Cost-Effectiveness of Virtual Reality Cognitive Behavioral Therapy for Psychosis: Health-Economic Evaluation Within a Randomized Controlled Trial.

BACKGROUND: Evidence was found for the effectiveness of virtual reality-based cognitive behavioral therapy (VR-CBT) for treating paranoia in psychosis, but health-economic evaluations are lacking. OBJECTIVE: This study aimed to determine the short-term cost-effectiveness of VR-CBT. METHODS: The health-economic evaluation was embedded in a randomized controlled trial evaluating VR-CBT in 116 patients with a psychotic disorder suffering from paranoid ideation. The control group (n=58) received treatment as usual (TAU) for psychotic disorders in accordance with the clinical guidelines. The experimental group (n=58) received TAU complemented with add-on VR-CBT to reduce paranoid ideation and social avoidance. Data were collected at baseline and at 3 and 6 months postbaseline. Treatment response was defined as a pre-post improvement of symptoms of at least 20% in social participation measures. Change in quality-adjusted life years (QALYs) was estimated by using Sanderson et al's conversion factor to map a change in the standardized mean difference of Green's Paranoid Thoughts Scale score on a corresponding change in utility. The incremental cost-effectiveness ratios were calculated using 5000 bootstraps of seemingly unrelated regression equations of costs and effects. The cost-effectiveness acceptability curves were graphed for the costs per treatment responder gained and per QALY gained. RESULTS: The average mean incremental costs for a treatment responder on social participation ranged between €8079 and €19,525, with 90.74%-99.74% showing improvement. The average incremental cost per QALY was €48,868 over the 6 months of follow-up, with 99.98% showing improved QALYs. Sensitivity analyses show costs to be lower when relevant baseline differences were included in the analysis. Average costs per treatment responder now ranged between €6800 and €16,597, while the average cost per QALY gained was €42,030. CONCLUSIONS: This study demonstrates that offering VR-CBT to patients with paranoid delusions is an economically viable approach toward improving patients' health in a cost-effective manner. Long-term effects need further research. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) 12929657; http://www.isrctn.com/ISRCTN12929657.

Daily-life stress reactivity and recovery following virtual-reality-based cognitive behavioral therapy in patients with a psychotic disorder.

Introduction: Studies have consistently demonstrated increased stress sensitivity in individuals with psychosis. Since stress sensitivity may play a role in the onset and maintenance of psychosis, this could potentially be a promising target for treatment. The current study was the first to investigate whether reactivity to and recovery from daily-life stressors in psychosis change in response to treatment, namely virtual-reality-based cognitive behavioral therapy (VR-CBT). Methods: 116 patients were randomized to either VR-CBT or the waiting list control group (WL). Pre-treatment and post-treatment participants completed a diary ten times a day during six to ten days. Multilevel analyses were used to model the time-lagged effects of daily stressful events on negative affect (NA) and paranoia symptoms to examine reactivity and recovery. Results: There was a significant difference in NA reactivity. VR-CBT showed higher NA at post-treatment compared to pre-treatment than WL (bpre=0.14; bpost=0.19 vs bpre=0.18; bpost=0.14). There was a significant difference in NA recovery and paranoia recovery between the groups at lag 1: VR-CBT showed relatively lower negative affect (bpre=0.07; bpost=-0.06) and paranoia (bpre= 0.08; bpost=-0.10) at post-treatment compared to pre-treatment than WL (bpre=0.08; bpost=0.08; bpre=0.04; bpost=0.03). Conclusion: Negative affect and paranoia recovery improved in response to treatment. Increased NA reactivity may be explained by a decrease in safety behavior in the VR-CBT group. The discrepancy between reactivity and recovery findings may be explained by the inhibitory learning theory that suggests that an original threat reaction may not erase but can be inhibited as a consequence of exposure therapy.

Digital technology for addressing cognitive impairment in recent-onset psychosis: A perspective.

