Combining Medication Treatments for Alcoholism

描述(申请人提供)：最近对联合治疗药物治疗酒精中毒的科学和临床兴趣是基于这样一个事实，即多种神经递质系统的紊乱可能是这种疾病的生物学易感性的基础。因此，将不同神经递质的有效药物结合起来，应该会产生协同作用，或者至少会产生额外的临床反应。 我们已经证明，与安慰剂相比，恩丹西酮(一种5-羟色胺-3拮抗剂)显著减少饮酒并增加EOA但不是LOA的戒酒，这可能是通过改善与早发性酒精中毒相关的潜在生物学(即5-羟色胺能)异常。也就是说，使用特定的5-羟色胺能药物恩丹西酮治疗，只会改善特定酒精亚型的饮酒结果。在初步的临床试验中，我们还表明托吡酯(一种氨基磺酸果糖衍生物)在改善EOA和LOA的饮酒结果方面优于安慰剂。我们推测，托吡酯的疗效与改善慢性饮酒引起的神经化学过程有关：由于促进伽马氨基丁酸(GABA)功能和抑制电压门控钙通道，显著减少了由于伽马氨基丁酸(GABA)功能而导致的全身性渴望症状。因此，我们假设：1)恩丹西酮和托吡酯的联合作用在EOA之间是相加的，可能是协同作用；2)EOA与LOA相比，对单独使用恩丹西酮更敏感；3)EOA和LOA对托吡酯治疗都有反应。 我们将通过检测恩丹西酮(4mcg/kg b.i.d)的有效性来检验这一假设的具体预测。和托吡酯(高达300毫克/天)，分别单独和联合治疗EOA和LOA(45名受试者/细胞×8个细胞，总N=360)，在为期12周(单盲安慰剂1周，双盲条件下11周)的随机、双盲、安慰剂对照的门诊临床试验中。所有受试者将接受人工驱动的标准化认知行为治疗，并在治疗后1、3、6和9个月进行随访。 这项研究支持NIAAA的使命，即开发有效的联合药物疗法，作为治疗酒精中毒的心理治疗的辅助手段。

DESCRIPTION (provided by applicant): Recent scientific and clinical interest in combining therapeutic agents for the treatment of alcoholism are based on the fact that derangement of multiple-neurotransmitter systems are likely to underlie biological predisposition to the disease. Thus, combining effective medications working at different neurotransmitters should produce a synergistic or at least an added clinical response. We have shown that ondansetron (a serotonin-3 antagonist), compared with placebo, significantly reduces drinking and increases abstinence among EOA but not LOA, presumably by ameliorating an underlying biological (i.e. serotonergic) abnormality which is associated with early onset alcoholism. That is, treatment with the specific serotonergic agent, ondansetron, results in improved drinking outcomes only for a particular alcoholic subtype. In a preliminary clinical trial, we also have shown that topiramate (a sulfamate fructo-pyranose derivative) is superior to placebo at improving the drinking outcomes of both EOA and LOA. We have postulated that topiramate's effectiveness is associated with amelioration of the neurochemical processes due to chronic drinking which occur in both EOA and LOA: notably reduction of generalized craving symptoms due to facilitation of gamma amino butyric acid (GABA) function and inhibition of voltage-gated calcium channels. We, therefore, hypothesize that: 1) the combination of ondansetron and topiramate effects would be additive and possibly synergistic, among EOA; 2) EOA, compared with LOA, will be more responsive to treatment with ondansetron alone, and 3) that both EOA and LOA will respond to topiramate treatment. We will test the specific predictions of this hypothesis by examining the effectiveness of ondansetron (4 mcg/kg b.i.d.) and topiramate (up to 300 mg/day), each alone and in combination, in treating EOA and LOA (45 subjects/cell x 8 cells, total N=360) in a randomized, double-blind, placebo-controlled, 12-week (1 week of single-blind placebo followed by 11 weeks of double-blind condition) outpatient clinical trial. All subjects will receive manual-driven standardized Cognitive Behavioral Therapy, and follow-up at 1, 3, 6, and 9 months post-treatment. This study supports NIAAA's mission to develop effective combinative pharmacotherapies as adjuncts to psychotherapy for the treatment of alcoholism.