Genetic liability for anxiety associates with treatment response to the monoamine stabilizer OSU6162 in alcohol dependence

Abstract

OSU6162, a monoamine stabilizer, has demonstrated efficacy in reducing alcohol and anxiety-related behaviors in preclinical settings. In a previous randomized, double-blind, placebo-controlled trial involving patients with alcohol dependence (AD), we found that OSU6162 significantly reduced craving for alcohol, but did not alter drinking behaviors. In the present study, we explored the hypothesis that genetic predispositions related to AD or associated traits, might influence the response to OSU6162 treatment in original trial participants (N=56). To investigate this, we calculated polygenic risk scores (PRSs) over several statistical significance thresholds from genome-wide association studies on (i) alcohol use disorder and alcohol consumption (N=200-202k), (ii) problematic alcohol use (N=435k), (iii) drinks per week (N=666k), (iv) major depression (N=500k), and (v) anxiety (using both case-control comparisons and quantitative anxiety factor scores, N=17-18k). Linear regression analyses assessing the interaction effects between PRSs and treatment type (OSU6162 or placebo) identified significant associations when considering anxiety factor scores (FDR<0.05). Specifically, in OSU6162-treated AD individuals, there was a negative correlation between anxiety factor PRS (at the genome-wide significance threshold that included one genetic variant) and several drinking outcomes, including number of drinks consumed, percentage of heavy drinking days, and changes in blood phosphatidylethanol (PEth) levels. These correlations were absent in the placebo group. While preliminary, these findings suggest the potential utility of anxiety PRS in predicting response to OSU6162 treatment in AD. Further research using larger cohorts and more comprehensive genetic data is necessary to confirm these results and to advance personalized medicine approaches in alcohol use disorder.