Automated virtual reality cognitive therapy versus virtual reality mental relaxation therapy for the treatment of persistent persecutory delusions in patients with psychosis (THRIVE): a parallel-group, single-blind, randomised controlled trial in England with mediation analyses

Background: Persecutory delusions are a major psychiatric problem that often do not respond sufficiently to standard pharmacological or psychological treatments. We developed a new brief automated virtual reality (VR) cognitive treatment that has the potential to be used easily in clinical services. We aimed to compare VR cognitive therapy with an alternative VR therapy (mental relaxation), with an emphasis on understanding potential mechanisms of action. Methods: THRIVE was a parallel-group, single-blind, randomised controlled trial across four UK National Health Service trusts in England. Participants were included if they were aged 16 years or older, had a persistent (at least 3 months) persecutory delusion held with at least 50% conviction, reported feeling threatened when outside with other people, and had a primary diagnosis from the referring clinical team of a non-affective psychotic disorder. We randomly assigned (1:1) patients to either THRIVE VR cognitive therapy or VR mental relaxation, using a permuted blocks algorithm with randomly varying block size, stratified by severity of delusion. Usual care continued for all participants. Each VR therapy was provided in four sessions over approximately 4 weeks, supported by an assistant psychologist or clinical psychologist. Trial assessors were masked to group allocation. Outcomes were assessed at 0, 2 (therapy mid-point), 4 (primary endpoint, end of treatment), 8, 16, and 24 weeks. The primary outcome was persecutory delusion conviction, assessed by the Psychotic Symptoms Rating Scale (PSYRATS; rated 0–100%). Outcome analyses were done in the intention-to-treat population. We assessed the treatment credibility and expectancy of the interventions and the two mechanisms (defence behaviours and safety beliefs) that the cognitive intervention was designed to target. This trial is prospectively registered with the ISRCTN registry, ISRCTN12497310. Findings: From Sept 21, 2018, to May 13, 2021 (with a pause due to COVID-19 pandemic restrictions from March 16, 2020, to Sept 14, 2020), we recruited 80 participants with persistent persecutory delusions (49 [61%] men, 31 [39%] women, with a mean age of 40 years [SD 13, range 18–73], 64 [80%] White, six [8%] Black, one [1%] Indian, three [4%] Pakistani, and six [8%] other race or ethnicity). We randomly assigned 39 (49%) participants assigned to VR cognitive therapy and 41 (51%) participants to VR mental relaxation. 33 (85%) participants who were assigned to VR cognitive therapy attended all four sessions, and 35 (85%) participants assigned to VR mental relaxation attended all four sessions. We found no significant differences between the two VR interventions in participant ratings of treatment credibility (adjusted mean difference –1·55 [95% CI –3·68 to 0·58]; p=0·15) and outcome expectancy (–0·91 [–3·42 to 1·61]; p=0·47). 77 (96%) participants provided follow-up data at the primary timepoint. Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater improvement in persecutory delusions (adjusted mean difference –2·16 [–12·77 to 8·44]; p=0·69). Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater reduction in use of defence behaviours (adjusted mean difference –0·71 [–4·21 to 2·79]; p=0·69) or a greater increase in belief in safety (–5·89 [–16·83 to 5·05]; p=0·29). There were 17 serious adverse events unrelated to the trial (ten events in seven participants in the VR cognitive therapy group and seven events in five participants in the VR mental relaxation group). Interpretation: The two VR interventions performed similarly, despite the fact that they had been designed to affect different mechanisms. Both interventions had high uptake rates and were associated with large improvements in persecutory delusions but it cannot be determined that the treatments accounted for the change. Immersive technologies hold promise for the treatment of severe mental health problems. However, their use will likely benefit from experimental research on the application of different therapeutic techniques and the effects on a range of potential mechanisms of action.The trial was funded by the Medical Research Council Developmental Pathway Funding Scheme (MR/P02629X/1). It was also supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (BRC-1215-2000). DF is an NIHR Senior Investigator. DMC is an Emeritus NIHR Senior Investigator. This paper presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. FW is funded by a Wellcome Trust Clinical Doctoral Fellowship (102176/B/13/Z). MS is supported by the European Research Council Grant MoTIVE (742989).Peer ReviewedArticle signat per 23 autors/es: Department of Experimental Psychology (Prof D Freeman DClinPsy, R Lister DClinPsy, F Waite DClinPsych, S Lambe DClinPsy, A Beckley MA, E Bold BSc, L Jenner BA, R Diamond DClinPsych, M Kirkham DClinPsych, E Twivy DClinPsych, C Causier MSc, L Carr BSc, S Saidel MSc, A Rovira PhD, Prof D M Clark DPhil, L Rosebrock PhD), Oxford Primary Care Clinical Trials Unit, Nuffield Department of Primary Care Health Sciences (U Galal MSc, L-M Yu PhD), University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK (Prof D Freeman, F Waite, S Lambe, R Diamond, A Rovira, Prof D M Clark, L Rosebrock); Black Country Healthcare NHS Foundation Trust, Dudley, UK (R Lister); Northamptonshire Healthcare NHS Foundation Trust, Kettering, UK (R Day BSc, A Ivins DClinPsych, R Nah DClinPsy); Event Lab, Faculty of Psychology Spain (A Beacco PhD, Prof M Slater DSc), Institute of Neurosciences (Prof M Slater), University of Barcelona, Barcelona, Spain; Universitat Politècnica de Catalunya, Barcelona, Spain (A Beacco); Central and North West London NHS Foundation Trust, London, UK (R Nah)Postprint (published version

