Antidepressant Efficacy of Antiglutamatergic in BPD
抗谷氨酸药在 BPD 中的抗抑郁功效
基本信息
- 批准号:6982746
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:NMDA receptorsantidepressantsbipolar depressiondrug interactionsdrug screening /evaluationglutamateshuman subjecthuman therapy evaluationinhibitor /antagonistmental disorder chemotherapyneural inhibitionneural transmissionneuropsychologypatient oriented researchpharmacokineticsreceptor sensitivitythiazoles
项目摘要
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. It is noteworthy that lamotrigine reduces glutamatergic neurotransmission, has antidepressant effects in bipolar depression, and a pilot study has suggested that N-methyl-D-aspartatic acid (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.
Riluzole, an agent that is FDA-approved for Amyotrophic Lateral Sclerosis has significant antiglutamatergic properties, may prove to have antidepressant properties in depressed patients. In this study, we propose to investigate the potential antidepressant efficacy of riluzole in bipolar depression, an agent which reduces glutamatergic throughput via inhibition of its release.
This is an 8-week single-arm, single-blind add-on study that will examine the efficacy and safety of riluzole in combination with a mood stabilizer in acutely depressed bipolar patients.
The study has two Study Periods. Study Period I is the washout phase that will last 7 days. Study Period II is an add-on 8-week acute treatment phase in which the efficacy and tolerability of riluzole is compared to baseline.
Patients, ages 18 or older with a diagnosis of bipolar disorder I or II current episode depressed (without psychotic features), will in this pilot study (single arm, single-blind) receive riluzole (50-200 mg/day) for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria.
Approximately 25 patients will enter the study to obtain 22 subjects who complete the 8 weeks of acute riluzole treatment. Therefore if 7/22 patients or greater have > 50% improvement on the primary efficacy measure, then based on statistically guidelines from the Optimal Two Stage Design for Clinical Trials, a controlled trial would be indicated to scientifically confirm the signal observed in the single arm trial.So far, approximately 16 bipolar patients entered into the study. All patients had previously failed to respond to adequate trials of at least two antidepressants. For the first fourteen, the mean duration of lithium treatment during the study was 62 days (SD=47.64). Significant improvement in mean change of Montgomery-Asberg Depression Rating Scale (MADRS)scores from baseline to endpoint (F=9.042 p=0.000) occurred and was also observed when the clinical global impression severity (CGI-S) scale was utilized (F=6.14, p=0.005). Response (50% decrease in MADRS) and remission (MADRS <12) by endpoint occurred in 50% of subjects. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated. These preliminary results suggest that riluzole may indeed have antidepressant efficacy in subjects with bipolar depression.
A double blind, placebo-controlled study is currently being proposed to investigate the antidepressant efficacy of Riluzole monotherapy in bipolar patients. Other glutamatergic medications are currently being investigated in double blind, placebo-controlled trials.
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。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,N-甲基-D-天冬氨酸(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。
利鲁唑是 FDA 批准用于治疗肌萎缩侧索硬化症的药物,具有显着的抗谷氨酸特性,可能被证明对抑郁症患者具有抗抑郁特性。在这项研究中,我们建议研究利鲁唑在双相抑郁症中的潜在抗抑郁功效,利鲁唑是一种通过抑制其释放来降低谷氨酸能吞吐量的药物。
这是一项为期 8 周的单组、单盲附加研究,将检验利鲁唑与情绪稳定剂联合治疗急性抑郁双相情感障碍患者的疗效和安全性。
该研究有两个研究期。研究阶段 I 是持续 7 天的清除阶段。研究阶段 II 是一个为期 8 周的附加急性治疗阶段,其中将利鲁唑的疗效和耐受性与基线进行比较。
年龄 18 岁或以上、诊断为 I 型或 II 型双相情感障碍当前发作抑郁(无精神病特征)的患者将在这项试点研究(单臂、单盲)中接受利鲁唑(50-200 毫克/天)治疗,为期 8 周。急性疗效将通过使用指定标准证明更高的反应率来确定。
大约25名患者将进入该研究,以获得22名完成8周急性利鲁唑治疗的受试者。因此,如果 7/22 名或更多的患者在主要疗效指标上有 > 50% 的改善,那么根据临床试验最佳两阶段设计的统计指南,将需要进行对照试验来科学地确认单臂试验中观察到的信号。到目前为止,大约有 16 名双相情感障碍患者进入了该研究。所有患者之前都未能对至少两种抗抑郁药的充分试验做出反应。对于前十四天,研究期间锂治疗的平均持续时间为 62 天 (SD=47.64)。蒙哥马利-阿斯伯格抑郁量表 (MADRS) 评分从基线到终点的平均变化显着改善 (F=9.042 p=0.000),并且在使用临床总体印象严重程度 (CGI-S) 量表时也观察到了这一情况 (F=6.14,p=0.005)。 50% 的受试者出现终点缓解(MADRS 降低 50%)和缓解(MADRS <12)。没有观察到转变为轻躁狂或躁狂。总体而言,利鲁唑的耐受性良好。这些初步结果表明,利鲁唑确实可能对双相抑郁症患者具有抗抑郁功效。
目前正在提议一项双盲、安慰剂对照研究,以调查利鲁唑单一疗法对双相情感障碍患者的抗抑郁功效。其他谷氨酸药物目前正在双盲、安慰剂对照试验中进行研究。
项目成果
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HUSSEINI K MANJI其他文献
HUSSEINI K MANJI的其他文献
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{{ truncateString('HUSSEINI K MANJI', 18)}}的其他基金
LITHIUM RESPONSIVE BIPOLAR DISORDER AND CNS MYO INOSITOL
锂反应性双相情感障碍和中枢神经系统肌醇
- 批准号:
2908653 - 财政年份:1999
- 资助金额:
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PKC SIGNALING AND THE TREATMENT OF BIPOLAR DISORDER
PKC 信号传导和双相情感障碍的治疗
- 批准号:
2702902 - 财政年份:1998
- 资助金额:
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PKC SIGNALING AND THE TREATMENT OF BIPOLAR DISORDER
PKC 信号传导和双相情感障碍的治疗
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2891036 - 财政年份:1998
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Neuronal-Glial Interaction in the Treatment of Bipolar
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6824400 - 财政年份:
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Microarray Studies -- Long Term Treatment for Bipolar
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6824378 - 财政年份:
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The Protein Kinase C Inhibitor Tamoxifen in Acute Mania
蛋白激酶 C 抑制剂他莫昔芬治疗急性躁狂症
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6982748 - 财政年份:
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Testing whether the enzyme GSK-3 is a therapeutically re
测试 GSK-3 酶是否具有治疗作用
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