Cognitive impairments in psychosis negatively impact functional recovery and quality of life. Existing interventions for improving cognitive impairment in recent-onset psychosis show inconsistent treatment efficacy, small effects, suboptimal engagement and limited generalizability to daily life functioning. In this perspective we explore how digital technology has the potential to address these limitations in order to improve cognitive and functional outcomes in recent-onset psychosis. Computer programs can be used for standardized, automated delivery of cognitive remediation training. Virtual reality provides the opportunity for learning and practicing cognitive skills in real-world scenarios within a virtual environment. Smartphone apps could be used for notification reminders for everyday tasks to compensate for cognitive difficulties. Internet-based technologies can offer psychoeducation and training materials for enhancing cognitive skills. Early findings indicate some forms of digital interventions for cognitive enhancement can be effective, with well-established evidence for human-supported computer-based cognitive remediation in recent-onset psychosis. Emerging evidence regarding virtual reality is favorable for improving social cognition. Overall, blending digital interventions with human support improves engagement and effectiveness. Despite the potential of digital interventions for enhancing cognition in recent-onset psychosis, few studies have been conducted to date. Implementation challenges affecting application of digital technologies for cognitive impairment in recent-onset psychosis are sustained engagement, clinical integration, and lack of quality in the commercial marketplace. Future opportunities lie in including motivational frameworks and behavioral change interventions, increasing service engagement in young people and lived experience involvement in digital intervention development.

Advances in immersive virtual reality interventions for mental disorders: A new reality?

Immersive virtual reality (VR) has been identified as a potentially revolutionary tool for psychological interventions. This study reviews current advances in immersive VR-based therapies for mental disorders. VR has the potential to make psychiatric treatments better and more cost-effective and to make them available to a larger group of patients. However, this may require a new generation of VR therapeutic techniques that use the full potential of VR, such as embodiment, and self-led interventions. VR-based interventions are promising, but further well-designed studies are needed that use novel techniques and investigate efficacy, efficiency, and cost-effectiveness of VR interventions compared with current treatments. This will be crucial for implementation and dissemination of VR in regular clinical practice.

Virtual reality based cognitive behavioral therapy for paranoia: Effects on mental states and the dynamics among them.

BACKGROUND: Negative affective processes may contribute to maintenance of paranoia in patients with psychosis, and vice versa. Successful treatment may break these pathological symptom networks. This study examined whether treatment with virtual reality based cognitive behavioral therapy (VR-CBT) for paranoia influences momentary affective states, and whether VR-CBT changes the adverse interplay between affective states and paranoia. METHODS: Patients with a psychotic disorder (n = 91) were randomized to 16-session VR-CBT or treatment as usual (TAU). With the experience sampling method (structured diary technique) mental states were assessed for 6-10 days at baseline, posttreatment and 6-month follow-up. Multilevel analysis were performed to establish treatment effects and time-lagged associations between mental states, that were visualized with networks of mental states. RESULTS: Average levels of paranoia (feeling suspicious [b = -032., p = .04], disliked [b = -49., p < .01] and hurt [b = -0.52, p < .01]) and negative affect (anxious [b = -0.37, p = .01], down [b = -0.33, p = .04] and insecure [b = -0.17, p = .03) improved more after VR-CBT than TAU, but positive affect did not. Baseline mental state networks had few significant connections, with most stable connections being autocorrelations of mental states. The interplay between affective states and paranoia did not change in response to treatment. A trend reduction in average intranode connections (autocorrelations) was found after VR-CBT (b = -0.07, p = .08), indicating that mental states reinforce themselves less after treatment. CONCLUSIONS: VR-CBT reduced paranoid symptoms and lowered levels of negative affect in daily life, but did not affect the extent to which mental states influenced each other. Findings do suggest that as a result of treatment mental states regain flexibility.

Inflammatory cytokines and growth factors were not associated with psychosis liability or childhood trauma.

Psychosis is a multifactorial condition arising from an interaction between genetic liability and exposure to environmental risk factors, in particular childhood trauma. Furthermore, accumulating evidence supports a role for the immune system in the aetiology of psychosis. Increased peripheral levels of pro-inflammatory cytokines and reduced neurotrophic factors are found in patients with psychosis. Childhood trauma is highly prevalent in psychosis patients and is also associated with increased pro-inflammatory cytokines and reduced neurotrophic factors. Recent studies suggest the increase in pro-inflammatory cytokines and decrease in neurotrophic factors seen in psychosis may be attributable to the effects of child maltreatment. The aim of this study was to improve understanding of the relation between childhood trauma, inflammation and psychosis. We examined separate and interaction effects of psychosis liability and childhood trauma on serum levels of BDNF, CCL-2, CRP, IFN-γ, IGFBP2, IL-6, PDGF, SCF and TNF-α in 40 patients with recent onset psychosis, 13 patients at Ultra-High Risk (UHR) for psychosis, 31 unaffected siblings of psychosis patients and 41 healthy controls. Childhood trauma was assessed retrospectively with the Childhood Trauma Questionnaire (CTQ). No statistically significant effects of psychosis liability or childhood trauma on concentrations of cytokines or growth factors in peripheral blood were found, nor were there any statistically significant interaction effects of psychosis liability with childhood trauma on serum levels of cytokines and growth factors.

