Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects.
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 non-responders. 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.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
H W
HW
Nam
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
V M
VM
Karpyak
1] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN, USA.
D J
DJ
Hinton
Department of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
J R
JR
Geske
1] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
A M C
AM
Ho
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
M L
ML
Prieto
1] Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
J M
JM
Biernacka
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.
M A
MA
Frye
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
R M
RM
Weinshilboum
1] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA [3] Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN, USA.
D-S
DS
Choi
D000077443:Acamprosate; D000427:Alcohol Deterrents / Q000097:blood / Q000627:therapeutic use; D019973:Alcohol-Related Disorders / Q000097:blood* / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D018698:Glutamic Acid / Q000097:blood*; D006801:Humans; D013654:Taurine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D016896:Treatment Outcome
D000427:Alcohol Deterrents; D015415:Biomarkers; D013654:Taurine; D018698:Glutamic Acid; D000077443:Acamprosate