<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.0 20040830//EN" "http://dtd.nlm.nih.gov/publishing/2.0/journalpublishing.dtd">
<article xmlns:xlink="http://www.w3.org/1999/xlink" article-type="review-article" dtd-version="2.0">
  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">JSG</journal-id>
      <journal-id journal-id-type="nlm-ta">JMIR Serious Games</journal-id>
      <journal-title>JMIR Serious Games</journal-title>
      <issn pub-type="epub">2291-9279</issn>
      <publisher>
        <publisher-name>JMIR Publications</publisher-name>
        <publisher-loc>Toronto, Canada</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">v10i1e29137</article-id>
      <article-id pub-id-type="pmid">35156932</article-id>
      <article-id pub-id-type="doi">10.2196/29137</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Review</subject>
        </subj-group>
        <subj-group subj-group-type="article-type">
          <subject>Review</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>The Effectiveness of Serious Games in Alleviating Anxiety: Systematic Review and Meta-analysis</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="editor">
          <name>
            <surname>Zary</surname>
            <given-names>Nabil</given-names>
          </name>
        </contrib>
      </contrib-group>
      <contrib-group>
        <contrib contrib-type="reviewer">
          <name>
            <surname>Khalifa</surname>
            <given-names>Mohamed</given-names>
          </name>
        </contrib>
        <contrib contrib-type="reviewer">
          <name>
            <surname>Chen</surname>
            <given-names>Hui</given-names>
          </name>
        </contrib>
      </contrib-group>
      <contrib-group>
        <contrib id="contrib1" contrib-type="author">
          <name name-style="western">
            <surname>Abd-alrazaq</surname>
            <given-names>Alaa</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <xref rid="aff2" ref-type="aff">2</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0001-7695-4626</ext-link>
        </contrib>
        <contrib id="contrib2" contrib-type="author">
          <name name-style="western">
            <surname>Alajlani</surname>
            <given-names>Mohannad</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff3" ref-type="aff">3</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-5691-7120</ext-link>
        </contrib>
        <contrib id="contrib3" contrib-type="author">
          <name name-style="western">
            <surname>Alhuwail</surname>
            <given-names>Dari</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff4" ref-type="aff">4</xref>
          <xref rid="aff5" ref-type="aff">5</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0001-5038-3044</ext-link>
        </contrib>
        <contrib id="contrib4" contrib-type="author">
          <name name-style="western">
            <surname>Schneider</surname>
            <given-names>Jens</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-0546-2816</ext-link>
        </contrib>
        <contrib id="contrib5" contrib-type="author">
          <name name-style="western">
            <surname>Akhu-Zaheya</surname>
            <given-names>Laila</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff6" ref-type="aff">6</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-4219-4005</ext-link>
        </contrib>
        <contrib id="contrib6" contrib-type="author">
          <name name-style="western">
            <surname>Ahmed</surname>
            <given-names>Arfan</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff2" ref-type="aff">2</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-4025-5767</ext-link>
        </contrib>
        <contrib id="contrib7" contrib-type="author" corresp="yes">
          <name name-style="western">
            <surname>Househ</surname>
            <given-names>Mowafa</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <address>
            <institution>Division of Information and Computing Technology, College of Science and Engineering</institution>
            <institution>Hamad Bin Khalifa University</institution>
            <institution>Qatar Foundation</institution>
            <addr-line>Doha</addr-line>
            <country>Qatar</country>
            <phone>974 55708566</phone>
            <email>mhouseh@hbku.edu.qa</email>
          </address>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-3648-6271</ext-link>
        </contrib>
      </contrib-group>
      <aff id="aff1">
        <label>1</label>
        <institution>Division of Information and Computing Technology, College of Science and Engineering</institution>
        <institution>Hamad Bin Khalifa University</institution>
        <institution>Qatar Foundation</institution>
        <addr-line>Doha</addr-line>
        <country>Qatar</country>
      </aff>
      <aff id="aff2">
        <label>2</label>
        <institution>Artificial Intelligence Center for Precision Health</institution>
        <institution>Weill Cornell Medicine-Qatar</institution>
        <institution>Qatar Foundation</institution>
        <addr-line>Doha</addr-line>
        <country>Qatar</country>
      </aff>
      <aff id="aff3">
        <label>3</label>
        <institution>Institute of Digital Healthcare, Warwick Manufacturing Group, University of Warwick</institution>
        <addr-line>Warwick</addr-line>
        <country>United Kingdom</country>
      </aff>
      <aff id="aff4">
        <label>4</label>
        <institution>Information Science Department, College of Life Sciences, Kuwait University</institution>
        <addr-line>Kuwait</addr-line>
        <country>Kuwait</country>
      </aff>
      <aff id="aff5">
        <label>5</label>
        <institution>Health Informatics Unit, Dasman Diabetes Institute</institution>
        <addr-line>Kuwait</addr-line>
        <country>Kuwait</country>
      </aff>
      <aff id="aff6">
        <label>6</label>
        <institution>Department of Adults Health Nursing, Nursing Faculty, Jordan University of Science and Technology</institution>
        <addr-line>Irbid</addr-line>
        <country>Jordan</country>
      </aff>
      <author-notes>
        <corresp>Corresponding Author: Mowafa Househ <email>mhouseh@hbku.edu.qa</email></corresp>
      </author-notes>
      <pub-date pub-type="collection">
        <season>Jan-Mar</season>
        <year>2022</year>
      </pub-date>
      <pub-date pub-type="epub">
        <day>14</day>
        <month>2</month>
        <year>2022</year>
      </pub-date>
      <volume>10</volume>
      <issue>1</issue>
      <elocation-id>e29137</elocation-id>
      <history>
        <date date-type="received">
          <day>31</day>
          <month>8</month>
          <year>2021</year>
        </date>
        <date date-type="rev-request">
          <day>12</day>
          <month>10</month>
          <year>2021</year>
        </date>
        <date date-type="rev-recd">
          <day>31</day>
          <month>10</month>
          <year>2021</year>
        </date>
        <date date-type="accepted">
          <day>6</day>
          <month>11</month>
          <year>2021</year>
        </date>
      </history>
      <copyright-statement>©Alaa Abd-alrazaq, Mohannad Alajlani, Dari Alhuwail, Jens Schneider, Laila Akhu-Zaheya, Arfan Ahmed, Mowafa Househ. Originally published in JMIR Serious Games (https://games.jmir.org), 14.02.2022.</copyright-statement>
      <copyright-year>2022</copyright-year>
      <license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/">
        <p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Serious Games, is properly cited. The complete bibliographic information, a link to the original publication on https://games.jmir.org, as well as this copyright and license information must be included.</p>
      </license>
      <self-uri xlink:href="https://games.jmir.org/2022/1/e29137" xlink:type="simple"/>
      <abstract>
        <sec sec-type="background">
          <title>Background</title>
          <p>Anxiety is a mental disorder characterized by apprehension, tension, uneasiness, and other related behavioral disturbances. One of the nonpharmacological treatments used for reducing anxiety is serious games, which are games that have a purpose other than entertainment. The effectiveness of serious games in alleviating anxiety has been investigated by several systematic reviews; however, they were limited by design and methodological weaknesses.</p>
        </sec>
        <sec sec-type="objective">
          <title>Objective</title>
          <p>This study aims to assess the effectiveness of serious games in alleviating anxiety by summarizing the results of previous studies and providing an up-to-date review.</p>
        </sec>
        <sec sec-type="methods">
          <title>Methods</title>
          <p>We conducted a systematic review of randomized controlled trials (RCTs). The following seven databases were searched: MEDLINE, CINAHL, PsycINFO, ACM Digital Library, IEEE Xplore, Scopus, and Google Scholar. We also conducted backward and forward reference list checking for the included studies and relevant reviews. Two reviewers independently carried out the study selection, data extraction, risk of bias assessment, and quality of evidence appraisal. We used a narrative and statistical approach, as appropriate, to synthesize the results of the included studies.</p>
        </sec>
        <sec sec-type="results">
          <title>Results</title>
          <p>Of the 935 citations retrieved, 33 studies were included in this review. Of these, 22 RCTs were eventually included in the meta-analysis. Very low–quality evidence from 9 RCTs and 5 RCTs showed no statistically significant effect of exergames (games entailing physical exercises) on anxiety levels when compared with conventional exercises (<italic>P</italic>=.70) and no intervention (<italic>P</italic>=.27), respectively. Although 6 RCTs demonstrated a statistically and clinically significant effect of computerized cognitive behavioral therapy games on anxiety levels when compared with no intervention (<italic>P</italic>=.01), the quality of the evidence reported was low. Similarly, low-quality evidence from 3 RCTs showed a statistically and clinically significant effect of biofeedback games on anxiety levels when compared with conventional video games (<italic>P</italic>=.03).</p>
        </sec>
        <sec sec-type="conclusions">
          <title>Conclusions</title>
          <p>This review shows that exergames can be as effective as conventional exercises in alleviating anxiety; computerized cognitive behavioral therapy games and exergames can be more effective than no intervention, and biofeedback games can be more effective than conventional video games. However, our findings remain inconclusive, mainly because there was a high risk of bias in the individual studies included, the quality of meta-analyzed evidence was low, few studies were included in some meta-analyses, patients without anxiety were recruited in most studies, and purpose-shifted serious games were used in most studies. Therefore, serious games should be considered complementary to existing interventions. Researchers should use serious games that are designed specifically to alleviate depression, deliver other therapeutic modalities, and recruit a diverse population of patients with anxiety.</p>
        </sec>
      </abstract>
      <kwd-group>
        <kwd>serious games</kwd>
        <kwd>exergames</kwd>
        <kwd>anxiety</kwd>
        <kwd>computerized cognitive behavioral therapy games</kwd>
        <kwd>biofeedback games</kwd>
        <kwd>systematic reviews</kwd>
        <kwd>meta-analysis</kwd>
        <kwd>mobile phone</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec sec-type="introduction">
      <title>Introduction</title>
      <sec>
        <title>Background</title>
        <p>Anxiety is a normal response to situations in human life. However, excessive anxiety may be indicative of anxiety disorders, which are mental disorders characterized by apprehension, tension, uneasiness, and other related behavioral disturbances. They are potentially coupled with other physiological symptoms, such as shortness of breath, headaches, nausea, and abdominal pain [<xref ref-type="bibr" rid="ref1">1</xref>,<xref ref-type="bibr" rid="ref2">2</xref>]. Anxiety disorders include separation anxiety disorder, phobia, social anxiety disorder, panic disorder, and substance- or medication-induced anxiety disorder [<xref ref-type="bibr" rid="ref3">3</xref>]. Globally, the prevalence of anxiety disorders in the general population is estimated to be 26.9% [<xref ref-type="bibr" rid="ref4">4</xref>]. Anxiety disorders affect all age groups, including children and adolescents [<xref ref-type="bibr" rid="ref5">5</xref>], and can be debilitating in nature, causing significant impairment in one’s social and professional functioning [<xref ref-type="bibr" rid="ref6">6</xref>]. Evidence has revealed a strong association between anxiety and mortality rates among healthy individuals [<xref ref-type="bibr" rid="ref7">7</xref>,<xref ref-type="bibr" rid="ref8">8</xref>]. Anxiety contributes to a decrease in quality of life and other health-related problems [<xref ref-type="bibr" rid="ref8">8</xref>]. Globally, over 45 million incidents are estimated to be attributed to anxiety disorders, which, in turn, are responsible for approximately 28.68 million disability-adjusted life years [<xref ref-type="bibr" rid="ref9">9</xref>,<xref ref-type="bibr" rid="ref10">10</xref>].</p>
        <p>Despite the prevalence of anxiety disorders, they often go undetected and undertreated [<xref ref-type="bibr" rid="ref11">11</xref>]. Anxiety requires treatment and management because of the stimulation of the sympathetic system, which can lead to adverse effects. Treatments for anxiety disorders can be divided into pharmacological treatments (eg, psychotropic medications) and nonpharmacological treatments (eg, cognitive behavioral therapy [CBT]) [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref13">13</xref>]. Although the use of pharmacological treatments can be effective for the treatment of anxiety disorders, they can cause many adverse events and would not be effective for everyone. Therefore, nonpharmacological treatments have been used to reduce anxiety levels [<xref ref-type="bibr" rid="ref14">14</xref>,<xref ref-type="bibr" rid="ref15">15</xref>].</p>
        <p>One of the nonpharmacological treatments used for reducing anxiety is serious games, which are games that have a purpose other than entertainment [<xref ref-type="bibr" rid="ref16">16</xref>-<xref ref-type="bibr" rid="ref19">19</xref>]. In recent years, the popularity and adoption of serious games have been on the rise because of their ability to educate and influence change in one’s experience or behaviors [<xref ref-type="bibr" rid="ref20">20</xref>,<xref ref-type="bibr" rid="ref21">21</xref>]. Evidence suggests that serious games can enable players to experience more meaningful, engaging, and challenging learning when compared with traditional interventions or other methods used to relieve anxiety [<xref ref-type="bibr" rid="ref22">22</xref>].</p>
        <p>Serious games come in a variety of types and formats, such as (1) exergames, or video games that entail physical exercises (eg, fitness and balance exercises) as part of the intended gameplay; (2) computerized CBT games, which are video games that provide CBT for the users; (3) biofeedback games, which are video games that use electrical sensors attached to the participant to receive information about the participant’s body state (eg, electrocardiogram sensors) and seek to influence some of the player body’s functions (eg, heart rate); (4) attention distraction games, which are video games that are used to direct a user’s attention away from another focus or a given event; (5) brain training games, which are video games that aim to maintain or improve users’ cognitive abilities (eg, working memory, executive function, processing speed, and attention), and (6) social skills training games that use computer-based games to improve social skills and mental health.</p>
      </sec>
      <sec>
        <title>Research Gap and Aim</title>
        <p>Various studies have assessed the effectiveness of serious games in alleviating anxiety. Examining and summarizing the evidence from these studies is critical to reach informed conclusions about the effectiveness of serious games in the treatment of anxiety disorders. Two published reviews summarized the evidence regarding the effectiveness of serious games on anxiety [<xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref17">17</xref>]. However, these reviews are undermined by certain shortcomings that limit the generalization of the findings. Specifically, these reviews (1) focused on only one type of serious games (ie, exergames) [<xref ref-type="bibr" rid="ref16">16</xref>]; (2) included non-randomized controlled trials (RCTs) [<xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref17">17</xref>]; (3) focused on a specific age group (eg, adolescents) [<xref ref-type="bibr" rid="ref17">17</xref>]; (4) did not search the main databases of the information technology and health care fields (eg, MEDLINE, PsycINFO, IEEE Xplore, and ACM Digital Library) [<xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref17">17</xref>], or (5) did not conduct meta-analyses [<xref ref-type="bibr" rid="ref17">17</xref>]. To address the existing gaps in the literature, this review aims to assess the effectiveness of serious games in alleviating anxiety by summarizing the results of previous studies and providing an up-to-date review.</p>
      </sec>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <p>We conducted a systematic review and meta-analysis per the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (<xref ref-type="supplementary-material" rid="app1">Multimedia Appendix 1</xref>) [<xref ref-type="bibr" rid="ref23">23</xref>]. The protocol for this review was registered at PROSPERO (International Prospective Register of Systematic Reviews; ID: CRD42021264126).</p>
      <sec>
        <title>Search Strategy</title>
        <sec>
          <title>Search Sources</title>
          <p>We searched the following bibliographic databases to retrieve the relevant studies: MEDLINE (via Ovid), PsycINFO (via EBSCO), CINAHL (EBSCO), IEEE Xplore, ACM Digital Library, and Scopus. These databases were searched on June 29, 2021, by the first author (A Abd-alrazaq). We also set up automatic alerts, as needed, to retrieve weekly searches for 12 weeks (ending on August 28, 2021). Furthermore, we searched <italic>Google Scholar</italic> to identify gray literature. We considered only the first 10 pages (ie, 100 hits), as Google Scholar retrieves a vast number of studies, and it organizes them based on their relevance. Finally, we conducted backward and forward reference list checking (ie, screening the reference lists of the included studies and relevant reviews and screening the studies that cited the included studies).</p>
        </sec>
        <sec>
          <title>Search Terms</title>
          <p>Two experts in digital mental health were consulted before developing the search query for this review, and systematic reviews of relevance to this review were checked. The search terms were chosen based on the target intervention (eg, serious games and exergames), target outcome (eg, anxiety), and target study design (eg, RCT and clinical trial). <xref ref-type="supplementary-material" rid="app2">Multimedia Appendix 2</xref> summarizes the search query used for searching each of the 8 databases.</p>
        </sec>
      </sec>
      <sec>
        <title>Study Eligibility Criteria</title>
        <p>Only RCTs that assessed the effectiveness of serious games in alleviating anxiety levels were included in this study. Specifically, the target intervention in this review was serious games that were delivered on digital platforms such as computers, consoles (Xbox, PlayStation, etc), mobile phones, tablets, handheld devices, or any other computerized devices. Furthermore, gaming had to be an integral and primary component of the intervention. The serious games must have been used for therapeutic or preventive purposes. Nondigital games and those used for other purposes, such as monitoring, screening, and diagnosis, were excluded. RCTs on whether there were parallel RCTs, cluster RCTs, crossover RCTs, or factorial RCTs were all included, but we excluded quasi-experiments, observational studies, and reviews.</p>
        <p>The outcome of interest in this review was <italic>anxiety level</italic>, regardless of the outcome measures. We included the outcome data measured immediately after the intervention rather than the follow-up data. Trials in the English language were eligible for inclusion in this review, and all other languages were excluded. Conference abstracts and posters, commentaries, preprints, proposals, and editorials were excluded. RCTs published as journal articles, conference proceedings, and dissertations were included. No restrictions related to the population, year of publication, country of publication, comparator, or study settings were applied.</p>
      </sec>
      <sec>
        <title>Study Selection</title>
        <p>We identified relevant studies in the following steps. First, we exported the retrieved studies into EndNote X8 software to identify and eliminate duplicate entries. In the second step, 2 reviewers (A Abd-alrazaq and MA) independently screened the titles and abstracts of all the retrieved studies. Finally, the full texts of the studies included in the previous step were screened independently by 2 reviewers. The 2 reviewers resolved any disagreements through discussion. The interrater agreement in steps 2 and 3 were Cohen κ=0.81 and Cohen κ=0.93, respectively, indicating a perfect level of interrater agreement [<xref ref-type="bibr" rid="ref24">24</xref>].</p>
      </sec>
      <sec>
        <title>Data Extraction</title>
        <p>Two independent reviewers used Microsoft Excel to extract the data from the included studies. <xref ref-type="supplementary-material" rid="app3">Multimedia Appendix 3</xref> shows the data extraction form that was used by the 2 reviewers to extract the data precisely and systematically from the included studies. We pilot-tested the form using the 5 included studies before proceeding. Disagreements between the reviewers were resolved via discussion. We observed an interrater agreement of 0.86, indicating a perfect level of agreement [<xref ref-type="bibr" rid="ref24">24</xref>]. Where outcome data such as mean, SD, and sample size were unavailable, we contacted the corresponding authors in an attempt to retrieve them. In this way, we managed to retrieve such information for an additional 5 studies.</p>
      </sec>
      <sec>
        <title>Risk of Bias Appraisal</title>
