Face Your Fears: Cognitive Behavioural Virtual Reality Therapy for Paranoia.

Study Overview
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Brief Summary
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The study is a randomised, assessor-blinded parallel-groups superiority clinical trial fulfilling the CONSORT criteria for non-pharmacological treatment. A total of 256 patients will be allocated to either Cognitive Behavioural Virtual Reality Therapy plus treatment as usual, versus traditional CBT for psychosis plus treatment as usual. All participants will be assessed at baseline and 3- and 9 months post baseline. A stratified block-randomisation with concealed randomisation sequence will be conducted. Independent assessors blinded to the treatment will evaluate outcome. Analysis of outcome will be carried out with the intention to treat principles.

Detailed Description
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Ideas of reference and ideas of persecution are among the most frequent symptoms in psychotic disorders, and they hinder patients in conducting daily activities such as leaving the home or using public transportation - as well as inflicting immensely on their quality of life. The social avoidance caused by these symptoms does not improve with antipsychotic mediation. Cognitive behavioural therapy (CBT) for psychosis has demonstrated beneficial effect on psychotic symptoms, but the average effect sizes are in the small to moderate range, and training and resource requirements mean that, in practice, therapy is not delivered to all those who might benefit. Hence, there is considerable interest in the development of novel therapies that draw on the principles of cognitive behavioural therapy for psychosis, but which are shorter, more effective, and are capable of being delivered by a wider workforce. Augmenting CBT with virtual reality exposure has the possibility of creating artificial experiences in real time, that make the user feel immersed and able to interact as if it was the real world. Additionally, virtual reality therapy allows for personalization of the therapy to match the specific social challenges of each patient. Preliminary findings suggest virtual reality exposure to lead to faster symptom reduction than traditional therapy. While the potential beneficial effects of virtual reality exposure to psychotic, and sub-threshold psychotic symptoms, such as ideas of reference and ideas of persecution, are evident and virtual reality therapies are promising in general, the research field is in an urgent need of evidence on the effectiveness of virtual reality therapy in patients with schizophrenia spectrum disorders. The proposed trial is hitherto the largest trial in the world to evaluate the effectiveness of cognitive behavioural virtual reality therapy (CBT-VR) compared to traditional CBT. The investigators expect to find CBT-VR to be more beneficial in reducing ideas of reference and ideas of persecution in patients with schizophrenia spectrum disorders. Additionally, the investigators expect it to result in improved depressive, anxiety-, and negative symptoms, as well as improved social cognition and psychosocial functioning and quality of life in patients with schizophrenia spectrum disorders. The target group in the trial also encompass patients with schizotypal disorder (often young adults), showing subthreshold psychotic symptoms (e.g. ideas of reference), that are at increased risk of developing manifest psychosis. The CBT-VR may show efficacy in preventing progression to an overt psychotic state in these patients. Hence, there is a great potential for CBT-VR in the treatment of patients with psychosis and sub-threshold psychosis, but studies are needed to establish evidence for the treatment. If the results of the current trial are positive, the manualised treatment can easily be implemented in clinical practise. Note: When the trial was initiated, the original primary outcome was ideas of persecution, measured with part B in Green Paranoid Thought Scale (GPTS) while ideas of social reference, measured with part A in Green Paranoid Thought Scale, was listed as a secondary outcome in the trial protocol, here on Clinicaltrials.gov and in the approval from the Committee on Health Research Ethics of the Capital Region Denmark. During our trial, our impressions in the clinical assessments were, that ideas of social reference seem to be a more appropriate primary outcome due to our population including people diagnosed with schizotypal disorders along with participants with manifest psychotic disorders. We observed that participants with schizotypal disorders experiencing ideas of social reference, that are more attenuated paranoid ideations, would often receive a low score on the GPTS part B. Therefore, listing GPTS part B as primary outcome would hypothetically only reflect the symptom level of part of the study population (patients with manifest psychosis), while not fully comprising the symptom level, and potential for change, found in the population of patients with schizotypal disorder. '' As of February, 23 2022, 10 months into the trial, where 79 participants out of 256 were included and had participated in baseline assessments, we decided after thorough consideration to exchange our primary outcome, GPTS part B, ideas of persecution, with our secondary outcome, GPTS part A, ideas of social reference, as this was intended to capture the symptom level in the total study population. The exchange did not affect participation in our trial or the informed consent. Intervention in both groups and measurements were unchanged. The two outcomes constitute together GPTS and the unifying concept we attempt to treat, namely paranoid ideations. As this is a blinded, methodologically sound trial, we had not (and still have not throughout the study period) access to preliminary data and therefore no knowledge of the distribution of our two intervention groups nor the potential effect of the intervention. The power calculation remains unchanged irrespective of the selection of primary outcome. (Ideas of persecution: relevant difference 6.0, SD 17.9, N=128*2, power= 80%). Due to the notions mentioned above, we did not find any reasons for ethical implications of the change of primary outcome - as we also were fully transparent with this change of outcome here on Clinicaltrials.gov. We therefore assumed that our ethical committee would approve of this change. However, on September 3 2022 we received a rejection from the Committee on Health Research Ethics of the Capital Region Denmark on changing outcomes, on the invariable grounds that the trial is commenced. This means that it is necessary to keep ideas of persecution, part B in Green Paranoid Thought Scale, as our primary outcome and keep ideas of social reference, part A in Green Paranoid Thought Scale as a secondary outcome. A design paper was published while we had ideas of social reference, part A in Green Paranoid Thought Scale, as a primary outcome. An Update, informing about this significant change in the form of changing back to the originally, approved, primary outcome, is in progress.

