Project Summary/Abstract Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are highly comorbid, presenting a clinical challenge with limited treatment efficacy. Treatments addressing both PTSD and AUD concurrently are more efficacious than treating each disorder separately due to their overlapping neurobiological basis involving alterations in incentive salience, stress/negative affect, and executive control network functioning. Despite this, no treatment has been clearly effective for both disorders. Topiramate, an FDA-approved anticonvulsant affecting GABAergic and glutamatergic signaling, has shown efficacy in treating AUD in several randomized clinical trials (RCTs) and has some evidence of effectiveness in treating PTSD from several open-label and small RCTs. Positive results in one open- label trial and one small RCT suggest topiramate may benefit both PTSD and AUD symptoms in patients with both disorders. Preclinical studies also support its efficacy in reducing anxiety-like behavior and altered stress responses in animal models. A recent study indicated that topiramate’s effects on alcohol use were moderated by a polymorphism of the GRIK1 gene (coding for the kainate receptor GluK1 subunit), with significant benefits observed only among rs2832407 C-allele homozygotes. Project 2 of the proposed center is a double-blind, 2-group RCT evaluating topiramate's effects versus placebo in patients with comorbid PTSD and moderate-to-severe AUD. This trial will rigorously test whether topiramate's effects in AUD extend to patients with co-occurring PTSD and whether it benefits PTSD symptoms in this population. It will also test if the rs2832407 genotype predicts clinical response to topiramate for AUD and PTSD. This study will contribute to understanding topiramate’s mechanisms in the comorbid AUD/PTSD population and discover predictors of treatment response. Supporting overall center aims, this trial will provide data for studies on topiramate’s effects on brain chemistry and function (Project 3) and relate plasma biomarkers to neuroimaging markers. The supplement request aims to secure additional time and funding to complete recruitment and achieve the study's objectives on topiramate’s therapeutic potential in individuals with co-occurring PTSD and moderate-to-severe AUD. With the extension until August 31, 2025, and additional funds, we aim to reach our goal of 150 subjects. This, combined with $200,000 in institutional matching funds, will ensure the study's successful completion, providing significant insights into integrated therapeutic approaches for these complex disorders.