2/2-Pramipexole in Bipolar Disorder: Targeting Cognition

2/2-普拉克索治疗双相情感障碍：针对认知

• 批准号: 8759812
• 负责人: Anil K Malhotra
• 金额: $ 29.49万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-23 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759812
• 关键词: Activities of Daily Living; Address; Adverse effects; Affect; Affective Symptoms; Agonist; Antipsychotic Agents; Attention; Biological Neural Networks; Bipolar Disorder; Bipolar I; Clinical; Clinical Trials Design; Cognition; Cognitive; Cognitive deficits; Collaborations; Communities; Complex; Consensus; Data; Databases; Disease; Disease remission; Dopamine; Dopamine Agonists; Dose; Double-Blind Method; Ensure; Evaluation; Functional disorder; Future; Gambling; Heterogeneity; Hospitals; Impaired cognition; Impairment; Intervention; Iowa; Label; Manic; Measures; Memory; Mental Depression; Modification; Mood Disorders; Moods; Neurocognition; Neurocognitive; Nootropic Agents; Outcome Measure; Paper; Parkinson Disease; Patient Monitoring; Patients; Performance; Persons; Pharmaceutical Preparations; Placebo Control; Placebos; Population; Quality of life; Randomized; Recording of previous events; Recovery; Relative (related person); Reporting; Research Design; Research Personnel; Restless Legs Syndrome; Risk; Safety; Sample Size; Sampling; Schizophrenia; Severities; Signal Transduction; Site; Social Adjustment; Symptoms; Testing; Visit; Work; affective neuroscience; base; clinically significant; cognitive control; cognitive enhancement; computerized; design; experience; follow-up; functional disability; improved; insight; medical schools; novel; pramipexol; primary outcome; public health relevance; response; reward processing; safety testing; skills; standard care; subthreshold depression; week trial

DESCRIPTION (provided by applicant): Despite advances in the treatment of bipolar disorder, most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction. These persistent features of the illness represent critical treatment targets, as they do not adequately improve with standard mood stabilizing medications and they are strongly associated with functional disability and poor quality of life. In prior work by our group (Burdick et al. 2012), we reported preliminary evidence of a significant efficacy signal in a subset of bipolar patients who participated in a controlled cognitive enhancement trial of the D2/D3 agonist, pramipexole (Mirapex(c)). In conducting this previous study, we noted several important methodological limitations and illness-related confounds that require follow-up using a modified approach in order to adequately test the safety and efficacy of this agent in treating cognitive dysfunction in bipolar disorder. Thus, we propose a 2-site, collaborative, 24-week, randomized, placebo-controlled, adjunctive study to evaluate the safety and efficacy of pramipexole on neurocognitive functioning in 100 affectively-stable bipolar patients. We have modified the design from the prior trial to optimize the likelihood of detecting a positive signalby addressing several of the identified previous limitations by: 1) increasing the maximum daily dose~ 2) including patients who are affectively-stable with objective evidence of cognitive impairment~ 3) stratifying randomization based upon concomitant antipsychotic treatment~ and 4) increasing the duration of the trial to 6 months in an effort to address longer term safety and efficacy as well as potential improvement in everyday functioning. Pramipexole is approved by the US FDA for Parkinson's disease and Restless Leg Syndrome. In an off-label application, we will administer flexibly-dosed pramipexole (1-3 mg/day) vs. placebo to 100 stable patients with bipolar I disorder for 24 weeks. We will measure patients' performance on tasks of attention, memory and higher order cognition, using several paper-pencil and computerized tests, before pramipexole is administered, at week 4, week 8, week 16, and again at the end of the 24-week study. In addition, we will include several novel affective-neuroscience-based measures to gain insight into pramipexole's effect on the neural networks associated with DA-based reward processing. Finally, we will also investigate the effects of pramipexole on measures of functional capacity and community functions. We will closely monitor patients for unforeseen changes in mood symptoms that are deemed to place them at risk for developing mania or depression and will discontinue the trial as deemed necessary. We expect that findings from this study will provide a definitive go/no-go decision regarding the pursuit of this agent as a cognitive enhancer in bipolar disorder. Regardless of primary outcome, we expect that this trial will provide additional important data related to D2/D3-based reward processing in affective disorders.

描述(由申请人提供)：尽管双相情感障碍的治疗取得了进展，但大多数患者并未实现完全的发作间歇期恢复，功能障碍是常见的。在相对缓解期，许多患者继续经历神经认知功能障碍。这种疾病的这些持续特征代表了关键的治疗目标，因为它们不能通过标准的情绪稳定药物充分改善，而且它们与功能残疾和较差的生活质量密切相关。在我们小组之前的工作中(Burdick等人2012)，我们报告了初步证据表明，在一个 参加D2/D3激动剂普拉克索(Mirapex(C))的受控认知增强试验的双相患者的子组。在进行这项先前的研究中，我们注意到了几个重要的方法限制和与疾病相关的混淆，需要使用改进的方法进行随访，以便充分测试该药物在治疗双相情感障碍认知功能障碍方面的安全性和有效性。因此，我们提出了一项为期24周的两点合作随机安慰剂对照的辅助研究，以评估普拉克索对100名情感稳定的双相情感障碍患者神经认知功能的安全性和有效性。我们对先前试验的设计进行了修改，以优化检测到阳性信号的可能性，方法是：1)增加每日最大剂量~2)包括有客观证据表明认知障碍的情感稳定的患者~3)根据伴随的抗精神病药物治疗进行分层随机分组~4)将试验持续时间延长至6个月，以努力解决更长期的安全性和 在日常功能方面的有效性以及潜在的改善。普拉克索被美国FDA批准用于帕金森氏症和不宁腿综合症。在标签外的应用中，我们将对100名双相I型障碍的稳定患者进行为期24周的灵活剂量的普拉克索(1-3毫克/天)与安慰剂的比较。我们将在使用普拉克索之前，在第4周、第8周、第16周，以及在24周研究结束时，使用几种纸笔和计算机测试来测量患者在注意力、记忆和高阶认知任务上的表现。此外，我们将包括几种基于情感神经科学的新方法，以深入了解普拉克索对与基于DA的奖励处理相关的神经网络的影响。最后，我们还将研究普拉克索对功能能力和社区功能测量的影响。我们将密切监测患者的情绪症状中不可预见的变化，这些症状被认为会使他们面临躁狂或抑郁的风险，并将在认为必要时停止试验。我们期望，这项研究的结果将提供一个明确的决定，关于追求这种药物作为双相情感障碍的认知增强剂。无论主要结果如何，我们期望这项试验将提供与情感障碍基于D2/D3的奖赏处理相关的更多重要数据。