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

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. 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. 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). 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. Medical Research Council Developmental Pathway Funding Scheme and National Institute for Health and Care Research Oxford Health Biomedical Research Centre.

Freeman D ，Lister R ，Waite F ，Galal U ，Yu LM ，Lambe S ，Beckley A ，Bold E ，Jenner L ，Diamond R ，Kirkham M ，Twivy E ，Causier C ，Carr L ，Saidel S ，Day R ，Beacco A ，Rovira A ，Ivins A ，Nah R ，Slater M ，Clark DM ，Rosebrock L ... -  《Lancet Psychiatry》

Comparison of a theoretically driven cognitive therapy (the Feeling Safe Programme) with befriending for the treatment of persistent persecutory delusions: a parallel, single-blind, randomised controlled trial.

There is a large clinical need for improved treatments for patients with persecutory delusions. We aimed to test whether a new theoretically driven cognitive therapy (the Feeling Safe Programme) would lead to large reductions in persecutory delusions, above non-specific effects of therapy. We also aimed to test treatment effect mechanisms. We did a parallel, single-blind, randomised controlled trial to test the Feeling Safe Programme against befriending with the same therapists for patients with persistent persecutory delusions in the context of non-affective psychosis diagnoses. Usual care continued throughout the duration of the trial. The trial took place in community mental health services in three UK National Health Service trusts. Participants were included if they were 16 years or older, had persecutory delusions (as defined by Freeman and Garety) for at least 3 months and held with at least 60% conviction, and had a primary diagnosis of non-affective psychosis from the referring clinical team. Patients were randomly assigned to either the Feeling Safe Programme or the befriending programme, using a permuted blocks algorithm with randomly varying block size, stratified by therapist. Trial assessors were masked to group allocation. If an allocation was unmasked then the unmasked assessor was replaced with a new masked assessor. Outcomes were assessed at 0 months, 6 months (primary endpoint), and 12 months. The primary outcome was persecutory delusion conviction, assessed within the Psychotic Symptoms Rating Scale (PSYRATS; rated 0-100%). Outcome analyses were done in the intention-to-treat population. Each intervention was provided individually over 6 months. This trial is registered with the ISRCTN registry, ISRCTN18705064. From Feb 8, 2016, to July 26, 2019, 130 patients with persecutory delusions (78 [60%] men; 52 [40%] women, mean age 42 years [SD 12·1, range 17-71]; 86% White, 9% Black, 2% Indian; 2·3% Pakistani; 2% other) were recruited. 64 patients were randomly allocated to the Feeling Safe Programme and 66 patients to befriending. Compared with befriending, the Feeling Safe Programme led to significant end of treatment reductions in delusional conviction (-10·69 [95% CI -19·75 to -1·63], p=0·021, Cohen's d=-0·86) and delusion severity (PSYRATS, -2·94 [-4·58 to -1·31], p<0·0001, Cohen's d=-1·20). More adverse events occurred in the befriending group (68 unrelated adverse events reported in 20 [30%] participants) compared with the Feeling Safe group (53 unrelated adverse events reported in 16 [25%] participants). The Feeling Safe Programme led to a significant reduction in persistent persecutory delusions compared with befriending. To our knowledge, these are the largest treatment effects seen for patients with persistent delusions. The principal limitation of our trial was the relatively small sample size when comparing two active treatments, meaning less precision in effect size estimates and lower power to detect moderate treatment differences in secondary outcomes. Further research could be done to determine whether greater effects could be possible by reducing the hypothesised delusion maintenance mechanisms further. The Feeling Safe Programme could become the recommended psychological treatment in clinical services for persecutory delusions. NIHR Research Professorship and NIHR Oxford Health Biomedical Research Centre.

Freeman D ，Emsley R ，Diamond R ，Collett N ，Bold E ，Chadwick E ，Isham L ，Bird JC ，Edwards D ，Kingdon D ，Fitzpatrick R ，Kabir T ，Waite F ，Oxford Cognitive Approaches to Psychosis Trial Study Group ... -  《Lancet Psychiatry》

Automated virtual reality therapy to treat agoraphobic avoidance and distress in patients with psychosis (gameChange): a multicentre, parallel-group, single-blind, randomised, controlled trial in England with mediation and moderation analyses.

