Clinical trial NCT05467683: CO2 Reactivity as a Biomarker of Non-Response to Exposure-Based Therapy
Official title: Carbon Dioxide (CO2) Reactivity as a Biomarker of Non-Response to Exposure-Based Therapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obsessive-Compulsive Disorder
Post Traumatic Stress Disorder
Generalized Anxiety Disorder
Social Anxiety Disorder
Panic Disorder
Lead sponsor: University of Texas at Austin
Sponsor class: OTHER
Collaborators: name: Boston University
name: National Institute of Mental Health (NIMH)
First posted: 2022-07-20
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Non-response to exposure-based therapy
timeFrame: Week 13 (post-treatment)
Secondary outcomes:
measure: Clinical Global Impression - Severity of Illness (CGI-S)
timeFrame: Weekly for 14 weeks + follow-up after 24 weeks
measure: Overall Anxiety Severity and Impairment Scale (OASIS)
timeFrame: Weekly for 14 weeks + follow-up after 24 weeks
measure: GAD-7
timeFrame: Weekly for 14 weeks + follow-up after 24 weeks
measure: Panic Disorder Severity Scale (PDSS)
timeFrame: Weekly for 14 weeks + follow-up after 24 weeks
measure: Social Phobia Inventory (SPIN)
timeFrame: Weekly for 14 weeks + follow-up after 24 weeks
measure: Dimensional Obsessive-Compulsive Scale (DOCS)
timeFrame: Weekly for 14 weeks + follow-up after 24 weeks
measure: PTSD Checklist for DSM-5 (PCL-5)
timeFrame: Weekly for 14 weeks + follow-up after 24 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Austin
country: United States
facility: The University of Texas at Austin
state: Texas
Study officials:
affiliation: The University of Texas at Austin
name: Jasper Smits, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston University
name: Michael Otto, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: