Outcomes of virtual reality technology in the management of generalised anxiety disorder: a systematic review and meta-analysis

ABSTRACT Introduction: Generalized anxiety disorder (GAD) is a chronic uncontrollable excessive anxiety towards a variety of topics. It is one of the most prevalent anxiety diseases, affecting approximately 6% worldwide. Virtual reality (VR) based interventions have received much attention from researchers for the management of mental health problems. This systematic review was conducted to assess the effects of immersive virtual reality techniques and non-immersive techniques in treating patients with GAD. Methods: An extensive systematic literature review was implemented, from inception up to 9 July 2021. Comparative clinical studies that assessed the outcomes of VRT in patients with GAD were included for meta-analysis. Single arm studies were included for systematic review only. Results: A total of six articles with 239 participants with GAD were included in systematic review. The mean age of the included participants ranged from 38.33 to 59.87 years. There was no statistically significant difference between VRT and control groups regarding the anxiety levels (SMD 0.01; 95%CI −0.52, 0.54; P = 0.97), mean depression scores (SMD 1.34; 95%CI −0.80, 3.49; P = 0.22), PSWQ (MD −4.26; 95%CI −10.93, 2.40; P = 0.21), and discomfort status (MD −1.41; 95%CI −3.86, 1.05; P = 0.22). Conclusions: VR improved relatively the manifestations of GAD, reflecting on the patient's quality of life. However, the existing evidence is inconclusive to support the superiority of VR as a substitute for traditional therapies.


Introduction
Anxiety is a normal feeling of fear, worry, apprehension, or nervousness in response to perceived or anticipating life threats.Anxiety disorders are characterised by overwhelming fear and worry that affect normal function (American Psychiatric Association, D. and A.P. Association 2013).Generalised anxiety disorder (GAD) is a chronic uncontrollable excessive anxiety towards a variety of topics.It is one of the most prevalent anxiety diseases, affecting approximately 6% worldwide (American Psychiatric Association, D. and A.P. Association 2013).GAD is more predominant in women and much more prevalent in young adults, accounting for 12% and 20%.Patients with GAD have trouble controlling worry feelings to the extent causing impairment in work and social settings (Wang et al. 2018).They tend to suffer from recurring intrusive thoughts, resulting in psychological and physical manifestations.These manifestations include irritability, fatigue, dizziness, sleep disturbances, restlessness, or muscle tension (Remes et al. 2016).GAD has multiple repercussions on the personal and societal aspects, negatively affecting patients' health-related quality of life.GAD leads to low social support, underemployment, underachievement, substance use and a higher risk of developing other psychological disturbances among youths.Furthermore, GAD had a significant economic burden on health care facilities, consuming considerable primary care resources (Roberge et al. 2015;Hunt, Issakidis, and Andrews 2002).The health costs per patient with GAD were 64% more costly than patients without GAD (Olfson and Gameroff 2007).
There are a lot of treatment modalities for GAD.This includes antidepressant medications, anticonvulsants and psychological therapies.These treatments offer various therapeutic options targeting beliefs around emotional disturbances and worry associated with GAD (Strawn et al. 2018;Barlow et al. 2017).The most promising therapies are cognitive treatment and relaxation therapy.The relaxation protocols positively impact anxiety reduction by accomplishing psychological benefits, including a sense of control over symptoms and distraction.However, high rates of drop-out during GAD treatment have been reported (Kim and Newman 2019;Hayes-Skelton et al. 2013).Cognitive-behavioural therapy (CBT) using exposure therapy, education, or cognitive restructuring is considered the traditional intervention for GAD (Revicki et al. 2012).However, access to CBT is limited due to insufficiently qualified therapists, incompatible scheduling, perceived stigma and long waiting lists (Comer and Barlow 2014).Digitally delivered cognitive therapy may mitigate these obstacles by delivering feasible and reliable services based on valid and effective cognitive interventions (Center, P. R. 2018;Stolz et al. 2018).
The emerging technologies are representing a substantial health interest.Virtual reality technology (VRT) is the most exciting technology that artificially creates a sensory experience, allowing the patients to manipulate their fears in the created virtual environment (Pasco 2013).VRT could facilitate relaxation status in anxious patients by visually presenting relaxing images.It can be provided using desktops or laptops connected to peripheral devices such as joysticks, head-mounted displays and different kinds of mobile devices.Compared to traditional relaxation methods, VRT can induce a sense of well-being and facilitate patient relaxation, allowing patients to experience a more authentic and vivid relaxation status (Anderson et al. 2013).This status triggers a broad empowerment process leading to a high sense of presence and desire for emotional status.The increased interest in VRT reflects recent innovations in commercial VRT headsets and mobile capabilities.These advancements allow more feasible and affordable employment of VRT in healthcare services (Hoffman, Patterson, and Carrougher 2000;Hoffman et al. 2003).Two types of VRT have existed, which included immersive and non-immersive techniques.Immersive VRT uses body-motion sensors, head-mounted displays, advanced interface devices and real-time graphics to stimulate a completely virtual environment.Non-impressive VRT uses screens and associated accessories to simulate the virtual environment (Morina et al. 2015;Didehbani et al. 2016).
The significant burden of GAD points out the importance of finding new strategies to treat it more efficiently.GAD requires fast dissemination of effective and reliable therapies to the targeted population.The short-term and long-term outcomes of VRT in the treatment of GAD are still doubtful in the literature (Gorini et al. 2010).Therefore, the current systematic review and meta-analysis was carried out to reveal the effectiveness of VRT in reducing anxiety in patients with GAD.Recognising such evidence could help neuropsychiatrists timely employ the most effective and feasible therapy for GAD.

