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

Study Overview
=================
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.

Official Title
-----------------
Carbon Dioxide (CO2) Reactivity as a Biomarker of Non-Response to Exposure-Based Therapy

Conditions
-----------------
Obsessive-Compulsive Disorder, Post Traumatic Stress Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder

Intervention / Treatment
-----------------
* Behavioral: Exposure-Based Therapy


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Open Exposure-Based Therapy (EBT)<br>All participants will receive a well-established psychological treatment. | Behavioral: Exposure-Based Therapy<br>* Treatment will consist of 12 one-hour sessions, delivered over the course of 12 weeks. EBT will be delivered by trained and experienced license-eligible clinicians. The study clinician will develop a personalized assessment and treatment plan for each patient. Consistent with contemporary models of EBT, exposure practice aims to help patients reestablish a sense of safety around feared cues. Hence, exposure exercises are planned to ensure violation of threat expectancies. That is, exposure practice is deemed appropriate and effective if it allows the patient to learn that what they feared would happen does not happen. Practice will occur across relevant contexts both within and outside the session (i.e., homework) and clinicians will guide patients in processing practice to facilitate the consolidation of safety learning. To achieve these ends, study clinicians will use the manual Personalized Exposure Therapy: A Person-Centered Transdiagnostic Approach.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-response to exposure-based therapy | 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. | Week 13 (post-treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression - Severity of Illness (CGI-S) | 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). | Weekly for 14 weeks + follow-up after 24 weeks | 
| Overall Anxiety Severity and Impairment Scale (OASIS) | 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). | Weekly for 14 weeks + follow-up after 24 weeks | 
| GAD-7 | 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. | Weekly for 14 weeks + follow-up after 24 weeks | 
| Panic Disorder Severity Scale (PDSS) | 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. | Weekly for 14 weeks + follow-up after 24 weeks | 
| Social Phobia Inventory (SPIN) | 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. | Weekly for 14 weeks + follow-up after 24 weeks | 
| Dimensional Obsessive-Compulsive Scale (DOCS) | 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. | Weekly for 14 weeks + follow-up after 24 weeks | 
| PTSD Checklist for DSM-5 (PCL-5) | 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. | Weekly for 14 weeks + follow-up after 24 weeks |