        <p>As recommended by the Cochrane Collaboration [<xref ref-type="bibr" rid="ref25">25</xref>], the risk of bias was assessed by 2 independent reviewers using the Risk-of-Bias 2 (RoB 2) tool. This tool appraises the risk of bias in five domains in RCTs: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result [<xref ref-type="bibr" rid="ref25">25</xref>]. The risk of bias judgments in these domains was used to determine the overall risk of bias for each included study. Disagreements in judgments between the 2 reviewers were resolved via discussion. Interrater agreement between the reviewers was perfect (Cohen κ=0.86) [<xref ref-type="bibr" rid="ref24">24</xref>].</p>
      </sec>
      <sec>
        <title>Data Synthesis</title>
        <p>We used a narrative and statistical approach to synthesize the extracted data. Specifically, in our narrative synthesis, we describe the characteristics of the included studies, population, intervention, comparator, and outcome measures using texts and tables. The findings of the included studies were summarized and grouped according to the type of serious games (eg, exergames, computerized CBT games, and biofeedback games). We also conducted a meta-analysis, where at least 3 studies of the same type of serious games reported sufficient data (ie, mean, SD, and number of participants in each intervention group).</p>
        <p>We used Review Manager (RevMan 5.4; The Cochrane Collaboration) to conduct the meta-analyses. The effect of each study and the overall effect was assessed using the standardized mean difference (SMD) because the type of data for the outcome of interest (anxiety level) was continuous, and the instruments used to evaluate the outcome were diverse among the included trials. We selected the random-effects model for the analysis because of the high clinical heterogeneity between the meta-analyzed studies in terms of serious game characteristics (eg, type, duration, frequency, and period), population characteristics (eg, sample size, mean age, and health condition), and outcome measures (eg, tools and follow-up period).</p>
        <p>When the meta-analysis showed a statistically significant difference between the groups, we examined whether this difference was clinically important. We used the concept of <italic>minimal clinically important difference</italic> (MCID), which refers to the smallest change in a measured outcome that a patient would deem as worthwhile and substantial enough to warrant a change in a patient’s therapy. MCID boundaries were calculated as −0.5 to +0.5 times the SMD of the meta-analyzed studies.</p>
        <p>We calculated <italic>I</italic><sup>2</sup> and a chi-square <italic>P</italic> value to examine the degree and statistical significance of heterogeneity, respectively, in the meta-analyzed studies. A chi-square <italic>P</italic> value of ≤.05 suggests heterogeneous meta-analyzed studies [<xref ref-type="bibr" rid="ref26">26</xref>]. When <italic>I</italic><sup>2</sup> ranged from 0% to 40%, 30% to 60%, 50% to 90%, and 75% to 100%, the degree of heterogeneity was judged as insignificant, moderate, substantial, or considerable, respectively [<xref ref-type="bibr" rid="ref26">26</xref>].</p>
        <p>We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the overall quality of evidence resulting from meta-analyses [<xref ref-type="bibr" rid="ref27">27</xref>]. The GRADE approach appraises the quality of evidence based on five domains: risk of bias, inconsistency (ie, heterogeneity), indirectness, imprecision, and publication bias [<xref ref-type="bibr" rid="ref27">27</xref>]. The overall quality of the meta-analyzed evidence was appraised separately by 2 reviewers, and any differences in decisions were addressed by discussion. The reviewers’ interrater agreement was deemed perfect (Cohen κ=0.96) [<xref ref-type="bibr" rid="ref24">24</xref>].</p>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <sec>
        <title>Search Results</title>
        <p>As shown in <xref rid="figure1" ref-type="fig">Figure 1</xref>, we identified 935 records by searching 7 electronic databases. Of these records, we identified and removed 198 duplicates using EndNote software. The screening of the titles and abstracts of the remaining 737 records led to the exclusion of 649 citations because (1) they did not use serious games (n=319); (2) the anxiety level was not a measured outcome (n=98); (3) they were not RCTs (n=186); (4) they were not peer-reviewed articles, theses, or conference proceedings (n=29); and (5) they were published in languages other than English (n=17). Reading the full text of the remaining 88 publications led to the exclusion of 59 publications for the following reasons: (1) the intervention did not use serious games (n=25), (2) the anxiety level was not a measured outcome (n=19), (3) they were not RCTs (n=13), and (4) they were published in a language other than English (n=2). We identified 4 additional RCTs through backward and forward reference list checking. A total of 33 RCTs were included in this review [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref60">60</xref>]. We conducted a meta-analysis when at least 3 studies of the same type of serious games reported sufficient data (ie, mean, SD, and number of participants in each intervention group). Therefore, 22 of the included RCTs were included in the meta-analysis [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref49">49</xref>-<xref ref-type="bibr" rid="ref51">51</xref>].</p>
        <fig id="figure1" position="float">
          <label>Figure 1</label>
          <caption>
            <p>Flowchart of the study selection process.</p>
          </caption>
          <graphic xlink:href="games_v10i1e29137_fig1.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
        </fig>
      </sec>
      <sec>
        <title>Characteristics of Included Reviews</title>
        <p>The included studies were published between 2012 and 2021 (<xref ref-type="table" rid="table1">Table 1</xref>). The year that witnessed the largest number of included studies was 2017 (n=8), followed by 2020 (n=6) and 2021 (n=6). The included studies were conducted in 16 different countries, as shown in <xref ref-type="table" rid="table1">Table 1</xref>. The country that published the largest number of included studies was the United States (n=6). All included studies were published in peer-reviewed journals, except for one that was a thesis. The trial type used in most of the included studies was parallel RCTs (n=31).</p>
        <table-wrap position="float" id="table1">
          <label>Table 1</label>
          <caption>
            <p>Characteristics of studies and populations.</p>
          </caption>
          <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
            <col width="140"/>
            <col width="50"/>
            <col width="100"/>
            <col width="110"/>
            <col width="80"/>
            <col width="70"/>
            <col width="80"/>
            <col width="80"/>
            <col width="190"/>
            <col width="100"/>
            <thead>
              <tr valign="top">
                <td>Study</td>
                <td>Year</td>
                <td>Country</td>
                <td>Publication type</td>
                <td>RCT<sup>a</sup> type</td>
                <td>Sample size, n</td>
                <td>Age (years), mean</td>
                <td>Sex (male), n (%)</td>
                <td>Target group or condition</td>
                <td>Setting</td>
              </tr>
            </thead>
            <tbody>
              <tr valign="top">
                <td>Adomaviciene et al [<xref ref-type="bibr" rid="ref28">28</xref>]</td>
                <td>2019</td>
                <td>Lithuania</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>60</td>
                <td>64.6</td>
                <td>40 (66.7)</td>
                <td>Stroke</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Carvalho et al [<xref ref-type="bibr" rid="ref29">29</xref>]</td>
                <td>2020</td>
                <td>Brazil</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>35</td>
                <td>51.3</td>
                <td>0 (0)</td>
                <td>Fibromyalgia</td>
                <td>Educational</td>
              </tr>
              <tr valign="top">
                <td>Meldrum et al [<xref ref-type="bibr" rid="ref30">30</xref>]</td>
                <td>2015</td>
                <td>Ireland</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>71</td>
                <td>54.1</td>
                <td>27 (38)</td>
                <td>Unilateral peripheral vestibular loss</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Schumacher et al [<xref ref-type="bibr" rid="ref31">31</xref>]</td>
                <td>2018</td>
                <td>Germany</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>42</td>
                <td>56.3</td>
                <td>25 (59.5)</td>
                <td>Hematopoietic stem cell transplantation recipients</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Ruivo et al [<xref ref-type="bibr" rid="ref32">32</xref>]</td>
                <td>2017</td>
                <td>Ireland</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>32</td>
                <td>59.9</td>
                <td>26 (81.3)</td>
                <td>Cardiovascular diseases</td>
                <td>Clinical, community, and educational</td>
              </tr>
              <tr valign="top">
                <td>Mazzoleni et al [<xref ref-type="bibr" rid="ref33">33</xref>]</td>
                <td>2014</td>
                <td>Italy</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>40</td>
                <td>71.2</td>
                <td>NR<sup>b</sup></td>
                <td>Chronic respiratory diseases</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Polat et al [<xref ref-type="bibr" rid="ref34">34</xref>]</td>
                <td>2021</td>
                <td>Turkey</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>40</td>
                <td>44.8</td>
                <td>0 (0)</td>
                <td>Fibromyalgia</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Lin et al [<xref ref-type="bibr" rid="ref35">35</xref>]</td>
                <td>2020</td>
                <td>Taiwan</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>80</td>
                <td>57.0</td>
                <td>39 (48.8)</td>
                <td>Knee osteoarthritis</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Vieira et al [<xref ref-type="bibr" rid="ref36">36</xref>]</td>
                <td>2017</td>
                <td>Portugal</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>46</td>
                <td>57.7</td>
                <td>NR</td>
                <td>Cardiovascular diseases</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Thomas et al [<xref ref-type="bibr" rid="ref37">37</xref>]</td>
                <td>2017</td>
                <td>United Kingdom</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>30</td>
                <td>49.3</td>
                <td>3 (10)</td>
                <td>Multiple sclerosis</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Wagener et al [<xref ref-type="bibr" rid="ref38">38</xref>]</td>
                <td>2012</td>
                <td>United States</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>41</td>
                <td>14.0</td>
                <td>14 (33.3)</td>
                <td>Obese adolescents</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Jahouh et al [<xref ref-type="bibr" rid="ref39">39</xref>]</td>
                <td>2021</td>
                <td>Spain</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>80</td>
                <td>84.2</td>
                <td>35 (44)</td>
                <td>Older adults</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Collado-Mateo et al [<xref ref-type="bibr" rid="ref40">40</xref>]</td>
                <td>2017</td>
                <td>Spain</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>83</td>
                <td>52.5</td>
                <td>0 (0)</td>
                <td>Fibromyalgia</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Cooney et al [<xref ref-type="bibr" rid="ref41">41</xref>]</td>
                <td>2017</td>
                <td>Ireland</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>52</td>
                <td>40.6</td>
                <td>20 (38.8)</td>
                <td>Anxiety, depression, or intellectual disability</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Donker et al [<xref ref-type="bibr" rid="ref42">42</xref>]</td>
                <td>2019</td>
                <td>Netherlands</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>193</td>
                <td>41.3</td>
                <td>64 (33.2)</td>
                <td>Acrophobia</td>
                <td>Community</td>
              </tr>
              <tr valign="top">
                <td>Fish et al [<xref ref-type="bibr" rid="ref43">43</xref>]</td>
                <td>2014</td>
                <td>United States</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>59</td>
                <td>30.0</td>
                <td>29 (49.2)</td>
                <td>Depression</td>
                <td>Clinical and educational</td>
              </tr>
              <tr valign="top">
                <td>Fleming et al [<xref ref-type="bibr" rid="ref44">44</xref>]</td>
                <td>2012</td>
                <td>New Zealand</td>
                <td>Journal article</td>
                <td>Crossover</td>
                <td>32</td>
                <td>14.9</td>
                <td>18 (56)</td>
                <td>Depression</td>
                <td>Educational</td>
              </tr>
              <tr valign="top">
                <td>Merry et al [<xref ref-type="bibr" rid="ref45">45</xref>]</td>
                <td>2012</td>
                <td>New Zealand</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>187</td>
                <td>15.6</td>
                <td>64 (34.2)</td>
                <td>Depression</td>
                <td>Clinical and educational</td>
              </tr>
              <tr valign="top">
                <td>Perry et al [<xref ref-type="bibr" rid="ref46">46</xref>]</td>
                <td>2017</td>
                <td>Australia</td>
                <td>Journal article</td>
                <td>Cluster</td>
                <td>540</td>
                <td>16.7</td>
                <td>199 (36.9)</td>
                <td>Secondary students</td>
                <td>Educational</td>
              </tr>
              <tr valign="top">
                <td>Schoneveld et al [<xref ref-type="bibr" rid="ref47">47</xref>]</td>
                <td>2018</td>
                <td>Netherlands</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>174</td>
                <td>10.0</td>
                <td>71 (40.8)</td>
                <td>Anxiety</td>
                <td>Educational</td>
              </tr>
              <tr valign="top">
                <td>Tsui [<xref ref-type="bibr" rid="ref48">48</xref>]</td>
                <td>2016</td>
                <td>Canada</td>
                <td>Thesis</td>
                <td>Parallel</td>
                <td>143</td>
                <td>13.6</td>
                <td>52 (36.1)</td>
                <td>Anxiety</td>
                <td>Clinical and educational</td>
              </tr>
              <tr valign="top">
                <td>Schoneveld et al [<xref ref-type="bibr" rid="ref49">49</xref>]</td>
                <td>2016</td>
                <td>Netherlands</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>136</td>
                <td>10.0</td>
                <td>61 (45.2)</td>
                <td>Anxiety</td>
                <td>Educational</td>
              </tr>
              <tr valign="top">
                <td>Wijnhoven et al [<xref ref-type="bibr" rid="ref50">50</xref>]</td>
                <td>2020</td>
                <td>Netherlands</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>109</td>
                <td>11.1</td>
                <td>84 (77.1)</td>
                <td>Anxiety and autism spectrum disorder</td>
                <td>Clinical and educational</td>
              </tr>
              <tr valign="top">
                <td>Scholten et al [<xref ref-type="bibr" rid="ref51">51</xref>]</td>
                <td>2016</td>
                <td>Netherlands</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>138</td>
                <td>13.3</td>
                <td>48 (35)</td>
                <td>Anxiety</td>
                <td>Educational</td>
              </tr>
              <tr valign="top">
                <td>Marechal et al [<xref ref-type="bibr" rid="ref52">52</xref>]</td>
                <td>2017</td>
                <td>France</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>118</td>
                <td>6.8</td>
                <td>83 (70.4)</td>
                <td>Children undergoing general anesthesia</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Sakızcı Uyar et al [<xref ref-type="bibr" rid="ref53">53</xref>]</td>
                <td>2021</td>
                <td>Turkey</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>138</td>
                <td>6.6</td>
                <td>61 (44)</td>
                <td>Adenoidectomy, adenotonsillectomy, or myringotomy</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Liu et al [<xref ref-type="bibr" rid="ref54">54</xref>]</td>
                <td>2020</td>
                <td>United States</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>53</td>
                <td>12.5</td>
                <td>37 (69.8)</td>
                <td>Otolaryngological conditions</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Butler et al [<xref ref-type="bibr" rid="ref55">55</xref>]</td>
                <td>2020</td>
                <td>Germany</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>40</td>
                <td>33.4</td>
                <td>40 (100)</td>
                <td>Posttraumatic stress disorder</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Bove et al [<xref ref-type="bibr" rid="ref56">56</xref>]</td>
                <td>2021</td>
                <td>United States</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>44</td>
                <td>51.1</td>
                <td>9 (20.5)</td>
                <td>Multiple sclerosis</td>
                <td>Clinical</td>
              </tr>
              <tr valign="top">
                <td>Sanchez et al [<xref ref-type="bibr" rid="ref57">57</xref>]</td>
                <td>2017</td>
                <td>United States</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>69</td>
                <td>NR</td>
                <td>41 (59.4)</td>
                <td>Social skills deficits</td>
                <td>Community and educational</td>
              </tr>
              <tr valign="top">
                <td>Beidel et al [<xref ref-type="bibr" rid="ref58">58</xref>]</td>
                <td>2021</td>
                <td>United States</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>42</td>
                <td>9.6</td>
                <td>16 (38.1)</td>
                <td>Social anxiety</td>
                <td>Community</td>
              </tr>
              <tr valign="top">
                <td>Haberkamp et al [<xref ref-type="bibr" rid="ref59">59</xref>]</td>
                <td>2021</td>
                <td>Germany</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>68</td>
                <td>22.8</td>
                <td>9 (13)</td>
                <td>Arachnophobia</td>
                <td>Educational</td>
              </tr>
              <tr valign="top">
                <td>Litvin et al [<xref ref-type="bibr" rid="ref60">60</xref>]</td>
                <td>2020</td>
                <td>United Kingdom</td>
                <td>Journal article</td>
                <td>Parallel</td>
                <td>709</td>
                <td>NR</td>
                <td>420 (59.3)</td>
                <td>Generally healthy employees</td>
                <td>Company</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="table1fn1">
              <p><sup>a</sup>RCT: randomized controlled trial.</p>
            </fn>
            <fn id="table1fn2">
              <p><sup>b</sup>NR: not reported.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>The sample size in the included studies ranged from 30 to 709, with an average of 112.8 (SD 93.2). The targeted participants were adults (aged &#62;18 years) in 18 studies, adolescents (aged 12-18 years) in 5 studies, children (aged 5-11 years) in 5 studies, and both children and adolescents in 3 studies. Specifically, the mean age of participants reported in 31 studies ranged between 6.6 and 84.2 years, with an average of 34.7 (SD 22.4) years. The percentage of males reported in 31 studies ranged from 0% to 100%, with an average of 43.2% (SD 23.8%). The participants’ health conditions varied between studies, and anxiety was the most common (n=7). The participants in most studies were recruited from clinical settings (n=22).</p>
        <p>Only serious games were used as interventions in 28 of the included studies, whereas the remainder used serious games combined with other interventions (<xref ref-type="table" rid="table2">Table 2</xref>). Nintendo Wii Fit (n=5) was the most common game used in the included studies, followed by MindLight (n=4). We identified eight types of serious games based on the therapeutic modality that they deliver: exergames (n=13), computerized CBT games (n=6), biofeedback games (n=5), attention distraction games (n=3), brain training games (n=2), social skills training games (n=2), exposure therapy games (n=1), and psychoeducation games (n=1). In 20 studies, games were designed with a <italic>serious</italic> purpose from the beginning (designed serious games); however, in the remaining 13 studies, they were not designed as serious games from the start but rather were used for a serious purpose (purpose-shifted games). The most common platforms used for playing games were computers (n=17) and video game consoles (n=8). The duration of the games in the included studies ranged from 5 to 150 minutes, but it was ≤60 minutes in most studies (n=28). The frequency of playing the games varied between only one time throughout the study and once a day, but it ranged between once a week and 3 times a week in 24 studies. The intervention period ranged from 1 to 24 weeks, but it ranged from 1 to 10 weeks in 25 studies.</p>
        <p>As shown in <xref ref-type="table" rid="table3">Table 3</xref>, the comparison groups received inactive interventions in 14 studies while they received active interventions in 21 studies (eg, conventional exercises, CBT programs, video games, medication, and psychotherapy). Note that the numbers do not add up because 2 studies delivered both active and inactive interventions as comparators. The duration of the active comparators ranged from 10 to 180 minutes. The frequency of the active comparators varied between only one time throughout the study and once a day, but it ranged between once a week and 3 times a week in about half of the studies (15/33, 45.5%. The period of active comparators varied between 1 week and 24 weeks. The outcome of interest (eg, anxiety level) was measured using 15 different tools, but the most common tools used by the included studies were the Spence Children’s Anxiety Scale (SCAS; n=8) and the Hospital Anxiety and Depression Scale (n=7). The outcome of interest was measured immediately after the intervention in all included studies, and the most common follow-up period was 3 months (n=10). Participant attrition was reported in 32 studies, ranging from 0 to 335.</p>
        <table-wrap position="float" id="table2">
          <label>Table 2</label>
          <caption>
            <p>Characteristics of interventions.</p>
          </caption>
          <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
            <col width="140"/>
            <col width="130"/>
            <col width="130"/>
            <col width="140"/>
            <col width="90"/>
            <col width="120"/>
            <col width="80"/>
            <col width="100"/>
            <col width="70"/>
            <thead>
              <tr valign="top">
                <td>Study</td>
                <td>Intervention</td>
                <td>Serious game name</td>
                <td>Serious game type</td>
                <td>Serious game genre</td>
                <td>Platform</td>
                <td>Duration (minute)</td>
                <td>Frequency (time per week)</td>
                <td>Period (week)</td>
              </tr>
            </thead>
            <tbody>
              <tr valign="top">
                <td>Adomaviciene et al [<xref ref-type="bibr" rid="ref28">28</xref>]</td>
                <td>Serious game</td>
                <td>N/A<sup>a</sup></td>
                <td>Exergame</td>
                <td>Designed</td>
                <td>Computer, Kinect</td>
                <td>45</td>
                <td>Once a day</td>
                <td>2</td>
              </tr>
              <tr valign="top">
                <td>Carvalho et al [<xref ref-type="bibr" rid="ref29">29</xref>]</td>
                <td>Serious game</td>
                <td>Wii Fit Plus</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Wii console, balance board, Wii remote plus</td>
                <td>60</td>
                <td>3</td>
                <td>7</td>
              </tr>
              <tr valign="top">
                <td>Meldrum et al [<xref ref-type="bibr" rid="ref30">30</xref>]</td>
                <td>Serious game</td>
                <td>Wii Fit Plus</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Wii console, balance board, Frii Board</td>
                <td>15</td>
                <td>5</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Schumacher et al [<xref ref-type="bibr" rid="ref31">31</xref>]</td>
                <td>Serious game</td>
                <td>Wii Fit, Wii Sports</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Wii console, balance board</td>
                <td>30</td>
                <td>5</td>
                <td>2</td>
              </tr>
              <tr valign="top">
                <td>Ruivo et al [<xref ref-type="bibr" rid="ref32">32</xref>]</td>
                <td>Serious game</td>
                <td>Wii Sports</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Wii console, Kinect</td>
                <td>60</td>
                <td>2</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Mazzoleni et al [<xref ref-type="bibr" rid="ref33">33</xref>]</td>
                <td>Serious game + pulmonary rehabilitation program</td>
                <td>Wii Fit Plus</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Wii console, balance board, Wii remote plus</td>
                <td>60</td>
                <td>7</td>
                <td>3</td>
              </tr>
              <tr valign="top">
                <td>Polat et al [<xref ref-type="bibr" rid="ref34">34</xref>]</td>
                <td>Serious game + cycling activity</td>
                <td>Kinect Sports (Beach Volleyball)</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Computer, Kinect</td>
                <td>35</td>
                <td>3</td>
                <td>4</td>
              </tr>
              <tr valign="top">
                <td>Lin et al [<xref ref-type="bibr" rid="ref35">35</xref>]</td>
                <td>Serious game + hot packs + transcutaneous electrical nerve stimulation</td>
                <td>Hot Plus</td>
                <td>Exergame</td>
                <td>Designed</td>
                <td>Computer, sensing pad</td>
                <td>20</td>
                <td>3</td>
                <td>4</td>
              </tr>
              <tr valign="top">
                <td>Vieira et al [<xref ref-type="bibr" rid="ref36">36</xref>]</td>
                <td>Serious game</td>
                <td>Kinect-RehabPlay</td>
                <td>Exergame</td>
                <td>Designed</td>
                <td>Computer, Kinect</td>
                <td>70-85</td>
                <td>3</td>
                <td>24</td>
              </tr>
              <tr valign="top">
                <td>Thomas et al [<xref ref-type="bibr" rid="ref37">37</xref>]</td>
                <td>Serious game</td>
                <td>Wii Fit Plus, Wii Sports, Wii Sports Resort</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Wii console, balance board, Wii remote controls</td>
                <td>27</td>
                <td>2</td>
                <td>24</td>
              </tr>
              <tr valign="top">
                <td>Wagener et al [<xref ref-type="bibr" rid="ref38">38</xref>]</td>
                <td>Serious game</td>
                <td>Dance Dance Revolution</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Computer, sensing pad</td>
                <td>40-75</td>
                <td>3</td>
                <td>10</td>
              </tr>
              <tr valign="top">
                <td>Jahouh et al [<xref ref-type="bibr" rid="ref39">39</xref>]</td>
                <td>Serious game</td>
                <td>Step, Nodding</td>
                <td>Exergame</td>
                <td>Purpose-shifted</td>
                <td>Wii console</td>
                <td>40-45</td>
                <td>2-3</td>
                <td>8</td>
              </tr>
              <tr valign="top">
                <td>Collado-Mateo et al [<xref ref-type="bibr" rid="ref40">40</xref>]</td>
                <td>Serious game</td>
                <td>VirtualEx-FM</td>
                <td>Exergame</td>
                <td>Designed</td>
                <td>Computer, Kinect</td>
                <td>60</td>
                <td>2</td>
                <td>8</td>
              </tr>
              <tr valign="top">
                <td>Cooney et al [<xref ref-type="bibr" rid="ref41">41</xref>]</td>
                <td>Serious game</td>
                <td>Pesky Gnats: The Feel Good Island</td>
                <td>CBT<sup>b</sup> game</td>
                <td>Designed</td>
                <td>Computer</td>
                <td>60</td>
                <td>1</td>
                <td>7</td>
              </tr>
              <tr valign="top">
                <td>Donker et al [<xref ref-type="bibr" rid="ref42">42</xref>]</td>
                <td>Serious game</td>
                <td>ZeroPhobia</td>
                <td>CBT game</td>
                <td>Designed</td>
                <td>Smartphone, wearables (VR<sup>c</sup> goggles)</td>
                <td>5-40</td>
                <td>2</td>
                <td>3</td>
              </tr>
              <tr valign="top">
                <td>Fish et al [<xref ref-type="bibr" rid="ref43">43</xref>]</td>
                <td>Serious game</td>
                <td>Bejeweled II, Peggle, Bookworm Adventures</td>
                <td>CBT game</td>
                <td>Purpose-shifted</td>
                <td>Computer</td>
                <td>30</td>
                <td>3</td>
                <td>4</td>
              </tr>
              <tr valign="top">
                <td>Fleming et al [<xref ref-type="bibr" rid="ref44">44</xref>]</td>
                <td>Serious game</td>
                <td>SPARX</td>
                <td>CBT game</td>
                <td>Designed</td>
                <td>Computer</td>
                <td>30</td>
                <td>1-2</td>
                <td>5</td>
              </tr>
              <tr valign="top">
                <td>Merry et al [<xref ref-type="bibr" rid="ref45">45</xref>]</td>
                <td>Serious game</td>
                <td>SPARX</td>
                <td>CBT game</td>
                <td>Designed</td>
                <td>Computer</td>
                <td>20-40</td>
                <td>1-2</td>
                <td>4-7</td>
              </tr>
              <tr valign="top">
                <td>Perry et al [<xref ref-type="bibr" rid="ref46">46</xref>]</td>
                <td>Serious game</td>
                <td>SPARX-R</td>
                <td>CBT game</td>
                <td>Designed</td>
                <td>Computer</td>
                <td>20-30</td>
                <td>1-2</td>
                <td>5-7</td>
              </tr>
              <tr valign="top">
                <td>Schoneveld et al [<xref ref-type="bibr" rid="ref47">47</xref>]</td>
                <td>Serious game</td>
                <td>MindLight</td>
                <td>Biofeedback game</td>
                <td>Designed</td>
                <td>Computer, wearables (EEG<sup>d</sup> headset)</td>
                <td>60</td>
                <td>1</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Tsui [<xref ref-type="bibr" rid="ref48">48</xref>]</td>
                <td>Serious game</td>
                <td>MindLight</td>
                <td>Biofeedback game</td>
                <td>Designed</td>
                <td>Computer</td>
                <td>60</td>
                <td>2</td>
                <td>3</td>
              </tr>
              <tr valign="top">
                <td>Schoneveld et al [<xref ref-type="bibr" rid="ref49">49</xref>]</td>
                <td>Serious game</td>
                <td>MindLight</td>
                <td>Biofeedback game</td>
                <td>Designed</td>
                <td>Computer, wearables (EEG headset)</td>
                <td>60</td>
                <td>2</td>
                <td>3</td>
              </tr>
              <tr valign="top">
                <td>Wijnhoven et al [<xref ref-type="bibr" rid="ref50">50</xref>]</td>
                <td>Serious game</td>
                <td>MindLight</td>
                <td>Biofeedback game</td>
                <td>Designed</td>
                <td>Computer, wearable (headset)</td>
                <td>60</td>
                <td>1</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Scholten et al [<xref ref-type="bibr" rid="ref51">51</xref>]</td>
                <td>Serious game</td>
                <td>Dojo</td>
                <td>Biofeedback game</td>
                <td>Designed</td>
                <td>Computer</td>
                <td>60</td>
                <td>2</td>
                <td>3</td>
              </tr>
              <tr valign="top">
                <td>Marechal et al [<xref ref-type="bibr" rid="ref52">52</xref>]</td>
                <td>Serious game</td>
                <td>N/A</td>
                <td>Attention distraction game</td>
                <td>Purpose-shifted</td>
                <td>Tablet</td>
                <td>20</td>
                <td>One time throughout the study</td>
                <td>N/A</td>
              </tr>
              <tr valign="top">
                <td>Sakızcı Uyar et al [<xref ref-type="bibr" rid="ref53">53</xref>]</td>
                <td>Serious game</td>
                <td>Angry Birds, Subway Surfers, Snail Bob</td>
                <td>Attention distraction game</td>
                <td>Purpose-shifted</td>
                <td>Tablet</td>
                <td>20</td>
                <td>One time throughout the study</td>
                <td>N/A</td>
              </tr>
              <tr valign="top">
                <td>Liu et al [<xref ref-type="bibr" rid="ref54">54</xref>]</td>
                <td>Serious game + topical analgesia</td>
                <td>SpaceBurgers</td>
                <td>Attention distraction game</td>
                <td>Designed</td>
                <td>Wearables (VR goggles), handheld controller</td>
                <td>NR</td>
                <td>One time throughout the study</td>
                <td>N/A</td>
              </tr>
              <tr valign="top">
                <td>Butler et al [<xref ref-type="bibr" rid="ref55">55</xref>]</td>
                <td>Serious game + eye movement desensitization and reprocessing (EMDR<sup>e</sup>) therapy</td>
                <td>Tetris</td>
                <td>Brain training game</td>
                <td>Purpose-shifted</td>
                <td>Nintendo DS XL console</td>
                <td>120-150</td>
                <td>Once a day (Tetris); 2 time a week (EMDR)</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Bove et al [<xref ref-type="bibr" rid="ref56">56</xref>]</td>
                <td>Serious game</td>
                <td>Band Togather</td>
                <td>Brain training game</td>
                <td>Designed</td>
                <td>Tablet</td>
                <td>25</td>
                <td>5</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Sanchez et al [<xref ref-type="bibr" rid="ref57">57</xref>]</td>
                <td>Serious game</td>
                <td>Adventures</td>
                <td>Social skills training game</td>
                <td>Designed</td>
                <td>Computer</td>
                <td>25</td>
                <td>1</td>
                <td>9</td>
              </tr>
              <tr valign="top">
                <td>Beidel et al [<xref ref-type="bibr" rid="ref58">58</xref>]</td>
                <td>Serious game</td>
                <td>Pegasys-VR</td>
                <td>Social skills training game (Social effectiveness therapy game)</td>
                <td>Designed</td>
                <td>Tablet</td>
                <td>60-120</td>
                <td>2</td>
                <td>12</td>
              </tr>
              <tr valign="top">
                <td>Haberkamp et al [<xref ref-type="bibr" rid="ref59">59</xref>]</td>
                <td>Serious game</td>
                <td>Spider app</td>
                <td>Exposure therapy game</td>
                <td>Designed</td>
                <td>Smartphone</td>
                <td>12</td>
                <td>2</td>
                <td>1</td>
              </tr>
              <tr valign="top">
                <td>Litvin et al [<xref ref-type="bibr" rid="ref60">60</xref>]</td>
                <td>Serious game</td>
                <td>eQuoo</td>
                <td>Psychoeducation game</td>
                <td>Designed</td>
                <td>Smartphone, tablet</td>
                <td>10-15</td>
                <td>1</td>
                <td>5</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="table2fn1">
              <p><sup>a</sup>N/A: not applicable.</p>
            </fn>
            <fn id="table2fn2">
              <p><sup>b</sup>CBT: cognitive behavioral therapy.</p>
            </fn>
            <fn id="table2fn3">
              <p><sup>c</sup>VR: virtual reality.</p>
            </fn>
            <fn id="table2fn4">
              <p><sup>d</sup>EEG: electroencephalography.</p>
            </fn>
            <fn id="table2fn5">
              <p><sup>e</sup>EMDR: Eye Movement Desensitization and Reprocessing.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <table-wrap position="float" id="table3">
          <label>Table 3</label>
          <caption>
            <p>Characteristics of comparators and outcomes.</p>
          </caption>
          <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
            <col width="160"/>
            <col width="160"/>
            <col width="100"/>
            <col width="100"/>
            <col width="80"/>
            <col width="150"/>
            <col width="170"/>
            <col width="80"/>
            <thead>
              <tr valign="top">
                <td>Study</td>
                <td>Comparator</td>
                <td>Duration (minute)</td>
                <td>Frequency (time per week)</td>
                <td>Period (week)</td>
                <td>Outcome measures</td>
                <td>Follow-up</td>
                <td>Attrition</td>
              </tr>
            </thead>
            <tbody>
              <tr valign="top">
                <td>Adomaviciene et al [<xref ref-type="bibr" rid="ref28">28</xref>]</td>
                <td>Robot-assisted trainings</td>
                <td>45</td>
                <td>Once a day</td>
                <td>2</td>
                <td>HADS<sup>a</sup></td>
                <td>Postintervention</td>
                <td>18</td>
              </tr>
              <tr valign="top">
                <td>Carvalho et al [<xref ref-type="bibr" rid="ref29">29</xref>]</td>
                <td>Conventional exercises</td>
                <td>60</td>
                <td>3</td>
                <td>7</td>
                <td>Fibromyalgia Impact Questionnaire</td>
                <td>Postintervention</td>
                <td>14</td>
              </tr>
              <tr valign="top">
                <td>Meldrum et al [<xref ref-type="bibr" rid="ref30">30</xref>]</td>
                <td>Conventional exercises</td>
                <td>15</td>
                <td>5</td>
                <td>6</td>
                <td>HADS</td>
                <td>Postintervention</td>
                <td>9</td>
              </tr>
              <tr valign="top">
                <td>Schumacher et al [<xref ref-type="bibr" rid="ref31">31</xref>]</td>
                <td>Conventional exercises (physiotherapy)</td>
                <td>30</td>
                <td>5</td>
                <td>2</td>
                <td>HADS</td>
                <td>Postintervention, 30- and 100-day follow-up</td>
                <td>11</td>
              </tr>
              <tr valign="top">
                <td>Ruivo et al [<xref ref-type="bibr" rid="ref32">32</xref>]</td>
                <td>Conventional exercises</td>
                <td>60</td>
                <td>2</td>
                <td>6</td>
                <td>HADS</td>
                <td>Postintervention, 2-month follow-up</td>
                <td>4</td>
              </tr>
              <tr valign="top">
                <td>Mazzoleni et al [<xref ref-type="bibr" rid="ref33">33</xref>]</td>
                <td>Conventional exercises (pulmonary rehabilitation program)</td>
                <td>60</td>
                <td>7</td>
                <td>3</td>
                <td>STAI<sup>b</sup></td>
                <td>Postintervention</td>
                <td>1</td>
              </tr>
              <tr valign="top">
                <td>Polat et al [<xref ref-type="bibr" rid="ref34">34</xref>]</td>
                <td>Conventional exercises + cycling activity</td>
                <td>35</td>
                <td>3</td>
                <td>4</td>
                <td>HADS</td>
                <td>Postintervention, 1-month follow-up</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Lin et al [<xref ref-type="bibr" rid="ref35">35</xref>]</td>
                <td>Conventional exercises + hot packs + transcutaneous electrical nerve stimulation</td>
                <td>20</td>
                <td>3</td>
                <td>4</td>
                <td>HADS</td>
                <td>Midintervention, postintervention, and 1 and 3-month follow-up</td>
                <td>1</td>
              </tr>
              <tr valign="top">
                <td>Vieira et al [<xref ref-type="bibr" rid="ref36">36</xref>]</td>
                <td>Conventional exercises, control</td>
                <td>70-85</td>
                <td>3</td>
                <td>24</td>
                <td>Depression Anxiety and Stress Scale 21</td>
                <td>Midintervention, postintervention</td>
                <td>13</td>
              </tr>
              <tr valign="top">
                <td>Thomas et al [<xref ref-type="bibr" rid="ref37">37</xref>]</td>
                <td>Control</td>
                <td>N/A<sup>c</sup></td>
                <td>N/A</td>
                <td>N/A</td>
                <td>HADS</td>
                <td>Postintervention</td>
                <td>2</td>
              </tr>
              <tr valign="top">
                <td>Wagener et al [<xref ref-type="bibr" rid="ref38">38</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Behavior Assessment System for Children-2</td>
                <td>Postintervention</td>
                <td>1</td>
              </tr>
              <tr valign="top">
                <td>Jahouh et al [<xref ref-type="bibr" rid="ref39">39</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Goldberg Anxiety and Depression Scale</td>
                <td>Postintervention</td>
                <td>N/A</td>
              </tr>
              <tr valign="top">
                <td>Collado-Mateo et al [<xref ref-type="bibr" rid="ref40">40</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Fibromyalgia Impact Questionnaire</td>
                <td>Postintervention</td>
                <td>7</td>
              </tr>
              <tr valign="top">
                <td>Cooney et al [<xref ref-type="bibr" rid="ref41">41</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Glasgow Anxiety Scale for people with an Intellectual Disability</td>
                <td>Postintervention, 3-month follow-up</td>
                <td>3</td>
              </tr>
              <tr valign="top">
                <td>Donker et al [<xref ref-type="bibr" rid="ref42">42</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Beck Anxiety Inventory, Acrophobia Questionnaire</td>
                <td>Postintervention, 3-month follow-up</td>
                <td>59</td>
              </tr>
              <tr valign="top">
                <td>Fish et al [<xref ref-type="bibr" rid="ref43">43</xref>]</td>
                <td>Educational website</td>
                <td>30</td>
                <td>3</td>
                <td>4</td>
                <td>State-Trait Anxiety Inventory</td>
                <td>Postintervention</td>
                <td>0</td>
              </tr>
              <tr valign="top">
                <td>Fleming et al [<xref ref-type="bibr" rid="ref44">44</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>SCAS<sup>d</sup></td>
