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：
8270569
负责人：
RAYMOND F ANTON
金额：
$ 51.24万
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 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270569
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.

酒精依赖影响着 18-2000 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非普遍适用，并且现有的治疗方法也并非普遍适用有效的。阿片类拮抗剂纳曲酮于 10 多年前获得 FDA 批准，是最有效的药物之一。对于酒精依赖有有效的药物治疗，但并未广泛使用，并且对酒精依赖不起作用每个人。它没有被广泛接受的原因包括它对安慰剂及其作用机制的了解不完全。药物遗传学和药物遗传学的最新进展神经影像学为研究这些问题提供了新的工具。例如，在 COMBINE 研究中，我们最近证实 mu 阿片受体 (OPRM1) 中有一个相对常见的遗传变异 (Asp40) 可能与纳曲酮较高的治疗反应有关。此外，使用先进的功能磁共振脑成像范例，我们的小组最近表明纳曲酮可以减弱酒精提示诱导的腹侧纹状体伏隔核和内侧前额叶皮层的激活积极饮酒、不寻求治疗的酗酒者。我们还发现类似的酒精提示诱导内侧前额叶区域的激活与治疗期间随后的大量饮酒有关酒精依赖者。该提案的目标是以前瞻性受控方式进行检查 OPRM1 受体的 Asp40 变体是否可以预测纳曲酮反应。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侧纹状体激活内侧前额叶皮层，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 Asp40 个体是否会具有更多的纳曲酮抑制酒精暗示的作用- 诱导大脑激活，以及这是否会通过期间观察到的基因型相互作用来介导药物治疗治疗。为此，将对 320 名酒精依赖者进行筛查，并将其中 160 名随机分为为期 16 周的研究组临床试验。 OPRM1 基因分型后，80 名个体至少携带一份 Asp40 等位基因，80 名个体携带至少一份 Asp40 等位基因拷贝。 Asn40 同质的个体将被随机分配到纳曲酮或安慰剂组，形成 2 药物（纳曲酮或安慰剂）由 2 OPRM1 基因型（Asp40 by Asn40）设计。所有科目都将经历在治疗随机化之前和治疗第 7-14 天之间再次进行酒精提示诱导的 fMRI 脑成像治疗期间，将在 16 周内（以及第 28 周和 40 周的随访期间）对饮酒和饮酒情况进行评估其他显着的结果变量。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（以及其他未来的阿片拮抗剂）并通过阐明机制（即，减少酒精暗示的显着性）这种药物和其他类似的药物可能有效。因此，改进可以大大加强对酒精依赖者的治疗。