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，往往危及生命的疾病。人们越来越认识到，正是这种疾病的抑郁阶段，造成了大部分的发病率和死亡率。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。 急性单相抑郁症的治疗方法已被广泛研究。然而，尽管抗抑郁药物种类繁多，但临床试验表明，30%至40%的抑郁症患者对一线抗抑郁药物治疗无效，尽管有足够的剂量、持续时间和依从性。很少有研究检查躯体治疗对双相抑郁症急性期的疗效。因此，显然需要开发新型且改进的双相抑郁症疗法。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。值得注意的是，拉莫三嗪可减少多巴胺能神经传递，在双相抑郁症中具有抗抑郁作用，一项初步研究表明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。 非氨酯（Felbatol？）二氨基甲酸酯是FDA批准的单一疗法和连续疗法，用于患有部分发作性癫痫发作的成人，伴有或不伴有继发性全身性发作，以及与儿童Lennox-Gastaut综合征相关的部分和全身性癫痫发作。非氨酯具有显著的抗精神病和神经保护特性，并可能证明在双相情感障碍患者中具有抗抑郁特性。在这项研究中，我们建议研究非氨酯的潜在疗效，它通过抑制谷氨酸释放和NMDA，AMPA和代谢型谷氨酸受体阻滞剂降低谷氨酸能的吞吐量。 这是一项为期8周的随机、双盲、安慰剂对照研究，旨在检查非氨酯在治疗抵抗的急性抑郁双相患者中的疗效和安全性。 本研究分为两个阶段。第一阶段是洗脱期，将持续7天。第二阶段是为期8周的急性治疗期，比较非氨酯和安慰剂的疗效和耐受性。如果记录到对该药物的部分应答，则在研究阶段I和II期间可以保留锂。完成8周双盲期的患者将接受临床治疗。将通过使用指定标准证明更高的缓解率来确定急性疗效。 年龄≥ 18岁、诊断为双相I型或II型障碍、抑郁（无精神病特征）的患者将随机接受双盲治疗，接受非氨酯（600-3000 mg/天）或安慰剂治疗8周。在此急性期后，患者将根据临床指征接受治疗。约52例难治性急性双相抑郁患者将入组本研究。