Antidepressant Efficacy of an Antiglutamatergic Agent in Bipolar Depression

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。临床数据表明，谷氨酸释放的抑制剂拉莫三嗪和NMDA拮抗剂氯胺酮可能具有抗抑郁作用。最后，我们小组最近在两项单独的研究中发现，谷氨酸调节剂利鲁唑对治疗难治性单相和双相抑郁有效(Zarate等人，2004；Zarate等人)。2005)。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。 在这项研究中，我们建议通过研究利鲁唑对双相情感障碍的双盲安慰剂对照研究的有效性，扩展我们对利鲁唑治疗难治性抑郁症的开放标签研究的发现。 被诊断为双相情感障碍I或II的患者，年龄在18岁至70岁之间，目前的抑郁发作(没有精神病特征)，将被随机分成双盲治疗，接受利鲁唑(50-200毫克/天)或安慰剂治疗，为期8周。急性疗效将通过使用特定标准显示更高的应答率来确定。 约78名急性双相抑郁患者将参加这项研究。 该项目现在与MH002857-04项目高度集成，用于快速和持续的抗抑郁效果，我们在研究中发现，谷氨酸能调节剂在4小时内导致快速抗抑郁效果，而这通常需要6周。在这个项目中测试的治疗双相抑郁的药物(利鲁唑)也在另一个项目中使用。在过去的一年里，我们还进行了利鲁唑的临床前研究，发现它增加了参与AMPA转运的AMPA受体的GluR1和GluR2亚单位的表达(Zarate和Manji 2008)。我们认为，AMPA交易的增加与突触增强有关，我们正在研究并认为这一过程与氯胺酮的快速抗抑郁作用有关。我们预计在未来一年半内完成目前项目的招聘工作。到那时，我们将确定利鲁唑是否真的为双相抑郁患者提供了一种新的治疗替代方案(基于一种与现有治疗不同的新作用机制)。

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. Clinical data suggests that lamotrigine an inhibitor of glutamate release and the NMDA antagonist ketamine may have antidepressant effects. Finally, our group recently found in two separate studies that the glutamate modulating agent riluzole was effective in treatment-resistant unipolar and bipolar depression (Zarate et al 2004; Zarate et al. 2005). Together, these data suggest 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 this study, we propose to extend our findings from open-label studies with riluzole in treatment-resistant depression by investigating its efficacy in a double-blind placebo-controlled study in bipolar depression. Patients, ages 18 to 70 years with a diagnosis of bipolar disorder I or II current episode depressed (without psychotic features), will be randomized to double-blind treated to receive either riluzole (50-200 mg/day) or placebo for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 78 patients with acute bipolar depression will be enrolled in this study. This project is now highly integrated with project MH002857-04 Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect where we found in our studies that a glutamatergic modulator led to rapid antidepressant effects in 4 hours what usually takes 6 weeks. The drug being tested in this project in bipolar depression (Riluzole) is also being used in the other project. During this past year, we have also conducted preclinical studies with riluzole and found that it increases expression of GluR1 and GluR2 subunits of the AMPA receptor involved in AMPA trafficking (Zarate and Manji 2008). Increasing AMPA trafficking we believe is involved in synaptic potentiation a process that we are studying and believe is involved in the rapid antidepressant effects of ketamine. We anticipate completing recruiting for the present project by next 1.5 years. At that time, we would then determine whether riluzole indeed offers a new treatment alternative (based on a new mechanism of action distinct from existing treatments) for patients with bipolar depression.