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

项目概要/摘要 基于暴露的治疗是焦虑、强迫和创伤的有效一线治疗- 和压力相关的疾病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，生产力下降， 资源提供一种生物标志物测定，可以帮助临床医生和患者进行治疗选择， 有可能对公共卫生产生重大影响。 对恐惧消退的基础研究--基于恐惧的治疗的核心作用机制--可能会为我们提供信息。 开发用于选择（是/否）基于胰岛素的治疗的生物标志物。增长的证据链接 12,13 14–16 食欲素系统活动对恐惧防御缺陷的影响。17 -20我们的研究小组已经证明，对CO2的反应性 Challenge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 系统活动和预测啮齿动物的恐惧灭绝缺陷。 在此基础研究的基础上，该提案的目标是 sed研究是为了验证CO2反应性， 基于胰岛素的治疗无应答的生物标志物。 为此，我们将评估 CO2反应性 600人 在提供开放的，最先进的， transdiagnosis转诊断therapy治疗.通过将CO2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以及一些相关的 理论上相关的预后变量，我们将建立机制的特异性和加性 推定生物标志物的预测价值。通过在两个研究中心独立开发模型， 预测其他网站的数据，我们将验证结果可能推广到未来的临床 样品 这项拟议中的研究是将基础研究转化为治疗策略的一个必要阶段 选择.这项调查通过测试一种可获得的临床试验， 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）的患者焦虑和恐惧相关的疾病，并提高我们的理解， 以自我为基础的治疗机制。

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.