Self-reported Cognitive Biases Moderate the Associations Between Social Stress and Paranoid Ideation in a Virtual Reality Experimental Study.

Introduction: Cognitive biases are associated with psychosis liability and paranoid ideation. This study investigated the moderating relationship between pre-existing self-reported cognitive biases and the occurrence of paranoid ideation in response to different levels of social stress in a virtual reality environment. Methods: This study included 170 participants with different levels of psychosis liability (55 recent onset psychosis, 20 ultrahigh risk for psychosis, 42 siblings of psychotic patients, and 53 controls). All participants were exposed to virtual environments with different levels of social stress. The level of experienced paranoia in the virtual environments was measured with the State Social Paranoia Scale. Cognitive biases were assessed with a self-report continuous measure. Also, cumulative number of cognitive biases was calculated using dichotomous measures of the separate biases, based on general population norm scores. Results: Higher belief inflexibility bias (Z = 2.83, P < .001), attention to threat bias (Z = 3.40, P < .001), external attribution bias (Z = 2.60, P < .001), and data-gathering bias (Z = 2.07, P < .05) were all positively associated with reported paranoid ideation in the social virtual environments. Level of paranoid response increased with number of cognitive biases present (B = 1.73, P < .001). The effect of environmental stressors on paranoid ideation was moderated by attention to threat bias (Z = 2.78, P < .01) and external attribution bias (Z = 2.75, P < .01), whereas data-gathering bias and belief inflexibility did not moderate the relationship. Conclusion: There is an additive effect of separate cognitive biases on paranoid response to social stress. The effect of social environmental stressors on paranoid ideation is further enhanced by attention to threat bias and external attribution bias.

Self-esteem moderates affective and psychotic responses to social stress in psychosis: A virtual reality study.

BACKGROUND: Higher liability to psychosis is associated with low self-esteem and increased sensitivity to social stress. Recently, we reported a positive relation between liability to psychosis and affective and psychotic responses to social stress. This study investigated how self-esteem moderates paranoia, peak subjective distress and stress reactivity of people with different psychosis liability in response to social stressors in virtual reality. METHODS: Ninety-four individuals with lower (41 siblings and 53 controls) and 75 persons with higher psychosis liability (55 with recent onset psychotic disorder and 20 at ultra-high risk for psychosis) explored five times a virtual café with various social stressors (crowdedness, ethnic minority status, and hostility). They rated momentary paranoia (State Social Paranoia Scale) after each experiment and subjective distress on a visual analogue scale before and after the experiments. Positive and negative self-esteem were assessed with the Self-Esteem Rating Scale. RESULTS: Momentary paranoia, peak subjective distress, and reactivity to social stressors were associated with negative self-esteem, but not positive self-esteem. Effects of both positive and negative self-esteem on psychotic and affective stress responses, but not stress reactivity, became significantly stronger when individuals were exposed to more stressful environments. Effects of self-esteem on momentary paranoia and peak subjective distress did not differ between the high liability and low liability group. Persons with lower psychosis liability had a stronger effect of negative self-esteem on stress reactivity than persons with higher liability. CONCLUSIONS: Positive and negative self-esteem may play an important role in affective and psychotic responses to social stress.

Anxiety Partially Mediates Cybersickness Symptoms in Immersive Virtual Reality Environments.