Methods
This systematic review and meta-analysis was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines (Moher et al. 2009) and the recommendations of Cochrane collaboration (Collaboration, C. 2008) (Supplementary Table 1).The study's methodology was documented in a protocol that was registered at http://www.crd.york.ac.uk/prospero/ (Registration number; CRD42021266468).

Eligibility criteria
Comparative clinical studies that assessed the outcomes of VRT in patients with GAD were included in this meta-analysis.Single-arm studies were included for systematic review only.There was no restriction on the patients' sex, race, or place.Studies included patients with previous depression episodes or patients with mental disorders were ousted.In this respect, studies that did not report the outcomes of VRT for GAD were excluded.Furthermore, studies in which data were unattainable to be extracted, guidelines, review articles, non-human studies, case reports, comments, letters, editorials, posters and book chapters were excluded.

Study designs
The study included all comparative clinical studies such as observational studies, cross-sectional studies, retrospective studies, randomised clinical trial, s, quasiexperimental designs and cohort studies.

Participants
Adult patients with a confirmed diagnosis of GAD that received VRT were included.They have to be free of depression attacks or suffered from a previous depressive episode that required therapy.They also must be free of any mental disorder related to the current complaints of GAD.

Intervention
Virtual reality technology.

Comparators
There were no limits on comparator.

Outcomes
Studies reporting the outcomes of interest were included for systematic review and meta-analysis.These included sense of presence, anxiety levels and depression levels.
A manual search was performed, comprehending the references of all retrieved studies to distinguish all additional conceivable articles that were not indexed in the searched databases.The cross-referencing method was carried out until no other relevant article was detected.

Search selection
The title, abstract and full-text screening process was performed independently by two reviewers to disclose the potentially relevant articles that met the inclusion criteria.The discussion dissolved the contradiction between the reviewers.The screening process and the causes of article exclusion were documented using PRISMA Flowchart.

Data collection process and data items extracted
The data were extracted from the finally included articles.This includes study characteristics (the title of the included study, the second name of the first author, year of publication, study design, study period and study region), and patients' demographic characteristics (age, sex, marital status, and employment status).The baseline psychological assessment was extracted, including Beck's Depression Inventory version II (BDI-II), Hospital Anxiety and Depression Scale (HADS), General Anxiety Disorder-7 (GAD-7), Five Facet Mindfulness Questionnaire (FFMQ), The Multidimensional Assessment of Interoceptive Awareness (MAIA)).The data relating to post-intervention emotional state (Happiness, Sadness, anger, surprise, anxiety and relaxation), psychological scales (BDI-II, HADS, GAD-7, FFMQ, MAIA) and sense of presence were extracted.The data were extracted independently by two reviewers in a well-structured Microsoft excel spreadsheet.

Risk of bias and quality assessment in individual studies
The risk of bias of the included randomised clinical trials was evaluated based on the Cochrane Collaboration's tool for assessing the risk of bias.This tool is composed of seven items; random sequence generation, allocation concealment (selection bias), blinding of participants and personnel performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other possible causes of bias (Higgins et al. 2011).The quality of the observational studies was assessed using the National Institute of Health (NIH) quality assessment tool (National Heart, L. and B. Institute 2014).The studies were assorted, based on this quality assessment, into good, fair and bad when the score was <65%, 30-65% and >30%, respectively.If the parameter was controlled, the domain was considered 'Yes' and vice versa.

