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Recent work found large effects of naltrexone among \u201creward drinkers,\u201d defined as individuals who drink primarily for the rewarding effects of alcohol. This study sought to replicate and extend these recent findings by examining whether the desire to drink mediated the effect of naltrexone among reward drinkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a secondary analysis of a 12\u2010week randomized clinical trial of daily or targeted naltrexone among problem drinkers (<jats:italic>n<\/jats:italic>\u00a0=\u00a0163), with a focus on 86 individuals (<jats:italic>n<\/jats:italic>\u00a0=\u00a045 naltrexone and <jats:italic>n<\/jats:italic>\u00a0=\u00a041 placebo) who received daily medication. Interactive voice response technology was used to collect daily reports of drinking and desire to drink. Factor mixture models were used to derive reward and relief phenotypes. Moderation analyses were used to evaluate naltrexone effects, with phenotype as a moderator variable. Multilevel mediation tested average desire to drink as a mediator.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Results indicated 4 phenotypes: low reward\/low relief; low reward\/high relief; high reward\/low relief; and high reward\/high relief. There was an interaction between the high reward\/low relief subgroup (<jats:italic>n<\/jats:italic>\u00a0=\u00a010) and daily naltrexone versus placebo on drinks per drinking day (DPDD; <jats:italic>p\u00a0<\/jats:italic>=<jats:italic>\u00a0<\/jats:italic>0.03), percent heavy drinking days (<jats:italic>p\u00a0<\/jats:italic>=<jats:italic>\u00a0<\/jats:italic>0.004), and daily drinking (<jats:italic>p\u00a0<\/jats:italic>=<jats:italic>\u00a0<\/jats:italic>0.02). As compared to placebo, individuals in the high reward\/low relief phenotype who received daily naltrexone had significantly fewer DPDD (Cohen's <jats:italic>d<\/jats:italic>\u00a0=\u00a02.05) and had a lower proportion of heavy drinking days (Cohen's <jats:italic>d<\/jats:italic>\u00a0=\u00a01.75). As hypothesized, reductions in average desire to drink mediated the effect of naltrexone on average daily drinking among the high reward\/low relief drinkers (moderated mediation effect: <jats:italic>p\u00a0<\/jats:italic>=<jats:italic>\u00a0<\/jats:italic>0.029).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This theory\u2010driven study replicates the empirical finding that naltrexone is particularly efficacious among high reward\/low relief drinkers. Our study brings the field a step closer to the potential of using a precision medicine approach to treating alcohol use disorder.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14183","type":"journal-article","created":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T13:12:15Z","timestamp":1566479535000},"page":"2395-2405","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Advancing Precision Medicine for Alcohol Use Disorder: Replication and Extension of Reward Drinking as a Predictor of Naltrexone Response"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1086-3067","authenticated-orcid":false,"given":"Katie","family":"Witkiewitz","sequence":"first","affiliation":[{"name":"From the Department of Psychology Center on Alcoholism, Substance Abuse, and Addictions University of New Mexico Albuquerque New Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey 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