The use of virtual reality (VR) in psychological treatment is expected to increase. Cybersickness (CS) is a negative side effect of VR exposure and is associated with treatment dropout. This study aimed to investigate the following: (a) if gender differences in CS can be replicated, (b) if differences in anxiety and CS symptoms between patients and controls can be replicated, and (c) whether the relationship between exposure to VR and CS symptoms is mediated by anxiety. A sample (N = 170) of participants with different levels of psychosis liability was exposed to VR environments. CS and anxiety were assessed with self-report measures before and after the VR experiment. This study replicated gender differences in CS symptoms, most of which were present before exposure to VR. It also replicated findings that a significant correlation between anxiety and CS can be found in healthy individuals, but not in patients. In a VR environment, anxiety partially mediated CS symptoms, specifically nausea and disorientation. A partial explanation for the differences found between patients and controls may lie in a ceiling effect for the symptoms of CS. A second explanation may be the partial overlap between CS symptoms and physiological anxiety responses. CS symptoms reported at baseline cannot be explained by exposure to VR, but are related to anxiety. Caution is required when interpreting studies on both CS and anxiety, until the specificity in measurements has been improved. Since anxiety mediated the CS symptoms, CS is expected to decline during treatment together with the reduction of anxiety.

Social environments and interpersonal distance regulation in psychosis: A virtual reality study.

BACKGROUND: Experimentally studying the influence of social environments on mental health and behavior is challenging, as social context is difficult to standardize in laboratory settings. Virtual Reality (VR) enables studying social interaction in terms of interpersonal distance in a more ecologically valid manner. Regulation of interpersonal distance may be abnormal in patients with psychotic disorders and influenced by environmental stress, symptoms or distress. AIMS: To investigate interpersonal distance in people with a psychotic disorder and at ultrahigh risk for psychosis (UHR) compared to siblings and controls in virtual social environments, and explore the relationship between clinical characteristics and interpersonal distance. METHODS: Nineteen UHR patients, 52 patients with psychotic disorders, 40 siblings of patients with a psychotic disorder and 47 controls were exposed to virtual cafés. In five virtual café visits, participants were exposed to different levels of social stress, in terms of crowdedness, ethnicity and hostility. Measures on interpersonal distance, distress and state paranoia were obtained. Baseline measures included trait paranoia, social anxiety, depressive, positive and negative symptoms. RESULTS: Interpersonal distance increased when social stressors were present in the environment. No difference in interpersonal distance regulation was found between the groups. Social anxiety and distress were positively associated with interpersonal distance in the total sample. CONCLUSION: This VR paradigm indicates that interpersonal distance regulation in response to environmental social stressors is unaltered in people with psychosis or UHR. Environmental stress, social anxiety and distress trigger both people with and without psychosis to maintain larger interpersonal distances in social situations.

Virtual-reality-based cognitive behavioural therapy versus waiting list control for paranoid ideation and social avoidance in patients with psychotic disorders: a single-blind randomised controlled trial.

BACKGROUND: Many patients with psychotic disorders have persistent paranoid ideation and avoid social situations because of suspiciousness and anxiety. We investigated the effects of virtual-reality-based cognitive behavioural therapy (VR-CBT) on paranoid thoughts and social participation. METHODS: In this randomised controlled trial at seven Dutch mental health centres, outpatients aged 18-65 years with a DSM-IV-diagnosed psychotic disorder and paranoid ideation in the past month were randomly assigned (1:1) via block randomisation to VR-CBT (in addition to treatment as usual) or the waiting list control group (treatment as usual). VR-CBT consisted of 16 individual therapy sessions (each 1 h long). Assessments were done at baseline, after treatment (ie, 3 months from baseline), and at a 6 month follow-up visit. The primary outcome was social participation, which we operationalised as the amount of time spent with other people, momentary paranoia, perceived social threat, and momentary anxiety. Analysis was by intention to treat. This trial was retrospectively registered with ISRCTN, number 12929657. FINDINGS: Between April 1, 2014, and Dec 31, 2015, 116 patients with a psychotic disorder were randomly assigned, 58 to the VR-CBT group and 58 to the waiting list control group. Compared with the control, VR-CBT did not significantly increase the amount of time spent with other people at the post-treatment assessment. Momentary paranoid ideation (b=-0·331 [95% CI -0·432 to -0·230], p<0·0001; effect size -1·49) and momentary anxiety (-0·288 [-0·438 to -0·1394]; p=0·0002; -0·75) were significantly reduced in the VR-CBT group compared with the control group at the post-treatment assessment, and these improvements were maintained at the follow-up assessment. Safety behaviour and social cognition problems were mediators of change in paranoid ideation. No adverse events were reported relating to the therapy or assessments. INTERPRETATION: Our results suggest that the addition of VR-CBT to standard treatment can reduce paranoid ideation and momentary anxiety in patients with a psychotic disorder. FUNDING: Fonds NutsOhra, Stichting tot Steun VCVGZ.

