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

描述(由申请者提供)：酒精依赖影响着1800-2000万美国人，每年给我们的社会造成超过1850亿美元的损失。这种疾病的治疗方法并不普遍，现有的治疗方法也不是普遍有效的。10多年前，FDA批准的阿片类拮抗剂纳曲酮是治疗酒精依赖最有效的药物之一，但并未广泛使用，也不是对所有人都有效。它没有被广泛接受的原因包括它比安慰剂有低到适度的改善，以及对其作用机制的不完全了解。药物遗传学和神经成像的最新进展为研究这些问题提供了新的工具。例如，在联合研究中，我们最近证实，MU阿片受体(OPRM1)中一个相对常见的基因变异(Asp40)可能与纳曲酮的治疗反应较高有关。此外，使用先进的功能磁共振脑成像范式，我们的团队最近表明，纳曲酮可以减弱酒精线索诱导的伏隔核腹侧纹状体和内侧前额叶皮质的激活，这些激活是积极饮酒而不寻求治疗的酗酒者的。我们还发现，类似的酒精提示诱导的内侧前额叶区域的激活与随后在酒精依赖患者治疗期间大量饮酒有关。这项建议的目的是以前瞻性的受控方式研究OPRM1受体的Asp40变体是否可以预测纳曲酮的反应。此外，我们将研究纳曲酮是否可以减少/抑制酒精诱导的腹侧纹状体和内侧前额叶皮质的激活，并探索这种抑制是否与治疗反应有关。最后，我们将评估Asp40患者是否会有更多的纳曲酮抑制酒精提示诱导的脑激活，以及这是否将通过在治疗过程中观察到的基因相互作用来调节药物治疗。为此，将对320名酒精依赖者进行筛查，并将160人随机纳入为期16周的临床试验。在OPRM1基因分型后，80名至少有一个Asp40等位基因拷贝的个体和80名Asn40基因同源的个体将被随机分成纳曲酮或安慰剂，形成由2个OPRM1基因型(Asp40 By Asn40)组成的2种药物(纳曲酮或安慰剂)设计。所有受试者都将在随机治疗前和治疗7-14天之间接受酒精诱导的fMRI脑成像，并将在16周(以及在第28周和40周的随访期间)评估饮酒情况和其他显著的结果变量。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。研究结果将有助于治疗提供者决定谁对纳曲酮(以及未来的其他阿片类拮抗剂)可能有更好的反应，并通过阐明这种药物和其他类似药物可能起作用的机制(即减少酒精提示的显着性)。如此一来，酒精依赖患者的治疗水平将大大提高。 与公共健康相关：这项研究将确定基因构成和大脑对酒精提示(图片)的反应是否可以预测纳曲酮的治疗反应，纳曲酮是一种已知在治疗酒精依赖方面有用的药物。结果将帮助治疗提供者决定谁可能对纳曲酮有更好的反应，因此，酒精依赖患者的治疗改进可能会大大加强。

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.