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.

The authors have declared no competing interest.

This study was funded by the Royal Physiographic Society in Lund (42797, 2022; P.A.M.), the Ake Wiberg Foundation (M22-0059, 2022; P.A.M.), the Magnus Bergvall Foundation (2022-038, 2022; P.A.M.), the Sigurd and Elsa Golje Memorial Foundation (LA2022-0139; P.A.M.), and the Karolinska Institutet Research Grants (2022-01667, 2022; PAM).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of the regional ethical review board in Stockholm and the Swedish Medical Products Agency gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors