Clinical Medication Development for Bipolar Disorder and Alcohol Use Disorders

 描述(申请人提供)：酒精使用障碍在双相情感障碍中非常常见，如果出现，与住院率增加、预后不良、对自己和他人的暴力以及不坚持双相情感障碍治疗有关。然而，关于这些患者的治疗数据很少。目前的应用是对PA-13-160(酒精使用障碍：治疗、服务和康复研究)的响应，该PA-13-160强调“药物开发”，需要“发现、开发和测试新的、更有效的药物来防止或减少饮酒”，以及“精神病/药物滥用/医学合并症的治疗”，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”。我们提出了一种创新的设计，将检查两种有前景的新药物疗法(胞二磷胆碱和孕烯醇酮)在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强大的神经保护特性，似乎可以减少人类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，孕烯醇酮还可以增强微管组装，这是神经可塑性的关键途径，在长期饮酒时会受到损害。孕烯醇酮可减少动物模型的酒精消耗量。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进行探索。在……里面 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，我们还提供了支持它们在双相情感障碍和酒精依赖患者中使用的试点数据。将实施一种名为“放弃输家”的创新适应性试验设计，以便试验将从两个主动治疗臂和一个安慰剂臂开始。在中期分析中，如果治疗无效，治疗臂可以被丢弃。在这一点上，这项研究将继续进行双臂试验，比较更有希望的药物和安慰剂。如果两种药物似乎都有效，那么试验将继续进行，有三个治疗武器。如果在中期分析中两种药物都没有前景，那么试验将被终止。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的动力试验。这项研究将在两个地点进行，使用两名首席调查人员，他们都是该领域经验丰富的研究人员。一位适应性临床试验专家将进行统计分析。两个站点将以高效的方式最大限度地利用实现具体目标所需的资源。其目标是开发一种有希望且亟需的治疗双相情感障碍和酒精使用的方法，并展示创新的临床试验方法在酒精治疗领域的实用性。

 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.