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: F₁(,)₂₉ = 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.

Conflict of interest statement

disclosures:

None of the authors has any conflicts of interest to declare.

Figures

Figure 1

CONSORT-graph showing the flow of study subjects

Figure 2

1H-MRS was carried out on a 3T scanner using the echo-time-averaged PRESS sequence that generates a chemical shift signal for glutamate without contamination from glutamine. Measurement was made from a single 2.5 × 2.5 × 2.5 cm3 voxel in the area of anterior cingulate (red box, inset). A sample spectrum is shown (main panel). From top to bottom: The automatically fitted model, raw spectrum, the residual of the automatic fit and raw spectrum. Glu: glutamate (2.35 ppm); Glx: composite glutamate/glutamine (3.75 ppm); NAA: N-acetyl aspartate (2.02 ppm); Cho: choline (3.35 ppm); Cre: Creatine (3.56 ppm); See Methods for details.

Figure 3

Using 1H-MRS, suppression of glutamate levels over time was observed in the cingulate cortex of acamprosate treated alcohol dependent patients following initiation of abstinence (p<0.001). Data are means ± SEM. For detailed statistics, see Results.

Figure 4

Cerebrospinal fluid (CSF) levels of glutamate were successfully obtained 4 weeks after initiation of abstinence in a subset of patients (n=20). CSF glutamate levels were unaffected by acamprosate treatment, and did not correlate with brain MRS measures. However, severity of alcohol dependence, as measured by the Alcohol Dependence Severity Scale (ADS) and CSF glutamate were strongly correlated, irrespective of treatment (R2 = 0.48, p<0.001). Additional analyses suggested that this did not reflect other patient characterstics. ○ placebo; ● acamprosate.