                <td>Postintervention</td>
                <td>5</td>
              </tr>
              <tr valign="top">
                <td>Merry et al [<xref ref-type="bibr" rid="ref45">45</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>SCAS</td>
                <td>Postintervention, 3-month follow-up</td>
                <td>17</td>
              </tr>
              <tr valign="top">
                <td>Perry et al [<xref ref-type="bibr" rid="ref46">46</xref>]</td>
                <td>Control (interactive web-based program)</td>
                <td>20-30</td>
                <td>1-2</td>
                <td>5-7</td>
                <td>SCAS</td>
                <td>Postintervention, 6- and 18-month follow-up</td>
                <td>134</td>
              </tr>
              <tr valign="top">
                <td>Schoneveld et al [<xref ref-type="bibr" rid="ref47">47</xref>]</td>
                <td>Conventional CBT<sup>e</sup></td>
                <td>60-90</td>
                <td>1</td>
                <td>8</td>
                <td>SCAS</td>
                <td>Postintervention, 3- and 6-month follow-up</td>
                <td>36</td>
              </tr>
              <tr valign="top">
                <td>Tsui [<xref ref-type="bibr" rid="ref48">48</xref>]</td>
                <td>Conventional CBT (web-based CBT)</td>
                <td>60</td>
                <td>2</td>
                <td>3</td>
                <td>SCAS, STAI</td>
                <td>Postintervention, 3-month follow-up</td>
                <td>19</td>
              </tr>
              <tr valign="top">
                <td>Schoneveld et al [<xref ref-type="bibr" rid="ref49">49</xref>]</td>
                <td>Video game</td>
                <td>60</td>
                <td>2</td>
                <td>3</td>
                <td>SCAS</td>
                <td>Postintervention, 3-month follow-up</td>
                <td>21</td>
              </tr>
              <tr valign="top">
                <td>Wijnhoven et al [<xref ref-type="bibr" rid="ref50">50</xref>]</td>
                <td>Video game</td>
                <td>60</td>
                <td>1</td>
                <td>6</td>
                <td>SCAS</td>
                <td>Postintervention, 3-month follow-up</td>
                <td>33</td>
              </tr>
              <tr valign="top">
                <td>Scholten et al [<xref ref-type="bibr" rid="ref51">51</xref>]</td>
                <td>Video game</td>
                <td>60</td>
                <td>2</td>
                <td>3</td>
                <td>SCAS</td>
                <td>Postintervention, 3-month follow-up</td>
                <td>9</td>
              </tr>
              <tr valign="top">
                <td>Marechal et al [<xref ref-type="bibr" rid="ref52">52</xref>]</td>
                <td>Midazolam</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Modified Yale Preoperative Anxiety Scale</td>
                <td>Postintervention, 2-hour follow-up</td>
                <td>3</td>
              </tr>
              <tr valign="top">
                <td>Sakızcı Uyar et al [<xref ref-type="bibr" rid="ref53">53</xref>]</td>
                <td>Midazolam, watching an informative cartoon</td>
                <td>N/A</td>
                <td>One time throughout the study</td>
                <td>N/A</td>
                <td>Modified Yale Preoperative Anxiety Scale</td>
                <td>Postintervention</td>
                <td>4</td>
              </tr>
              <tr valign="top">
                <td>Liu et al [<xref ref-type="bibr" rid="ref54">54</xref>]</td>
                <td>Control (topical analgesia)</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Subjective Units of Distress</td>
                <td>Postintervention</td>
                <td>0</td>
              </tr>
              <tr valign="top">
                <td>Butler et al [<xref ref-type="bibr" rid="ref55">55</xref>]</td>
                <td>Eye Movement Desensitization and Reprocessing therapy</td>
                <td>60-90</td>
                <td>2</td>
                <td>6</td>
                <td>STAI</td>
                <td>Postintervention, 6-month follow-up</td>
                <td>0</td>
              </tr>
              <tr valign="top">
                <td>Bove et al [<xref ref-type="bibr" rid="ref56">56</xref>]</td>
                <td>Video game</td>
                <td>25</td>
                <td>5</td>
                <td>6</td>
                <td>STAI</td>
                <td>Postintervention, 2-month follow-up</td>
                <td>4</td>
              </tr>
              <tr valign="top">
                <td>Sanchez et al [<xref ref-type="bibr" rid="ref57">57</xref>]</td>
                <td>Control</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>N/A</td>
                <td>Social Anxiety Scale for Children-Revised</td>
                <td>Postintervention</td>
                <td>24</td>
              </tr>
              <tr valign="top">
                <td>Beidel et al [<xref ref-type="bibr" rid="ref58">58</xref>]</td>
                <td>Social effectiveness therapy</td>
                <td>60-180</td>
                <td>2</td>
                <td>12</td>
                <td>SPAI-C<sup>f</sup></td>
                <td>Postintervention</td>
                <td>4</td>
              </tr>
              <tr valign="top">
                <td>Haberkamp et al [<xref ref-type="bibr" rid="ref59">59</xref>]</td>
                <td>Video game</td>
                <td>12</td>
                <td>2</td>
                <td>1</td>
                <td>Survey developed by the authors</td>
                <td>Midintervention, Postintervention</td>
                <td>6</td>
              </tr>
              <tr valign="top">
                <td>Litvin et al [<xref ref-type="bibr" rid="ref60">60</xref>]</td>
                <td>Conventional CBT, control</td>
                <td>10</td>
                <td>1</td>
                <td>5</td>
                <td>Survey developed by the authors</td>
                <td>Midintervention, Postintervention</td>
                <td>355</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="table3fn1">
              <p><sup>a</sup>HADS: Hospital Anxiety and Depression Scale.</p>
            </fn>
            <fn id="table3fn2">
              <p><sup>b</sup>STAI: State-Trait Anxiety Inventory.</p>
            </fn>
            <fn id="table3fn3">
              <p><sup>c</sup>N/A: not applicable.</p>
            </fn>
            <fn id="table3fn4">
              <p><sup>d</sup>SCAS: Spence Children’s Anxiety Scale.</p>
            </fn>
            <fn id="table3fn5">
              <p><sup>e</sup>CBT: cognitive behavioral therapy.</p>
            </fn>
            <fn id="table3fn6">
              <p><sup>f</sup>SPAI-C: Social Phobia and Anxiety Inventory for Children.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
      </sec>
      <sec>
        <title>Results of Risk of Bias Appraisal</title>
        <p>Approximately 70% (23/33) of the included studies generated an appropriate random allocation sequence for the randomization process. The allocation sequence in 14 studies was concealed until the participants were assigned to the interventions. The groups were comparable at baseline in the 29 studies. On the basis of these judgments, the risk of bias because of the randomization process was rated as low in 12 studies (<xref rid="figure2" ref-type="fig">Figure 2</xref>).</p>
        <p>Participants and those who were delivering the interventions were blinded to the assigned interventions during the trial in 4 and 5 studies, respectively. In 2 studies, there was a deviation from the intended intervention, which occurred because of the experimental contexts. An appropriate analysis (eg, intention-to-treat or modified intention-to-treat analyses) was used in 26 studies to estimate the effect of the intervention. According to these judgments, the risk of bias because of deviations from the intended interventions was low in 20 studies (<xref rid="figure2" ref-type="fig">Figure 2</xref>).</p>
        <p>Outcome data were available for more than 95% of the participants only in 12 studies. There was evidence that the findings were not biased by the missing outcome data in only 7 studies. In 8 studies, the missing outcome data resulted from reasons that were documented and not related to the outcome. Accordingly, 27 studies were judged as having a low risk of bias in the <italic>missing outcome data</italic> domain.</p>
        <p>Four studies assessed the outcome of interest (ie, anxiety levels) using inappropriate measures. The measurement methods were comparable across the intervention groups in all included studies. The assessor of the outcome was aware of the assigned interventions in the 20 studies. Given that the outcome measure was subjective in all studies, the assessment of the outcome could have been affected by knowledge of the intervention received. Accordingly, only 9 studies were rated as having a low risk of bias in the <italic>measuring the outcome</italic> domain (<xref rid="figure2" ref-type="fig">Figure 2</xref>).</p>
        <fig id="figure2" position="float">
          <label>Figure 2</label>
          <caption>
            <p>Review authors’ judgments about each risk of bias domain.</p>
          </caption>
          <graphic xlink:href="games_v10i1e29137_fig2.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
        </fig>
        <p>There was a prespecified analysis plan (ie, protocol) for the 15 studies. Only 3 studies reported outcome measurements that differed from those specified in the analysis plan. In all studies, there was no evidence that they selected their results from many results produced from multiple eligible analyses of the data. Accordingly, the risk of bias because of the selection of the reported results was considered low in 15 studies (<xref rid="figure2" ref-type="fig">Figure 2</xref>).</p>
        <p>In the last domain, <italic>overall bias</italic>, the risk of bias was considered high in 21 studies as they were judged as having a high risk of bias in at least one domain. Ten studies were judged to raise some concerns in the domain of <italic>overall bias</italic>, as they had some concerns in at least one of the domains and were not at high risk for any domain. The 2 remaining studies were judged to be at low risk of bias for the domain of <italic>overall bias</italic>, given that it was rated as having a low risk of bias for all domains. Reviewers’ judgments about each <italic>risk of bias</italic> domain for each included study are presented in <xref ref-type="supplementary-material" rid="app4">Multimedia Appendix 4</xref> [<xref ref-type="bibr" rid="ref29">29</xref>-<xref ref-type="bibr" rid="ref60">60</xref>].</p>
      </sec>
      <sec>
        <title>Results of Studies</title>
        <p>In this review, serious games were classified into eight types based on the therapeutic modality that they deliver: exergames [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref40">40</xref>], computerized CBT games [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref46">46</xref>], biofeedback games [<xref ref-type="bibr" rid="ref47">47</xref>-<xref ref-type="bibr" rid="ref51">51</xref>], attention distraction games [<xref ref-type="bibr" rid="ref52">52</xref>-<xref ref-type="bibr" rid="ref54">54</xref>], brain training games [<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref56">56</xref>], social skills training games [<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref58">58</xref>], exposure therapy games [<xref ref-type="bibr" rid="ref59">59</xref>], and psychoeducation games [<xref ref-type="bibr" rid="ref60">60</xref>]. The results of the included studies are shown in the following subsections based on the types of serious games.</p>
      </sec>
      <sec>
        <title>Exergames</title>
        <sec>
          <title>Exergames Versus Conventional Exercises</title>
          <p>In total, 9 studies compared the effects of exergames with conventional exercises on the level of anxiety [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref36">36</xref>]. While 7 studies did not find a statistically significant difference in the anxiety levels between the groups [<xref ref-type="bibr" rid="ref30">30</xref>-<xref ref-type="bibr" rid="ref36">36</xref>], the 2 remaining studies showed a statistically significant difference in the anxiety level between the groups (one of them favored exergames over conventional exercises [<xref ref-type="bibr" rid="ref29">29</xref>] while the other favored conventional exercises over exergames [<xref ref-type="bibr" rid="ref28">28</xref>]).</p>
          <p>The results of the 9 studies were meta-analyzed as shown in <xref rid="figure3" ref-type="fig">Figure 3</xref> [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref36">36</xref>]. No statistically significant difference (<italic>P</italic>=.70) in the anxiety levels was found between the exergame group and conventional exercise group (SMD −0.07, 95% CI −0.45 to 0.30). The degree of evidence heterogeneity was substantial (<italic>P</italic>=.002; <italic>I</italic><sup>2</sup>=67%). The quality of the evidence was very low, as it was downgraded by 6 levels because of a high risk of bias, heterogeneity, and imprecision (<xref ref-type="supplementary-material" rid="app5">Multimedia Appendix 5</xref>).</p>
          <p>We ran a sensitivity analysis, given that some effect sizes seem to be outliers. Specifically, we removed the study conducted by Adomaviciene et al [<xref ref-type="bibr" rid="ref28">28</xref>] for two reasons: (1) the anxiety level at baseline was statistically higher (<italic>P</italic>&#60;.001) in the exergame group (mean 9.16, SD 4.59) than in the conventional exercise group (mean 5.52, SD 2.37) and (2) the comparator was conventional exercises guided by robotic devices, which is not the case in other studies. Although the degree of heterogeneity decreased significantly from 67% to 30% by excluding Adomaviciene et al [<xref ref-type="bibr" rid="ref28">28</xref>], there was still no statistically significant difference (<italic>P</italic>=.18) in the anxiety levels between groups (SMD −0.18, 95% CI −0.45 to 0.08; <xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref> [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref60">60</xref>]).</p>
          <p>We also reran the meta-analysis after excluding another study [<xref ref-type="bibr" rid="ref36">36</xref>] because the anxiety level at baseline was considerably higher in the conventional exercise group (mean 8.0, SD 9.1) than in the exergame group (mean 2.7, SD 2.0). Similar to the first sensitivity analysis, the degree of heterogeneity decreased significantly from 30% to 13% by excluding Vieira et al [<xref ref-type="bibr" rid="ref36">36</xref>]; however, there was still no statistically significant difference (<italic>P</italic>=.38) in the anxiety levels between groups (SMD −0.11, 95% CI −0.35 to 0.13; <xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>).</p>
          <fig id="figure3" position="float">
            <label>Figure 3</label>
            <caption>
              <p>Forest plot of 9 studies comparing the effect of exergames to that of conventional exercises on the anxiety level [<xref ref-type="bibr" rid="ref28">28</xref>-<xref ref-type="bibr" rid="ref36">36</xref>]. Std: standardized.</p>
            </caption>
            <graphic xlink:href="games_v10i1e29137_fig3.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
        </sec>
        <sec>
          <title>Exergames Versus No Intervention</title>
          <p>Five studies compared the effect of exergames with no intervention or inactive intervention on anxiety levels [<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref40">40</xref>]. Whereas 4 studies did not find a statistically significant difference in anxiety levels between the groups [<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref39">39</xref>], the remaining study showed a statistically significant difference in the anxiety levels between the groups, favoring exergames over no intervention [<xref ref-type="bibr" rid="ref40">40</xref>].</p>
          <p>A meta-analysis of the results of the 5 studies showed no statistically significant difference (<italic>P</italic>=.27) in the anxiety levels between the exergame group and the no intervention group (SMD −0.23, 95% CI −0.63 to 0.18; <xref rid="figure4" ref-type="fig">Figure 4</xref> [<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref40">40</xref>]). The heterogeneity of the meta-analyzed evidence was substantial (<italic>P</italic>=.03; <italic>I</italic><sup>2</sup>=63%). The quality of the evidence was very low, as it was downgraded by 6 levels because of a high risk of bias, heterogeneity, and imprecision (<xref ref-type="supplementary-material" rid="app5">Multimedia Appendix 5</xref>).</p>
          <fig id="figure4" position="float">
            <label>Figure 4</label>
            <caption>
              <p>Forest plot of 5 studies comparing the effect of exergames to that of no intervention on the anxiety level [<xref ref-type="bibr" rid="ref36">36</xref>-<xref ref-type="bibr" rid="ref40">40</xref>]. Std: standardized.</p>
            </caption>
            <graphic xlink:href="games_v10i1e29137_fig4.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
          <p>We ran a sensitivity analysis because some effect sizes seemed to be outliers. Specifically, we excluded a study conducted by Thomas et al [<xref ref-type="bibr" rid="ref37">37</xref>], given that the anxiety level at baseline was statistically higher (<italic>P</italic>=.01) in the exergame group (mean 8.53, SD 3.62) than in the control group (mean 6.27, SD 3.28). The degree of heterogeneity decreased significantly from 63% to 28% when excluding the results in Thomas et al [<xref ref-type="bibr" rid="ref37">37</xref>]. The difference in anxiety levels between the groups was statistically significant (<italic>P</italic>=.02; SMD −0.38, 95% CI −0.71 to −0.06), favoring exergames over no intervention (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>). This difference was also clinically important as the overall effect was outside the MCID boundaries (−0.19 to +0.19) and its CI did not cross the <italic>no-effect</italic> line (zero effect). We also performed a sensitivity analysis after excluding another study [<xref ref-type="bibr" rid="ref36">36</xref>] because anxiety levels at baseline were considerably higher in the control group (mean 6.9, SD 7.4) than in the exergame group (mean 2.7, SD 2.0). However, the degree of heterogeneity and total effect size did not change significantly (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>).</p>
        </sec>
        <sec>
          <title>Computerized CBT Games</title>
          <p>Six studies compared the effect of computerized CBT games with no intervention on anxiety levels [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref46">46</xref>]. While 3 studies did not find a statistically significant difference in anxiety levels between the groups [<xref ref-type="bibr" rid="ref44">44</xref>-<xref ref-type="bibr" rid="ref46">46</xref>], the 3 remaining studies showed a statistically significant difference in the anxiety levels between the groups, favoring computerized CBT games over no intervention [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref43">43</xref>].</p>
          <p>The results of these 6 studies were included in the meta-analysis. Three of these studies assessed anxiety levels using 2 different measures (Acrophobia Questionnaire [AQ] and Beck Anxiety Inventory [BAI] [<xref ref-type="bibr" rid="ref42">42</xref>], State-Trait Anxiety Inventory [STAI]–State and STAI-Trait [<xref ref-type="bibr" rid="ref43">43</xref>], SCAS–Generalized Anxiety Disorder, and SCAS-Social Anxiety [<xref ref-type="bibr" rid="ref46">46</xref>]). Therefore, we included the results of all these measures in the meta-analysis to form 9 comparisons (<xref rid="figure5" ref-type="fig">Figure 5</xref> [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref46">46</xref>]). The meta-analysis showed a statistically significant difference in the anxiety levels (<italic>P</italic>=.01) between computerized CBT games and control groups, favoring computerized CBT games over no intervention (SMD −0.36, 95% CI −.63 to −0.08). This difference was also clinically important as the overall effect was outside the MCID boundaries (−0.18 to +0.18) and its CI neither crossed the <italic>no-effect</italic> line (zero effect) nor any of the 2 MCID boundaries. For this outcome, MCID boundaries were calculated as −0.5 to +0.5 times the SMD value (−0.36). The statistical heterogeneity of the evidence was considerable (<italic>P</italic>&#60;.001; <italic>I</italic><sup>2</sup>=84%). The quality of the evidence was very low, as it was downgraded by 5 levels because of a high risk of bias, heterogeneity, and imprecision (<xref ref-type="supplementary-material" rid="app5">Multimedia Appendix 5</xref>).</p>
          <fig id="figure5" position="float">
            <label>Figure 5</label>
            <caption>
              <p>Forest plot of 6 studies (9 comparisons) comparing the effect of CBT games to that of no intervention on the severity of depressive symptoms [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref46">46</xref>]. CBT: cognitive behavioral therapy; Std: standardized.</p>
            </caption>
            <graphic xlink:href="games_v10i1e29137_fig5.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
          <p>It is noteworthy that 3 of the 6 studies in the group targeted adults [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref43">43</xref>] while the reminders targeted adolescents [<xref ref-type="bibr" rid="ref44">44</xref>-<xref ref-type="bibr" rid="ref46">46</xref>]. Therefore, we conducted a subgroup analysis to assess whether the effect of computerized CBT differs between adults and adolescents. The subgroup analysis showed that the effect of computerized CBT on anxiety was statistically different (<italic>P</italic>&#60;.001) between adults and adolescents (<xref rid="figure6" ref-type="fig">Figure 6</xref> [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref46">46</xref>]). Specifically, while there was no statistically significant difference (<italic>P</italic>=.33) in the anxiety levels between the exergame group and the no intervention group among adolescents (SMD −0.06, 95% CI −0.18 to 0.06), there was a statistically significant difference in the anxiety levels (<italic>P</italic>&#60;.001) between computerized CBT games and control groups among adults (favoring computerized CBT games over no intervention [SMD −0.68, 95% CI −1.02 to −0.34]). The statistically significant difference among adults was also clinically important as the overall effect was outside the MCID boundaries (−0.34 to +0.34) and its CI neither crossed the <italic>no-effect</italic> line (Zero effect) nor any of the 2 MCID boundaries. For this outcome, MCID boundaries were calculated as −0.5 to +0.5 times the SMD value (−0.68). The statistical heterogeneity of the evidence was substantial (<italic>P</italic>=.007; <italic>I</italic><sup>2</sup>=71%). The quality of the evidence was very low, as it was downgraded by 4 levels because of a high risk of bias and heterogeneity (<xref ref-type="supplementary-material" rid="app5">Multimedia Appendix 5</xref>).</p>
