Noradrenergic Manipulation and Virtual Reality Exposure Therapy in Phobic Participants

Study Overview
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Brief Summary
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Recent advances in animal research have identified pharmacological agents that appear to both accelerate and consolidate extinction learning. One cognitive enhancers is Yohimbine hydrochloride (YOH). A finding in animal literature is that the administration of YOH during extinction trials accelerates fear reduction and may convert ineffective exposures in to successful ones. It is thought that the mechanism of enhanced emotional memory is through elevated norepinephrine. However, recent findings demonstrate mixed results. In a randomized controlled trial claustrophobic participants underwent exposure in combination with YOH or placebo. The YOH group showed significantly better results on anxiety improvement than the placebo group. In a more recent study with participants with fear of flying no additional benefits of YOH were demonstrated. Therefore, we intend to replicate and extend these studies by enhancing the dose of YOH in combination with VRET and by extending our experimental design with another group which receives propranolol in combination with VRET. Propranolol is β-adrenergic receptor antagonist, which has proven to disrupt reconsolidation in healthy humans. In this randomized controlled trial a between groups design is chosen to further characterize the differential within and between trial extinction and to enhance possible between groups effects. Sixty participants with fear of flying or fear of heights will be randomly assigned to one of the following three conditions 1) VRET plus YOH, 2) VRET plus Propranolol, or 3) VRET plus placebo. Participants in all conditions will be offered three sessions of VRET over a period of two weeks.

Official Title
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Noradrenergic Manipulation and Virtual Reality Exposure Therapy in Phobic Participants

Conditions
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Phobic Disorders

Intervention / Treatment
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* Behavioral: Virtual Reality Exposure Therapy (VRET)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Marked fear of flying or acrophobia, indicated by a subjective fear rating of moderate or higher on anxiety specific measures. Being older than 18 years and younger than 75 years. Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: VRET plus Yohimbine<br>Virtual Reality Exposure Therapy combined with the administration of yohimbine. | Behavioral: Virtual Reality Exposure Therapy (VRET)<br>* Graded exposure to feared specific stimulus by computer-generated 3D virtual environments.<br>|
| Active Comparator: VRET plus propranolol<br>Virtual Reality Exposure Therapy combined with the administration of propranolol | Behavioral: Virtual Reality Exposure Therapy (VRET)<br>* Graded exposure to feared specific stimulus by computer-generated 3D virtual environments.<br>|
| Placebo Comparator: VRET plus placebo<br>Virtual Reality Exposure Therapy combined with the administration of a non-active placebo pill | Behavioral: Virtual Reality Exposure Therapy (VRET)<br>* Graded exposure to feared specific stimulus by computer-generated 3D virtual environments.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FAS (Flight Anxiety Situations Questionnaire) | The FAS is 32-item, self-report inventory designed to measure anxiety related to flying experienced in different situations. The FAS is divided into three subscales: the Anticipation scale, which represents situations before the actual flight, the In-flight scale, which refers to situations during a flight and the Generalized flight scale. | Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 
| AQ (Acrophobia Questionnaire) | The AQ (Cohen, 1977) is a 40-item self-report measure to assess anxiety in height situations. The AQ measures anxiety and avoidance behavior relative to height situations. Subject can express their fear on a scale ranging from 0-6, whereby 0 stands for no fear at all and 6 for almost panic (ranging from 0-120). | Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 
| WAQ (Weekly Anxiety Questionnaire) | The WAQ is an author-constructed transdiagnostic anxiety questionnaire to rate severity of experienced general anxiety. The WAQ is a 10-item self-report measure on which participants can rate their experienced anxieties. Ratings can be scored on a five-point Likert scale ranging from not at all to permanently. | In session 1, 2 and 3 and Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FAM (Flight Anxiety Modalities Questionnaire) | The FAM is 23-item, self-report inventory designed to measure how fear of flying can be expressed. On a five-point-likert scale the intensity of fear can be rated. The FAM is divided into two subscales: the Somatic Modality, which represents the physical symptoms and the Cognitive Modality, which measures distressing cognitions. | Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 
| ATHQ (Attitude towards heights questionnaire) | The ATHQ contains six questions assessing the attitude towards heights (range 0-60). | Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 
| DASS (Depression Anxiety Stress Scale) | The DASS is 42-item self-report measure that assesses level of depression, anxiety, and stress over the previous week. Each scale consists of 14 items, which are grouped into smaller subscales. The depression scale consists of the following subscales: dysphoria, hopelessness, devaluation of life, self-deprecation, lack of interest/involvement, anhedonia and inertia. The anxiety scale consists of: autonomic arousal, skeletal musculature effects, situational anxiety and subjective experience of anxious affect. The stress scale consists of: difficulty relaxing, nervous arousal, easily agitated, irritable/overreactive and impatient. The internal consistency of the DASs is good to excellent (Cronbach's alpha ranging from .88 to .96; Brown et al., 1997). | Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 
| PIT (Prospective Imagery Task) | The PIT is based on MacLeod and Byrne, (1996) and Stöber, (2000) and will be used to measure imagery for 10 positive and 10 negative prospective events. As in Holmes, Lang, et al. (2008), subjects will be asked to rate the vividness of prospective positive events (e.g., You will have lots of energy and enthusiasm) or negative events (e.g., Someone close to you will reject you) on a 5-point scale (1 = no image at all; 5 = very vivid). | Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 
| ASI (Anxiety Sensitivity Inventory) | The ASI is a 16-items self-report questionnaire, measuring fear of anxiety-related symptoms. Each item is rated on a five-point likert scale ranging from 0 (very little) to 4 (very much). The ASI is scored by summing all items; possible scores range from 0 to 64, with higher scores reflecting higher levels of anxiety sensitivity. | Pre- (baseline) and post-assessment (after treatment termination, within 3 weeks after first treatment session) and 3 month follow up (3 month after post assessment) | 
| SUDs (Subjective Units of Discomfort) | Subjective Units of Discomfort (SUDs) will be taken every 3 minutes to monitor patients' subjective anxiety (Wolpe, 1990). | Every 3 minutes during exposure (exposure will be done twicely 25 minutes every therapy session. Thus, starting at minute 1 every 3 minute a SUD will be asked. After a break of 10 minutes, exposure will start again (25 minutes). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phobic Disorders (Fear of Flying and acrophobia), Virtual Reality Exposure Therapy, Fear extinction, propranolol, Yohimbine