Synthesis of results
Weighted mean difference (WMD) or standardised mean difference (SMD) was used for analyzing the continuous variables.Data reported in median and range or mean and range were converted to mean and standard deviation (SD) based on Hozo, Djulbegovic, and Hozo 2005 equations (Hozo, Djulbegovic, and Hozo 2005).The fixed-effect model was implemented when a fixed population effect size is assumed; otherwise, the random-effects model was used.

Heterogeneity and pooling (metaanalysis) across studies
Statistical heterogeneity was appreciated using Higgins I 2 statistic, at the value of >50%, and the Cochrane Q (Chi 2 test), at the value of P < 0.10 (Higgins et al. 2003).The random-effects model was employed to account for this heterogeneity.Publication bias was assumed in the presence of an asymmetrical funnel plot and based on Egger's regression test (P-value < 0.10).Herein, the trim and fill method of Duvall and Tweedie was used (Duval and Tweedie 2000).Data analysis was performed using Review Manager version

Results
An extensive literature search yielded a total of 238 articles.Of them, 37 articles were duplicates, yielding 201 articles eligible for the title and abstract screening.Out of them, 10 articles were included for full-text screening, of which four articles were excluded.Six articles were eligible for data extraction in which one article was excluded being overlapped data.One article was identified through manual search, yielding six articles suitable for systematic review.The process of the systematic literature search of databases is shown in the Supplementary Table 1 and Figure 1.

Summaries of included studies
Of the included 6 studies in current review, 4 assessed the effects of Immersive VRT while 2 assessed the effects of non-immersive technique.Firstly, In (Guitard et al. 2019), Guitard et al performed a study investigating catastrophic scenario in VR or a personalised scenario using single-arm observational study design.In (Wang et al. 2020), Wang et al. (2020) performed a study investigating virtual nature or a virtual abstract painting using experimental study design.Similarly, In (Wang et al. 2019), Wang et al. (2020) conducted a study investigating projection-based virtual environment using observational study design.In (Malbos et al. 2020)

Study demographic characteristics
A total of six articles including 239 patients with GAD, were included for systematic review.Three studies were of prospective design, while two studies were of randomised controlled design.Two studies were conducted in Taiwan, whereby one study was conducted in France, Italy, Spain and Canada separately.All the included studies were published throughout the entire period from 2011 to 2020 (Table 1).

Participants
Out of the included patients, 121 patients received VRT, whereby 118 patients were in the control group.The mean age of the included patients ranged from 38.33 to 59.87 years.The mean GAD-7 score ranged from 12.43 to 14.05 and 12.73 to 14.80 among the VRT and control groups, respectively (Tables 1 and 2).

Intervention characteristics
Immersive VRT was implemented in four articles while non-immersive technique was used in two studies.The number of sessions ranged from four to eight sessions and the session duration ranged from 10 to 90 min.It should be noted that only three of the included studies were clinical trials which assessed the effects of VRT while the remaining three studies were observational studies (Table 2).

Risk of bias and quality assessment
Based on the NIH quality assessment tool, the included observational studies were of good quality.The included randomised clinical trials showed a low risk of selection, performance and reporting biases, while they reported unclear risk of selection and detection biases (Table 1 and Figure 2).

Anxiety
Three studies, which included 57 patients with GAD, reported the mean anxiety levels after VRT.In the random-effects model (I 2 = 0%, P = 0.88), there was no statistically significant difference between VRT and control groups (SMD 0.01; 95%CI −0.52, 0.54; P = 0.97).There was no significant evidence of publication bias based on the symmetrical distribution of studies along the null line of the funnel plot and based on Egger's regression test (Intercept = −0.79,P = 0.56).Subgroup analysis based on the anxiety assessment tool revealed no statistically significant difference between both groups regarding the mean levels of GAD-7 scale (MD 0.49; 95%CI −2.57, 3.55; P = 0.74) and STAI-YA scale (MD −6.84; 95%CI −16.40, 2.73; P = 0.16) (Figure 3(A-C).

