Antidepressant Efficacy of an Antiglutamatergic Agent in Bipolar Depression

抗谷氨酸药物对双相抑郁症的抗抑郁功效

• 批准号: 7735168
• 负责人: Carlos Zarate
• 金额: $ 23.29万
• 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/7735168
• 关键词: Acute; Age; Antidepressive Agents; Bipolar Depression; Bipolar Disorder; Chemosensitization; Class; Clinical Data; Clinical Trials; Controlled Study; DSM-IV; Data; Depressed mood; Diagnosis; Disease; Double-Blind Method; Enrollment; Functional disorder; GluR2 subunit AMPA receptor; Glutamates; Hour; Ketamine; Label; Measures; Mental Depression; N-Methylaspartate; Patients; Pharmaceutical Preparations; Phase; Placebos; Play; Process; Randomized; Range; Rate; Recruitment Activity; Research; Resistance; Riluzole; Role; Score; Specific qualifier value; Synapses; System; Testing; Therapeutic; Time; Unipolar Depression; Week; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; day; depressive symptoms; dosage; improved; inhibitor/antagonist; lamotrigine; neurotransmission; novel; placebo controlled study; preclinical study; response; trafficking; Acute; Age; Antidepressive Agents; Bipolar Depression; Bipolar Disorder; Chemosensitization; Class; Clinical Data; Clinical Trials; Controlled Study; DSM-IV; Data; Depressed mood; Diagnosis; Disease; Double-Blind Method; Enrollment; Functional disorder; GluR2 subunit AMPA receptor; Glutamates; Hour; Ketamine; Label; Measures; Mental Depression; N-Methylaspartate; Patients; Pharmaceutical Preparations; Phase; Placebos; Play; Process; Randomized; Range; Rate; Recruitment Activity; Research; Resistance; Riluzole; Role; Score; Specific qualifier value; Synapses; System; Testing; Therapeutic; Time; Unipolar Depression; Week; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; day; depressive symptoms; dosage; improved; inhibitor/antagonist; lamotrigine; neurotransmission; novel; placebo controlled study; preclinical study; response; trafficking

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.

急性单极抑郁症的治疗已得到广泛研究。然而，尽管有多种抗抑郁药的可用性，但临床试验表明，尽管有足够的剂量，持续时间和依从性，但30％至40％的抑郁症患者仍未对一线抗抑郁治疗做出反应。很少有研究检查了体细胞处理对双相抑郁症的急性期的功效。因此，显然需要开发新颖和改善双相抑郁症的治疗剂。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，拉莫三嗪是谷氨酸释放的抑制剂，NMDA拮抗剂氯胺酮可能具有抗抑郁作用。最后，我们的小组最近在两项单独的研究中发现，谷氨酸调节剂riluzole在耐治疗的单极和躁郁症抑郁症中有效（Zarate等，2004； Zarate等，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学和治疗中起作用，并且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型的抗抑郁药。 在这项研究中，我们建议通过研究双极抑郁症的双盲安慰剂对照研究，从对治疗抑郁症的瑞唑的开放标签研究中扩展我们的发现。 年龄在18至70岁之间的患者诊断为躁郁症I或II当前发作（无精神病特征），将被随机分为双盲治疗，以接受Riluzole（50-200 mg/day）或安慰剂，或安慰剂为期8周。急性功效将通过使用指定标准证明更高的响应率来确定。 这项研究将招募大约78例急性躁郁症抑郁症患者。 现在，该项目与项目MH002857-04高度整合在一起，用于快速和持续的抗抑郁效应，在我们的研究中发现，谷氨酸能调节剂在4个小时内导致了通常需要6周的谷氨酸能调节剂。在该项目中，该项目在躁郁症抑郁症（Riluzole）中进行了测试。在过去的一年中，我们还通过Riluzole进行了临床前研究，发现它增加了参与AMPA运输的AMPA受体的GlUR1和GlUR2亚基的表达（Zarate and Manji 2008）。我们认为，增加AMPA贩运活动参与了我们正在研究的突触增强过程，并认为这参与了氯胺酮的快速抗抑郁作用。我们预计将在接下来的1。5年之前完成本项目的招聘。然后，我们将确定Riluzole是否确实为双相抑郁症患者提供了一种新的治疗方法（基于与现有治疗不同的新作用机理）。