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

纳曲酮治疗酒精中毒疗效的遗传和脑机制

基本信息

批准号：
8912020
负责人：
RAYMOND F ANTON
金额：
$ 4.05万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912020
关键词：
Abstinence Accounting Admission activity Adverse effects Adverse event Affect African American Alcohol abuse Alcohol dependence Alcoholism Alcohols Alleles American Area Brain Brain imaging Burn Units Clinical Clinical Trials Controlled Clinical Trials Data Development Disease FDA approved Functional Magnetic Resonance Imaging Future Genes Genetic Genetic Variation Genotype Goals Health Expenditures Health Personnel Heavy Drinking Heterozygote Homozygote Individual Intensive Care Knowledge Life Light Low Prevalence Magnetic Resonance Manuals Measures Medial Mediating Medical Naltrexone Narcotic Antagonists Nucleus Accumbens Opioid Receptor Outcome Patients Pharmaceutical Preparations Pharmacogenetics Placebos Prefrontal Cortex Property Psychological reinforcement Randomized Reaction Relapse Research Risk Societies Treatment Efficacy Treatment outcome Variant Ventral Striatum Work alcohol abuse therapy alcohol cue alcohol response alcoholism therapy automobile accident base cost craving cue reactivity design drinking follow-up genetic variant improved medication compliance mu opioid receptors neuroimaging problem drinker productivity loss prospective receptor research study response secondary outcome tool treatment duration treatment effect treatment response

项目摘要

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.

酒精依赖会影响18-2000万美国人，并使我们的社会每年损失超过1850亿美元的损失。对这种疾病的治疗在不普遍访问中，并且存在的治疗并非普遍有效的。 10年前，FDA批准的阿片类药物拮抗剂Naltrexone是最多的。酒精依赖的有效药物治疗，但不广泛使用，也不适用于每个人。缺乏广泛接受的原因包括其低到中等的改善安慰剂和对其作用机理的不完整知识。药物遗传学和神经影像学提供了调查这些问题的新工具。例如，在联合研究中我们最近已经证实，在MU阿片受体（OPRM1）中，相对常见的遗传变异（ASP40）可能与对纳曲酮的较高治疗反应有关。另外，使用高级功能磁共振脑成像范式，我们的小组最近表明纳曲酮可以钝化酒精提示引起的腹纹状体核核和内侧前额叶皮层的激活，积极饮酒的非治疗寻求酗酒者。我们还发现类似的酒精提示引起的内侧前额叶区域的激活与随后的大量饮酒有关酒精依赖的人。该提案的目的是以潜在的控制方式进行检查 OPRM1受体的ASP40变体是否会预测纳曲酮反应。此外，我们将检查纳曲酮是否可以减少/抑制酒精提示诱导的腹纹状体激活和内侧前额叶皮层并探索这种阻尼是否可能与治疗反应有关。最后，我们将评估ASP40个个体是否会使酒精提示的纳曲酮减弱 - 诱导大脑的激活，如果这将通过观察到的基因型相互作用来介导药物治疗。为此，将筛选320个依赖酒精的人，并将160个随机分为16周临床试验。 OPRM1基因分型后，80个具有至少一个ASP40等位基因副本和80个的个体均质ASN40的个体将被随机分为纳曲酮或安慰剂，形成2 用2个OPRM1基因型（ASN40）设计的药物（Naltrexone或安慰剂）设计。所有主题都会经历酒精提示在治疗随机分组之前，在第7-14天之间再次诱导了fMRI大脑成像治疗并将在16周内（在第28周和40周的随访期间）进行饮酒和评估其他显着结果变量。主要结果变量将是饮酒百分比的差异，临床全球结果。结果将有助于治疗提供者决定谁可能更好地回应纳曲酮（以及通过扩展的其他未来阿片类拮抗剂），并通过哪种机制阐明降低酒精提示的显着性）这种和其他类似的药物可能起作用。因此，改进对酒精依赖的人的治疗可以大大增强。