Antidepressant Efficacy--Dopamine Agonist in BPD

抗抑郁功效--多巴胺激动剂在BPD中的应用

• 批准号: 7136802
• 负责人: HUSSEINI K MANJI
• 金额: --
• 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/7136802
• 关键词: antidepressants; behavioral /social science research tag; bipolar depression depressed phase; brain imaging /visualization /scanning; clinical trials; dopamine agonists; dopamine receptor; drug screening /evaluation; human subject; human therapy evaluation; magnetic resonance imaging; mental disorder chemotherapy; neurochemistry; neuropharmacologic agent; neurotrophic factors; pathologic process; patient oriented research; pharmacokinetics; positron emission tomography; psychopharmacology; thiazoles

Bipolar affective disorder (BPD, manic-depressive illness) is a common, severe, chronic and often life-threatening illness. Increasingly, the depressive phase of the illness is recognized as contributing much of the morbidity and mortality. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Suicide is the cause of death in 10-20% of individuals with either bipolar or recurrent depressive disorders. 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 (unipolar) 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. A deficiency of dopamine systems stands as a prime candidate for involvement in the pathophysiology of depression. Preliminary studies suggest that pramipexole (Mirapex), a dopaminergic-agent that is FDA-approved for Parkinson?s disease, may have antidepressant properties in unipolar and bipolar patients as well as neurotrophic properties. In this study, we propose to investigate the potential efficacy of pramipexole, which enhances dopaminergic throughput via D2 and D3 receptors and exerts robust neurotrophic effects via direct intracellular mechanisms. This is a 6-week randomized double-blind, placebo-controlled add-on study that will examine the efficacy of pramipexole in acutely depressed Bipolar II patients. This study has three phases. The first phase is the washout phase that will last for 14 days. The second phase is a 6-week double-blind acute phase in which the efficacy and tolerability of adjunctive pramipexole and placebo are compared. Patients who complete the 6-week double-blind phase will receive either open-label pramipexole or clinical treatment. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Patients, ages 18 to 70, with a diagnosis of Bipolar II disorder, depressed (without psychotic features), will be randomized to double-blind treatment to receive either pramipexole (0.375-4.5 mg/day) or placebo in combination with a mood stabilizer for a period of 6 weeks. Following this acute period, the patients will receive either open-label pramipexole or treatment as clinically indicated. Approximately 100 patients with acute Bipolar II depression will be enrolled in the study. Imaging and pharmacokinetic studies will be obtained during the study. So far, twenty one patients with DSM-IV bipolar II disorder, depressive phase were randomly assigned to treatment with pramipexole (N=10) or placebo (N=11). Primary efficacy was assessed by change from baseline in scores of the Montgomery-Asberg Depression rating scale. All subjects except for one in each group completed the study. The Analysis of Covariance (ANCOVA) for total Montgomery-Asberg Depression Rating Scale (MADRS) scores showed a significant treatment effect with no time effect or interaction between treatment and time. Response (>50 decrease in MADRS from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p=.02). Mean percentages in improvement from baseline MADRS depression ratings were greater with pramipexole (47%) than placebo (12.4%) (p<.05). One subject on pramipexole and two on placebo developed hypomanic symptoms. The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression. This suggests that a deficiency in the dopaminergic system may be involved in the pathophysiology of this disorder. Brain neuroimaging investigation is currently undergoing to determine volumetric (MRI), functional (PET), and neurochemical (MRS) changes related with the administration and antidepressant response associated to pramipexole.

双极情感障碍（BPD，躁狂抑郁症）是一种常见，严重，慢性且通常是威胁生命的疾病。越来越多的疾病抑郁阶段被认为造成了许多发病率和死亡率。抑郁症引起的身体和社会功能受损可能与其他慢性医学疾病一样严重。自杀是10-20％的双极或复发性抑郁症患者死亡的原因。 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％的抑郁症患者中有30％至40％未能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。多巴胺系统的缺乏是参与抑郁症病理生理学的主要候选人。 初步研究表明，Pramipexole（Mirapex）是一种帕金森氏病的多巴胺能批准的多巴胺能代理，在单极和双极患者以及神经营养特性中可能具有抗抑郁特性。在这项研究中，我们建议研究普拉己烯的潜在疗效，从而通过D2和D3受体增强了多巴胺能吞吐量，并通过直接细胞内机制发挥强大的神经营养作用。 这是一项为期6周的随机双盲，安慰剂对照的附加组件，它将检查普拉米己烯在急性抑郁的双极II患者中的功效。这项研究有三个阶段。第一阶段是将持续14天的冲洗阶段。第二阶段是一个为期6周的双盲急性期，其中比较了辅助额曲和安慰剂的功效和耐受性。完成为期6周的双盲阶段的患者将接受开放标签的定胺或临床治疗。急性功效将通过使用指定标准证明更高的响应率来确定。 18至70岁的患者诊断为双极II疾病，抑郁症（无精神病特征），将被随机分配给双盲治疗，以接受普拉米己烯（0.375-4.5 mg/day）或安慰剂与情绪稳定剂结合使用6周。在此急性期之后，患者将按照临床表明的方式接受开放标签的普拉己核或治疗。该研究将招募大约100例急性双极II抑郁症患者。在研究期间将获得成像和药代动力学研究。到目前为止，将二十一名DSM-IV双极II疾病患者随机分配给用pramipexole（n = 10）或安慰剂（n = 11）治疗。蒙哥马利 - 阿斯伯格抑郁量表评分的基线变化评估了一级疗效。除每组中的一个外，所有受试者均完成了研究。对蒙哥马利 - 阿斯伯格抑郁量表（MADRS）得分的协方差分析（ANCOVA）显示出显着的治疗效果，没有治疗和时间之间的时间效应或相互作用。 60％服用普拉米己核的患者和安慰剂9％的患者发生反应（MADR的降低> 50降低）（p = .02）。基线MADRS抑郁症评级的平均百分比比安慰剂（47％）高于安慰剂（12.4％）（p <.05）。一位在普拉米己烯和安慰剂上的受试者出现了躁狂症状。发现多巴胺激动剂的肾上腺己醇对双极II抑郁症患者具有显着的抗抑郁作用。这表明多巴胺能系统的缺乏可能与该疾病的病理生理有关。 目前正在进行大脑神经影像学调查，以确定与给药和抗抑郁相关的给药和抗抑郁反应有关的体积（MRI），功能（PET）和神经化学（MRS）的变化。