Clinical Medication Development for Bipolar Disorder and Alcohol Use Disorders

 描述（由申请人提供）：酒精使用障碍在双相情感障碍中极为常见，并且当存在时，与住院率增加、不良结局、对自己和他人的暴力以及不依从双相情感障碍治疗相关。然而，关于这些患者的治疗数据很少。当前申请是对PA-13-160的响应（酒精使用障碍：治疗，服务和恢复研究），强调“药物开发”，需要“发现，开发和测试新的，更有效的药物，以防止或减少饮酒”，和“治疗精神病/药物滥用/医疗并发症”，以及需要“开发和实施新的，有效的适应性临床试验设计和统计分析”。我们提出了一个创新的设计，将检查两个有前途的新的药物治疗（胞磷胆碱和双相情感障碍和酒精使用障碍）。胞二磷胆碱在动物模型中具有有效的神经保护作用，似乎可以减少人类对可卡因和酒精的使用。孕烯醇酮是GABA能神经类固醇的前体。除了对GABA和其他神经递质的影响外，双烯醇酮还能增强微管组装，这是一种在长期饮酒中受损的神经可塑性所必需的途径。孕烯醇酮减少动物模型中的酒精消耗。因此，这两种化合物都具有与酒精依赖有关的新特性，但尚未在临床试验中探索。在 除了支持这些药物治疗情绪症状和酒精依赖的临床前和临床文献外，我们还提供了支持其用于双相情感障碍和酒精依赖患者的试验数据。将实施一种称为“放弃失败者”的创新适应性试验设计，试验将从两个活性治疗组和一个安慰剂组开始开始，在中期分析时，如果无效，可以放弃一个治疗组。在这一点上，这项研究将继续作为一个两组试验比较更有前途的药物与安慰剂。如果两种药物似乎都有效，则试验将继续进行三个治疗组。如果在中期分析时两种药物均无前景，则将中止试验。该方法允许对多种治疗进行快速评估，以及对一种治疗进行充分把握度的试验。本研究将在两个研究中心进行，由两名主要研究者进行，他们是该领域经验丰富的研究人员。适应性临床试验专家将进行统计分析。这两个地点将最大限度地利用所需资源，以高效率的方式实现具体目标。我们的目标是开发一种有前途的，迫切需要的，双相情感障碍和酒精使用的治疗，并证明在酒精治疗领域的创新临床试验方法的实用性。

 DESCRIPTION (provided by applicant): Alcohol use disorders are extremely common in bipolar disorder and, when present, are associated with increased rates of hospitalization, poor outcomes, violence towards self and others, and non- adherence to bipolar disorder treatment. However, minimal data are available on the treatment of these patients. The current application is in response to PA-13-160 (Alcohol Use Disorders: Treatment, Services, and Recovery Research) that emphasizes "medications development", the need to "Discover, develop, and test new, more effective agents to prevent or reduce drinking", and the "Treatment for Psychiatric/Substance Abuse/Medical Comorbidity", as well as the need to "Develop and implement new, efficient adaptive clinical trial designs and statistical analyses". We propose an innovative design that will examine two promising novel pharmacotherapies (citicoline and pregnenolone) in bipolar disorder and alcohol use disorders. Citicoline has potent neuroprotective properties in animal models and appears to decrease both cocaine and alcohol use in humans. Pregnenolone is a precursor to GABAergic neurosteroids. In addition to effects on GABA and other neurotransmitters, pregnenolone enhances microtubule assembly, a pathway essential for neuroplasticity that is impaired in chronic alcohol use. Pregnenolone reduces alcohol consumption in animal models. Thus, both compounds have novel properties that are pertinent to alcohol dependence but that have not yet been explored in clinical trials. In addition to the preclinical and clinical literature supporting these agents for mood symptoms and alcohol dependence, we present pilot data supporting their use in patients with bipolar disorder and alcohol dependence. An innovative adaptive trial design called "drop-the-loser" will be implemented such that the trial will begin with two active treatment arms and a placebo arm. At interim analysis, a treatment arm can be dropped if ineffective. At this point, the study will continue as a two-arm trial comparing the more promising agent against placebo. If both agents seem effective then the trial will continue with three treatment arms. If neither agent appears promising at interim analysis then the trial will be discontinued. The approach allows for rapid assessment of multiple treatments as well as an adequately powered trial of one treatment. The study will be conducted at two sites using two principal investigators, who are highly experienced researchers in the field. An expert on adaptive clinical trials will conduct the statistical analysis. Two sites will maximize the use of resources needed to achieve specific aims in an efficient manner. The goal is both to develop a promising, and badly needed, treatment for bipolar disorder and alcohol use, and demonstrate the utility of an innovative clinical trial methodology in the alcohol treatment field.