March 28, 2017
For more than a decade, acamprosate has been widely used in the United States for treatment of alcohol dependence. The medication is known to reduce some patients' cravings and prolong abstinence. However, only a subset of patients responds to acamprosate, and predictors of response have yet to be fully identified.
Researchers at Mayo Clinic's campus in Rochester, Minnesota, have made significant progress in elucidating acamprosate's mechanism of action, paving the way for more-individualized treatment of patients with alcohol use disorders (AUDs).
Glutamate in the brain of a clinical study participant
Expertise in neuroradiology facilitates the measurement of glutamate levels in the brains of clinical-study participants.
In a study published in the Journal of Clinical Psychopharmacology in 2016, the Mayo Clinic researchers found that acamprosate can normalize a hyperglutamatergic state in recently withdrawn patients with alcohol dependence. Before treatment, study participants with alcohol dependence had significantly elevated levels of anterior cingulate cortex glutamate compared with controls. Four weeks of acamprosate treatment reduced glutamate levels — an effect that wasn't observed in study participants who chose not to take the medication. Mayo Clinic's expertise in neuroradiology facilitates the measurement of glutamate levels in the brains of clinical study participants.
The findings follow the Mayo Clinic researchers' discovery of genetic markers that might identify patients who would benefit from treatment with acamprosate. That international study, published in Translational Psychiatry in 2014, was the first report of a replicated association of genetic markers with the length of abstinence in patients with alcohol dependence treated with acamprosate.
"Our translational research projects directly reflect problems of patients we treat in our clinical practice," says Victor M. Karpyak, M.D., Ph.D., a consultant in Addiction Medicine and director of Addiction Services at Mayo Clinic's campus in Minnesota. "If we can reliably identify potential responders to acamprosate, we can improve treatment outcomes for these patients and consider alternative treatment options for the others."
"We are committed to developing tools to help clinicians better individualize their treatment of patients," adds Mark A. Frye, M.D., chair of Psychiatry and Psychology at Mayo Clinic's campus in Minnesota. "We want our clinical research trials to make an impact on what we do in our clinical practice every day."
The search for biomarkers
At Mayo Clinic, translational research is promoted through close collaboration across specialties. Dr. Frye notes that a significant number of patients with AUDs have mood disorders and may self-medicate with alcohol in times of stress and negative affect. "We have strong programs in both addiction and mood disorders. That overlap prompted our thinking about the merits of acamprosate, which can relieve cravings triggered by negative affect," Dr. Frye says.
Mayo Clinic has a strong commitment to basic science laboratory research that has applications for psychiatric studies. "Team science is an important part of our success," says Joanna M. Biernacka, Ph.D., director of Mayo Clinic's Psychiatric Genomics and Pharmacogenomics Program. "In addition to clinicians, we have scientists who do basic research in pharmacogenomics, metabolomics, clinical neurosciences and radiology, as well as statisticians and data analysts dedicated to analysis of psychiatric clinical and biomarker data."
The psychiatric genomics group played an important role in Mayo Clinic's discovery of genetic markers associated with the results of treatment with acamprosate. That work was a candidate gene study; candidate genes were selected using a pathway-based approach to systematically investigate genes involved in encoding enzymes that affect levels of glutamate and other neurotransmitters in the brain that may be involved in acamprosate-associated treatment outcomes in human or animal studies.
"Candidate gene studies are notorious, however, for finding false positives that cannot be replicated. It's very exciting that our findings were replicated," Dr. Biernacka says. "Nonetheless, a single biomarker doesn't have enough predictive accuracy to select people who will or will not respond to acamprosate. We certainly have a long way to go."
Glutamate levels in the brains of clinical study participants. Image reprinted with permission from Translational Psychiatry.
To further identify pharmaco-metabolomic biomarkers of acamprosate results, the Mayo Clinic researchers analyzed serum samples from 120 subjects with alcohol dependency, including 71 who maintained continuous abstinence and 49 who used alcohol during 12 weeks of acamprosate treatment. The study, published in Translational Psychiatry in 2015, found that baseline serum glutamate levels were significantly higher in responders compared with nonresponders, suggesting that among patients who respond to acamprosate, the medication reduces elevated serum glutamate levels.
"Considering the complexity of alcohol dependency, there is no single solution for this disease," says Doo-Sup Choi, Ph.D., director of the Samuel C. Johnson Genomics of Addiction Program and a molecular pharmacologist in the Molecular Pharmacology and Experimental Therapeutics department. "This elevated glutamate in serum aligns with our finding with elevated glutamate in the brain. Our goal is to continue to fill in gaps — to find and replicate genomic and metabolomics biomarkers for response to acamprosate so that ultimately we can individualize treatment for patients."
"Acamprosate came to market because of well-designed, placebo-controlled trials with hundreds of patients," Dr. Frye adds. "So when I write a prescription for acamprosate, I'm prescribing a medication that is evidence-based. But the individual biology of the patient I'm treating wasn't part of the clinical trials that led to evidence-based approval. That, to me, is what individualized medicine is all about — using drugs that are already available, but with greater precision."
For more information
Frye MA, et al. Anterior cingulate glutamate is reduced by acamprosate treatment in patients with alcohol dependence. Journal of Clinical Psychopharmacology. 2016;36:669.
Karpyak VM, et al. Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate. Translational Psychiatry. 2014;4e:453.
Nam HW, et al. Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects. Translational Psychiatry. 2015;5e:621.