Virtual Reality Therapy for Voice Hearing (VR-VOICES): a Randomized Controlled Trial (VR-VOICES)

Rationale: Auditory verbal hallucinations (AVH) - hearing voices that others cannot hear - are common in mental illnesses. For many people AVH are distressing, disabling and persistent, despite medication. Current psychological interventions show low to medium effects. Preliminary studies suggest that an innovative empowering psychological therapy using computer simulations representing the AVH (avatars) can be effective for reducing AVH distress and frequency. Virtual reality (VR) has the potential to improve this treatment. Therefore, we developed a novel VR treatment for this problem. In this study, the effect of this treatment will be investigated. Objective: To test the effect of a novel VR treatment for AVH (VR-VOICES) on distress and frequency of AVH in patients with a psychiatric disorder. Furthermore, to investigate the effect of VR-VOICES on clinical symptoms, quality of life, and healthcare costs of the treatment.

Study design: Single-blind randomized controlled intervention trial (RCT) with two arms: VR-VOICES as intervention and treatment as usual (TAU) as a control condition. Study population: Patients with a DSM-5 diagnosis who have experienced distressing AVH for at least 3 months, who are 16 years or older (N=112). Intervention: VR-VOICES intervention: 7-10 sessions of 45-60 minutes of individual VR assisted therapy and two booster sessions, in addition to TAU. Participants allocated to VR-VOICES create together with their therapist a VR digital representation (avatar with face, body and voice) of the voice that bothers them most. Patients have dialogues with the avatar, voiced by the therapist. As indicated in the treatment protocol, over the sessions the avatar will become less hostile and the participant will gain more power and resilience over the avatar. Control: TAU as described in the current Dutch treatment guidelines, which generally exists of pharmacological treatment, supportive counseling, and psychological interventions such as CBT and coping strategies. Main study parameters/endpoints: Assessments will be obtained at baseline, within some VR-VOICES sessions, posttreatment (12 weeks after baseline), and at 6-month follow-up. Primary outcome: severity of AVH (total score on the auditory hallucinations scale of the PSYRATS) at post-treatment. Secondary outcomes: in-depth characteristics of AVH such as the frequency, voice impact, beliefs about voices, power relative to voices, levels of anxiety, distress and impact on daily life as measured with questionnaires and diary assessments in the flow of daily life. Other secondary outcomes include clinical symptoms, cost-effectiveness and quality of life.

7-10 sessions of 45-60 minutes of individual VR assisted therapy and two booster sessions, in addition to TAU. Participants allocated to VR-VOICES create together with their therapist a VR digital representation (avatar with face, body and voice) of the voice that bothers them most. Patients have dialogues with the avatar, voiced by the therapist. As indicated in the treatment protocol, over the sessions the avatar will become less hostile and the participant will gain more power and resilience over the avatar.

TAU as described in the current Dutch treatment guidelines, which generally exists of pharmacological treatment, supportive counseling, and psychological interventions such as CBT and coping strategies. This will vary per individual.

7-10 individual VR assisted therapy for voice-hearing session and two booster sessions, in addition to TAU.

The Psychotic Symptoms Rating Scales (PSYRATS) is a semi-structured interview to assess characteristics of hallucinations and delusions. The auditory hallucinations subscale (AHS), which is used as the primary outcome, has 11 items.

The Psychotic Symptoms Rating Scales (PSYRATS) is a semi-structured interview to assess characteristics of hallucinations and delusions. The auditory hallucinations subscale (AHS) has 11 items.The delusions subscale (DS) has six items.

Beliefs about voice power, voice intent and responding styles (Beliefs about Voices Questionnaire-Revised, BAVQ-R)

The BAVQ-R has 54 items, measured on a four-point scale: "disagree" (0), "unsure" (1), "slightly agree" (2), "strongly agree"(3).

The SCRS has 11 items measuring characteristics of the participants as compared to their voices on a 10-point likert scale ranging from 1-10.

