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

2/2-CO2 反应性作为暴露治疗无反应的生物标志物

• 批准号: 10614510
• 负责人: Michael W. Otto
• 金额: $ 56.54万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614510
• 关键词: Address; Adult; Aftercare; Algorithms; Animals; Anxiety; Anxiety Disorders; Area; Basic Science; Benchmarking; Biological Assay; Biological Markers; Boston; Carbon Dioxide; Classification; Clinic; Clinical; Clinical assessments; DSM-V; Data; Development; Diagnosis; Diagnostic; Disease; Disease remission; Elements; Enrollment; Exposure to; Extinction; Fright; Future; Genotype; Goals; Human Resources; Hypercapnia; Hyperventilation; Impairment; Intervention; Investigation; Link; Measures; Mediating; Middle Hypothalamus; Modeling; National Institute of Mental Health; Neurons; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Panic Disorder; Participant; Patients; Phenotype; Plasma; Post-Traumatic Stress Disorders; Prediction of Response to Therapy; Predictive Value; Procedures; Protocols documentation; Proxy; Public Health; ROC Curve; Rattus; Recovery; Research; Resources; Rodent; Role; Saliva; Sample Size; Sampling; Selection for Treatments; Severities; Signal Transduction; Site; Specificity; Speed; Strategic Planning; Structure; Symptoms; System; Testing; Translating; Translations; Trauma; Treatment Cost; Work; anxiety treatment; anxiety-related disorders; austin; biomarker identification; biomarker performance; biomarker selection; clinical practice; design; effective therapy; follow-up; hypocretin; improved; indexing; meetings; novel marker; personalized medicine; predictive modeling; productivity loss; prognostic; prospective; receptor; respiratory challenge; response; sound; stressor; translation to humans; treatment strategy

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.

项目概要/摘要 基于暴露的疗法是治疗焦虑症、强迫症和创伤症的有效一线治疗方法 和压力源相关的疾病。 1-6 然而，许多患者未能通过暴露做出反应或达到缓解- 基于治疗，7-11 导致“不必要的”长期痛苦、生产力损失和使用不当 资源。提供可以帮助临床医生和患者选择治疗方法的生物标志物检测方法 可能对公共卫生产生重大影响。 关于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 开发用于选择（是/否）基于暴露的治疗的生物标志物。越来越多的证据链接 12,13 14–16 食欲素系统活动对恐惧消退的缺陷。17-20 我们的小组已经证明，对二氧化碳的反应性 Challenge是一种安全、负担得起且易于实施的程序，可以作为食欲素的替代品 系统活动并预测啮齿类动物的恐惧消退缺陷21 在此基础研究的基础上，该提案的目标 sed 研究旨在验证 CO2 反应性 基于暴露的治疗无反应的生物标志物。 为此，我们将评估 CO2 反应性 600 名成人 在提供开放的、最先进的技术之前，会见一种或多种与恐惧或焦虑相关的疾病， 基于跨诊断暴露的治疗。通过将 CO2 反应性纳入多元模型预测 治疗无反应，还包括对过度换气的反应以及许多相关和 理论上相关的预后变量，我们将建立机械特异性和加性 假定的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 预测其他站点的数据，我们将验证结果是否可能推广到未来的临床 样品。 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。该调查通过测试可访问的临床解决了一个重要的公共卫生问题 评估策略——以基础研究为基础——可能会导致更有效的治疗选择 （个性化医疗）为患有焦虑和恐惧相关疾病的患者提供帮助，并增强我们对 基于暴露的治疗的控制机制。