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Individualized Medicine
Science Saturday: Seeking biomarkers for precise alcohol abuse therapies
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Mayo Clinic research is bringing together knowledge of psychiatry, genetics, metabolomics, pharmacogenomics and artificial intelligence to seek biological markers associated with alcohol use disorder and treatment response. Finding the molecular drivers of alcohol use disorder commonly known as alcoholism, could help predict who is most likely to develop this disorder and who might respond to medications approved for treatment. It might also reveal insights into new medications when standard drugs don’t work and could guide health care providers to precise treatments.
“Alcohol use disorder is one of the most prominent mental health problems in the world, second only to depression in terms of burden of disease,” says Victor Karpyak, M.D., Ph.D., a Mayo Clinic psychiatrist, co-principal investigator and leader of the integrated study team. “Only about 10 percent of those with alcohol use disorder seek therapeutic help. We believe that’s because people don’t expect medications to be efficient and helpful in treatment, which is unfortunate and factually incorrect.”
The Food and Drug Administration has approved three medications for treatment of alcohol use disorder. However, they don’t work for everyone. There are no known biomarkers that reliably predict which patients would be good candidates for these therapies.
“Tragically, there are some people who have biological characteristics which make them more susceptible to alcoholism. What we’d like to do is better understand the genetic and molecular underpinnings of this susceptibility, so we can understand drug response and take an individualized approach to helping these patients overcome alcohol use disorder,” says Richard Weinshilboum, M.D., one of the researchers involved in this project and co-director of the Mayo Clinic Center for Individualized Medicine Pharmacogenomics program.
In a team science approach, Mayo Clinic will launch a coordinated study in conjunction with and funded by two National Institute on Alcohol Abuse and Alcoholism grants. The study will focus on the search for genetic markers of response to the drug acamprosate, which has been shown to help alcoholics stay sober.
“For some of our patients, the medicine known as acamprosate is a remarkably effective supplement to the clinical therapy and peer support, helping to curb cravings during and after treatment,” says Marvin D. Seppala, M.D., chief medical officer of the Hazelden Betty Ford Foundation, which is collaborating on the study. “Unfortunately, we have no idea who it will work for and who it won’t, so we just provide it to patients and hope that it helps.”
The five-year study expands previous pharmacogenetic research completed by the Mayo Clinic Department of Psychiatry by scanning the entire genome and metabolome in search for biological markers — clues to disease cause and treatment.
“Knowledge of the biology of alcohol use disorder and response to medication may allow us to zero down on meaningful molecular targets and see how we can intervene with genetic manipulations or new medications to reduce a person’s vulnerability to this disease,” says Dr. Karpyak.
Applying pharmacogenetics for an individualized treatment approach on a large scale
Researchers will follow 800 people receiving care for alcohol use disorder through Mayo Clinic affiliates as well as at the Hazelden Betty Ford Ford Foundation’s residential treatment facility in Center City, Minnesota. Study participants will have genetic testing to identify variants to help predict their response to the use of acamprosate or placebo.
The study will then combine pharmacogenomics — how the body processes and responds to medication — and metabolomics — small molecules known as metabolites that interact in the body — to try to better understand why the drug works for some but not others.
“We will look at the metabolites in their blood and bring together metabolomics with genomics. We hope that using the drug as a molecular probe will help us determine if there are different genes that might affect how each individual responds to anti-alcohol therapy,” says Dr. Weinshilboum, co-principal investigator of this study. “When we have used this approach before for psychiatric diseases like depression, we identified genes that we had never heard of before that appeared to be related to drug response, and then we used artificial intelligence and machine learning techniques to incorporate that information into a predictive algorithm.”
Researchers hope that if they find new genes linked to alcoholism treatment response, they might be able to identify new therapies compatible with a patient’s genetic fingerprint. That’s important in part because alcohol use disorder is linked to a number of other mental health conditions as well as conditions such as fetal alcohol spectrum disorders, hypertension, cardiovascular diseases, type 2 diabetes and liver cirrhosis.
This study reflects many years of collaborative work and support between the Mayo Clinic Department of Psychiatry and Psychology, the Mayo Clinic Center for Individualized Medicine Pharmacogenomics Program, and the Samuel C. Johnson Genomics of Addiction Program.
Beside Dr. Karpyak and Dr. Weinshilboum, the study team includes:
Joanna Biernacka, Ph.D., co-principal investigator
Doo-Sup Choi, Ph.D., co-principal investigator
Mark Frye, M.D. chair, Mayo Clinic Department of Psychiatry and Psychology
The research team would like to give special recognition to the late David Mrazek, M.D., upon whose pioneering work this study builds.
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