Elevated baseline serum glutamate as a pharmacometabolomic biomarker for Acamprosate treatment outcome in alcohol-dependent subjects

H. W. Nam, Victor M Karpyak, D. J. Hinton, J. R. Geske, A. M C Ho, M. L. Prieto, Joanna M Biernacka, Mark A Frye, Richard M Weinshilboum, Doo Sup Choi

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Abstract

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.

Original languageEnglish (US)
Article number120
JournalTranslational Psychiatry
Volume5
Issue number8
DOIs
StatePublished - 2015

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Glutamic Acid
Biomarkers
Alcohols
Serum
acamprosate
Glutamate-Ammonia Ligase
United States Food and Drug Administration
Therapeutics
Glutamine
Ammonia
Animal Models
Brain

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience

Cite this

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title = "Elevated baseline serum glutamate as a pharmacometabolomic biomarker for Acamprosate treatment outcome in alcohol-dependent subjects",
abstract = "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.",
author = "Nam, {H. W.} and Karpyak, {Victor M} and Hinton, {D. J.} and Geske, {J. R.} and Ho, {A. M C} and Prieto, {M. L.} and Biernacka, {Joanna M} and Frye, {Mark A} and Weinshilboum, {Richard M} and Choi, {Doo Sup}",
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T1 - Elevated baseline serum glutamate as a pharmacometabolomic biomarker for Acamprosate treatment outcome in alcohol-dependent subjects

AU - Nam, H. W.

AU - Karpyak, Victor M

AU - Hinton, D. J.

AU - Geske, J. R.

AU - Ho, A. M C

AU - Prieto, M. L.

AU - Biernacka, Joanna M

AU - Frye, Mark A

AU - Weinshilboum, Richard M

AU - Choi, Doo Sup

PY - 2015

Y1 - 2015

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