Genetic and brain mechanisms of naltrexone's treatment efficacy for alcoholism

酒精依赖影响着1800万至2000万美国人，每年给我们的社会造成的损失超过1850亿美元。这种疾病的治疗并不普遍，现有的治疗方法也不是普遍有效的。阿片类药物拮抗剂纳洛酮，10多年前被FDA批准，是治疗酒精依赖最有效的药物之一，但并没有广泛使用，也不是对每个人都有效。其缺乏广泛接受的原因包括其相对于安慰剂的低至中度改善以及对其作用机制的不完全了解。药物遗传学和神经影像学的最新进展为研究这些问题提供了新的工具。例如，在联合收割机研究中，我们最近证实，μ阿片受体（OPRM 1）中相对常见的遗传变异（Asp 40）可能与纳洛酮的更高治疗反应相关。此外，使用先进的功能性磁共振脑成像范例，我们的小组最近表明，纳洛酮可以钝化主动饮酒的非寻求治疗的酗酒者的腹侧纹状体-中脑核和内侧前额叶皮层中酒精线索诱导的激活。我们还发现，类似的酒精线索诱导激活的内侧前额叶区与酒精依赖者治疗期间随后的大量饮酒有关。本提案的目的是以前瞻性对照方式检查OPRM 1受体的Asp 40变体是否能预测纳洛酮反应。此外，我们将研究纳洛酮是否可能减少/抑制酒精线索诱导的腹侧纹状体和内侧前额叶皮层的激活，并探讨这种抑制是否可能与治疗反应有关。最后，我们将评估Asp 40个体是否会有更多的纳洛酮抑制酒精线索诱导的脑激活，以及这是否会介导治疗期间观察到的药物与基因型相互作用。为此，将筛选320名酒精依赖者，并将160名随机分配到为期16周的临床试验中。在OPRM 1基因分型后，将80名具有至少一个Asp 40等位基因拷贝的个体和80名Asn 40同源的个体随机分配至纳曲酮或安慰剂组，形成2种药物（纳曲酮或安慰剂）乘2种OPRM 1基因型（Asp 40乘Asn 40）设计。所有受试者将在治疗随机化之前和治疗第7-14天之间再次接受酒精提示诱导的fMRI脑成像，并将在16周内（以及第28周和第40周的随访期间）评估饮酒和其他显著结局变量。主要结果变量将是重度饮酒天数百分比和临床总体结果的差异。结果将有助于治疗提供者决定谁可能更好地响应纳洛酮（以及扩展其他未来的阿片类拮抗剂），并通过阐明什么机制（即，减少酒精提示显着性）这种和其他类似的药物可能会工作。因此，可以大大加强对酒精依赖者的治疗。 公共卫生相关性：这项研究将确定基因组成的差异和大脑对酒精线索的反应（图片）是否可以预测对纳洛酮的治疗反应，纳洛酮是一种已知可用于治疗酒精依赖的药物。结果将有助于治疗提供者决定谁可能更好地响应纳洛酮，因此，改善酒精依赖者的治疗可以大大提高。

DESCRIPTION (provided by applicant): Alcohol dependence affects 18-20 million Americans and costs our society over $185 billion annually. Treatment for this disorder in not universally accessible and those treatments that exist are not universally effective. The opioid antagonist, naltrexone, approved by the FDA more than 10 years ago, is one of the most efficacious medication treatments for alcohol dependence, but is not widely used and does not work for everyone. Reasons for its lack of widespread acceptance include its low to moderate improvement over placebo and incomplete knowledge of its mechanism of action. Recent advances in pharmacogenetics and neuroimaging have provided new tools to investigate these issues. For instance, in the COMBINE Study we have recently confirmed that a relatively common genetic variant (Asp40) in a mu opioid receptor (OPRM1) may be associated with a higher treatment response to naltrexone. In addition, using advanced functional magnetic resonance brain imaging paradigms, our group has recently shown that naltrexone can blunt the alcohol cue-induced activation in the ventral striatum-nucleus accumbens and in medial prefrontal cortex, of actively-drinking non-treatment seeking alcoholics. We have also discovered that similar alcohol cue-induced activation of the medial prefrontal area is associated with subsequent heavy drinking during treatment of alcohol dependent individuals. The goal of this proposal is to examine in a prospective controlled fashion whether the Asp40 variant of the OPRM1 receptor will predict naltrexone response. In addition, we will examine whether naltrexone might reduce/dampen alcohol cue-induced activation of the ventral-striatum and medial prefrontal cortex and explore whether this dampening might be associated with treatment response. Finally, we will evaluate whether Asp40 individuals will have more naltrexone dampening of alcohol cue- induced brain activation and if this will mediate the medication by genotype interaction observed during treatment. To that end, 320 alcohol dependent individuals will be screened and 160 randomized into a 16-week clinical trial. After OPRM1 genotyping, 80 individuals with at least one copy of the Asp40 allele and 80 individuals who are homogenous for Asn40 will be randomized to naltrexone or placebo, forming a 2 medication (naltrexone or placebo) by 2 OPRM1 genotype (Asp40 by Asn40) design. All subjects will undergo alcohol cue-induced fMRI brain imaging prior to treatment randomization and again between days 7-14 of treatment and will be evaluated over 16 weeks (and during follow-up at weeks 28 and 40) for drinking and other salient outcome variables. Main outcome variables will be differences in percent heavy drinking days and clinical global outcome. Results will assist treatment providers in deciding who might better respond to naltrexone (and by extension other future opioid antagonists) and by elucidating by what mechanism (i.e., reduced alcohol cue salience) this and other similar medications might work. As such, improvement in the treatment of individuals with alcohol dependence could be greatly enhanced. PUBLIC HEALTH RELEVANCE: This research study will determine whether differences in genetic makeup, and brain response to alcohol cues (pictures), might predict treatment response to naltrexone, a medication known to be useful in the treatment of alcohol dependence. Results will assist treatment providers in deciding who might better respond to naltrexone and, as such, improvement in the treatment of individuals with alcohol dependence could be greatly enhanced.