Virtual Reality-Assisted Therapy Compared to Cognitive Behavioral Therapy for Patients With Treatment-Resistant Schizophrenia: Assessor-Blind Randomized Controlled Trial.

BACKGROUND: Auditory verbal hallucinations (AVH) are among the most disabling symptoms of schizophrenia and often persist despite treatment. Virtual reality-assisted therapies (VRTs) are a new generation of relational interventions for AVH, but comparative evidence against active interventions is currently lacking. OBJECTIVE: This study aimed to assess whether VRT (9 sessions) is superior to a short course of cognitive behavioral therapy (CBT) targeting AVH (9 sessions) in reducing AVH in individuals with treatment-resistant schizophrenia. METHODS: In this assessor-blind, parallel-group randomized controlled trial conducted from 2019 to 2026 at an academic center in Montreal (Canada), adults with schizophrenia or schizoaffective disorder and persistent AVH were either referred by their health care team or self-referred. A total of 136 participants were randomly assigned 1:1 to VRT or CBT, stratified by sex and clozapine use status. Both 9-session interventions targeted maladaptive beliefs and relationships with voices and were administered by trained psychotherapists. The predetermined primary outcome was the evolution of AVH severity over time, measured at baseline, post treatment, and 3 months post therapy using the auditory hallucination subscale of the Psychotic Symptoms Rating Scale. Secondary outcomes notably included the general psychotic symptomatology measured using the Positive and Negative Syndrome Scale. Linear mixed-effects models were used to assess time-by-treatment interactions. Psychotherapy sessions and assessments were conducted primarily in person, with CBT being occasionally delivered via videoconferencing during the COVID-19 pandemic. RESULTS: Participants had a mean age of 40.3 (SD 12.8) years, 63.2% (86/136) were male, and 56.6% (77/136) received clozapine. Intention-to-treat analyses (VRT, n=67; CBT, n=69) showed a significant time-by-treatment interaction favoring VRT (P=.013) with a moderate effect size at 3 months post therapy (Cohen d=0.614). Both therapies showed significant within-group improvements in the primary outcome, with large effect sizes for VRT (Cohen d=0.81 post therapy and Cohen d=1.17 at 3 months) and moderate for CBT (Cohen d=0.58 post therapy and Cohen d=0.39 at 3 months). While there were no between-group differences for secondary outcomes, within-group improvements were observed in psychotic symptoms, emotional regulation, and voice acceptance for both therapies, and VRT also reduced maladaptive beliefs about voices and improved self-esteem. CONCLUSIONS: VRT outperformed a targeted short course of CBT in reducing persistent AVH for up to 3 months after the intervention in a North American population with treatment-resistant schizophrenia. Improvements were also seen in some secondary outcomes, such as general psychotic symptomatology, and those were similar for both interventions. Overall, these findings support the value of VRT as a personalized and clinically effective intervention.