          <fig id="figure6" position="float">
            <label>Figure 6</label>
            <caption>
              <p>Forest plot of 6 studies (9 comparisons) comparing the effect of CBT games to that of no intervention on the anxiety level among adults and adolescents [<xref ref-type="bibr" rid="ref41">41</xref>-<xref ref-type="bibr" rid="ref46">46</xref>]. CBT: cognitive behavioral therapy; Std: standardized.</p>
            </caption>
            <graphic xlink:href="games_v10i1e29137_fig6.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
          <p>Donker et al [<xref ref-type="bibr" rid="ref42">42</xref>] used two different questionnaires to assess anxiety levels: BAI and AQ-anxiety. The BAI is used to measure general anxiety symptoms while AQ-anxiety measures a specific type of anxiety, which is height-related anxiety [<xref ref-type="bibr" rid="ref61">61</xref>]. We performed a sensitivity analysis by excluding the AQ-related results reported by Donker et al [<xref ref-type="bibr" rid="ref61">61</xref>] because all studies in the meta-analysis assessed general anxiety symptoms. The sensitivity analysis showed a significant decrease in the degree of heterogeneity (from 84% to 56%), and the difference in anxiety levels between the groups remained statistically significant (<italic>P</italic>=.01; SMD −0.23, 95% CI −0.41 to −0.05), favoring computerized CBT games over no intervention (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>). This difference remained clinically important as the overall effect was outside the MCID boundaries (−0.12 to +0.12) and its CI did not cross the <italic>no-effect</italic> line (zero effect). We also performed a sensitivity analysis after excluding another study [<xref ref-type="bibr" rid="ref44">44</xref>] because its sample size (n=30) was relatively small compared with other studies. However, the degree of heterogeneity and total effect size did not change significantly (<xref ref-type="supplementary-material" rid="app6">Multimedia Appendix 6</xref>).</p>
        </sec>
        <sec>
          <title>Biofeedback Games</title>
          <p>Biofeedback games were used as interventions in 5 studies [<xref ref-type="bibr" rid="ref47">47</xref>-<xref ref-type="bibr" rid="ref51">51</xref>]. Two studies examined the effect of a biofeedback game (MindLight) and conventional CBT on anxiety levels (measured by the SCAS) among children with anxiety [<xref ref-type="bibr" rid="ref47">47</xref>,<xref ref-type="bibr" rid="ref48">48</xref>]. Both studies found no statistically significant difference in anxiety levels between the biofeedback game group and the conventional CBT group [<xref ref-type="bibr" rid="ref47">47</xref>,<xref ref-type="bibr" rid="ref48">48</xref>].</p>
          <p>The 3 remaining studies examined the effect of biofeedback games and conventional video games on anxiety levels (measured by the SCAS) among children with anxiety [<xref ref-type="bibr" rid="ref49">49</xref>-<xref ref-type="bibr" rid="ref51">51</xref>]. While 2 studies did not find a statistically significant difference in anxiety levels between the groups [<xref ref-type="bibr" rid="ref50">50</xref>,<xref ref-type="bibr" rid="ref51">51</xref>], the remaining study showed a statistically significant difference in the anxiety level between the groups, favoring biofeedback games over conventional video games [<xref ref-type="bibr" rid="ref49">49</xref>]. A meta-analysis of the results of these 3 studies demonstrated a statistically significant difference in the anxiety levels (<italic>P</italic>=.03) between the biofeedback game group and conventional CBT group, favoring biofeedback games over conventional video games (SMD −0.23, 95% CI −0.43 to −0.03; <xref rid="figure7" ref-type="fig">Figure 7</xref> [<xref ref-type="bibr" rid="ref49">49</xref>-<xref ref-type="bibr" rid="ref51">51</xref>]). This difference was also clinically important as the overall effect was outside the MCID boundaries (−0.115 to +0.115) and its CI neither crossed the <italic>no-effect</italic> line (zero effect) nor any of the 2 MCID boundaries. For this outcome, MCID boundaries were calculated as −0.5 to +0.5 times the SMD value (−0.23). The heterogeneity of the evidence was considered insignificant (<italic>P</italic>=.38; <italic>I</italic><sup>2</sup>=0%). The quality of the evidence was low, as it was downgraded by 2 levels because of a high risk of bias and imprecision.</p>
          <fig id="figure7" position="float">
            <label>Figure 7</label>
            <caption>
              <p>Forest plot of 3 studies comparing the effect of biofeedback games to that of conventional video games on the anxiety level [<xref ref-type="bibr" rid="ref49">49</xref>-<xref ref-type="bibr" rid="ref51">51</xref>]. Std: standardized.</p>
            </caption>
            <graphic xlink:href="games_v10i1e29137_fig7.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
        </sec>
        <sec>
          <title>Attention Distraction Games</title>
          <p>Distraction games were used as interventions in 3 studies. Attention distraction games were interventions in 3 studies [<xref ref-type="bibr" rid="ref52">52</xref>-<xref ref-type="bibr" rid="ref54">54</xref>]. While 2 studies found a statistically significant effect of attention distraction games [<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref54">54</xref>], the remaining study did not [<xref ref-type="bibr" rid="ref52">52</xref>]. Specifically, Marechal et al [<xref ref-type="bibr" rid="ref52">52</xref>] compared the effect of attention distraction games with medication (ie, midazolam) on anxiety levels (measured by the Modified Yale Preoperative Anxiety Scale) among children undergoing general anesthesia for minor surgical procedures. No statistically significant difference (<italic>P</italic>=.99) in anxiety levels was detected between the 2 groups [<xref ref-type="bibr" rid="ref52">52</xref>]. The second study examined the effect of attention distraction games (Angry Birds, Subway Surfers, or Snail Bob), medication (midazolam), and watching an informative cartoon on the anxiety level (measured by the Modified Yale Preoperative Anxiety Scale) among children undergoing adenoidectomy, adenotonsillectomy, or myringotomy [<xref ref-type="bibr" rid="ref53">53</xref>]. The study showed a statistically significant difference (<italic>P</italic>&#60;.001) in the anxiety level between the groups, favoring the attention distraction games over medication (midazolam) and watching an informative cartoon. In the third study [<xref ref-type="bibr" rid="ref54">54</xref>], the effect of an attention distraction game (SpaceBurgers) on anxiety levels (measured by Subjective Units of Distress) among children with otolaryngological issues was compared with topical analgesia. The study found a statistically significant difference (<italic>P</italic>&#60;.001) in the anxiety levels between the groups, favoring attention distraction games over topical analgesia [<xref ref-type="bibr" rid="ref54">54</xref>].</p>
        </sec>
        <sec>
          <title>Brain Training Games</title>
          <p>Brain training games were interventions in 2 studies [<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref56">56</xref>]. The first study compared the effect of a brain training game (Tetris) to eye movement desensitization and reprocessing therapy on the levels of trait anxiety (measured by STAI) among patients with posttraumatic stress disorder [<xref ref-type="bibr" rid="ref55">55</xref>]. The study did not detect any statistically significant difference (<italic>P</italic>=.81) in the level of trait anxiety postintervention [<xref ref-type="bibr" rid="ref55">55</xref>]. The second study compared the effects of a brain training game (Band Together) and traditional video games on the level of anxiety (measured by STAI) in patients with multiple sclerosis [<xref ref-type="bibr" rid="ref56">56</xref>]. No statistically significant difference in the levels of state anxiety (<italic>P</italic>=.95) and trait anxiety (<italic>P</italic>=.75) between the 2 groups was detected.</p>
        </sec>
        <sec>
          <title>Social Skills Training Games</title>
          <p>Social skills training games were an intervention in 2 studies [<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref58">58</xref>]. The first study investigated the effect of a social skills training game (Adventures) on the anxiety level (measured by the Social Anxiety Scale for Children-Revised) among patients with social skills deficits in comparison with no intervention. The study showed no statistically significant difference (<italic>P</italic>=.10) in anxiety levels between the groups. In the second study, the effect of a social skills training game (Pegasys-Virtual Reality) and social effectiveness therapy on the anxiety level (measured by Social Phobia and Anxiety Inventory for Children) among children with social anxiety were examined. The study demonstrated no statistically significant difference (<italic>P</italic>=.23) in anxiety levels between the groups.</p>
        </sec>
        <sec>
          <title>Other Types of Serious Games</title>
          <p>One study compared the effect of an exposure therapy game (Spider App) to an entertainment video game (Bubble Shooter) on anxiety levels among patients with arachnophobia [<xref ref-type="bibr" rid="ref59">59</xref>]. No statistically significant difference in anxiety level was detected between the groups postintervention [<xref ref-type="bibr" rid="ref59">59</xref>].</p>
          <p>Litvin et al [<xref ref-type="bibr" rid="ref60">60</xref>] examined the effect of a psychoeducation game (eQuoo), conventional CBT, and no intervention on anxiety levels among healthy employees. The study did not find any statistically significant difference (<italic>P</italic>=.95) in anxiety levels between the 3 groups [<xref ref-type="bibr" rid="ref60">60</xref>].</p>
        </sec>
      </sec>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <sec>
        <title>Principal Findings</title>
        <p>This review examined the effectiveness of serious games on anxiety levels, as reported by RCTs. Of the 33 RCTs included in the current review, 20 were included in 4 main meta-analyses. The review found no statistically significant effect of exergames on anxiety levels, though it showed a statistically significant effect of computerized CBT games and biofeedback games on anxiety levels. Owing to the paucity of evidence, no statistical analysis was carried out for other types of serious games included in this review.</p>
        <p>Very low–quality evidence from 9 RCTs showed no statistically significant effect of exergames on anxiety levels as compared with conventional exercises. This insignificant effect can be attributed to the fact that exergames are comparable with conventional exercises; therefore, it should not be surprising that comparing the effect of 2 very similar interventions did not produce a significant difference. This indicates that conventional exercises are at least as effective as conventional exercises. Our findings are similar to those of previous reviews [<xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref62">62</xref>]. Specifically, a meta-analysis of 5 RCTs showed no statistically significant difference (<italic>P</italic>=.81) in anxiety levels between the exergames group and the usual care group (ie, conventional exercises) [<xref ref-type="bibr" rid="ref16">16</xref>]. Similarly, no statistically significant difference (<italic>P</italic>=.12) in <italic>depression</italic> levels between the exergames group and conventional exercises was found in another meta-analysis of 7 RCTs [<xref ref-type="bibr" rid="ref62">62</xref>].</p>
        <p>Very low–quality evidence from 5 RCTs showed no statistically significant effect when compared with the effects of exergames on anxiety levels as opposed to no intervention. However, a sensitivity analysis of 4 RCTs showed a statistically and clinically significant effect of exergames on anxiety level when compared with no intervention.</p>
        <p>This finding is consistent with that of a previous review [<xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref62">62</xref>]. Specifically, a meta-analysis of 8 studies showed a statistically significant difference (<italic>P</italic>=.004) in <italic>depression</italic> levels between the exergames group and the control group. In contrast, exergames have a statistically and clinically significant effect on <italic>depression</italic> levels when compared with no intervention, according to a meta-analysis of 8 studies [<xref ref-type="bibr" rid="ref62">62</xref>].</p>
        <p>Very low–quality evidence from 6 RCTs demonstrated a statistically and clinically significant effect of computerized CBT games on anxiety levels when compared with no intervention. A subgroup analysis showed that the effect of computerized CBT on anxiety was significantly higher among adults than among adolescents. However, this finding may not be generalizable to older adults as participants in all the 6 studies were, on average, ≤41.3 years. To the best of our knowledge, no previous reviews have examined the effect of computerized CBT games on anxiety, although many reviews have assessed the effect of computerized CBT in general (ie, games are not part of the intervention) [<xref ref-type="bibr" rid="ref63">63</xref>-<xref ref-type="bibr" rid="ref66">66</xref>]. However, our findings are in line with a previous review focusing on depression, which found a statistically and clinically significant effect of computerized CBT games on depression level according to a meta-analysis of 6 RCTs.</p>
        <p>Low-quality evidence from 3 RCTs showed a statistically and clinically significant effect of biofeedback games on anxiety levels when compared with conventional video games. It is worth mentioning that the studies used biofeedback games specifically for alleviating anxiety and recruited participants with anxiety. The generalizability of this finding may be limited because of the following reasons: (1) participants in the 3 studies were adolescents (10-13.3 years), (2) all studies were conducted in the Netherlands, and (3) there was a small number of studies included in the meta-analysis.</p>
        <p>Meta-analyses were not conducted to assess the effect of other types of serious games because of the small number of studies. Individual studies found no statistically significant effect of brain training games, social skills training games, exposure therapy games, and psychoeducation games on anxiety levels. However, other studies have shown contradictory results regarding the effects of attention distraction games on anxiety levels.</p>
      </sec>
      <sec>
        <title>Strengths and Limitations</title>
        <sec>
          <title>Strengths</title>
          <p>This review can be considered more comprehensive than the 2 previous reviews [<xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref17">17</xref>] because it was not restricted to a certain type of serious games, age group, or comparator, and it searched the main databases in health and information technology fields. This review was conducted according to highly recommended guidelines (ie, PRISMA) and included only RCTs. Therefore, it can be considered a robust and high-quality review.</p>
          <p>The risk of publication bias is not a concern in this review because we sought to retrieve as many relevant studies as possible by searching the most popular databases in information technology, health fields, and gray literature databases, conducting backward and forward reference list checking, using a comprehensive search query, and not restricting our search to a certain country, year, setting, population, and comparator.</p>
          <p>There is no concern about the risk of selection bias in this review, given that 2 reviewers independently performed the study selection, data extraction, risk of bias assessment, and quality of evidence evaluation with a perfect interrater agreement for all processes. The quality of the evidence was appraised using the GRADE approach to enable the reader to draw more accurate conclusions. When possible, we synthesized data statistically, which improved the power of the studies and increased the estimates of the likely size of the effect of serious games on anxiety.</p>
        </sec>
        <sec>
          <title>Limitations</title>
          <p>This review excluded studies that used serious games delivered on nondigital platforms and those used for other purposes (eg, screening or diagnosis). Therefore, this review cannot comment on the effectiveness of these types of serious games. This review focused on the effectiveness of serious games on anxiety only; thus, we cannot comment on the effectiveness of serious games on other diseases.</p>
          <p>Numerous studies were excluded as they were quasi-experiments and written in languages other than English. Therefore, it is likely that we missed relevant studies. We excluded these studies because quasi-experiments have lower internal validity than RCTs [<xref ref-type="bibr" rid="ref67">67</xref>] and, owing to practical constraints, it was not possible to translate all non-English studies. Participants in most studies did not have anxiety before the intervention; therefore, the effect of serious games could not be significant.</p>
          <p>This review meta-analyzed postintervention data rather than follow-up data; thus, this review cannot comment on the long-term effects of serious games on anxiety. Postintervention outcome data were selected given that about half of the included studies (16/33, 48.5%) did not follow-up with participants to measure the outcome data, and the follow-up period in the other half of the studies (17/33, 51.5%) was not consistent between studies.</p>
          <p>We used postintervention data for each group to assess the effect size for each meta-analyzed study rather than the pre–post intervention change for each group; therefore, it is likely that the effect size is overestimated or underestimated. We used postintervention outcome data because most studies did not report the SD for pre- or postintervention change for each group, and preintervention outcome data were significantly different between groups in only 2 studies [<xref ref-type="bibr" rid="ref36">36</xref>,<xref ref-type="bibr" rid="ref37">37</xref>].</p>
        </sec>
      </sec>
      <sec>
        <title>Research and Practical Implications</title>
        <sec>
          <title>Research Implications</title>
          <p>Although anxiety was one of the measured outcomes in all the included studies, only 6 studies targeted the recruitment of people experiencing anxiety. This may lead to a severe underestimation of the effect of serious games on anxiety levels. This finding is consistent with a similar study that investigated the effects of depression [<xref ref-type="bibr" rid="ref62">62</xref>]. Similarly, we recommend purposefully recruiting participants who have anxiety and establishing a baseline to objectively assess the effectiveness of serious games in reducing anxiety levels.</p>
          <p>We would like to point out that several studies recruited very small samples, with a minimum of only 30 patients. Gaining statistically reliable insights from such small samples can be difficult and may be an additional reason why our meta-analyses provide no conclusive answer to the question of whether serious games can improve or augment traditional anxiety treatment. Thus, we encourage researchers to recruit a sample size that is sufficient to achieve a power of at least 80%.</p>
          <p>Most of the included studies were conducted in a clinical setting. Although this could offer a controlled environment to run the studies, it could also introduce stress to the participants because of the nature of such a setting. Conducting more studies in the community and educational settings could present different findings as people usually play games outside of the traditional clinical setting.</p>
          <p>The current literature focused mainly on exergames and computerized CBT games, while the effect of other types of serious games was investigated in only a few studies. There are opportunities to enrich the body of evidence on the effectiveness of serious games delivered through other therapeutic modalities such as psychoeducation games, biofeedback games, exposure therapy games, and brain training games.</p>
          <p>Although serious games can be used for several purposes and many diseases, we focused on serious games that were used for therapeutic or prevention purposes and anxiety only. Researchers should conduct systematic reviews to assess the effectiveness of serious games used for other purposes (eg, monitoring, screening, and diagnosing) and for other diseases.</p>
          <p>In only 2 studies, the overall risk of bias was low given that most studies had issues in the randomization process, measurement of the outcome, and selection of the reported result. Outcome data were missing from several studies; therefore, they were not included in the meta-analyses. Accordingly, researchers should avoid the abovementioned biases by conducting and reporting RCTs according to recommended guidelines or tools (eg, RoB 2 [<xref ref-type="bibr" rid="ref25">25</xref>]).</p>
          <p>Finally, most of the included studies were conducted in high-income countries, which, in turn, can limit the generalizability of our findings to low-income nations. There is a need to conduct more studies in low-income countries, especially given the varying nature of their cultures, socioeconomic conditions, and sources of stress and anxiety (eg, overpopulated cities, poor socioeconomic areas, and refugee camps). Furthermore, more studies are needed to determine any variance in the effectiveness of serious games that are designed specifically to reduce and alleviate anxiety levels intergenerationally.</p>
        </sec>
        <sec>
          <title>Practical Implications</title>
