Antidepressant Efficacy of an Antiglutamatergic Agent in Bipolar Depression

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，显然需要开发新的和改进的双相抑郁症的治疗方法。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。临床资料提示谷氨酸释放抑制剂拉莫三嗪和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独立的研究中发现，谷氨酸调节剂利鲁唑对难治性单相和双相抑郁症有效（Zarate et al 2004; Zarate et al. 2005）。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。 在这项研究中，我们建议通过在双相抑郁症的双盲安慰剂对照研究中调查利鲁唑治疗难治性抑郁症的疗效来扩展我们的研究结果。 年龄18 - 70岁、诊断为双相情感障碍I或II型、当前发作抑郁（无精神病特征）的患者将随机接受双盲治疗，接受利鲁唑（50-200 mg/天）或安慰剂治疗8周。将通过使用指定标准证明更高的缓解率来确定急性疗效。 本研究将入组约78例急性双相抑郁患者。 该项目现在与项目MH 002857 -04谷氨酸能调节剂快速和持续抗抑郁作用高度整合，我们在研究中发现谷氨酸能调节剂在4小时内产生快速抗抑郁作用，通常需要6周。在这个项目中测试的双相抑郁症药物（阿舒唑）也被用于另一个项目。在过去的一年中，我们还对利鲁唑进行了临床前研究，发现它增加了参与AMPA转运的AMPA受体GluR 1和GluR 2亚基的表达（Zarate和Manji 2008）。我们认为AMPA的运输增加与突触增强有关，我们正在研究这一过程，并认为这与氯胺酮的快速抗抑郁作用有关。我们预计在未来1.5年内完成本项目的招聘工作。届时，我们将确定利鲁唑是否确实为双相抑郁患者提供了一种新的治疗选择（基于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.