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Background: Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive–compulsive, and trauma- and stressor-related disorders; however, many patients do not improve, resulting in prolonged suffering and poorly used resources. Basic research on fear extinction may inform the development of a biomarker for the selection of exposure-based therapy. Growing evidence links orexin system activity to deficits in fear extinction and we have demonstrated that reactivity to an inhaled carbon dioxide (CO2) challenge—a safe, affordable, and easy-to-implement procedure—can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents. Building upon this basic research, the goal for the proposed study is to validate CO2 reactivity as a biomarker of exposure-based therapy non-response. Methods: We will assess CO2 reactivity in 600 adults meeting criteria for one or more fear- or anxiety-related disorders prior to providing open exposure-based therapy. By incorporating CO2 reactivity into a multivariate model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related predictor variables, we will establish the mechanistic specificity and the additive predictive utility of the potential CO2 reactivity biomarker. By developing models independently within two study sites (University of Texas at Austin and Boston University) and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples. Discussion: Representing a necessary stage in translating basic research, this investigation addresses an important public health issue by testing an accessible clinical assessment strategy that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders, and enhanced understanding of the mechanisms governing exposure-based therapy. Trial registration: ClinicalTrials.gov Identifier: NCT05467683 (20/07/2022). [ABSTRACT FROM AUTHOR]