Abstract
Using acamprosate as a probe medication, we aim to discover serum biomarkers to predict antidipsotropic treatment outcome and to uncover metabolic pathways associated with the pharmacological effect of these medications in patients with alcohol use disorder. We analyzed serum samples from 84 alcohol dependent subjects collected at baseline (before treatment) and after 3 months of acamprosate treatment using an untargeted global metabolomics approach. Subjects were classified as responders if they maintained complete abstinence during the treatment period. Based on our findings, we performed functional studies in mice. At baseline, 48 metabolites were significantly different between response groups and 26 of these metabolites remained different after 3 months of acamprosate treatment. Comparing metabolites at the 3-month time point to baseline, responders showed significant changes in 100 metabolites whereas non-responders only showed changes in 16 metabolites. Five metabolites were similarly changed in both groups. Pathway analysis with 95 metabolites, which were uniquely changed in the responders, identified a significant enrichment in caffeine metabolism. Specifically, caffeine metabolites were increased at the 3-month time point in responders compared to non-responders. Animal studies showed that caffeine co-administration improves the pharmacological effect of acamprosate in reducing ethanol intake. We identified a panel of baseline metabolites that is associated with acamprosate treatment response. In addition, after 3 months of acamprosate treatment, we identified that caffeine metabolites are associated with acamprosate treatment response, indicating serum metabolite biomarkers will be useful for the personalized treatment in alcoholism.