          <p>This review showed that exergames are as effective as conventional exercises in alleviating anxiety and that computerized CBT games and biofeedback games are more effective than no intervention and conventional video games, respectively. However, health professionals and decision-makers should be careful when interpreting these findings for the following reasons: the quality of meta-analyzed evidence ranged from very low to low, the overall risk of bias was high in most of the included studies, the heterogeneity of the evidence was high in the 3 meta-analyses, participants in most studies did not have anxiety, and many studies did not use serious games that were designed specifically to alleviate anxiety. Accordingly, psychologists and psychiatrists should consider offering serious games as complementary and not a substitute for existing interventions until further, more robust evidence is available.</p>
          <p>Although anxiety can be alleviated by many nonpharmacological interventions, there are no or few serious games that deliver nonpharmacological interventions other than exercises and CBT in this review. This may be attributed to the lack of such serious games in real life. Therefore, developers should consider developing serious games that deliver nonpharmacological interventions such as breathing techniques, mindfulness training, problem-solving, attention distraction, biofeedback, psychoeducation, relaxation-based exercises, and rational emotive behavioral therapy.</p>
          <p>Only a handful (n=7) of studies used mobile devices (smartphones and tablets) as the platform for their intervention. Mobile devices are particularly appealing because they are cheaper than computers and more pervasive than gaming consoles. Moreover, mobile devices are more accessible than computers and gaming consoles; it is estimated that there are approximately 15 billion mobile devices and more than 7.1 mobile users worldwide in 2021 [<xref ref-type="bibr" rid="ref68">68</xref>]. This could present a lucrative opportunity for app and game developers to develop serious games that target anxiety and can be played via mobile devices.</p>
          <p>Few studies have been conducted in developing countries, and this may be attributed to the lack of serious games in these countries. Given that there is a greater shortage of mental health professionals in developing countries than in developed countries (0.1 per 1 million people [<xref ref-type="bibr" rid="ref69">69</xref>] versus 90 per 1 million people [<xref ref-type="bibr" rid="ref70">70</xref>]), it is likely that individuals in developing countries are more in need of serious games than those in developed countries. Therefore, more serious games should be developed to alleviate anxiety among people in developing countries.</p>
          <p>We would like to point out that a significant portion of the studies (n=12) investigated intervention methods using now-discontinued platforms: Wii (n=8, end of life in 2017), Kinect (n=5, end of life in 2017), and Nintendo DS (n=1, end of life in 2014). Only in one case, other platforms will readily fill the gap in only one case (using Tetris [<xref ref-type="bibr" rid="ref52">52</xref>]). For interventions using Microsoft’s Kinect sensor, computer vision–based pose estimation on mobile phones or desktop PCs could fill the gap but will result in a different setup. Finally, some of the included studies using Wiimote (Wii Remote) and none of the more specialized Wii input devices could be recreated using newer Nintendo controllers. These considerations raise a few questions of practical importance: (1) How well can studies relying on legacy and specialized hardware be reproduced? (2) How useful are interventions that rely on platforms designed to undergo comparatively short life cycles? (3) Are off-the-shelf video games (purpose-shifted games) adequate intervention tools?</p>
          <p>We believe that some of the included studies relying on legacy hardware could probably be salvaged, following the comments outlined above, but caution should be taken to fall victim to the novelty effect of emerging game controllers and proprietary input devices. The video game industry evolves quickly and is known to experiment with novel technology to spirit gamers away from competitors. Consequently, purpose-shifted games are not only very prone to depreciate quickly, but the same is true for the platforms they were designed for. We believe that researchers in this space should best assume the role of game designers, who focus on the game mechanics and purpose. In the second step, researchers are probably best advised to seek the help of a professional software development company to bring out the product in a timely fashion.</p>
          <p>In addition, although we cannot rule out that off-the-shelf games that have undergone, first, a purpose-shift to become a serious game and yet another one to become part of a therapy (eg, Tetris) have a measurable effect, we also have little reason to assume that they do. It seems tempting to explain the effects of serious games on anxiety by their distractive nature, but studies do not agree with this question.</p>
          <p>There is also an urgent need for an inclusive approach when developing these apps and games to include professionals from the gaming industry as well as mental health experts. Technologists and developers are usually very aware of the aforementioned concerns but need medical professionals to avoid falling prey to the temptation of purpose-shifting existing games or designing games for goals that are different from anxiety relief.</p>
        </sec>
      </sec>
      <sec>
        <title>Conclusions</title>
        <p>Evidence from this study suggests that serious games have the potential to reduce anxiety levels. Specifically, exergames can be as effective as conventional exercises in alleviating anxiety; computerized CBT games and exergames can be more effective than no intervention, and biofeedback games can be more effective than conventional video games. However, definitive conclusions regarding the effectiveness of serious games in reducing anxiety remain inconclusive, mainly because of the high risk of bias in the individual studies included, the low quality of meta-analyzed evidence, the low number of studies included in some meta-analyses, participants without anxiety in most studies, and using purpose-shifted serious games in most studies. Until further, more robust evidence is available, serious games should be deemed as complementary to existing interventions and not as a substitute for them. To obtain adequate and robust evidence, researchers should use serious games specifically designed to alleviate depression and deliver other therapeutic modalities, recruit patients with anxiety, and minimize the risk of bias by recommended guidelines for conducting and reporting RCTs (eg, RoB 2).</p>
      </sec>
    </sec>
  </body>
  <back>
    <app-group>
      <supplementary-material id="app1">
        <label>Multimedia Appendix 1</label>
        <p>PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist.</p>
        <media xlink:href="games_v10i1e29137_app1.docx" xlink:title="DOCX File , 26 KB"/>
      </supplementary-material>
      <supplementary-material id="app2">
        <label>Multimedia Appendix 2</label>
        <p>Search strategy.</p>
        <media xlink:href="games_v10i1e29137_app2.docx" xlink:title="DOCX File , 24 KB"/>
      </supplementary-material>
      <supplementary-material id="app3">
        <label>Multimedia Appendix 3</label>
        <p>Data extraction form.</p>
        <media xlink:href="games_v10i1e29137_app3.docx" xlink:title="DOCX File , 19 KB"/>
      </supplementary-material>
      <supplementary-material id="app4">
        <label>Multimedia Appendix 4</label>
        <p>Reviewers’ judgments about each risk of bias domain for each included study.</p>
        <media xlink:href="games_v10i1e29137_app4.docx" xlink:title="DOCX File , 47 KB"/>
      </supplementary-material>
      <supplementary-material id="app5">
        <label>Multimedia Appendix 5</label>
        <p>Grading of Recommendations Assessment, Development, and Evaluation profile for the comparison of serious games to control or conventional exercises for anxiety.</p>
        <media xlink:href="games_v10i1e29137_app5.docx" xlink:title="DOCX File , 17 KB"/>
      </supplementary-material>
      <supplementary-material id="app6">
        <label>Multimedia Appendix 6</label>
        <p>Sensitivity analyses.</p>
        <media xlink:href="games_v10i1e29137_app6.docx" xlink:title="DOCX File , 76 KB"/>
      </supplementary-material>
    </app-group>
    <glossary>
      <title>Abbreviations</title>
      <def-list>
        <def-item>
          <term id="abb1">AQ</term>
          <def>
            <p>Acrophobia Questionnaire</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb2">BAI</term>
          <def>
            <p>Beck Anxiety Inventory</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb3">CBT</term>
          <def>
            <p>cognitive behavioral therapy</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb4">GRADE</term>
          <def>
            <p>Grading of Recommendations Assessment, Development, and Evaluation</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb5">MCID</term>
          <def>
            <p>minimal clinically important difference</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb6">PRISMA</term>
          <def>
            <p>Preferred Reporting Items for Systematic Reviews and Meta-Analyses</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb7">PROSPERO</term>
          <def>
            <p>International Prospective Register of Systematic Reviews</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb8">RCT</term>
          <def>
            <p>randomized controlled trial</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb9">RoB 2</term>
          <def>
            <p>Risk-of-Bias 2</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb10">SCAS</term>
          <def>
            <p>Spence Children’s Anxiety Scale</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb11">SMD</term>
          <def>
            <p>standardized mean difference</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb12">STAI</term>
          <def>
            <p>State-Trait Anxiety Inventory</p>
          </def>
        </def-item>
      </def-list>
    </glossary>
    <fn-group>
      <fn fn-type="conflict">
        <p>None declared.</p>
      </fn>
    </fn-group>
    <ref-list>
      <ref id="ref1">
        <label>1</label>
        <nlm-citation citation-type="book">
          <person-group person-group-type="author">
            <collab>American Psychiatric Association</collab>
          </person-group>
          <source>Diagnostic and statistical manual of mental disorders (DSM-5). 5th edition</source>
          <year>2013</year>
          <publisher-loc>Virginia</publisher-loc>
          <publisher-name>American Psychiatric Publishing</publisher-name>
        </nlm-citation>
      </ref>
      <ref id="ref2">
        <label>2</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Testa</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Giannuzzi</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Sollazzo</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Petrongolo</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Bernardini</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Daini</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title>Psychiatric emergencies (part I): psychiatric disorders causing organic symptoms</article-title>
          <source>Eur Rev Med Pharmacol Sci</source>
          <year>2013</year>
          <volume>17 Suppl 1</volume>
          <fpage>55</fpage>
          <lpage>64</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://www.europeanreview.org/article/3083"/>
          </comment>
          <pub-id pub-id-type="medline">23436668</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref3">
        <label>3</label>
        <nlm-citation citation-type="web">
          <article-title>What are anxiety disorders?</article-title>
          <source>American Psychiatric Association</source>
          <year>2015</year>
          <access-date>2021-08-18</access-date>
          <publisher-loc>Washington, D.C</publisher-loc>
          <publisher-name>American Psychiatric Association</publisher-name>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.psychiatry.org/patients-families/anxiety-disorders/what-are-anxiety-disorders">https://www.psychiatry.org/patients-families/anxiety-disorders/what-are-anxiety-disorders</ext-link>
          </comment>
        </nlm-citation>
      </ref>
      <ref id="ref4">
        <label>4</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Nochaiwong</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Ruengorn</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Thavorn</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Hutton</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Awiphan</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Phosuya</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Ruanta</surname>
              <given-names>Y</given-names>
            </name>
            <name name-style="western">
              <surname>Wongpakaran</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Wongpakaran</surname>
              <given-names>T</given-names>
            </name>
          </person-group>
          <article-title>Global prevalence of mental health issues among the general population during the coronavirus disease-2019 pandemic: a systematic review and meta-analysis</article-title>
          <source>Sci Rep</source>
          <year>2021</year>
          <volume>11</volume>
          <issue>1</issue>
          <fpage>10173</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://doi.org/10.1038/s41598-021-89700-8"/>
          </comment>
          <pub-id pub-id-type="doi">10.1038/s41598-021-89700-8</pub-id>
          <pub-id pub-id-type="medline">33986414</pub-id>
          <pub-id pub-id-type="pii">10.1038/s41598-021-89700-8</pub-id>
          <pub-id pub-id-type="pmcid">PMC8119461</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref5">
        <label>5</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Higa-McMillan</surname>
              <given-names>CK</given-names>
            </name>
            <name name-style="western">
              <surname>Francis</surname>
              <given-names>SE</given-names>
            </name>
            <name name-style="western">
              <surname>Rith-Najarian</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Chorpita</surname>
              <given-names>BF</given-names>
            </name>
          </person-group>
          <article-title>Evidence base update: 50 years of research on treatment for child and adolescent anxiety</article-title>
          <source>J Clin Child Adolesc Psychol</source>
          <year>2016</year>
          <volume>45</volume>
          <issue>2</issue>
          <fpage>91</fpage>
          <lpage>113</lpage>
          <pub-id pub-id-type="doi">10.1080/15374416.2015.1046177</pub-id>
          <pub-id pub-id-type="medline">26087438</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref6">
        <label>6</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>White</surname>
              <given-names>SW</given-names>
            </name>
            <name name-style="western">
              <surname>Simmons</surname>
              <given-names>GL</given-names>
            </name>
            <name name-style="western">
              <surname>Gotham</surname>
              <given-names>KO</given-names>
            </name>
            <name name-style="western">
              <surname>Conner</surname>
              <given-names>CM</given-names>
            </name>
            <name name-style="western">
              <surname>Smith</surname>
              <given-names>IC</given-names>
            </name>
            <name name-style="western">
              <surname>Beck</surname>
              <given-names>KB</given-names>
            </name>
            <name name-style="western">
              <surname>Mazefsky</surname>
              <given-names>CA</given-names>
            </name>
          </person-group>
          <article-title>Psychosocial treatments targeting anxiety and depression in adolescents and adults on the autism spectrum: review of the latest research and recommended future directions</article-title>
          <source>Curr Psychiatry Rep</source>
          <year>2018</year>
          <volume>20</volume>
          <issue>10</issue>
          <fpage>82</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://europepmc.org/abstract/MED/30155584"/>
          </comment>
          <pub-id pub-id-type="doi">10.1007/s11920-018-0949-0</pub-id>
          <pub-id pub-id-type="medline">30155584</pub-id>
          <pub-id pub-id-type="pii">10.1007/s11920-018-0949-0</pub-id>
          <pub-id pub-id-type="pmcid">PMC6421847</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref7">
        <label>7</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Janszky</surname>
              <given-names>I</given-names>
            </name>
            <name name-style="western">
              <surname>Ahnve</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Lundberg</surname>
              <given-names>I</given-names>
            </name>
            <name name-style="western">
              <surname>Hemmingsson</surname>
              <given-names>T</given-names>
            </name>
          </person-group>
          <article-title>Early-onset depression, anxiety, and risk of subsequent coronary heart disease: 37-year follow-up of 49,321 young Swedish men</article-title>
          <source>J Am Coll Cardiol</source>
          <year>2010</year>
          <volume>56</volume>
          <issue>1</issue>
          <fpage>31</fpage>
          <lpage>7</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(10)01562-7"/>
          </comment>
          <pub-id pub-id-type="doi">10.1016/j.jacc.2010.03.033</pub-id>
          <pub-id pub-id-type="medline">20620714</pub-id>
          <pub-id pub-id-type="pii">S0735-1097(10)01562-7</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref8">
        <label>8</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Tolmunen</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Lehto</surname>
              <given-names>SM</given-names>
            </name>
            <name name-style="western">
              <surname>Julkunen</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Hintikka</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Kauhanen</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Trait anxiety and somatic concerns associate with increased mortality risk: a 23-year follow-up in aging men</article-title>
          <source>Ann Epidemiol</source>
          <year>2014</year>
          <volume>24</volume>
          <issue>6</issue>
          <fpage>463</fpage>
          <lpage>8</lpage>
          <pub-id pub-id-type="doi">10.1016/j.annepidem.2014.03.001</pub-id>
          <pub-id pub-id-type="medline">24731699</pub-id>
          <pub-id pub-id-type="pii">S1047-2797(14)00103-3</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref9">
        <label>9</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <collab>GBD 2019 Diseases and Injuries Collaborators</collab>
          </person-group>
          <article-title>Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019</article-title>
          <source>Lancet</source>
          <year>2020</year>
          <volume>396</volume>
          <issue>10258</issue>
          <fpage>1204</fpage>
          <lpage>22</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(20)30925-9"/>
          </comment>
          <pub-id pub-id-type="doi">10.1016/S0140-6736(20)30925-9</pub-id>
          <pub-id pub-id-type="medline">33069326</pub-id>
          <pub-id pub-id-type="pii">S0140-6736(20)30925-9</pub-id>
          <pub-id pub-id-type="pmcid">PMC7567026</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref10">
        <label>10</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Yang</surname>
              <given-names>X</given-names>
            </name>
            <name name-style="western">
              <surname>Fang</surname>
              <given-names>Y</given-names>
            </name>
            <name name-style="western">
              <surname>Chen</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Zhang</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Yin</surname>
              <given-names>X</given-names>
            </name>
            <name name-style="western">
              <surname>Man</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Yang</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Lu</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title>Global, regional and national burden of anxiety disorders from 1990 to 2019: results from the Global Burden of Disease Study 2019</article-title>
          <source>Epidemiol Psychiatr Sci</source>
          <year>2021</year>
          <volume>30</volume>
          <fpage>e36</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://europepmc.org/abstract/MED/33955350"/>
          </comment>
          <pub-id pub-id-type="doi">10.1017/S2045796021000275</pub-id>
          <pub-id pub-id-type="medline">33955350</pub-id>
          <pub-id pub-id-type="pii">S2045796021000275</pub-id>
          <pub-id pub-id-type="pmcid">PMC8157816</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref11">
        <label>11</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Quek</surname>
              <given-names>TT</given-names>
            </name>
            <name name-style="western">
              <surname>Tam</surname>
              <given-names>WW</given-names>
            </name>
            <name name-style="western">
              <surname>Tran</surname>
              <given-names>BX</given-names>
            </name>
            <name name-style="western">
              <surname>Zhang</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Zhang</surname>
              <given-names>Z</given-names>
            </name>
            <name name-style="western">
              <surname>Ho</surname>
              <given-names>CS</given-names>
            </name>
            <name name-style="western">
              <surname>Ho</surname>
              <given-names>RC</given-names>
            </name>
          </person-group>
          <article-title>The global prevalence of anxiety among medical students: a meta-analysis</article-title>
          <source>Int J Environ Res Public Health</source>
          <year>2019</year>
          <volume>16</volume>
          <issue>15</issue>
          <fpage>2735</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.mdpi.com/resolver?pii=ijerph16152735"/>
          </comment>
          <pub-id pub-id-type="doi">10.3390/ijerph16152735</pub-id>
          <pub-id pub-id-type="medline">31370266</pub-id>
          <pub-id pub-id-type="pii">ijerph16152735</pub-id>
          <pub-id pub-id-type="pmcid">PMC6696211</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref12">