Depression
The difference between VRT and control groups regarding the mean depression levels was reported within two studies, including 49 patients.There was no statistically significant difference between VRT and control groups (SMD 1.34; 95%CI −0.80, 3.49; P = 0.22) in the random-effects model (I 2 = 0%, P = 0.54) (Figure 3(D)).

Discussion
Throughout the past era, VRT has evolved as an effective and feasible intervention for many mental disorders.The current CBT choices cannot be afforded to all patients with mental health disorders.This points out the need for enjoyable and affordable intervention to be included as an adjunct to current treatments or as an exclusive therapy (Welty et al. 2019;Mestre, Ewald, and Maiano 2011).Whereas many published studies encourage VRT employment for GAD, the effectiveness value of VRT deserves further investigation.
The literature is still limited to the psychological and functional outcomes of VRT in patients with GAD.This is because of the lack of well-structured randomised clinical trials and prospective cohort studies that could answer these questions (Morina et al. 2015).Therefore, this meta-analysis was performed to reveal the effectiveness of VRT in managing patients with GAD.
The evidence revealed in this meta-analysis revealed that VRT had relative beneficial effects on the functional and psychological outcomes of GAD.Notably, patients  who received VRT experienced lower anxiety levels and less discomfort status.These findings were reflected on the quality of patients' life in which VRT improved the mean quality of life scores.These findings should be cautiously interpreted as they did not attain statistical significance.These results imply that VRT could be a potential treatment choice for GAD with the achievement of effective psychological outcomes compared to traditional treatment options.Of the three clinical trials included in current review, none showed significant effects of VRT on anxiety which suggest further investigation of VRT in patients with GAD.
Parallel to the findings of the current systematic review, Zeng et al. 2018 reported considerable improvements in anxiety and depression scales after virtual reality exercise (Zeng et al. 2018).This was consistent with Horigome et al. (2020) review which notified acceptable long-lasting results of VRT for social anxiety disorders.
However, these results were not statistically significant when compared with combined psychotherapy or treatment as usual (Horigome et al. 2020).The latter finding was concomitant with Oing and Prescott who reported a non-significant difference between VRT and CBT regarding the post-treatment anxiety levels (Oing and Prescott 2018).The lack of statistically significant difference between VRT and other traditional therapies might be attributed to the limited sample size and the difference in VRT exposure periods.Ioannou et al. (2020) reported that VRT could effectively reduce the anxiety symptoms in different diseases and contexts in comparison to standard treatments (Ioannou et al. 2020).In this concern, Wu et al. (2021) reported statistically significant improvements in the anxiety and depression scales after employment of virtual reality-assisted cognitive behavioural therapy in contrast to traditional interventions (Wu et al. 2021).Based on these findings, it may be proposed that VRT may not be enough to treat GAD, and the combination of the cognitive component with VRT may accomplish the desired psychological outcomes (Kampmann et al. 2016).
The evidence beyond VRT is based on the emotionprocessing theory.This theory states that fear memories contain and structures information regarding fear meaning, stimuli and responses.VRT adjusts and triggers fear structures by presenting conflicting information and promoting emotional processing (Maples-Keller et al. 2017).The virtual environment is a setup based on the brain emotional network processing model.The network is activated when the patient confronts a threatening event resulting in a fear reaction.The more integration of the conflicting information in the emotional network, the more elimination and habituation of fear helps patients with GAD.This process manipulates the fear structure, rendering the fear stimulus less threatening.The patients must remain under-stimulation until fear and anxiety are declined to the level resulting in therapeutic effect (Wiederhold and Riva;Garcia-Palacios et al. 2007).In the recent era, the innovations in the VRT could depict a variety of tasks and provide more convenient grading exposure.This enhances the perceived orientation, provides more inhibitory learning for patients and improves recovery (Safir, Wallach, and Bar-Zvi 2012).The changes caused by VRT allowed for a decline in fear felt in real-world situations, improving the anxiety symptoms and decreasing the relapse of GAD manifestations.
Despite the potential advantages of VRT, it is not devoid of potential disadvantages.The use of consumer-oriented head-mounted display devices is associated with motion sickness.Thus, caution should be taken for patients at higher risk of motion sickness and patients with epilepsy symptoms.Meanwhile, the equipment used for VRT is expensive relative to traditional exercises, resulting in a high economic burden to employ it as a treatment option in the healthcare systems.There may be a risk of dependence and obsession with VRT, which should be considered while treating patients with other mental disorders.The majority of VRT devices are under development and widely unexplored, requiring more research to be warranted (Craft and Perna 2004;Wegner et al. 2014;Proffitt and Lange 2015;Geraets et al. 2019).
We didn't include the studies of Guitard et al. ( 2019) and Wang et al. (2020) in meta-analysis because there was no relevant information in these studies to be included meta-analysis (Guitard et al. 2019;Wang et al. 2020).In addition, the study design of these studies was also not appropriate to be included in the meta-analysis.In both these studies, there was no control condition, that's why we included these studies only in systematic review and does not include in meta-analysis.

