Antidepressant Efficacy of an Antiglutamatergic Agent in

急性单相抑郁症的治疗方法已经得到了广泛的研究。然而，尽管有多种抗抑郁药物可供选择，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，尽管剂量、持续时间和依从性都足够。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，有一个明确的需要开发新的和改进治疗双相抑郁症。最近的临床前研究表明，抗抑郁药可能对谷氨酸系统产生延迟的间接影响。临床资料表明，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极和双相抑郁症有效（Zarate et al. 2004; Zarate et al. 2005）。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和治疗中发挥作用，而更直接地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。

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.