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

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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 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.

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          Most cited references38

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          Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts.

          Mitochondria participate in key metabolic reactions of the cell and regulate crucial signaling pathways including apoptosis. Although several approaches are available to study mitochondrial function in situ are available, investigating functional mitochondria that have been isolated from different tissues and from cultured cells offers still more unmatched advantages. This protocol illustrates a step-by-step procedure to obtain functional mitochondria with high yield from cells grown in culture, liver and muscle. The isolation procedures described here require 1-2 hours, depending on the source of the organelles. The polarographic analysis can be completed in 1 hour.
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            Lifetime prevalence of specific psychiatric disorders in three sites.

            Lifetime rates are presented for 15 DSM-III psychiatric diagnoses evaluated in three large household samples on the basis of lay interviewers' use of the Diagnostic Interview Schedule. The most common diagnoses were alcohol abuse and dependence, phobia, major depressive episode, and drug abuse and dependence. Disorders that most clearly predominated in men were antisocial personality and alcohol abuse and dependence. Disorders that most clearly predominated in women were depressive episodes and phobias. The age group with highest rates for most disorders was found to be young adults (aged 25 to 44 years). Correlates with race, education, and urbanization are presented.
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              Metabolomics: a global biochemical approach to drug response and disease.

              Metabolomics is the study of metabolism at the global level. This rapidly developing new discipline has important potential implications for pharmacologic science. The concept that metabolic state is representative of the overall physiologic status of the organism lies at the heart of metabolomics. Metabolomic studies capture global biochemical events by assaying thousands of small molecules in cells, tissues, organs, or biological fluids-followed by the application of informatic techniques to define metabolomic signatures. Metabolomic studies can lead to enhanced understanding of disease mechanisms and to new diagnostic markers as well as enhanced understanding of mechanisms for drug or xenobiotic effect and increased ability to predict individual variation in drug response phenotypes (pharmacometabolomics). This review outlines the conceptual basis for metabolomics as well as analytical and informatic techniques used to study the metabolome and to define metabolomic signatures. It also highlights potential metabolomic applications to pharmacology and clinical pharmacology.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                August 2015
                18 August 2015
                1 August 2015
                : 5
                : 8
                : e621
                Affiliations
                [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
                [4 ]Department of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine , Rochester, MN, USA
                Author notes
                [* ]Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine , 200 First Street SW, Rochester, MN 55905, USA. E-mail: choids@ 123456mayo.edu
                [5]

                Current address: Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Science Center, Shreveport, LA, USA.

                [6]

                Current address: Universidad de los Andes, Facultad de Medicina, Departamento de Psiquiatría, Santiago, Chile.

                [7]

                These authors contributed equally to this work.

                Article
                tp2015120
                10.1038/tp.2015.120
                4564571
                26285131
                9fed9033-c834-4115-a9c3-ba4af139a650
                Copyright © 2015 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 04 March 2015
                : 04 June 2015
                : 12 July 2015
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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