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We aimed to determine whether alcohol\u2010metabolizing enzyme polymorphisms, specifically\n                      <jats:italic>ADH1B<\/jats:italic>\n                      rs1229984 and\n                      <jats:italic>ALDH2<\/jats:italic>\n                      rs671, modify the treatment response to nalmefene for alcohol dependence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Secondary analysis of a Japanese randomized clinical trial, in which participants were randomly assigned (4:3:4) to placebo, 10\u00a0mg nalmefene or 20\u2009mg nalmefene groups for 24\u2009weeks, accompanied by a brief psychosocial intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>80 addiction outpatient clinics across Japan.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>A subset of 531 individuals (mean age 49.2\u00a0years, standard deviation 11.5; 69.9% male), including 196 in the placebo group and 335 in the nalmefene group, who agreed to DNA preservation and had available DNA data between February 2015 and July 2016.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements<\/jats:title>\n                    <jats:p>\n                      Genotyping was performed to determine\n                      <jats:italic>ADH1B<\/jats:italic>\n                      rs1229984 polymorphism (AA, AG, GG) and\n                      <jats:italic>ALDH2<\/jats:italic>\n                      rs671 polymorphism (GG, GA, AA) in participants. Primary endpoint was change from baseline in monthly heavy drinking days (HDD, days\/month) over the 24 treatment weeks. The key secondary endpoint was change from baseline in daily total alcohol consumption (TAC, g\/day) over the 24 treatment weeks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>\n                      A mixed\u2010effects model for repeated measures analyses showed a statistically significant gene\u2010treatment interaction with\n                      <jats:italic>ADH1B<\/jats:italic>\n                      rs1229984 for TAC [10.71 (95% confidence interval = 4.03\u201317.39) g\/day,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.002], but not for HDD [1.65 (\u22120.38 to 3.67) days\/month,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.110]: as the G allele of rs1229984 increased, the efficacy regarding TAC decreased. In contrast, no statistically significant gene\u2010treatment interaction was seen with\n                      <jats:italic>ALDH2<\/jats:italic>\n                      rs671 for either TAC [4.46 (\u22127.88 to 16.80) g\/day,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.478] or HDD [\u22120.91 (\u22124.60 to 2.78) days\/month,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.630]. In the\n                      <jats:italic>ADH1B<\/jats:italic>\n                      rs1229984 variant, the number needed to treat for two category shifts in drinking risk level, as defined by the World Health Organization, was 3.7 for AA carriers, 6.6 for AG carriers and 18.5 for GG carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>ADH1B<\/jats:italic>\n                      rs1229984 polymorphism appears to moderate the response to nalmefene in Japanese patients with alcohol dependence. Specifically, nalmefene appears to show efficacy in individuals with the\n                      <jats:italic>ADH1B<\/jats:italic>\n                      rs1229984 AA genotype.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/add.70160","type":"journal-article","created":{"date-parts":[[2025,8,9]],"date-time":"2025-08-09T06:44:06Z","timestamp":1754721846000},"page":"2423-2434","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effect modification in therapeutic impact of nalmefene on alcohol dependence by\n                    <i>ADH1B<\/i>\n                    polymorphism: A secondary analysis of a Japanese randomized clinical trial"],"prefix":"10.1111","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4605-2378","authenticated-orcid":false,"given":"Nozomu","family":"Hashimoto","sequence":"first","affiliation":[{"name":"Department of Neuropsychiatry Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Kita\u2010ku Japan"},{"name":"Okayama Psychiatric Medical Center  Okayama Kita\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7371-2821","authenticated-orcid":false,"given":"Manabu","family":"Takaki","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Kita\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitsugu","family":"Kojima","sequence":"additional","affiliation":[{"name":"Medical Affairs Otsuka Pharmaceutical  Tokyo Minato\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izuru","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Medical Affairs Otsuka Pharmaceutical  Tokyo Minato\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke D.","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Office of Bioinformatics, Department of Drug Discovery Strategy Otsuka Pharmaceutical  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Okayama University Hospital  Okayama Kita\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Okahisa","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry Okayama University Hospital  Okayama Kita\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soshi","family":"Takao","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Kita\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keitaro","family":"Matsuo","sequence":"additional","affiliation":[{"name":"Division of Cancer Epidemiology and Prevention Aichi Cancer Center Research Institute  Nagoya Chikusa\u2010ku Japan"},{"name":"Department of Cancer Epidemiology Nagoya University Graduate School of Medicine  Nagoya Showa\u2010ku Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"World Health Organization.Alcohol. 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