2/2-CO2 Reactivity as a Biomarker of Non-Response to Exposure-Based Therapy

项目摘要/摘要 暴露疗法是治疗焦虑症、强迫症和创伤的有效一线疗法。 以及应激源相关的障碍。1-6然而，许多患者在暴露后没有反应或缓解- 基于治疗，7-11导致“不必要的”长期痛苦、生产力丧失和使用不当 资源。提供一种可以帮助临床医生和患者选择治疗方案的生物标记物检测方法 有可能对公共卫生产生相当大的影响。 对恐惧消退的基础研究--暴露疗法的核心作用机制--可能会提供信息 用于选择(是/否)基于暴露的治疗的生物标记物的开发。越来越多的证据联系 12，13 14-16 食欲素系统活性对恐惧消退的缺乏。17-20我们的小组已经证明了对二氧化碳的反应性 Challengle是一种安全、负担得起且易于实施的程序，可以作为增食欲素的替代品 系统活动并预测啮齿类动物的恐惧灭绝缺陷。 在这项基础研究的基础上，提案的目标是 SED研究旨在验证二氧化碳的反应性 暴露治疗无反应的生物标志物。 为此，我们将评估 二氧化碳的反应性 600名成年人 在提供开放的、最先进的、 基于暴露的跨诊断治疗。通过将二氧化碳反应性纳入多变量模型预测 治疗无反应，还包括对过度换气的反应性以及一些相关和 理论上相关的预测变量，我们将建立机制特异性和加性 推测的生物标志物的预测价值。通过在两个研究站点内独立开发模型和 预测其他站点的数据，我们将验证结果可能推广到未来的临床 样本。 拟议的研究是将基础研究转化为治疗策略的必要阶段 选择。这项调查通过测试一个可访问的诊所来解决一个重要的公共卫生问题 评估策略--由基础研究提供信息--可能导致更有效的治疗选择 (个性化医疗)为焦虑和恐惧相关障碍的患者提供帮助，并增强我们对 以暴露为基础的治疗机制。

PROJECT SUMMARY/ABSTRACT Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive and trauma- and stressor-related disorders. 1–6 However, many patients fail to respond or achieve remission with exposure- based therapy, 7–11 resulting in “unnecessary” prolonged suffering, loss of productivity, and poorly used resources. Making available a biomarker assay that can aid clinicians and patients in treatment selection has the potential to have considerable public health impact. Basic research on fear extinction - a core mechanism of action of exposure-based therapy - may inform the development of a biomarker for the selection (yes/no) of exposure-based therapy. Growing evidence links 12,13 14–16 orexin system activity to deficits in fear extinction.17–20 Our group has demonstrated that reactivity to CO2 challenge, which is a safe, affordable and easy-to-implement procedure, can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents.21 Building upon this basic research, the goal for the propo sed study is to validate CO2 reactivity as a biomarker of exposure-based therapy non-response. To this end, we will assess CO2 reactivity in 600 adults meeting for one or more fear- or anxiety-related disorders prior to providing open, state-of-the art, transdiagnostic 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 and theoretically-relevant prognostic variables, we will establish the mechanistic specificity and the additive predictive value of the putative biomarker. By developing models independently within two study sites and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples. The proposed study represents a necessary stage in translating basic research to strategies for treatment selection. The investigation addresses an important public health issue by testing an accessible clinical assessment strategy - informed by basic research - that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders and enhance our understanding of the mechanisms governing exposure-based therapy.