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

Not Applicable

Recruiting

• Conditions: Generalized Anxiety Disorder; Post Traumatic Stress Disorder; Obsessive-Compulsive Disorder; Panic Disorder; Social Anxiety Disorder

• Registration Number: NCT05467683
• Lead Sponsor: University of Texas at Austin

Brief Summary

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?"

Detailed Description

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.

Study Timeline

• Study First Submitted: 2022-06-27
• Study First Submitted QC: 2022-07-19
• Study First Posted: 2022-07-20
• Study Start: 2022-11-02
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-18
• Last Update Posted: 2025-06-25
• Primary Completion: 2026-12-01
• Study Completion: 2027-02-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 600

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Non-response to exposure-based therapy	Week 13 (post-treatment)	Participants will be classified as non-responders if their Clinical Global Impression - Global Improvement (CGI-I) score is 3 or above OR if their Overall Anxiety Severity and Impairment Scale (OASIS) score has not improved by at least 4 points.

Secondary Outcome Measures

Name	Time	Method
Overall Anxiety Severity and Impairment Scale (OASIS)	Weekly for 14 weeks + follow-up after 24 weeks	The OASIS is a self-report rating scale that comprises five items to assess the frequency and severity of anxiety, avoidance, work/school/home interference, and social interference due to anxiety. Participants select among five different response options for each item, which are coded 0-4 and are summed to obtain a total score (0-20).
PTSD Checklist for DSM-5 (PCL-5)	Weekly for 14 weeks + follow-up after 24 weeks	For participants with post-traumatic stress disorder (PTSD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 80, with higher scores indicating more severe distress and impairment.
Dimensional Obsessive-Compulsive Scale (DOCS)	Weekly for 14 weeks + follow-up after 24 weeks	For participants with obsessive compulsive disorder (OCD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 80, with higher scores indicating more severe distress and impairment.
GAD-7	Weekly for 14 weeks + follow-up after 24 weeks	For participants with generalized anxiety disorder (GAD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 21, with higher scores indicating more severe distress and impairment.
Panic Disorder Severity Scale (PDSS)	Weekly for 14 weeks + follow-up after 24 weeks	For participants with panic disorder (PD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 28, with higher scores indicating more severe distress and impairment.
Clinical Global Impression - Severity of Illness (CGI-S)	Weekly for 14 weeks + follow-up after 24 weeks	A 7 point widely used clinician rating scale for indexing the how mentally ill a patient is at the time using a 7 point scale ranging from 1(normal, not at all ill); 2 (borderline mentally ill); 3 (mildly ill); 4 (moderately ill); 5 (markedly ill); 6 (severely ill); 7(among the most extremely ill patients).
Social Phobia Inventory (SPIN)	Weekly for 14 weeks + follow-up after 24 weeks	For participants with social anxiety disorder (SAD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 68, with higher scores indicating more severe distress and impairment.

Trial Locations

Locations (2)

Boston University; 🇺🇸 Boston, Massachusetts, United States

The University of Texas at Austin; 🇺🇸 Austin, Texas, United States