Strengths and limitations
This meta-analysis gathered the rapidly emerging controversial evidence regarding the psychological outcomes of VRT in patients with GAD.It was conducted in a systematic approach following the PRISMA and Cochrane guidelines, limiting the potential bias.Furthermore, meta-analysis was considered for several outcomes to assess the outcomes of VRT.Though there were only few studies included in metaanalysis, nonetheless there are previous reviews which draw conclusions based on limited number of studies (Tobaiqy et al. 2020;Uphoff et al. 2020;Arsh et al. 2021;Khan et al. 2022).Conversely, some limitations should be put into consideration while interpreting the yielded evidence in this meta-analysis.Most of the included articles were observational designs, revealing a potential risk of selection bias.Additionally, there was significant heterogeneity between the included studies.This heterogeneity might evolve due to demographic characteristics, assessment methods, virtual reality rationale, virtual reality device, VRT protocol, comparative arm and follow-up periods.Furthermore, caution is required when interpreting the findings of this meta-analysis.This is because many confounders could contribute to the outcomes of VRT in patients with GAD.

Conclusions
VRT may have improved the manifestations of GAD, reflected in the patient's quality of life.However, these results were not statistically significant.Improving current treatment by incorporating relaxation techniques with CBT in an immersive environment is needed.Therefore, future clinical research is required to verify whether mindfulness and relaxation via an immersive environment are effective for adults with GAD.The integration of this research into the treatment guidelines might help healthcare providers to improve the outcomes of VRT in patients with GAD.This could increase the patient's desire to adhere to the treatment, improve their performance and enhance their psychological status and sense of well-being.However, the existing evidence is inconclusive to support the superiority of VRT as a substitute for traditional therapies.Therefore, further studies should be conducted to mitigate the potential limitations of the present metaanalysis.
5.4 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Comprehensive Meta-Analysis v3 software (Borenstein et al. 2005; Cochrane Collaboration %J Copenhagen, D.T.N.C.C., Cochrane Collaboration 2014).The significant difference was established at the value of P < 0.05.
, Malbos et al. conducted a clinical trial to investigate efficacy of VR in GAD patients.In a similar approach Repetto et al. (2013) conducted a phase 2 clinical trial to assess the effects of VR and mobile phones in the treatment of GAD.Navarro-Haro et al. (2019) conducted a pilot study to evaluate the effectiveness of mindfulness-based intervention with and without VR.

Figure 1 .
Figure 1.PRISMA Flow chart showing the process of the literature search, title, abstract, and full-text screening, systematic review and meta-analysis.

Figure 2 .
Figure 2. (A) Risk of bias graph (B) Risk of bias summary: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3 .
Figure 3. Forest plot of summary analysis of the (A) Standardised Mean difference and 95% CI of the mean anxiety levels between virtual reality treatment and control groups.(B) Mean difference and 95% CI of the mean Generalised Anxiety Disorder −7 questions scale between virtual reality treatment and control groups.(C) Mean difference and 95% CI of the State Trait Anxiety Inventory scale between virtual reality treatment and control groups.(D) Standardised Mean difference and 95% CI of the mean depression levels between virtual reality treatment and control groups.(E) Mean difference and 95% CI of the mean discomfort status between virtual reality treatment and control groups.Size of the green square is proportional to the statistical weight of each trial.The grey diamond represents the pooled point estimate.The positioning of both diamonds and squares (along with 95% CIs) beyond the vertical line (unit value) suggests a significant outcome (IV = inverse variance).

Figure 3
Figure 3 Continued

Table 1 .
Demographic characteristics of the included studies.Randomised Clinical Trial *Data reported using median and range, NR = Non-Reported, SD = Standard deviation.

Table 2 .
Baseline Psychological assessment and Virtual Reality Related data.