Automated virtual reality cognitive therapy versus virtual reality mental relaxation therapy for the treatment of persistent persecutory delusions in patients with psychosis (THRIVE): a parallel-group, single-blind, randomised controlled trial in England with mediation analyses

Background: Persecutory delusions are a major psychiatric problem that often do not respond sufficiently to standard pharmacological or psychological treatments. We developed a new brief automated virtual reality (VR) cognitive treatment that has the potential to be used easily in clinical services. We aimed to compare VR cognitive therapy with an alternative VR therapy (mental relaxation), with an emphasis on understanding potential mechanisms of action. Methods: THRIVE was a parallel-group, single-blind, randomised controlled trial across four UK National Health Service trusts in England. Participants were included if they were aged 16 years or older, had a persistent (at least 3 months) persecutory delusion held with at least 50% conviction, reported feeling threatened when outside with other people, and had a primary diagnosis from the referring clinical team of a non-affective psychotic disorder. We randomly assigned (1:1) patients to either THRIVE VR cognitive therapy or VR mental relaxation, using a permuted blocks algorithm with randomly varying block size, stratified by severity of delusion. Usual care continued for all participants. Each VR therapy was provided in four sessions over approximately 4 weeks, supported by an assistant psychologist or clinical psychologist. Trial assessors were masked to group allocation. Outcomes were assessed at 0, 2 (therapy mid-point), 4 (primary endpoint, end of treatment), 8, 16, and 24 weeks. The primary outcome was persecutory delusion conviction, assessed by the Psychotic Symptoms Rating Scale (PSYRATS; rated 0–100%). Outcome analyses were done in the intention-to-treat population. We assessed the treatment credibility and expectancy of the interventions and the two mechanisms (defence behaviours and safety beliefs) that the cognitive intervention was designed to target. This trial is prospectively registered with the ISRCTN registry, ISRCTN12497310. Findings: From Sept 21, 2018, to May 13, 2021 (with a pause due to COVID-19 pandemic restrictions from March 16, 2020, to Sept 14, 2020), we recruited 80 participants with persistent persecutory delusions (49 [61%] men, 31 [39%] women, with a mean age of 40 years [SD 13, range 18–73], 64 [80%] White, six [8%] Black, one [1%] Indian, three [4%] Pakistani, and six [8%] other race or ethnicity). We randomly assigned 39 (49%) participants assigned to VR cognitive therapy and 41 (51%) participants to VR mental relaxation. 33 (85%) participants who were assigned to VR cognitive therapy attended all four sessions, and 35 (85%) participants assigned to VR mental relaxation attended all four sessions. We found no significant differences between the two VR interventions in participant ratings of treatment credibility (adjusted mean difference –1·55 [95% CI –3·68 to 0·58]; p=0·15) and outcome expectancy (–0·91 [–3·42 to 1·61]; p=0·47). 77 (96%) participants provided follow-up data at the primary timepoint. Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater improvement in persecutory delusions (adjusted mean difference –2·16 [–12·77 to 8·44]; p=0·69). Compared with VR mental relaxation, VR cognitive therapy did not lead to a greater reduction in use of defence behaviours (adjusted mean difference –0·71 [–4·21 to 2·79]; p=0·69) or a greater increase in belief in safety (–5·89 [–16·83 to 5·05]; p=0·29). There were 17 serious adverse events unrelated to the trial (ten events in seven participants in the VR cognitive therapy group and seven events in five participants in the VR mental relaxation group). Interpretation: The two VR interventions performed similarly, despite the fact that they had been designed to affect different mechanisms. Both interventions had high uptake rates and were associated with large improvements in persecutory delusions but it cannot be determined that the treatments accounted for the change. Immersive technologies hold promise for the treatment of severe mental health problems. However, their use will likely benefit from experimental research on the application of different therapeutic techniques and the effects on a range of potential mechanisms of action. Funding: Medical Research Council Developmental Pathway Funding Scheme and National Institute for Health and Care Research Oxford Health Biomedical Research Centre

