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Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study.

ABSTRACT: CONTEXT:Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking. OBJECTIVE:To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol-dependent patients as measured using proton nuclear magnetic resonance spectroscopy (¹H-MRS). DESIGN:A 4-week, double-blind, placebo-controlled, randomized controlled experimental medicine study, with ¹H-MRS measures obtained on days 4 and 25. SETTING:An inpatient research unit at the NIH Clinical Center. Patients Thirty-three patients who met the DSM-IV criteria for alcohol dependence and who were admitted for medically supervised withdrawal from ongoing alcohol use. Intervention Four weeks of acamprosate (initial oral loading followed by 1998 mg daily) or matched placebo, initiated at the time of admission. MAIN OUTCOME MEASURES:The glutamate to creatine ratio as determined using single-voxel ¹H-MRS in the anterior cingulate. Exploratory neuroendocrine, biochemical, and behavioral outcomes were also collected, as were safety- and tolerability-related measures. RESULTS:There was a highly significant suppression of the glutamate to creatine ratio across time by acamprosate (time × treatment interaction: F?(,)?? = 13.5, P < .001). Cerebrospinal fluid levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and unaffected by treatment but were strongly correlated (R² = 0.48, P < .001) with alcohol dependence severity. Other exploratory outcomes, including repeated dexamethasone-corticotropin-releasing hormone tests, and psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate-treated individuals, in agreement with the established profile of acamprosate. CONCLUSION:The MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00106106.

SUBMITTER: Umhau JC

PROVIDER: S-EPMC3583213 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study.

Umhau John C JC Momenan Reza R Schwandt Melanie L ML Singley Erick E Lifshitz Mariel M Doty Linda L Adams Lauren J LJ Vengeliene Valentina V Spanagel Rainer R Zhang Yan Y Shen Jun J George David T DT Hommer Daniel D Heilig Markus M

Archives of general psychiatry 20101001 10

<h4>Context</h4>Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.<h4>Objective</h4>To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol-dependent pa ...[more]

PMID: 20921123

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Project description:ImportanceMajor depressive disorder (MDD) is one of the most prevalent illnesses worldwide. Perturbations of the major inhibitory and excitatory neurotransmitters, γ-aminobutyric acid (GABA) and glutamate (Glu), respectively, as well as Glx (Glu or glutamine [Gln]) have been extensively reported in a multitude of brain areas of individuals with depression, but few studies have examined changes in Gln, the metabolic counterpart of synaptic Glu.ObjectiveTo investigate changes in GABA, Glx, Glu, and Gln levels in a voxel in the left dorsolateral prefrontal cortex of participants with no, past, and current MDD using proton magnetic resonance spectroscopy (1H-MRS).Design, setting, and participantsThis community-based study used a cross-sectional design using 3-T 1H-MRS in participants not taking MDD medication recruited from the community. The sample consisted of 251 healthy controls, 98 participants with a history of past MDD, and 47 participants who met the diagnostic criteria for current MDD. Diagnostic groups were comparable regarding age, education, income, and diet. Data were collected from March 2014 to October 2021, and data were analyzed from October 2021 to June 2022.Main outcomes and measuresGABA, Glx, Glu, and Gln concentrations in the left dorsolateral prefrontal cortex.ResultsOf 396 included participants, 258 (65.2%) were female, and the mean (SD) age was 25.0 (4.7) years. Compared with healthy controls, those with past MDD and current MDD had lower GABA concentrations (mean [SEM] concentration: healthy controls, 2.70 [0.03] mmol/L; past MDD, 2.49 [0.05] mmol/L; current MDD, 2.54 [0.07] mmol/L; 92 with past MDD vs 236 healthy controls: r = 0.18; P = .002; 44 with current MDD vs 236 healthy controls: r = 0.13; P = .04). Compared with healthy controls, those with past MDD also had lower Glu concentrations (mean [SEM] concentration: healthy controls, 7.52 [0.06] mmol/L; past MDD, 7.23 [0.11] mmol/L; 93 with past MDD vs 234 healthy controls: r = 0.16; P = .01) and higher Gln concentrations (mean [SEM] concentration: healthy controls, 1.63 [0.04] mmol/L; past MDD, 1.84 [0.07] mmol/L; 66 with past MDD 153 healthy controls: r = 0.17; P = .04).Conclusions and relevanceIn a large, mostly medication-free community sample, reduced prefrontal GABA concentrations were associated with past MDD, consistent with histopathologic studies reporting reduced glial cell and GABA cell density in the prefrontal cortex in individuals with depression. Patients with MDD also demonstrated increased Gln levels, indicative of increased synaptic Glu release, adding to previous evidence for the Glu hypothesis of MDD.

Dataset Information

Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study.

Publications

Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study.

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