Antidepressant Efficacy of Antiglutamatergic w/Neurotrop

抗谷氨酸药与 Neurotrop 的抗抑郁功效

• 批准号: 6982747
• 负责人: HUSSEINI K MANJI
• 金额: --
• 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/6982747
• 关键词: NMDA receptors; antidepressants; clinical trials; data collection methodology /evaluation; drug screening /evaluation; glutamates; human subject; inhibitor /antagonist; major depression; mental disorder chemotherapy; neural inhibition; neural transmission; neuroimaging; neuropharmacologic agent; neuropsychology; neuroregulation; neurotrophic factors; patient oriented research; pharmacogenetics; positron emission tomography; receptor sensitivity

Major affective disorders are common, severe, chronic and often life-threatening illnesses. Major depression contributes to significant morbidity and mortality. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Suicide is the cause of death in 10-20% of individuals with either bipolar or recurrent depressive disorders. Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Thus, there is a clear need to develop novel and improved therapeutics for unipolar and bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Furthermore, a growing body of data suggests that mood disorders are associated with regional volumetric reductions, and cell loss and atrophy. It is thus noteworthy that lamotrigine, which, among other effects reduces glutamate release, has antidepressant effects, and a pilot study has suggested that N-methyl-D-aspartatic acid (NMDA) antagonists may have antidepressant effects. Together, this data suggests that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents, which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants. In an open-label study, we tested riluzole, an agent that is Food and Drug Administration-approved for Amyotrophic Lateral Sclerosis that has significant antiglutamatergic and neuroprotective properties in patients with treatment-resistant major depression and found that it had significant antidepressant properties. Our research now extends to test NMDA antagonists in major depression in a placebo-controlled trial. We are obtaining neuroimaging, neuropsychological, neurophysiological, and genetic data.Nineteen treatment-resistant depressed patients were recruited for this protocol (53% of them were classified as Stage 2 treatment-resistance). They received riluzole at a mean daily dose of 169 mg. Significant improvement occurred on weeks 3 through 6 for all patients and weeks 2 through 6 for completers (all p<0.05). These preliminary results indicate that riluzole may have antidepressant properties in some patients. Our research now extends to test NMDA antagonists in major depression in a placebo-controlled trial. We are obtaining neuroimaging, neuropsychological, neurophysiologic, and genetic data. Similarly, Riluzole is being now investigated in a population of Bipolar Disorder patients.

严重的情感障碍是常见的、严重的、慢性的、常常危及生命的疾病。重度抑郁症导致显著的发病率和死亡率。抑郁症导致的身体和社会功能障碍可能与其他慢性疾病一样严重。自杀是10-20%的双相或复发性抑郁症患者的死亡原因。 尽管抗抑郁药物种类繁多，但临床试验表明，30%至40%的重性抑郁症患者对一线抗抑郁药物治疗无效，尽管剂量、持续时间和依从性足够。因此，显然需要开发用于单极和双相抑郁症的新的和改进的治疗剂。最近的临床前研究表明，抗抑郁药可能会对多巴胺能系统产生延迟的间接影响。此外，越来越多的数据表明，情绪障碍与区域体积减少，细胞丢失和萎缩有关。因此，值得注意的是，拉莫三嗪具有抗抑郁作用，其作用之一是减少谷氨酸释放，一项初步研究表明N-甲基-D-谷氨酸（NMDA）拮抗剂可能具有抗抑郁作用。总之，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发挥作用，并且更直接地减少多巴胺能神经传递的药物可能代表一类新的抗抑郁药。 在一项开放标签研究中，我们测试了利鲁唑，一种经食品和药物管理局批准用于肌萎缩侧索硬化症的药物，在难治性抑郁症患者中具有显著的抗抑郁和神经保护特性，并发现它具有显著的抗抑郁特性。 我们的研究现在扩展到在安慰剂对照试验中测试NMDA拮抗剂在重度抑郁症中的作用。我们正在获取神经影像学、神经心理学、神经生理学和遗传学数据，19名难治性抑郁症患者被纳入本方案（其中53%被归类为第2阶段难治性）。他们接受了平均每日剂量为169 mg的利鲁唑。所有患者在第3周至第6周以及完成者在第2周至第6周均出现显著改善（所有p<0.05）。这些初步结果表明，利鲁唑可能对某些患者具有抗抑郁作用。 我们的研究现在扩展到在安慰剂对照试验中测试NMDA拮抗剂在重度抑郁症中的作用。我们正在获取神经影像学、神经心理学、神经生理学和遗传学数据。同样，阿曲唑目前正在双相情感障碍患者人群中进行研究。