Official Title
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Face Your Fears: An Assessor-blinded, RCT Evaluating the Effectiveness of Cognitive Behavioural Virtual Reality Therapy Versus Cognitive Behavioural Therapy in Patients With Schizophrenia Spectrum Disorders.

Conditions
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Paranoid Schizophrenia, Schizophrenia and Related Disorders, Schizophrenia Prodromal, Schizotypal Disorder, Paranoid Ideation, Paranoid Delusion, Ideas of Reference, Psychosis Paranoid, Psychotic Disorders, Psychotic Paranoia, Psychotic; Disorder, Delusional

Intervention / Treatment
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* Other: Cognitive Behavioural Virtual Reality Therapy.
* Other: Traditional Cognitive Behavioural Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - years Ability to give informed consent A schizophrenia spectrum disorder (ICD-10 code: F20 -F29) Green Paranoid Thought Scale total score ≥ 40 Exclusion Criteria: Rejecting informed consent A diagnosis of organic brain disease IQ of 70 or lower (known mental retardation as assessed by medical record) A command of spoken Danish or English inadequate for engaging in therapy Inability to tolerate the assessment process

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: A randomised, assessor-blinded parallel-groups superiority clinical trial.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cognitive Behavioural Virtual Reality Therapy (CBT-VR)<br>The CBT-VR consists of traditional CBT with the augmentation of virtual reality exposure. The virtual reality exposure comprises four virtual social environments (a bus, café, street, and supermarket). These are daily social situations that generally elicit paranoid thinking in patients with a schizophrenia spectrum disorder. While virtually engaging in these distressing situations, the therapist will facilitate a CBT dialogue aimed at generating alternative (i.e. non-threatening) thinking, diminishing safety behaviours (e.g. social isolation), and building up new coping strategies. This is expected to alleviate distress, anxiety, and improve daily social functioning. Preliminary findings reveal this virtual reality program to be well-tolerated and highly effective in reducing paranoia and anxiety in psychosis. Patients will be offered 10 individual sessions. | Other: Cognitive Behavioural Virtual Reality Therapy.<br>* Cognitive Behavioural Therapy augmented with Virtual Reality.<br>|
| Active Comparator: Traditional Cognitive Behavioural Therapy<br>The treatment in the CBT group will follow the core principles of CBT used for psychotic disorders. The CBT treatment facilitates an individualised, problem-oriented approach, and uses key CBT techniques such as developing a problem and goal list, normalising psychotic-like experiences, evaluation of appraisals, and removing or diminishing safety behaviour. Patients will be offered 10 individual sessions. | Other: Traditional Cognitive Behavioural Therapy<br>* Traditional Cognitive Behavioural Therapy for psychosis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (GPTS) Green Paranoid Thought Scale Part B: Ideas of persecution. | The primary outcome is level of ideas of persecution measured with Green Paranoid Thought Scale at cessation of treatment at 3-months. The Green Paranoid Thought Scale has displayed good reliability and validity in patients with psychosis, displaying paranoid, persecutory delusions, and has also been used in patients at-risk for psychosis showing subthreshold psychotic symptoms. Minimum total score: 32. Maximum total score: 160. Part A (Ideas of social reference) minimum score: 16 and maximum score: 80. Part B (ideas of persecution) minimum score 16 and maximum score: 80. Part B score = or > 45 are assumed to be threshold for development of persecutory delusion. Higher score means worse outcome. | 3 months from inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SIAS (Social Interaction Anxiety Scale) | Minimum score: 0 Maximum score: 20*4=80. Item 5,9 and 11 have reverse score. Higher score means worse outcome. | 3 and 9 months from inclusion | 
| SBQ (Safety Behaviour Questionnaire) | Minimum score: 0. Maximum score is in theory unlimited depending on the number of identified, specific safety behaviours. | 3 and 9 months from inclusion | 
| PSP (Personal and Social Performance Scale) | Minimum score: 1 Maximum score: 100. Higher score means better outcome. | 3 and 9 months from inclusion | 
| CANTAB ERT (Emotion Recognition Task) |  | 3 and 9 months from inclusion | 
| (GPTS) Green Paranoid Thought Scale Part A: Ideas of social reference | Minimum total score: 32. Maximum total score: 160. Part A (Ideas of social reference) minimum score: 16 and maximum score: 80. Part B (Ideas of persecution) minimum score 16 and maximum score: 80. Part B score = or > 45 are assumed to be threshold for development of delusion. Higher score means worse outcome. | 3 and 9 months from inclusion | 
| (GPTS) Green Paranoid Thought Scale Part B: Ideas of persecution | Minimum total score: 32. Maximum total score: 160. Part A (Ideas of social reference) minimum score: 16 and maximum score: 80. Part B (Ideas of persecution) minimum score 16 and maximum score: 80. Part B score = or > 45 are assumed to be threshold for development of delusion. Higher score means worse outcome. | 9 months from inclusion |