Study protocol for an adaptive, multi-arm, multi-stage (MAMS) randomised controlled trial of brief remotely delivered psychosocial interventions for people with serious mental health problems who have experienced a recent suicidal crisis: Remote Approaches to Psychosocial Intervention Delivery (RAPID)

Background People with serious mental health problems (SMHP) are more likely to be admitted to psychiatric hospital following contact with crisis services. Admissions can have significant personal costs, be traumatic and are the most expensive form of mental health care. There is an urgent need for treatments to reduce suicidal thoughts and behaviours and reduce avoidable psychiatric admissions.Methods A multi-stage, multi-arm (MAMS) randomised controlled trial (RCT) with four arms conducted over two stages to determine the clinical and cost effectiveness of three psychosocial treatments, compared to treatment as usual (TAU), for people with SMHP who have had recent suicidal crisis. Primary outcome is any psychiatric hospital admissions over a 6-month period. We will assess the impact on suicidal thoughts and behaviour, hope, recovery, anxiety and depression. The remote treatments delivered over 3 months are structured peer support (PREVAIL); a safety planning approach (SAFETEL) delivered by assistant psychologists; and a CBT-based suicide prevention app accessed via a smartphone (BrighterSide). Recruitment is at five UK sites. Stage 1 includes an internal pilot with a priori progression criteria. In stage 1, the randomisation ratio was 1:1:1:2 in favour of TAU. This has been amended to 2:2:3 in favour of TAU following an unplanned change to remove the BrighterSide arm following the release of efficacy data from an independent RCT. Randomisation is via an independent remote web-based randomisation system using randomly permuted blocks, stratified by site. An interim analysis will be performed using data from the first 385 participants from PREVAIL, SAFETEL and TAU with outcome data at 6 months. If one arm is dropped for lack of benefit in stage 2, the allocation ratio of future participants will be 1:1. The expected total sample size is 1064 participants (1118 inclusive of BrighterSide participants).Discussion There is a need for evidence-based interventions to reduce psychiatric admissions, via reduction of suicidality. Our focus on remote delivery of established brief psychosocial interventions, utilisation of different modalities of delivery that can provide sustainable and scalable solutions, which are also suitable for a pandemic or national crisis context, will significantly advance treatment options.Trial registration ISRCTN33079589. Registered on June 20, 2022

Estimating the Economic Value of Automated Virtual Reality Cognitive Therapy for Treating Agoraphobic Avoidance in Patients With Psychosis: Findings From the gameChange Randomized Controlled Clinical Trial

Background:An automated virtual reality cognitive therapy (gameChange) has demonstrated its effectiveness to treat agoraphobia in patients with psychosis, especially for high or severe anxious avoidance. Its economic value to the health care system is not yet established.Objective:In this study, we aimed to estimate the potential economic value of gameChange for the UK National Health Service (NHS) and establish the maximum cost-effective price per patient.Methods:Using data from a randomized controlled trial with 346 patients with psychosis (ISRCTN17308399), we estimated differences in health-related quality of life, health and social care costs, and wider societal costs for patients receiving virtual reality therapy in addition to treatment as usual compared with treatment as usual alone. The maximum cost-effective prices of gameChange were calculated based on UK cost-effectiveness thresholds. The sensitivity of the results to analytical assumptions was tested.Results:Patients allocated to gameChange reported higher quality-adjusted life years (0.008 QALYs, 95% CI –0.010 to 0.026) and lower NHS and social care costs (–£105, 95% CI –£1135 to £924) compared with treatment as usual (£1=US $1.28); however, these differences were not statistically significant. gameChange was estimated to be worth up to £341 per patient from an NHS and social care (NHS and personal social services) perspective or £1967 per patient from a wider societal perspective. In patients with high or severe anxious avoidance, maximum cost-effective prices rose to £877 and £3073 per patient from an NHS and personal social services perspective and societal perspective, respectively.Conclusions:gameChange is a promising, cost-effective intervention for the UK NHS and is particularly valuable for patients with high or severe anxious avoidance. This presents an opportunity to expand cost-effective psychological treatment coverage for a population with significant health needs.Trial Registration:ISRCTN Registry ISRCTN17308399; https://www.isrctn.com/ISRCTN1730839

