Efficacy of an Antiglutamatergic Agents in Treament-Resistant Deprepression

抗谷氨酸药物治疗难治性抑郁症的疗效

• 批准号: 8556946
• 负责人: Carlos Zarate
• 金额: $ 21.19万
• 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/8556946
• 关键词: Acute; Antidepressive Agents; Bipolar Depression; Bipolar Disorder; Caring; Clinical Trials; Controlled Study; Data; Depressed mood; Disease remission; Dose; Double-Blind Method; Enhancers; Functional disorder; General Hospitals; Glutamates; Hour; Infusion procedures; Intravenous; Intravenous infusion procedures; Ketamine; Major Depressive Disorder; Massachusetts; Measures; Mental Depression; Montgomery and Asberg depression rating scale; Mood Disorders; N-Methylaspartate; National Institute of Mental Health; Neurotransmitters; Patients; Phase; Placebos; Randomized; Recruitment Activity; Relapse; Reporting; Resistance; Riluzole; Selective Serotonin Reuptake Inhibitor; Site; System; Testing; Therapeutic Agents; Time; Unipolar Depression; Universities; Validation; Work; blind; college; depressive symptoms; dosage; efficacy testing; improved; inhibitor/antagonist; novel; novel therapeutics; open label; placebo controlled study; response; reuptake; trafficking

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. a) The efficacy of riluzole in treatment-resistant bipolar depression is currently being tested in a double-blind placebo-controlled study. b) We are also testing the efficacy of riluzole in a 4-site study (Massachusetts General Hospital, Baylor College, Yale University and NIMH) as an add-on treatment in treatment-resistant depression. This study is still ongoing and will be reported under MH002927-03 Target validation of novel therapeutic agents in mood disorders. Acute efficacy will be determined by demonstrating a greater response rate in the Montgomery-Asberg Depression Rating scale. This controlled study is still ongoing and actively recruiting subjects. The study blind has not been broken. Results of the add-on riluzole study in treatment-resistant unipolar depression should be completed in 2-3 years. This study will be reported under MH002927-03 Target validation of novel therapeutic agents in mood disorders. c) Forty-two subjects (18-65) with TRD and a MADRS score of 22 received a single intravenous infusion of ketamine (0.5&#8201;mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200&#8201;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.

迫切需要开发新的治疗难治性抑郁症的新靶点。在开发改善的情绪障碍治疗方法中，神经元能系统是一个重要的目标。在以前的工作中，我们发现谷氨酸调节剂利鲁唑（谷氨酸释放抑制剂，AMPA运输和谷氨酸再摄取增强剂）在治疗难治性单相和双相抑郁症中有效。这些数据表明，多巴胺能系统可能在抑郁症的病理生理学和治疗中起关键作用，并且调节这种神经递质系统的药物可能代表一类新型抗抑郁药。 a）利鲁唑治疗难治性双相抑郁症的疗效目前正在一项双盲安慰剂对照研究中进行测试。 B）我们还在一项4中心研究（马萨诸塞州总医院、贝勒学院、耶鲁大学和NIMH）中测试利鲁唑作为难治性抑郁症的附加治疗的疗效。本研究仍在进行中，将在MH 002927 -03心境障碍新型治疗药物的目标验证中报告。 将通过证明蒙哥马利-阿斯伯格抑郁评定量表的缓解率更高来确定急性疗效。 这项对照研究仍在进行中，并积极招募受试者。研究设盲尚未破盲。在难治性单相抑郁症中添加利鲁唑的研究结果应在2-3年内完成。本研究将在MH 002927 -03心境障碍新型治疗药物的目标验证中报告。 c）42名患有TRD且MADRS评分为22的受试者（18-65）接受氯胺酮（0.5mg/kg）的单次静脉内输注。输注后4 - 6小时，受试者随机接受利鲁唑（100-200 mg/天; n=21）或安慰剂（n=21）双盲治疗4周。每天对抑郁症状进行评分。发现MADRS评分较基线有显著改善（P<0.001），氯胺酮改善的效应量最初较大，在整个28天的试验中保持中等水平。总体而言，27%的氯胺酮应答者在单次氯胺酮输注后4周内未复发。平均复发时间为13.2天。然而，利鲁唑和安慰剂治疗组之间的差异不显著，表明利鲁唑与氯胺酮联合治疗不会显著改变对氯胺酮单独治疗的抗抑郁反应的过程。