Antidepressant Efficacy of Antiglutamatergic Agent

抗谷氨酸药的抗抑郁功效

• 批准号: 6824387
• 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/6824387
• 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; 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 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.

重大情感障碍是常见的、严重的、慢性的、常常危及生命的疾病。重度抑郁症会导致严重的发病率和死亡率。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%双相或复发性抑郁症患者死亡的原因。