Anxiety-, obsessive-compulsive and trauma- and stressor-related disorders reflect a significant public health problem. This study is designed to evaluate the predictive power of a novel biomarker based on a CO2 challenge, thus addressing the central question "can this easy-to-administer assay aid clinicians in deciding whether or not to initiate exposure-based therapy?"

Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive and trauma- and stressor-related disorders. However, many patients fail to respond or achieve remission with exposure-based therapy, resulting in 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 orexin system activity to deficits in fear extinction. 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.

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. 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 multivariable 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.

Inclusion Criteria:

• A primary DSM-5 diagnosis of panic disorder (with or without an agoraphobia diagnosis), social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, or post-traumatic stress disorder as assessed by the Structured Clinical Interview for the DSM-5 (SCID-5)
• A score of 8 or greater on the Overall Anxiety Severity and Impairment Scale (OASIS)
• Ages 18 to 70
• Willingness and ability to provide informed consent and comply with the requirements of the study protocol.
• Proficiency in English (because assessment instruments have only been validated in English)

Exclusion Criteria:

• A lifetime history of bipolar or psychotic disorders, substance use disorders (other than nicotine) or eating disorder in the past 6 months; serious cognitive impairment.
• Active suicidal ideation with at least some intent to act with or without specific plan (a rating of 4 for suicidal ideation on the Columbia-Suicide Severity Rating Scale) or suicidal behaviors (actual attempt, interrupted attempt, aborted or self-interrupted attempt, or preparatory acts or behavior) within the past 6 months.
• Medical conditions contraindicating CO2 inhalation or hyperventilation challenge (e.g., cardiac arrhythmia, cardiac failure, asthma, lung fibrosis, high blood pressure, epilepsy, or stroke).
• Pregnancy or lactation
• Ongoing psychotherapy directed toward the primary disorder.
• Pharmacological treatment started within 8 weeks prior to the screen (patients "stable" on their medication regimen will be included and their medication status will be included as a variable in the model)

In line with National Institute of Mental Health (NIMH) guidance, we will share de-identified data derived from this study via the National Data Archive (NDA), along with supporting documentation to enable efficient and appropriate use of the data. Data sharing is now a requirement for all NIMH-funded awards (NOT-MH-14-015). Consistent with the National Database for Clinical Trials related to Mental Illness (NDCT) guidelines, we will share data in a two-tiered approach. The first tier involves semi-annual uploading of descriptive and raw data while the study is ongoing, including data from standard assessments, standard clinical measures, demographic data, and raw behavioral data. The second tier includes analyzed data that result from publications. We will ensure that submitted data will conform to relevant data and terminology standards. Throughout our resource sharing plan, we will comply with NDCT guidelines.

Descriptive/raw data will be shared on a semi-annual basis (on or before January 15 and July 15, beginning six months after the award budget period has begun). Analyzed data will be submitted prior to publication/public dissemination (whether the findings are positive or negative) using the NDA Study feature that links data deposited in the NDA with publications/findings.

We agree that data will be deposited and made available through NDA, and that these data will be shared with investigators working at an institution with a Federal Wide Assurance (FWA) and could be used for secondary study purposes. All submitted data (both descriptive/raw and analyzed data) will be made available for access by qualified members of the research community according to the provisions defined in the NIMH Data Repositories Data Access Agreement and Use Certification.