Respiratory Training vs Interoceptive Exposure in the Treatment of Transdiagnostic Pathological Anxiety

Study Overview
=================
Brief Summary
-----------------
Purpose of the Research: The primary aim of the proposed study is to conduct a randomized parallel-group 3-arm clinical trial comparing two mechanistically distinct interventions for pathological anxiety - (1) Interoceptive Exposure (IE) utilizing graduated exposure to somatic cues (respiratory, cardiac, vestibular) with the primary aim of reducing fear responding to the presence of interoceptive perturbations; (2) Capnometry-Guided Respiratory Intervention (CGRI) aimed at raising end-tidal CO2 levels thereby lowering hyperventilation-induced respiratory alkalosis and its associated fear-eliciting somatic reactions; and (3) Psycho-education about anxiety and its effects (PsyEd), which will serve as a credible control comparator.

Detailed Description
-----------------
Anxiety sensitivity - the tendency to perceive anxiety as threatening - is a widely recognized risk factor for the development of panic disorder and other anxiety-related psychopathology. Interoceptive exposure therapy consisting of repeated exposure to interoceptive cues using respiratory provocation challenges such as hyperventilation and inhalation of various concentrations of CO2-enriched air have shown promise in reducing AS and are often included in cognitive-behavioral treatments of panic disorder with or without agoraphobia.However, some patients are unwilling to undergo exposure-based treatments, while others who do show only partial response or subsequent relapse. Alternatively, low end-tidal CO2 (ETCO2), which is an accompanying feature of hyperventilation, has been associated with a variety of anxiety disorders, including panic disorder and social phobia. More recently, researchers have examined the efficacy of capnometry-guided respiratory intervention (CGRI) as a method for increasing ETCO2 and thereby reducing hyperventilation-induced anxiety/panic symptoms. Promising preliminary efficacy studies have shown that CGRI results in decreased panic symptom frequency and severity at a rate comparable to that of cognitive therapy. A recent uncontrolled proof-of-concept study showed that CGRI led to significant reductions in trauma symptoms in a sample of patients meeting DSM-5 criteria for PTSD. However, neither IE or CGRI has been adequately evaluated in the treatment of anxiety disorders other than panic disorder with or without agoraphobia.

Official Title
-----------------
Respiratory Training vs Interoceptive Exposure in the Treatment of Transdiagnostic Pathological Anxiety: A Randomized Clinical Trial

Conditions
-----------------
Anxiety Disorders, Trauma, Generalized Anxiety Disorder, Panic Disorder, Agoraphobia, Illness Anxiety Disorder, Social Anxiety Disorder, Posttraumatic Stress Disorder, Acute Stress Disorder, Adjustment Disorder With Anxious Mood

Intervention / Treatment
-----------------
* Behavioral: Interoceptive Exposure
* Device: Capnometry-Guided Respiratory Intervention
* Behavioral: Psycho-Education


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinically elevated anxiety as indicated by an eight or higher on the Overall Anxiety Severity and Impairment Scale (OASIS). Meets DSM-5 criteria for one or more of the following anxiety or trauma-related disorders as their primary mental disorder: Generalized Anxiety Disorder Panic Disorder Health Anxiety Agoraphobia Social Anxiety Disorder Posttraumatic Stress Disorder Acute Stress Disorder Adjustment Disorder with primary anxious mood Anxiety disorder not otherwise specified No current use of psychotropic medications or stable on current medications for at least 6 weeks Age 18+. Able to arrange transportation to our laboratory for study appointments. Fluent in English. Exclusion Criteria: No history of medical conditions that would contraindicate participation in fear-provocation or respiratory challenges, including: Cardiovascular or respiratory disorders High blood pressure Epilepsy Strokes Seizures History of fainting Pregnant or lactating Not currently receiving other psychological treatment for anxiety. No history of a suicide attempt within the past 6 months. No history of psychosis within the past 6 months. No history of moderate to severe alcohol or substance use disorder (with the exception of nicotine) within the past 3 months. Does not endorse COVID-19 symptoms during the screening phase.

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study will utilize a 3 x 3 randomized controlled trial design with intervention type as a between-subjects factor with three levels (IE, CGRI, PsyEd) and time points (baseline, posttreatment, 2-month follow-up) as a three-level within-subjects factor.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interoceptive Exposure (IE)<br>Participants assigned to the interoceptive exposure condition will receive twice-weekly 90-minute in-person treatment sessions for four weeks. This treatment will include education about anxiety and factors that maintain anxiety symptoms. In addition, participants will be asked to perform exercises designed to activate potentially distressing - but harmless - bodily sensations that are commonly associated with stress and anxiety. Participants will also be encouraged to practice these exercises daily at home. | Behavioral: Interoceptive Exposure<br>* See: Arm/group descriptions<br>* Other names: IE;|
| Experimental: Capnometry-Guided Respiratory Intervention (CGRI)<br>If assigned to this condition, participants will be expected to complete twice-daily 17-minute tablet-assisted breathing exercises at home for four weeks. They will also receive brief phone check-ins with their study therapist weekly to review progress and troubleshoot any problems they may be experiencing. Last, these participants will have access to a paced-breathing app that provides audio recordings to maintain specified breathing rates for up to 10 minutes. | Device: Capnometry-Guided Respiratory Intervention<br>* See: Arm/group descriptions<br>* Other names: CGRI;|
| Active Comparator: Psycho-Education (PsyEd)<br>If assigned to the psycho-education condition, participants will undergo once-weekly 20-minute video conferencing session with a therapist for four weeks. During these sessions, they will be provided information about the nature and causes of anxiety-related disorders and learn tips for coping with anxiety symptoms when they arise. At the end of their sessions with the therapist, they will receive handouts that will help reinforce what they've learned. | Behavioral: Psycho-Education<br>* See: Arm/group descriptions<br>* Other names: PsyEd;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Anxiety Severity and Impairment Scale | Change from baseline in self-reported transdiagnostic anxiety symptoms (range = 0 - 20, with higher scores indexing more symptoms). | Pre-Treatment (Week 0), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) | 
| Computerized Hamilton Anxiety Scale | Change from baseline in anxiety symptom severity. Each item is assessed both in terms of frequency and severity. Scores on these probes are summed and divided by the number of response options. Higher scores index higher severity. | Pre-Treatment (Week 0), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sheehan Disability Scale | Change from baseline in overall disability (range = 0 - 30, with higher scores indexing more disability). | Pre-Treatment (Week 0), Weekly Assessments (Weeks 1 - 4), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) | 
| PROMIS - Global Health (Mental Health Subdomain) | Change from baseline in quality of life (range = 4 - 20, with higher scores indexing higher quality of life). | Pre-Treatment (Week 0), Weekly Assessments (Weeks 1 - 4), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) | 
| Anxiety Sensitivity Composite Measure | This composite measure will incorporate scores on the Anxiety Sensitivity Index-3 (ASI-3), Body Sensations Questionnaire (BSQ), and Texas Multi-Factor Anxiety Sensitivity Scale (TMASS). Scores on each of these individual measures will be transformed into z scores and then averaged to derive this composite index. We will measure change from baseline in anxiety sensitivity. | Pre-Treatment (Week 0), Weekly Assessments (Weeks 1 - 4), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) | 
| Modified DIAMOND | Change from baseline in DIAMOND Diagnostic Interview + Health Anxiety Questionnaire scores. | Pre-Treatment (Week 0), 2-Month Follow-Up (Week 13) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Psychoeducation, Respiratory training, Interoceptive exposure, Transdiagnostic, Intervention