High psychosis liability is associated with altered autonomic balance during exposure to Virtual Reality social stressors.

BACKGROUND: Social stressors are associated with an increased risk of psychosis. Stress sensitisation is thought to be an underlying mechanism and may be reflected in an altered autonomic stress response. Using an experimental Virtual Reality design, the autonomic stress response to social stressors was examined in participants with different liability to psychosis. METHOD: Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra-high risk for psychosis, 42 siblings of patients with psychosis and 53 controls were exposed to social stressors (crowdedness, ethnic minority status and hostility) in a Virtual Reality environment. Heart rate variability parameters and skin conductance levels were measured at baseline and during Virtual Reality experiments. RESULTS: High psychosis liability groups had significantly increased heart rate and decreased heart rate variability compared to low liability groups both at baseline and during Virtual Reality experiments. Both low frequency (LF) and high frequency (HF) power were reduced, while the LF/HF ratio was similar between groups. The number of virtual social stressors significantly affected heart rate, HF, LF/HF and skin conductance level. There was no interaction between psychosis liability and amount of virtual social stress. CONCLUSION: High liability to psychosis is associated with decreased parasympathetic activity in virtual social environments, which reflects generally high levels of arousal, rather than increased autonomic reactivity to social stressors.

Effect of virtual reality exposure therapy on social participation in people with a psychotic disorder (VRETp): study protocol for a randomized controlled trial.

BACKGROUND: Many patients with a psychotic disorder participate poorly in society. When psychotic disorders are in partial remission, feelings of paranoia, delusions of reference, social anxiety and self-stigmatization often remain at diminished severity and may lead to avoidance of places and people. Virtual reality exposure therapy (VRET) is an evidence-based treatment for several anxiety disorders. For patients with a psychotic disorder, the VRETp was developed to help them experience exposure to feared social situations. The present study aims to investigate the effects of VRETp on social participation in real life among patients with a psychotic disorder. METHODS/DESIGN: The study is a single-blind randomized controlled trial with two conditions: the active condition, in which participants receive the virtual reality treatment together with treatment as usual (TAU), and the waiting list condition, in which participants receive TAU only. The two groups are compared at baseline, at 3 months posttreatment and at 6 months follow-up. All participants on the waiting list are also offered the virtual reality treatment after the follow-up measurements are completed. The primary outcome is social participation. Secondary outcomes are quality of life, interaction anxiety, depression and social functioning in general. Moderator and mediator analyses are conducted with stigma, cognitive schemata, cognitive biases, medication adherence, simulator sickness and presence in virtual reality. If effective, a cost-effectiveness analysis will be conducted. DISCUSSION: Results from the posttreatment measurement can be considered strong empirical indicators of the effectiveness of VRETp. The 6-month follow-up data may provide reliable documentation of the long-term effects of the treatment on the outcome variables. Data from pre-treatment and mid-treatment can be used to reveal possible pathways of change. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN12929657 . Date of registration: 8 September 2015.

Environmental Social Stress, Paranoia and Psychosis Liability: A Virtual Reality Study.

The impact of social environments on mental states is difficult to assess, limiting the understanding of which aspects of the social environment contribute to the onset of psychotic symptoms and how individual characteristics moderate this outcome. This study aimed to test sensitivity to environmental social stress as a mechanism of psychosis using Virtual Reality (VR) experiments. Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra high risk for psychosis, 42 siblings of patients with psychosis, and 53 controls walked 5 times in a virtual bar with different levels of environmental social stress. Virtual social stressors were population density, ethnic density and hostility. Paranoia about virtual humans and subjective distress in response to virtual social stress exposures were measured with State Social Paranoia Scale (SSPS) and self-rated momentary subjective distress (SUD), respectively. Pre-existing (subclinical) symptoms were assessed with the Community Assessment of Psychic Experiences (CAPE), Green Paranoid Thoughts Scale (GPTS) and the Social Interaction Anxiety Scale (SIAS). Paranoia and subjective distress increased with degree of social stress in the environment. Psychosis liability and pre-existing symptoms, in particular negative affect, positively impacted the level of paranoia and distress in response to social stress. These results provide experimental evidence that heightened sensitivity to environmental social stress may play an important role in the onset and course of psychosis.