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，躁郁症)是一种常见的、严重的、慢性的、往往危及生命的疾病。越来越多的人认识到，这是疾病的抑郁阶段，是导致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损害可能与其他慢性疾病一样严重。自杀是双相情感障碍或复发性抑郁障碍患者中10-20%的死亡原因。 治疗急性单相抑郁的方法已被广泛研究。然而，尽管有广泛的抗抑郁药物可用，临床试验表明，尽管有足够的剂量、持续时间和依从性，30%到40%的抑郁症患者对一线抗抑郁药物治疗没有反应。很少有研究考察躯体疗法对双相抑郁急性期的疗效。因此，显然有必要开发新的和改进的治疗双相抑郁的方法。最近的临床前研究表明，抗抑郁药可能对谷氨酸能系统产生延迟的间接影响。此外，越来越多的数据表明，情绪障碍与局部体积缩小、细胞丢失和萎缩有关。值得注意的是，拉莫三嗪减少谷氨酸能神经传递，在双相抑郁中具有抗抑郁作用，一项初步研究表明，NMDA拮抗剂可能具有抗抑郁作用。综上所述，这些数据表明，谷氨酸能系统可能在抑郁症的病理生理和治疗中发挥作用，而更直接减少谷氨酸能神经传递的药物可能代表了一类新的抗抑郁药物。 非巴马特(Felbatol？)二氨基甲酸酯是FDA批准的一种单一疗法和辅助疗法，用于成人部分发作伴或不伴二次泛化发作，以及儿童Lennox-Gastaut综合征相关的部分性和全身性发作。非氨基甲酸酯具有显著的抗谷氨酸能和神经保护特性，可能被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，我们建议研究非氨基甲酸酯的潜在疗效，它通过抑制谷氨酸释放和NMDA、AMPA和代谢性谷氨酸受体阻断来减少谷氨酸能吞吐量。 这是一项为期8周的随机、双盲、安慰剂对照研究，将检验非氨基甲酸酯在急性抑郁症双相情感障碍患者中的有效性和安全性，这些患者被认为是治疗耐药。 这项研究分为两个阶段。第一阶段是冲刷阶段，将持续7天。第二阶段是为期8周的急性治疗阶段，比较非氨基甲酸酯和安慰剂的疗效和耐受性。如果记录了对该制剂的部分反应，锂可以保留在研究I和II期间。完成8周双盲期的患者将接受临床治疗。急性疗效将通过使用特定标准显示更高的应答率来确定。 年龄在18岁或以上，被诊断为I型或II型双相情感障碍、抑郁(没有精神病特征)的患者将被随机分成双盲治疗组，接受非氨基甲酸酯(600-3000毫克/天)或安慰剂治疗，为期8周。在这一急性期之后，患者将接受临床指示的治疗。约52名难治性急性双相抑郁患者将参加这项研究。