The VIS has 24 items measured on a 10-point likert scale ranging from 1 (totally disagree) to 10 (totally agree).

Section A of the VAAS has 12 items and section B 27. Items are rated on a 5-point scale: strongly disagree, disagree, unsure or neutral, or strongly agree.

The BAI has 21 items. Items are rated on a 4-point scale ranging from 0 (not at all), 1 ( a little to 3 (severly).

The IDS-SR is a 30-item questionnaire. Each item has four statements that reflect various degrees of symptom severity, scored on a four-point scale from 0 to 3.

The R-GPTS part A consists of 8 items, and B of 10 items. Items are rated on a 5-point scale ranging from 0 (not at all) to 4 (totally).

The SERS has 20 items which are rated on a 7-point likert scale from 1 (strongly disagree) -7 (strongly agree).

The TiC-P is a self-report questionnaire that consists of two parts. The first part includes 38 structured questions, starting with yes/no questions and followed by a question on the volume of medical consumption.

The TiC-P is a self-report questionnaire that consists of two parts. The second part deals with 12 questions about work to collect data on productivity losses due to health problems.

The SDS is a brief, 5-item self-report tool that assesses functional impairment in work/school, social life, and family life on a scale from 0-10, and assess how many days someone missed work/school/responsibilities and how many days someone was unproductive.

The first 25 items of this questionnaires are based on five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The patient is asked to indicate their health status by choosing the most appropriate level: no problems, slight problems, moderate problems, severe problems, and extreme problems. The last question indicates their current health status on a scale from 0 to 100.

ESM of auditory verbal hallucinations and mental states measured in the flow of daily life. ESM is a structured diary method for reporting momentary experiences 18. Individuals complete short questionnaires on their mobile device, by pressing a link in a text message. Participants will complete ESM 5x daily for 7 days, completion takes ±1 minute. Participants have to complete the questionnaire within 30 minutes after the text message notification, the interval between measurements is 3 hours.

Use of prescribed medication in the past 3 months, type of medication, were the medication is for, how often it was used and what amount (in milligram)

Use of substances, number of glasses of alcohol in the past month. Use of softdrugs and harddrugs in the past 3 months, type of drugs, how often the drugs were used, how much was used each time.

Frequency of use of 21 types of psychological interventions and training in the past 30 days. There is also an option 'other', where specific other interventions and the frequency can be noted down.

The WAV has 36 items for the participant and 36 items for the therapist. Items are rated on a 5-point scale ranging from ''never'' to ''always''

Assessment at the end of VR-VOICES session 7 (only for the VR-VOICES group), which will be between 7and 10 weeks after baseline is completed.

Assessment during VR-VOICES session 3 & 7 (only for the VR-VOICES group), , which will be between 3-7 weeks (for session 3) and 7-10 weeks (for session 7) after baseline is completed.

Experience of fit of the voice and avatar to the actual voice (two single items on a scale from 1-100).

Assessment during VR-VOICES session 7 (only for the VR-VOICES group), which will be between 7and 10 weeks after baseline is completed.

Frequency and duration of use of the session recordings by the participant, duration, protocol deviations

Assessment during each VR-VOICES therapy session (only VR-VOICES group), between baseline and 3 months (follow-up)

After the VR-VOICES intervention, in-depth interviews will be performed to collect the experiences of patients with VR-VOICES. This will be done in a subsample of participants (n=20)

Inclusion Criteria: Having a DSM-5 diagnosis of a psychiatric disorder Distressing AVH for minimally 3 months. Age 16 years or older Exclusion Criteria: Insufficient command of the Dutch language Unable to provide informed consent Primary diagnosis of a substance use disorder, or organic brain disease (such as dementia) A degree of substance abuse that hinders treatment adherence Auditory verbal hallucinations in a language not spoken by therapists Patients cannot receive CBT specifically focused at gaining empowerment over voices during the study period or 6 months prior to enrolment.