Study protocol for an adaptive, multi-arm, multi-stage (MAMS) randomised controlled trial of brief remotely delivered psychosocial interventions for people with serious mental health problems who have experienced a recent suicidal crisis: Remote Approaches to Psychosocial Intervention Delivery (RAPID)

Background: People with serious mental health problems (SMHP) are more likely to be admitted to psychiatric hospital following contact with crisis services. Admissions can have significant personal costs, be traumatic and are the most expensive form of mental health care. There is an urgent need for treatments to reduce suicidal thoughts and behaviours and reduce avoidable psychiatric admissions. Methods: A multi-stage, multi-arm (MAMS) randomised controlled trial (RCT) with four arms conducted over two stages to determine the clinical and cost effectiveness of three psychosocial treatments, compared to treatment as usual (TAU), for people with SMHP who have had recent suicidal crisis. Primary outcome is any psychiatric hospital admissions over a 6-month period. We will assess the impact on suicidal thoughts and behaviour, hope, recovery, anxiety and depression. The remote treatments delivered over 3 months are structured peer support (PREVAIL); a safety planning approach (SAFETEL) delivered by assistant psychologists; and a CBT-based suicide prevention app accessed via a smartphone (BrighterSide). Recruitment is at five UK sites. Stage 1 includes an internal pilot with a priori progression criteria. In stage 1, the randomisation ratio was 1:1:1:2 in favour of TAU. This has been amended to 2:2:3 in favour of TAU following an unplanned change to remove the BrighterSide arm following the release of efficacy data from an independent RCT. Randomisation is via an independent remote web-based randomisation system using randomly permuted blocks, stratified by site. An interim analysis will be performed using data from the first 385 participants from PREVAIL, SAFETEL and TAU with outcome data at 6 months. If one arm is dropped for lack of benefit in stage 2, the allocation ratio of future participants will be 1:1. The expected total sample size is 1064 participants (1118 inclusive of BrighterSide participants). Discussion: There is a need for evidence-based interventions to reduce psychiatric admissions, via reduction of suicidality. Our focus on remote delivery of established brief psychosocial interventions, utilisation of different modalities of delivery that can provide sustainable and scalable solutions, which are also suitable for a pandemic or national crisis context, will significantly advance treatment options

A safe place to learn: a peer research qualitative investigation of automated virtual reality cognitive therapy (gameChange)

Background Automated virtual reality (VR) therapy has the potential to increase access to evidence-based psychological treatments substantially. The results of a multi-centre randomised controlled trial show that gameChange VR cognitive therapy reduces the agoraphobic avoidance of people diagnosed with psychosis, especially for those with severe avoidance. Objective We set out to use a peer research approach to explore the participant experience of gameChange VR therapy. This in-depth experiential exploration of the user experience may inform implementation in clinical services and future VR therapy development. Method Peer-led semi-structured remote interviews were conducted with twenty people with a diagnosis of psychosis who had received gameChange as part of the clinical trial (ISRCTN17308399). Data were analysed using Interpretative Phenomenological Analysis and Template Analysis. A multi-perspectival approach was taken to explore subgroups. Credibility checks were conducted with the study Lived Experience Advisory Panel. Results Participants reported the significant impact before the VR intervention of anxious avoidance on their lives, leaving some housebound and isolated. Those who were struggling the most with agoraphobic avoidance expressed the most appreciation for and gains from the gameChange therapy. The VR scenarios provided ‘a place to practise’. Immersion within the VR scenarios triggered anxiety, yet participants were able to observe this and respond in different ways to usual. The ‘security of knowing the VR scenarios are not real’ created a safe place to learn about fears. The ‘balance of safety and anxiety’ could be calibrated to the individual. The new learning made in VR was ‘taken into the real world’ through practise and distilling key messages, with support from the delivery staff member. Conclusion Automated VR can provide a therapeutic simulation that allows people diagnosed with psychosis to learn and embed new ways of responding to the situations that challenge them. An important process in anxiety reduction is enabling presentation of stimuli that induces the original anxious fears yet allows learning of safety. In gameChange the interaction of anxiety and safety could be calibrated to provide a safe place to learn about fears and build confidence. This navigation of therapeutic learning can be successfully managed by patients themselves in an automated therapy, with staff support, that provides users with personalized control. The clinical improvements for people with severe anxious avoidance, the positive experience of VR, and maintenance of the sense of control are likely to facilitate implementation.</p