        <label>12</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Park</surname>
              <given-names>SC</given-names>
            </name>
            <name name-style="western">
              <surname>Oh</surname>
              <given-names>HS</given-names>
            </name>
            <name name-style="western">
              <surname>Oh</surname>
              <given-names>DH</given-names>
            </name>
            <name name-style="western">
              <surname>Jung</surname>
              <given-names>SA</given-names>
            </name>
            <name name-style="western">
              <surname>Na</surname>
              <given-names>KS</given-names>
            </name>
            <name name-style="western">
              <surname>Lee</surname>
              <given-names>HY</given-names>
            </name>
            <name name-style="western">
              <surname>Kang</surname>
              <given-names>RH</given-names>
            </name>
            <name name-style="western">
              <surname>Choi</surname>
              <given-names>YK</given-names>
            </name>
            <name name-style="western">
              <surname>Lee</surname>
              <given-names>MS</given-names>
            </name>
            <name name-style="western">
              <surname>Park</surname>
              <given-names>YC</given-names>
            </name>
          </person-group>
          <article-title>Evidence-based, non-pharmacological treatment guideline for depression in Korea</article-title>
          <source>J Korean Med Sci</source>
          <year>2014</year>
          <volume>29</volume>
          <issue>1</issue>
          <fpage>12</fpage>
          <lpage>22</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://jkms.org/DOIx.php?id=10.3346/jkms.2014.29.1.12"/>
          </comment>
          <pub-id pub-id-type="doi">10.3346/jkms.2014.29.1.12</pub-id>
          <pub-id pub-id-type="medline">24431900</pub-id>
          <pub-id pub-id-type="pmcid">PMC3890462</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref13">
        <label>13</label>
        <nlm-citation citation-type="book">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Barlow</surname>
              <given-names>DH</given-names>
            </name>
          </person-group>
          <source>Clinical handbook of psychological disorders: a step-by-step treatment manual. 6th edition</source>
          <year>2021</year>
          <publisher-loc>New York</publisher-loc>
          <publisher-name>The Guilford Press</publisher-name>
        </nlm-citation>
      </ref>
      <ref id="ref14">
        <label>14</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Hardoerfer</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Jentschke</surname>
              <given-names>E</given-names>
            </name>
          </person-group>
          <article-title>Effect of yoga therapy on symptoms of anxiety in cancer patients</article-title>
          <source>Oncol Res Treat</source>
          <year>2018</year>
          <volume>41</volume>
          <issue>9</issue>
          <fpage>526</fpage>
          <lpage>32</lpage>
          <pub-id pub-id-type="doi">10.1159/000488989</pub-id>
          <pub-id pub-id-type="medline">30086538</pub-id>
          <pub-id pub-id-type="pii">000488989</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref15">
        <label>15</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Stephens</surname>
              <given-names>I</given-names>
            </name>
          </person-group>
          <article-title>Medical yoga therapy</article-title>
          <source>Children (Basel)</source>
          <year>2017</year>
          <volume>4</volume>
          <issue>2</issue>
          <fpage>12</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.mdpi.com/resolver?pii=children4020012"/>
          </comment>
          <pub-id pub-id-type="doi">10.3390/children4020012</pub-id>
          <pub-id pub-id-type="medline">28208599</pub-id>
          <pub-id pub-id-type="pii">children4020012</pub-id>
          <pub-id pub-id-type="pmcid">PMC5332914</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref16">
        <label>16</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Viana</surname>
              <given-names>RB</given-names>
            </name>
            <name name-style="western">
              <surname>Dankel</surname>
              <given-names>SJ</given-names>
            </name>
            <name name-style="western">
              <surname>Loenneke</surname>
              <given-names>JP</given-names>
            </name>
            <name name-style="western">
              <surname>Gentil</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Vieira</surname>
              <given-names>CA</given-names>
            </name>
            <name name-style="western">
              <surname>Andrade</surname>
              <given-names>MD</given-names>
            </name>
            <name name-style="western">
              <surname>Vancini</surname>
              <given-names>RL</given-names>
            </name>
            <name name-style="western">
              <surname>de Lira</surname>
              <given-names>CA</given-names>
            </name>
          </person-group>
          <article-title>The effects of exergames on anxiety levels: a systematic review and meta-analysis</article-title>
          <source>Scand J Med Sci Sports</source>
          <year>2020</year>
          <volume>30</volume>
          <issue>7</issue>
          <fpage>1100</fpage>
          <lpage>16</lpage>
          <pub-id pub-id-type="doi">10.1111/sms.13654</pub-id>
          <pub-id pub-id-type="medline">32171032</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref17">
        <label>17</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Barnes</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Prescott</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Empirical evidence for the outcomes of therapeutic video games for adolescents with anxiety disorders: systematic review</article-title>
          <source>JMIR Serious Games</source>
          <year>2018</year>
          <volume>6</volume>
          <issue>1</issue>
          <fpage>e3</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://games.jmir.org/2018/1/e3/"/>
          </comment>
          <pub-id pub-id-type="doi">10.2196/games.9530</pub-id>
          <pub-id pub-id-type="medline">29490893</pub-id>
          <pub-id pub-id-type="pii">v6i1e3</pub-id>
          <pub-id pub-id-type="pmcid">PMC5852274</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref18">
        <label>18</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Zayeni</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Raynaud</surname>
              <given-names>JP</given-names>
            </name>
            <name name-style="western">
              <surname>Revet</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title>Therapeutic and preventive use of video games in child and adolescent psychiatry: a systematic review</article-title>
          <source>Front Psychiatry</source>
          <year>2020</year>
          <volume>11</volume>
          <fpage>36</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://doi.org/10.3389/fpsyt.2020.00036"/>
          </comment>
          <pub-id pub-id-type="doi">10.3389/fpsyt.2020.00036</pub-id>
          <pub-id pub-id-type="medline">32116851</pub-id>
          <pub-id pub-id-type="pmcid">PMC7016332</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref19">
        <label>19</label>
        <nlm-citation citation-type="book">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Michael</surname>
              <given-names>DR</given-names>
            </name>
            <name name-style="western">
              <surname>Chen</surname>
              <given-names>SL</given-names>
            </name>
          </person-group>
          <source>Serious games: games that educate, train, and inform</source>
          <year>2005</year>
          <publisher-loc>Michigan</publisher-loc>
          <publisher-name>Cengage Learning PTR</publisher-name>
        </nlm-citation>
      </ref>
      <ref id="ref20">
        <label>20</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Dias</surname>
              <given-names>LP</given-names>
            </name>
            <name name-style="western">
              <surname>Barbosa</surname>
              <given-names>JL</given-names>
            </name>
            <name name-style="western">
              <surname>Vianna</surname>
              <given-names>HD</given-names>
            </name>
          </person-group>
          <article-title>Gamification and serious games in depression care: a systematic mapping study</article-title>
          <source>Telemat Inform</source>
          <year>2018</year>
          <volume>35</volume>
          <issue>1</issue>
          <fpage>213</fpage>
          <lpage>24</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://doi.org/10.1016/j.tele.2017.11.002"/>
          </comment>
          <pub-id pub-id-type="doi">10.1016/j.tele.2017.11.002</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref21">
        <label>21</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Chatham</surname>
              <given-names>RE</given-names>
            </name>
          </person-group>
          <article-title>Games for training</article-title>
          <source>Commun ACM</source>
          <year>2007</year>
          <volume>50</volume>
          <issue>7</issue>
          <fpage>36</fpage>
          <lpage>43</lpage>
          <pub-id pub-id-type="doi">10.1145/1272516.1272537</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref22">
        <label>22</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Lau</surname>
              <given-names>HM</given-names>
            </name>
            <name name-style="western">
              <surname>Smit</surname>
              <given-names>JH</given-names>
            </name>
            <name name-style="western">
              <surname>Fleming</surname>
              <given-names>TM</given-names>
            </name>
            <name name-style="western">
              <surname>Riper</surname>
              <given-names>H</given-names>
            </name>
          </person-group>
          <article-title>Serious games for mental health: are they accessible, feasible, and effective? A systematic review and meta-analysis</article-title>
          <source>Front Psychiatry</source>
          <year>2017</year>
          <volume>7</volume>
          <fpage>209</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://doi.org/10.3389/fpsyt.2016.00209"/>
          </comment>
          <pub-id pub-id-type="doi">10.3389/fpsyt.2016.00209</pub-id>
          <pub-id pub-id-type="medline">28149281</pub-id>
          <pub-id pub-id-type="pmcid">PMC5241302</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref23">
        <label>23</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Liberati</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Altman</surname>
              <given-names>DG</given-names>
            </name>
            <name name-style="western">
              <surname>Tetzlaff</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Mulrow</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Gøtzsche</surname>
              <given-names>PC</given-names>
            </name>
            <name name-style="western">
              <surname>Ioannidis</surname>
              <given-names>JP</given-names>
            </name>
            <name name-style="western">
              <surname>Clarke</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Devereaux</surname>
              <given-names>PJ</given-names>
            </name>
            <name name-style="western">
              <surname>Kleijnen</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Moher</surname>
              <given-names>D</given-names>
            </name>
          </person-group>
          <article-title>The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration</article-title>
          <source>BMJ</source>
          <year>2009</year>
          <volume>339</volume>
          <fpage>b2700</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://europepmc.org/abstract/MED/19622552"/>
          </comment>
          <pub-id pub-id-type="doi">10.1136/bmj.b2700</pub-id>
          <pub-id pub-id-type="medline">19622552</pub-id>
          <pub-id pub-id-type="pmcid">PMC2714672</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref24">
        <label>24</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Landis</surname>
              <given-names>JR</given-names>
            </name>
            <name name-style="western">
              <surname>Koch</surname>
              <given-names>GG</given-names>
            </name>
          </person-group>
          <article-title>An application of hierarchical kappa-type statistics in the assessment of majority agreement among multiple observers</article-title>
          <source>Biometrics</source>
          <year>1977</year>
          <volume>33</volume>
          <issue>2</issue>
          <fpage>363</fpage>
          <lpage>74</lpage>
          <pub-id pub-id-type="medline">884196</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref25">
        <label>25</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Sterne</surname>
              <given-names>JA</given-names>
            </name>
            <name name-style="western">
              <surname>Savović</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Page</surname>
              <given-names>MJ</given-names>
            </name>
            <name name-style="western">
              <surname>Elbers</surname>
              <given-names>RG</given-names>
            </name>
            <name name-style="western">
              <surname>Blencowe</surname>
              <given-names>NS</given-names>
            </name>
            <name name-style="western">
              <surname>Boutron</surname>
              <given-names>I</given-names>
            </name>
            <name name-style="western">
              <surname>Cates</surname>
              <given-names>CJ</given-names>
            </name>
            <name name-style="western">
              <surname>Cheng</surname>
              <given-names>HY</given-names>
            </name>
            <name name-style="western">
              <surname>Corbett</surname>
              <given-names>MS</given-names>
            </name>
            <name name-style="western">
              <surname>Eldridge</surname>
              <given-names>SM</given-names>
            </name>
            <name name-style="western">
              <surname>Emberson</surname>
              <given-names>JR</given-names>
            </name>
            <name name-style="western">
              <surname>Hernán</surname>
              <given-names>MA</given-names>
            </name>
            <name name-style="western">
              <surname>Hopewell</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Hróbjartsson</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Junqueira</surname>
              <given-names>DR</given-names>
            </name>
            <name name-style="western">
              <surname>Jüni</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Kirkham</surname>
              <given-names>JJ</given-names>
            </name>
            <name name-style="western">
              <surname>Lasserson</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Li</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>McAleenan</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Reeves</surname>
              <given-names>BC</given-names>
            </name>
            <name name-style="western">
              <surname>Shepperd</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Shrier</surname>
              <given-names>I</given-names>
            </name>
            <name name-style="western">
              <surname>Stewart</surname>
              <given-names>LA</given-names>
            </name>
            <name name-style="western">
              <surname>Tilling</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>White</surname>
              <given-names>IR</given-names>
            </name>
            <name name-style="western">
              <surname>Whiting</surname>
              <given-names>PF</given-names>
            </name>
            <name name-style="western">
              <surname>Higgins</surname>
              <given-names>JP</given-names>
            </name>
          </person-group>
          <article-title>RoB 2: a revised tool for assessing risk of bias in randomised trials</article-title>
          <source>BMJ</source>
          <year>2019</year>
          <volume>366</volume>
          <fpage>l4898</fpage>
          <pub-id pub-id-type="doi">10.1136/bmj.l4898</pub-id>
          <pub-id pub-id-type="medline">31462531</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref26">
        <label>26</label>
        <nlm-citation citation-type="book">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Deeks</surname>
              <given-names>JJ</given-names>
            </name>
            <name name-style="western">
              <surname>Higgins</surname>
              <given-names>JP</given-names>
            </name>
            <name name-style="western">
              <surname>Altman</surname>
              <given-names>DG</given-names>
            </name>
          </person-group>
          <person-group person-group-type="editor">
            <name name-style="western">
              <surname>Higgins</surname>
              <given-names>JP</given-names>
            </name>
            <name name-style="western">
              <surname>Green</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title>Chapter 9: Analysing data and undertaking meta-analyses</article-title>
          <source>Cochrane handbook for systematic reviews of interventions. Version 5.0.1</source>
          <year>2008</year>
          <publisher-loc>Sussex</publisher-loc>
          <publisher-name>John Wiley &#38; Sons</publisher-name>
          <fpage>243</fpage>
          <lpage>96</lpage>
        </nlm-citation>
      </ref>
      <ref id="ref27">
        <label>27</label>
        <nlm-citation citation-type="book">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Schunemann</surname>
              <given-names>HJ</given-names>
            </name>
            <name name-style="western">
              <surname>Oxman</surname>
              <given-names>AD</given-names>
            </name>
            <name name-style="western">
              <surname>Vist</surname>
              <given-names>GE</given-names>
            </name>
            <name name-style="western">
              <surname>Higgins</surname>
              <given-names>JP</given-names>
            </name>
            <name name-style="western">
              <surname>Deeks</surname>
              <given-names>JJ</given-names>
            </name>
            <name name-style="western">
              <surname>Glasziou</surname>
              <given-names>P</given-names>
            </name>
          </person-group>
          <person-group person-group-type="editor">
            <name name-style="western">
              <surname>Higgins</surname>
              <given-names>JP</given-names>
            </name>
            <name name-style="western">
              <surname>Green</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title>Chapter 12: Interpreting results and drawing conclusions</article-title>
          <source>Cochrane handbook for systematic reviews of interventions</source>
          <year>2008</year>
          <publisher-loc>Sussex</publisher-loc>
          <publisher-name>John Wiley &#38; Sons</publisher-name>
          <fpage>359</fpage>
          <lpage>87</lpage>
        </nlm-citation>
      </ref>
      <ref id="ref28">
        <label>28</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Adomavičienė</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Daunoravičienė</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Kubilius</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Varžaitytė</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Raistenskis</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Influence of new technologies on post-stroke rehabilitation: a comparison of Armeo spring to the Kinect system</article-title>
          <source>Medicina (Kaunas)</source>
          <year>2019</year>
          <volume>55</volume>
          <issue>4</issue>
          <fpage>98</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.mdpi.com/resolver?pii=medicina55040098"/>
          </comment>
          <pub-id pub-id-type="doi">10.3390/medicina55040098</pub-id>
          <pub-id pub-id-type="medline">30970655</pub-id>
          <pub-id pub-id-type="pii">medicina55040098</pub-id>
          <pub-id pub-id-type="pmcid">PMC6524064</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref29">
        <label>29</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>de Carvalho</surname>
              <given-names>MS</given-names>
            </name>
            <name name-style="western">
              <surname>Carvalho</surname>
              <given-names>LC</given-names>
            </name>
            <name name-style="western">
              <surname>de Silva Menezes</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Frazin</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>da Costa Gomes</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Iunes</surname>
              <given-names>DH</given-names>
            </name>
          </person-group>
          <article-title>Effects of exergames in women with fibromyalgia: a randomized controlled study</article-title>
          <source>Games Health J</source>
          <year>2020</year>
          <volume>9</volume>
          <issue>5</issue>
          <fpage>358</fpage>
          <lpage>67</lpage>
          <pub-id pub-id-type="doi">10.1089/g4h.2019.0108</pub-id>
          <pub-id pub-id-type="medline">32379982</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref30">
        <label>30</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Meldrum</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Herdman</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Vance</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Murray</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Malone</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Duffy</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Glennon</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>McConn-Walsh</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title>Effectiveness of conventional versus virtual reality-based balance exercises in vestibular rehabilitation for unilateral peripheral vestibular loss: results of a randomized controlled trial</article-title>
