Felbamate for Treatment-Resistant Bipolar Depression

非氨酯治疗难治性双相抑郁症

• 批准号: 6982741
• 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/6982741
• 关键词: AMPA receptors; NMDA receptors; aminoacid inhibitor; anticonvulsants; antidepressants; bipolar depression; carbamates; clinical trials; drug screening /evaluation; glutamate receptor; glutamates; human subject; human therapy evaluation; mental disorder chemotherapy; neural transmission; neuropsychological tests; patient oriented research

Bipolar affective disorder (BPD, manic-depressive illness) is a common, severe, chronic and often life-threatening illness. Increasingly, it is being recognized that it is the depressive phase of the illness, which contributes much of the 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. The treatments for acute unipolar depression have been extensively researched. However, despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of depressed patients fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Very few studies have examined the efficacy of somatic treatments for the acute phase of bipolar depression. Thus, there is a clear need to develop novel and improved therapeutics for 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 noteworthy that lamotrigine reduces glutamatergic neurotransmission, has antidepressant effects in bipolar depression, 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. Felbamate (Felbatol?) a dicarbamate, is FDA-approved as monotherapy and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and in partial and generalized seizures associated with Lennox-Gastaut syndrome in children. Felbamate has significant antiglutamatergic and neuroprotective properties, and may prove to have antidepressant properties in bipolar patients. In this study, we propose to investigate the potential efficacy of felbamate, which reduces glutamatergic throughput via inhibition of glutamate release and NMDA, AMPA, and metabotropic glutamate receptor blockade. This is an 8-week randomized, double-blind, placebo-controlled study that will examine the efficacy and safety of felbamate in acutely depressed bipolar patients who are considered treatment-resistant. This study has two phases. The first phase is the washout phase that will last for 7 days. The second phase is an 8-week acute treatment phase in which the efficacy and tolerability of felbamate and placebo are compared. Lithium can remain during Study Periods I and II if partial response to this agent is documented. Patients who complete the 8-week double-blind phase will receive clinical treatment. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Patients, ages 18 or older, with a diagnosis of Bipolar I or II disorder, depressed (without psychotic features), will be randomized to double-blind treatment to receive either felbamate (600-3000 mg/day) or placebo for a period of 8 weeks. Following this acute period, the patients will receive treatment as clinically indicated. Approximately 52 patients with treatment-resistant acute bipolar depression will be enrolled in the study.

双相情感障碍（BPD，躁狂抑郁症）是一种常见的、严重的、慢性的、经常危及生命的疾病。越来越多的人认识到，这种疾病的抑郁阶段是造成发病率和死亡率的主要原因。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。