Automated delivery of psychological therapy using immersive technologies such as virtual reality (VR) might greatly increase the availability of effective help for patients. We aimed to evaluate the efficacy of an automated VR cognitive therapy (gameChange) to treat avoidance and distress in patients with psychosis, and to analyse how and in whom it might work. We did a parallel-group, single-blind, randomised, controlled trial across nine National Health Service trusts in England. Eligible patients were aged 16 years or older, with a clinical diagnosis of a schizophrenia spectrum disorder or an affective diagnosis with psychotic symptoms, and had self-reported difficulties going outside due to anxiety. Patients were randomly assigned (1:1) to either gameChange VR therapy plus usual care or usual care alone, using a permuted blocks algorithm with randomly varying block size, stratified by study site and service type. gameChange VR therapy was provided in approximately six sessions over 6 weeks. Trial assessors were masked to group allocation. Outcomes were assessed at 0, 6 (primary endpoint), and 26 weeks after randomisation. The primary outcome was avoidance of, and distress in, everyday situations, assessed using the self-reported Oxford Agoraphobic Avoidance Scale (O-AS). Outcome analyses were done in the intention-to-treat population (ie, all participants who were assigned to a study group for whom data were available). We performed planned mediation and moderation analyses to test the effects of gameChange VR therapy when added to usual care. This trial is registered with the ISRCTN registry, 17308399. Between July 25, 2019, and May 7, 2021 (with a pause in recruitment from March 16, 2020, to Sept 14, 2020, due to COVID-19 pandemic restrictions), 551 patients were assessed for eligibility and 346 were enrolled. 231 (67%) patients were men and 111 (32%) were women, 294 (85%) were White, and the mean age was 37·2 years (SD 12·5). 174 patients were randomly assigned to the gameChange VR therapy group and 172 to the usual care alone group. Compared with the usual care alone group, the gameChange VR therapy group had significant reductions in agoraphobic avoidance (O-AS adjusted mean difference -0·47, 95% CI -0·88 to -0·06; n=320; Cohen's d -0·18; p=0·026) and distress (-4·33, -7·78 to -0·87; n=322; -0·26; p=0·014) at 6 weeks. Reductions in threat cognitions and within-situation defence behaviours mediated treatment outcomes. The greater the severity of anxious fears and avoidance, the greater the treatment benefits. There was no significant difference in the occurrence of serious adverse events between the gameChange VR therapy group (12 events in nine patients) and the usual care alone group (eight events in seven patients; p=0·37). Automated VR therapy led to significant reductions in anxious avoidance of, and distress in, everyday situations compared with usual care alone. The mediation analysis indicated that the VR therapy worked in accordance with the cognitive model by reducing anxious thoughts and associated protective behaviours. The moderation analysis indicated that the VR therapy particularly benefited patients with severe agoraphobic avoidance, such as not being able to leave the home unaccompanied. gameChange VR therapy has the potential to increase the provision of effective psychological therapy for psychosis, particularly for patients who find it difficult to leave their home, visit local amenities, or use public transport. National Institute of Health Research Invention for Innovation programme, National Institute of Health Research Oxford Health Biomedical Research Centre.

Freeman D ，Lambe S ，Kabir T ，Petit A ，Rosebrock L ，Yu LM ，Dudley R ，Chapman K ，Morrison A ，O'Regan E ，Aynsworth C ，Jones J ，Murphy E ，Powling R ，Galal U ，Grabey J ，Rovira A ，Martin J ，Hollis C ，Clark DM ，Waite F ，gameChange Trial Group ... -  《Lancet Psychiatry》

Automated psychological therapy using virtual reality (VR) for patients with persecutory delusions: study protocol for a single-blind parallel-group randomised controlled trial (THRIVE).

Freeman D ，Lister R ，Waite F ，Yu LM ，Slater M ，Dunn G ，Clark D ... -  《Trials》

Effects of cognitive behaviour therapy for worry on persecutory delusions in patients with psychosis (WIT): a parallel, single-blind, randomised controlled trial with a mediation analysis.

Worry might be a contributory causal factor in the occurrence of persecutory delusions in patients with psychotic disorders. Therefore we postulated that reducing worry with cognitive behaviour therapy (CBT) would reduce persecutory delusions. For our two-arm, assessor-blinded, randomised controlled trial (Worry Intervention Trial [WIT]), we recruited patients aged 18-65 years with persistent persecutory delusions but non-affective psychosis from two centres: the Oxford Health National Health Service (NHS) Foundation Trust (Oxford, UK) and the Southern Health NHS Foundation Trust (Southampton, UK). The key inclusion criteria for participants were a score of at least 3 on the Psychotic Symptoms Rating Scale (PSYRATS) denoting a current persecutory delusion; that the delusion had persisted for at least 3 months; a clinical diagnosis of schizophrenia, schizoaffective disorder, or delusional disorder; and a clinically significant level of worry. We randomly assigned (1:1) eligible patients, using a randomly permuted block procedure with variable block sizes and division by four strata, to either six sessions of worry-reduction CBT intervention done over 8 weeks added to standard care (the CBT-intervention group), or to standard care alone (the control group). The assessors were masked to patient allocations and did their assessments at week 0 (baseline), 8 weeks (end of treatment), and 24 weeks, follow-up. The primary outcomes were worry measured by the Penn State Worry Questionnaire (PSWQ) and delusions measured by the PSYRATS-delusion scale; we did the analyses in the intention-to-treat population, and also did a planned mediation analysis. This trial is registered with the ISRCTN Registry (number ISRCTN23197625) and is closed to new participants. From Nov 1, 2011, to Sept 9, 2013, we recruited 150 eligible participants and randomly assigned 73 to the CBT intervention group, and 77 to the control group. 143 patients (95%) provided primary outcome follow-up data. Compared with standard care alone, at 8 weeks the CBT intervention significantly reduced worry (mean difference 6·35 [SE 1·56] PSWQ units, 95% CI 3·30-9·40; p<0·001) and persecutory delusions (2·08 [SE 0·73] PSYRATS units, 95% CI 0·64-3·51; p=0·005). The reductions were maintained to 24 weeks follow-up. The mediation analysis suggested that the change in worry accounted for 66% of the change in delusion. No patients died or were admitted to secure units during our study. Six suicide attempts (two in the CBT intervention group, and four in the control group) and two serious violent incidents (one in each group) were noted, but no adverse events were deemed related to the treatments or the assessments. To our knowledge, this is the first large trial focused on persecutory delusions. We have shown that long-standing delusions were significantly reduced by a brief intervention targeted on worry, although the limitations for our study include no determination of the key elements within the intervention. Our results suggest that worry might cause paranoia, and that worry intervention techniques might be a beneficial addition to the standard treatment of psychosis. Efficacy and Mechanism Evaluation programme, which is a UK Medical Research Council and National Institute of Health Research partnership.

Freeman D ，Dunn G ，Startup H ，Pugh K ，Cordwell J ，Mander H ，Černis E ，Wingham G ，Shirvell K ，Kingdon D ... -  《Lancet Psychiatry》