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Pharmacogenomics and Pharmacometabolomics of Acamprosate Treatment Outcome

Design and aims:

The overarching goal of the study was to identify genetic markers associated with response to acamprosate treatment of alcohol use disorder (AUD).

Specifically, the study aimed to enroll patients with AUD and randomize them to acamprosate or placebo treatment to allow identification of genetic markers associated with treatment outcomes, including acamprosate-specific pharmacogenomic effects. Genome-wide association analyses were completed using the newly collected data; subsequently, meta-analyses were performed to combine the new data with data from a prior genome-wide association study (GWAS) of AUD treatment outcomes that included the Mayo Clinic Center for Individualized Treatment of Addiction (CITA1) study, the COMBINE study and the PREDICT study (Biernacka et al., Neuropsychopharmacology, 2021). Here, the newly collected sample is referred to as CITA2.

For CITA2, participants with AUD were recruited from Mayo Clinic sites in Rochester, MN and Albert Lea, MN (Fountain Center Residential Treatment Program), as well as Hazelden-Betty Ford affiliated treatment facilities in Center City, MN and Newberg, OR. Participants with comorbid depression and/or anxiety were treated with escitalopram or other SSRIs. Participants were randomized to acamprosate vs. placebo treatment, using stratified randomization within sites and within antidepressant (vs. no antidepressant) groups. Study participants and clinical personnel remained blinded to acamprosate or placebo assignment.

Participants were evaluated by Psychiatric Research Interview for Substance and Mental Disorders (PRISM) at baseline to confirm alcohol use disorder diagnosis, and no secondary diagnosis of active other substance use disorder was present. Additional testing was done to rule out subjects with renal impairment or advanced liver disease. Participants were required to be willing to stop chronic/daily use of prescribed benzodiazepines, opioids, stimulants, cannabis related medication such as CBD or medical marijuana during participation. Review of medications including anti-depressants was done.

Alcohol consumption was assessed by Timeline Follow Back (TLFB) at baseline and 1, 2 and 3 months during treatment.

Treatment outcomes were derived from TLFB data and included continuous sobriety (yes/no) during 3 months of treatment, as well as the number of days until first alcohol use, the number of days until first relapse (≥ 5 drinks/day for men and ≥ 4 drinks/day for women) , and cumulative abstinence duration proportion, defined as the proportion of days over the length of follow-up during which a participant was completely abstinent from alcohol use.

Population information:

The total number of subjects that consented for the study was 379, with 288 randomized to acamprosate or placebo.

Molecular Technologies:

DNA was extracted and genotyping was performed using the Illumina Infinium Global Diversity Array.

Principal Findings:

Genome-wide association analyses were performed for time until relapse to any drinking ("time until relapse"), and time until relapse to heavy drinking ("time until heavy relapse") across all treatment groups. The analyses of the newly collected (CITA2) data identified no genome-wide significant associations with time until relapse or time until heavy relapse. Meta-analyses with data previously analyzed in Biernacka et al. (Neuropsychopharmacology, 2021) also did not identify significant associations with time until relapse or time until heavy relapse in the primary analyses.

Data available:

Genome-wide genetic data for participants recruited for this study will be available in dbGaP, along with demographic data and AUD treatment outcomes data.