Background and Aims: Topiramate is widely prescribed to treat a variety of conditions, including alcohol use disorder (AUD). We used electronic health record (EHR) data to examine the effects of topiramate on drinking in individuals differentiated by a history of AUD. Design: Parallel-groups comparison of patients prescribed topiramate and a propensity-score matched comparison group. Setting: A large U.S. integrated healthcare system. Participants: Patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores prior to and after a minimum of 180 days of topiramate prescription for any indication and a propensity-score matched group. The sample included 5,918 AUD+ patients (1,738 topiramate exposed and 4,180 controls) and 23,614 AUD- patients (6,324 topiramate exposed and 17,290 controls). Measurements: Regression analyses compared difference-in-difference (DiD) estimates on the AUDIT-C score between exposure groups separately by AUD history. Effects of baseline AUDIT-C score and daily topiramate dosage were also tested. Findings: After matching. exposure groups in both the AUD+ and AUD- subgroups were comparable on baseline measures. At follow-up, AUD+ patients showed comparable reductions in AUDIT-C scores irrespective of exposure group. Among AUD- patients, topiramate-treated patients showed a greater reduction (-0.11) than matched controls (-0.04), resulting in a DiD score of -0.07 (95% CI= -0.11,-0.03; p=0.002), with the greatest effect among AUD- patients with a baseline AUDIT-C score of 4+ (DiD = -0.35, 95% CI=-0.49, -0.21; p=<0.0001) and those prescribed >150 mg/day of the medication (DiD = -0.15, 95%CI=-0.23, -0.07; p<0.001). Discussion: The lack of an effect of topiramate on drinking levels in AUD+ patients contrasts with the robust reductions seen in topiramate clinical trials. Research is needed to ascertain whether AUDIT-C scores from EHR data accurately reflect medication effects on drinking and whether patient characteristics can be used to select patients most likely to reduce their drinking when treated with topiramate.

Dr. Kranzler is an advisory board member for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals and Enthion Pharmaceuticals. He is a consultant for Sobrera Pharmaceuticals and a recipient from Alkermes of funds and study medication for investigator-initiated research. Dr. Kranzler is a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. Dr. Kranzler holds U.S. patent #10,900,082 titled: "Genotype-guided dosing of opioid agonists," issued 26 January 2021.

This study was funded by the Mental Illness Research, Education and Clinical Center, Veterans Integrated Service Network 4, Crescenz Veterans Affairs Medical Center

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

Institutional Review Board, Crescenz VAMC, Philadelphia, PA

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All data produced in the present study are available upon reasonable request to the authors, within the constraints of the Department of Veterans Affairs regulations.