Acamprosate has been widely used since the Food and Drug Administration approved the medication for treatment of alcohol use disorders (AUDs) in 2004. Although the detailed molecular mechanism of acamprosate remains unclear, it has been largely known that acamprosate inhibits glutamate action in the brain. However, AUD is a complex and heterogeneous disorder. Thus, biomarkers are required to prescribe this medication to patients who will have the highest likelihood of responding positively. To identify pharmacometabolomic biomarkers of acamprosate response, we utilized serum samples from 120 alcohol-dependent subjects, including 71 responders (maintained continuous abstinence) and 49 non-responders (any alcohol use) during 12 weeks of acamprosate treatment. Notably, baseline serum glutamate levels were significantly higher in responders compared with nonresponders. Importantly, serum glutamate levels of responders are normalized after acamprosate treatment, whereas there was no significant glutamate change in non-responders. Subsequent functional studies in animal models revealed that, in the absence of alcohol, acamprosate activates glutamine synthetase, which synthesizes glutamine from glutamate and ammonia. These results suggest that acamprosate reduces serum glutamate levels for those who have elevated baseline serum glutamate levels among responders. Taken together, our findings demonstrate that elevated baseline serum glutamate levels are a potential biomarker associated with positive acamprosate response, which is an important step towards development of a personalized approach to treatment for AUD.
Bibliographical noteFunding Information:
We dedicate this manuscript to the late Dr David Mrazek, the founding director of the Samuel C Johnson Genomics of Addiction program at Mayo and an inspiring leader who relentlessly advocated for the advancement of research in pharmacometabolomics, pharmacogenomics and biological psychiatry to improve clinical care for alcohol use disorders. We thank Drs Yu Sam Kim, Hoil Choi, Xiaofan Li, Mario Hitschfeld and Osama Abulseoud for their helpful discussions, Ms Michelle Skime and Ms Lisa Seymour for their assistance in obtaining clinical information. This work was supported by the Samuel C Johnson for Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, the Godby Foundation, David Lehr Research Award from American Society for Pharmacology and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism (AA017830 and AA018779) and National Center for Advancing Translational Sciences (TR000135).