel class of antidepressants. We studied 42 subjects (18-65) with TRD and a MADRS score of 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days. However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone. We have continued to enroll subjects in the search of biomarkers of treatment response. Preliminary data indicates that subjects with a) family history of alcohol use disorders have a better antidepressant response to ketamine than subjects without a family history of alcohol use disorders, and b) subjects with anxious depression have a better antidepressant response to ketamine than subjects without anxious depression. Studies are examining genetics, ketamine metabolites, and other biomarkers that might be associated with treatment response. Identifying biomarkers of response would ultimately facilitate drug discovery and development and to individualize or personalize treatment interventions. We recently found that riluzole lacks efficacy in patients with treatment-resistant depression who did not respond to ketamine. This project will be terminated and merged with the other ongoing project: "Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect" which is under the same theme.

该报告涉及根据协议03-m-0092（NCT00054704）和04-M-0222（NCT00088699）收集的工作。迫切需要开发新的治疗治疗方法来开发新的治疗方法。谷氨酸能体系对于追求改进的情绪障碍的治疗方法是一个重要的目标。在先前的工作中，我们发现谷氨酸调节剂riluzole（谷氨酸释放的抑制剂以及AMPA运输和谷氨酸再摄取的增强子）在耐药的单极和双极抑郁症中有效。这些数据表明，谷氨酸能系统可能在抑郁症的病理生理学和治疗中具有关键作用，并且调节该神经递质系统的药物可能代表了一种新型的抗抑郁药。我们研究了42名受试者（18-65），其中有TRD和22个MADR分数接受了单次静脉输注氯胺酮（0.5 mg/kg）。输入后四到六个小时，受试者被随机分配给双盲治疗，用riluzole（100-200 mg/day; n = 21）或安慰剂（n = 21），持续4周。每天评估抑郁症状。发现了基线的MADRS分数有显着改善（P <0.001）。氯胺酮改善的效果大小最初是很大的，在整个28天试验中仍然保持中等。总体而言，一次氯胺酮输注后，有27％的氯胺酮反应者没有复发4周。平均复发时间为13.2天。然而，里鲁唑和安慰剂治疗组之间的差异并不显着，这表明瑞唑与氯胺酮治疗的组合并没有显着改变单独对氯胺酮的抗抑郁反应的过程。我们继续招募受试者，以寻找治疗反应的生物标志物。初步数据表明，患有a）酒精使用障碍的家族史对氯胺酮的抗抑郁反应比没有酒精使用障碍的家族病史的受试者更好，b）焦虑抑郁症的受试者对氯胺酮对氯胺酮的反应比没有焦虑抑郁症的受试者更好。研究正在研究遗传学，氯胺酮代谢产物和其他可能与治疗反应相关的生物标志物。确定反应的生物标志物最终将促进药物发现和开发，并个性化或个性化治疗干预措施。我们最近发现，Riluzole缺乏对耐氯胺酮反应的耐药性抑郁症患者的功效。该项目将被终止并与另一个正在进行的项目合并：“谷氨酸能调节剂，用于快速和持续的抗抑郁效应”，这是相同主题的。