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、严重、慢性且常常危及生命的疾病。人们越来越认识到，疾病的抑郁阶段是发病率和死亡率的主要原因。抑郁症造成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 10-20% 的双相情感障碍或复发性抑郁症患者的死亡原因。 急性单相抑郁症的治疗已得到广泛研究。然而，尽管有多种抗抑郁药物可供使用，但临床试验表明，尽管有足够的剂量、持续时间和依从性，但仍有 30% 至 40% 的抑郁症患者对一线抗抑郁治疗没有反应。很少有研究检验躯体治疗对双相抑郁症急性期的疗效。因此，显然需要开发新的和改进的双相抑郁疗法。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减少、细胞损失和萎缩有关。值得注意的是，拉莫三嗪可减少谷氨酸能神经传递，对双相抑郁症具有抗抑郁作用，一项初步研究表明，NMDA 拮抗剂可能具有抗抑郁作用。总之，这些数据表明谷氨酸能系统可能在抑郁症的病理生理学和治疗中发挥作用，并且更直接减少谷氨酸能神经传递的药物可能代表一类新型抗抑郁药。 Felbamate（Felbatol？）是一种二氨基甲酸酯，已获得 FDA 批准作为单一疗法和辅助疗法，用于治疗伴有或不伴有继发性全身性部分性癫痫发作的成人以及与 Lennox-Gastaut 综合征相关的儿童部分性和全身性癫痫发作。非氨酯具有显着的抗谷氨酸和神经保护特性，并且可能被证明对双相情感障碍患者具有抗抑郁特性。在这项研究中，我们建议研究非氨酯的潜在功效，它通过抑制谷氨酸释放和 NMDA、AMPA 和代谢型谷氨酸受体阻断来降低谷氨酸能吞吐量。 这是一项为期 8 周的随机、双盲、安慰剂对照研究，将检验非氨酯对治疗耐药的急性抑郁双相情感障碍患者的疗效和安全性。 这项研究分为两个阶段。第一阶段是持续7天的清除阶段。第二阶段是为期8周的急性治疗阶段，其中比较非氨酯和安慰剂的疗效和耐受性。如果记录了对该药物的部分反应，则在研究期 I 和 II 期间可以保留锂。完成8周双盲阶段的患者将接受临床治疗。急性疗效将通过使用指定标准证明更高的反应率来确定。 18 岁或以上、诊断为 I 型或 II 型双相情感障碍、抑郁（无精神病特征）的患者将被随机接受双盲治疗，接受非氨酯（600-3000 毫克/天）或安慰剂，为期一段时间8周。在此急性期之后，患者将接受临床指示的治疗。大约 52 名患有难治性急性双相抑郁症的患者将参加该研究。