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

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。 对这种疾病的治疗并不是普遍可用的，现有的治疗方法也不是普遍适用的 有效。阿片类拮抗剂，纳曲酮，10多年前被FDA批准，是最多的 治疗酒精依赖的有效药物疗法，但并未广泛使用，对 所有人。它没有被广泛接受的原因包括它对 安慰剂和对其作用机制的不完全了解。药物遗传学和药物遗传学的最新进展 神经成像为研究这些问题提供了新的工具。例如，在联合研究中，我们 最近证实了Mu阿片受体(OPRM1)中一种相对常见的遗传变异(Asp40) 可能与纳曲酮的治疗反应较高有关。此外，使用高级功能 磁共振脑成像范例，我们的小组最近表明纳曲酮可以钝化 酒精刺激引起伏隔腹侧纹状体核和内侧前额叶皮质的激活 积极饮酒，不寻求治疗的酗酒者。我们还发现，类似的酒精线索诱导 内侧前额叶区域激活与随后在治疗期间大量饮酒有关 酒精依赖者。这项提案的目标是以一种前瞻性的、受控的方式进行审查 OPRM1受体的Asp40变异体是否能预测纳曲酮反应。此外，我们还将 检查纳曲酮是否可以减少/抑制酒精诱导的腹侧纹状体的激活 内侧前额叶皮质，探讨这种抑制是否可能与治疗反应有关。 最后，我们将评估Asp40个体是否会有更多的纳曲酮抑制酒精提示- 诱导大脑激活，以及这是否会通过观察到的基因交互作用来调节药物治疗 治疗。为此，将对320名酒精依赖者进行筛查，并将160人随机分成16周 临床试验。在OPRM1基因分型后，80名个体至少有一份Asp40等位基因，80名个体 Asn40基因同质性的个体将随机接受纳曲酮或安慰剂治疗，形成2 用药(纳曲酮或安慰剂)按2个OPRM1基因型(Asp40由Asn40)设计。所有受试者都将接受 酒精线索诱发的fMRI脑成像在随机治疗前和在第7-14天之间再次进行 将在16周内(以及在第28周和40周的随访期间)对饮酒和 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。结果将帮助治疗提供者决定谁可能更好地应对 纳曲酮(以及未来的其他阿片类拮抗剂)，并通过阐明是什么机制(即， 减少酒精提示突出)这种药物和其他类似的药物可能会起作用。因此，改善了 对酒精依赖患者的治疗可以得到极大的加强。

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.