          <source>Arch Phys Med Rehabil</source>
          <year>2015</year>
          <volume>96</volume>
          <issue>7</issue>
          <fpage>1319</fpage>
          <lpage>28.e1</lpage>
          <pub-id pub-id-type="doi">10.1016/j.apmr.2015.02.032</pub-id>
          <pub-id pub-id-type="medline">25842051</pub-id>
          <pub-id pub-id-type="pii">S0003-9993(15)00289-0</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref31">
        <label>31</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Schumacher</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Stüwe</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Kropp</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Diedrich</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Freitag</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Greger</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Junghanss</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Freund</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Hilgendorf</surname>
              <given-names>I</given-names>
            </name>
          </person-group>
          <article-title>A prospective, randomized evaluation of the feasibility of exergaming on patients undergoing hematopoietic stem cell transplantation</article-title>
          <source>Bone Marrow Transplant</source>
          <year>2018</year>
          <volume>53</volume>
          <issue>5</issue>
          <fpage>584</fpage>
          <lpage>90</lpage>
          <pub-id pub-id-type="doi">10.1038/s41409-017-0070-8</pub-id>
          <pub-id pub-id-type="medline">29335629</pub-id>
          <pub-id pub-id-type="pii">10.1038/s41409-017-0070-8</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref32">
        <label>32</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Ruivo</surname>
              <given-names>JM</given-names>
            </name>
            <name name-style="western">
              <surname>Karim</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>OʼShea</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Oliveira</surname>
              <given-names>RC</given-names>
            </name>
            <name name-style="western">
              <surname>Keary</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>OʼBrien</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Gormley</surname>
              <given-names>JP</given-names>
            </name>
          </person-group>
          <article-title>In-class active video game supplementation and adherence to cardiac rehabilitation</article-title>
          <source>J Cardiopulm Rehabil Prev</source>
          <year>2017</year>
          <volume>37</volume>
          <issue>4</issue>
          <fpage>274</fpage>
          <lpage>8</lpage>
          <pub-id pub-id-type="doi">10.1097/HCR.0000000000000224</pub-id>
          <pub-id pub-id-type="medline">28350640</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref33">
        <label>33</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Mazzoleni</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Montagnani</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Vagheggini</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Buono</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Moretti</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Dario</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Ambrosino</surname>
              <given-names>N</given-names>
            </name>
          </person-group>
          <article-title>Interactive videogame as rehabilitation tool of patients with chronic respiratory diseases: preliminary results of a feasibility study</article-title>
          <source>Respir Med</source>
          <year>2014</year>
          <volume>108</volume>
          <issue>10</issue>
          <fpage>1516</fpage>
          <lpage>24</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://linkinghub.elsevier.com/retrieve/pii/S0954-6111(14)00242-X"/>
          </comment>
          <pub-id pub-id-type="doi">10.1016/j.rmed.2014.07.004</pub-id>
          <pub-id pub-id-type="medline">25087837</pub-id>
          <pub-id pub-id-type="pii">S0954-6111(14)00242-X</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref34">
        <label>34</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Polat</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Kahveci</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Muci</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Günendi</surname>
              <given-names>Z</given-names>
            </name>
            <name name-style="western">
              <surname>Kaymak Karataş</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title>The effect of virtual reality exercises on pain, functionality, cardiopulmonary capacity, and quality of life in fibromyalgia syndrome: a randomized controlled study</article-title>
          <source>Games Health J</source>
          <year>2021</year>
          <volume>10</volume>
          <issue>3</issue>
          <fpage>165</fpage>
          <lpage>73</lpage>
          <pub-id pub-id-type="doi">10.1089/g4h.2020.0162</pub-id>
          <pub-id pub-id-type="medline">33689452</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref35">
        <label>35</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Lin</surname>
              <given-names>YT</given-names>
            </name>
            <name name-style="western">
              <surname>Lee</surname>
              <given-names>WC</given-names>
            </name>
            <name name-style="western">
              <surname>Hsieh</surname>
              <given-names>RL</given-names>
            </name>
          </person-group>
          <article-title>Active video games for knee osteoarthritis improve mobility but not WOMAC score: a randomized controlled trial</article-title>
          <source>Ann Phys Rehabil Med</source>
          <year>2020</year>
          <volume>63</volume>
          <issue>6</issue>
          <fpage>458</fpage>
          <lpage>65</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://linkinghub.elsevier.com/retrieve/pii/S1877-0657(20)30022-1"/>
          </comment>
          <pub-id pub-id-type="doi">10.1016/j.rehab.2019.11.008</pub-id>
          <pub-id pub-id-type="medline">31981832</pub-id>
          <pub-id pub-id-type="pii">S1877-0657(20)30022-1</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref36">
        <label>36</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Vieira</surname>
              <given-names>Á</given-names>
            </name>
            <name name-style="western">
              <surname>Melo</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Machado</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Gabriel</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Virtual reality exercise on a home-based phase III cardiac rehabilitation program, effect on executive function, quality of life and depression, anxiety and stress: a randomized controlled trial</article-title>
          <source>Disabil Rehabil Assist Technol</source>
          <year>2018</year>
          <volume>13</volume>
          <issue>2</issue>
          <fpage>112</fpage>
          <lpage>23</lpage>
          <pub-id pub-id-type="doi">10.1080/17483107.2017.1297858</pub-id>
          <pub-id pub-id-type="medline">28285574</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref37">
        <label>37</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Thomas</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Fazakarley</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Thomas</surname>
              <given-names>PW</given-names>
            </name>
            <name name-style="western">
              <surname>Collyer</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Brenton</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Perring</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Scott</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Thomas</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Thomas</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Jones</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Hickson</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Hillier</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
          <article-title>Mii-vitaliSe: a pilot randomised controlled trial of a home gaming system (Nintendo Wii) to increase activity levels, vitality and well-being in people with multiple sclerosis</article-title>
          <source>BMJ Open</source>
          <year>2017</year>
          <volume>7</volume>
          <issue>9</issue>
          <fpage>e016966</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://bmjopen.bmj.com/lookup/pmidlookup?view=long&#38;pmid=28954791"/>
          </comment>
          <pub-id pub-id-type="doi">10.1136/bmjopen-2017-016966</pub-id>
          <pub-id pub-id-type="medline">28954791</pub-id>
          <pub-id pub-id-type="pii">bmjopen-2017-016966</pub-id>
          <pub-id pub-id-type="pmcid">PMC5623500</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref38">
        <label>38</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Wagener</surname>
              <given-names>TL</given-names>
            </name>
            <name name-style="western">
              <surname>Fedele</surname>
              <given-names>DA</given-names>
            </name>
            <name name-style="western">
              <surname>Mignogna</surname>
              <given-names>MR</given-names>
            </name>
            <name name-style="western">
              <surname>Hester</surname>
              <given-names>CN</given-names>
            </name>
            <name name-style="western">
              <surname>Gillaspy</surname>
              <given-names>SR</given-names>
            </name>
          </person-group>
          <article-title>Psychological effects of dance-based group exergaming in obese adolescents</article-title>
          <source>Pediatr Obes</source>
          <year>2012</year>
          <volume>7</volume>
          <issue>5</issue>
          <fpage>e68</fpage>
          <lpage>74</lpage>
          <pub-id pub-id-type="doi">10.1111/j.2047-6310.2012.00065.x</pub-id>
          <pub-id pub-id-type="medline">22767495</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref39">
        <label>39</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Jahouh</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>González-Bernal</surname>
              <given-names>JJ</given-names>
            </name>
            <name name-style="western">
              <surname>González-Santos</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Fernández-Lázaro</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Soto-Cámara</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Mielgo-Ayuso</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
          <article-title>Impact of an intervention with Wii video games on the autonomy of activities of daily living and psychological-cognitive components in the institutionalized elderly</article-title>
          <source>Int J Environ Res Public Health</source>
          <year>2021</year>
          <volume>18</volume>
          <issue>4</issue>
          <fpage>1570</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.mdpi.com/resolver?pii=ijerph18041570"/>
          </comment>
          <pub-id pub-id-type="doi">10.3390/ijerph18041570</pub-id>
          <pub-id pub-id-type="medline">33562249</pub-id>
          <pub-id pub-id-type="pii">ijerph18041570</pub-id>
          <pub-id pub-id-type="pmcid">PMC7915676</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref40">
        <label>40</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Collado-Mateo</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Dominguez-Muñoz</surname>
              <given-names>FJ</given-names>
            </name>
            <name name-style="western">
              <surname>Adsuar</surname>
              <given-names>JC</given-names>
            </name>
            <name name-style="western">
              <surname>Garcia-Gordillo</surname>
              <given-names>MA</given-names>
            </name>
            <name name-style="western">
              <surname>Gusi</surname>
              <given-names>N</given-names>
            </name>
          </person-group>
          <article-title>Effects of exergames on quality of life, pain, and disease effect in women with fibromyalgia: a randomized controlled trial</article-title>
          <source>Arch Phys Med Rehabil</source>
          <year>2017</year>
          <volume>98</volume>
          <issue>9</issue>
          <fpage>1725</fpage>
          <lpage>31</lpage>
          <pub-id pub-id-type="doi">10.1016/j.apmr.2017.02.011</pub-id>
          <pub-id pub-id-type="medline">28322760</pub-id>
          <pub-id pub-id-type="pii">S0003-9993(17)30155-7</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref41">
        <label>41</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Cooney</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Jackman</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Coyle</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>O'Reilly</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title>Computerised cognitive-behavioural therapy for adults with intellectual disability: randomised controlled trial</article-title>
          <source>Br J Psychiatry</source>
          <year>2017</year>
          <volume>211</volume>
          <issue>2</issue>
          <fpage>95</fpage>
          <lpage>102</lpage>
          <pub-id pub-id-type="doi">10.1192/bjp.bp.117.198630</pub-id>
          <pub-id pub-id-type="medline">28596245</pub-id>
          <pub-id pub-id-type="pii">S0007125000281877</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref42">
        <label>42</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Donker</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Cornelisz</surname>
              <given-names>I</given-names>
            </name>
            <name name-style="western">
              <surname>van Klaveren</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>van Straten</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Carlbring</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Cuijpers</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>van Gelder</surname>
              <given-names>JL</given-names>
            </name>
          </person-group>
          <article-title>Effectiveness of self-guided app-based virtual reality cognitive behavior therapy for acrophobia: a randomized clinical trial</article-title>
          <source>JAMA Psychiatry</source>
          <year>2019</year>
          <volume>76</volume>
          <issue>7</issue>
          <fpage>682</fpage>
          <lpage>90</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://europepmc.org/abstract/MED/30892564"/>
          </comment>
          <pub-id pub-id-type="doi">10.1001/jamapsychiatry.2019.0219</pub-id>
          <pub-id pub-id-type="medline">30892564</pub-id>
          <pub-id pub-id-type="pii">2728184</pub-id>
          <pub-id pub-id-type="pmcid">PMC6583672</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref43">
        <label>43</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Fish</surname>
              <given-names>MT</given-names>
            </name>
            <name name-style="western">
              <surname>Russoniello</surname>
              <given-names>CV</given-names>
            </name>
            <name name-style="western">
              <surname>O'Brien</surname>
              <given-names>K</given-names>
            </name>
          </person-group>
          <article-title>The efficacy of prescribed casual videogame play in reducing symptoms of anxiety: a randomized controlled study</article-title>
          <source>Games Health J</source>
          <year>2014</year>
          <volume>3</volume>
          <issue>5</issue>
          <fpage>291</fpage>
          <lpage>5</lpage>
          <pub-id pub-id-type="doi">10.1089/g4h.2013.0092</pub-id>
          <pub-id pub-id-type="medline">26192483</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref44">
        <label>44</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Fleming</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Dixon</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Frampton</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Merry</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title>A pragmatic randomized controlled trial of computerized CBT (SPARX) for symptoms of depression among adolescents excluded from mainstream education</article-title>
          <source>Behav Cogn Psychother</source>
          <year>2012</year>
          <volume>40</volume>
          <issue>5</issue>
          <fpage>529</fpage>
          <lpage>41</lpage>
          <pub-id pub-id-type="doi">10.1017/S1352465811000695</pub-id>
          <pub-id pub-id-type="medline">22137185</pub-id>
          <pub-id pub-id-type="pii">S1352465811000695</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref45">
        <label>45</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Merry</surname>
              <given-names>SN</given-names>
            </name>
            <name name-style="western">
              <surname>Stasiak</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Shepherd</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Frampton</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Fleming</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Lucassen</surname>
              <given-names>MF</given-names>
            </name>
          </person-group>
          <article-title>The effectiveness of SPARX, a computerised self help intervention for adolescents seeking help for depression: randomised controlled non-inferiority trial</article-title>
          <source>BMJ</source>
          <year>2012</year>
          <volume>344</volume>
          <fpage>e2598</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://www.bmj.com/lookup/pmidlookup?view=long&#38;pmid=22517917"/>
          </comment>
          <pub-id pub-id-type="doi">10.1136/bmj.e2598</pub-id>
          <pub-id pub-id-type="medline">22517917</pub-id>
          <pub-id pub-id-type="pmcid">PMC3330131</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref46">
        <label>46</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Perry</surname>
              <given-names>Y</given-names>
            </name>
            <name name-style="western">
              <surname>Werner-Seidler</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Calear</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Mackinnon</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>King</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Scott</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Merry</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Fleming</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Stasiak</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Christensen</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Batterham</surname>
              <given-names>PJ</given-names>
            </name>
          </person-group>
          <article-title>Preventing depression in final year secondary students: school-based randomized controlled trial</article-title>
          <source>J Med Internet Res</source>
          <year>2017</year>
          <volume>19</volume>
          <issue>11</issue>
          <fpage>e369</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.jmir.org/2017/11/e369/"/>
          </comment>
          <pub-id pub-id-type="doi">10.2196/jmir.8241</pub-id>
          <pub-id pub-id-type="medline">29097357</pub-id>
          <pub-id pub-id-type="pii">v19i11e369</pub-id>
          <pub-id pub-id-type="pmcid">PMC5691241</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref47">
        <label>47</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Schoneveld</surname>
              <given-names>EA</given-names>
            </name>
            <name name-style="western">
              <surname>Lichtwarck-Aschoff</surname>
              <given-names>AL</given-names>
            </name>
            <name name-style="western">
              <surname>Granic</surname>
              <given-names>I</given-names>
            </name>
          </person-group>
          <article-title>Preventing childhood anxiety disorders: is an applied game as effective as a cognitive behavioral therapy-based program?</article-title>
          <source>Prev Sci</source>
          <year>2018</year>
          <volume>19</volume>
          <issue>2</issue>
          <fpage>220</fpage>
          <lpage>32</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://europepmc.org/abstract/MED/28956222"/>
          </comment>
          <pub-id pub-id-type="doi">10.1007/s11121-017-0843-8</pub-id>
          <pub-id pub-id-type="medline">28956222</pub-id>
          <pub-id pub-id-type="pii">10.1007/s11121-017-0843-8</pub-id>
          <pub-id pub-id-type="pmcid">PMC5801383</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref48">
        <label>48</label>
        <nlm-citation citation-type="web">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Tsui</surname>
              <given-names>T</given-names>
            </name>
          </person-group>
          <article-title>The efficacy of a novel video game intervention (MindLight) in reducing children's anxiety</article-title>
          <source>Qspace</source>
          <year>2016</year>
          <access-date>2022-02-08</access-date>
          <publisher-loc>Canada</publisher-loc>
          <publisher-name>Queen's University</publisher-name>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://qspace.library.queensu.ca/handle/1974/14821">https://qspace.library.queensu.ca/handle/1974/14821</ext-link>
          </comment>
        </nlm-citation>
      </ref>
      <ref id="ref49">
        <label>49</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Schoneveld</surname>
              <given-names>EA</given-names>
            </name>
            <name name-style="western">
              <surname>Malmberg</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Lichtwarck-Aschoff</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Verheijen</surname>
              <given-names>GP</given-names>
            </name>
            <name name-style="western">
              <surname>Engels</surname>
              <given-names>RC</given-names>
            </name>
            <name name-style="western">
              <surname>Granic</surname>
              <given-names>I</given-names>
            </name>
          </person-group>
          <article-title>A neurofeedback video game (MindLight) to prevent anxiety in children: a randomized controlled trial</article-title>
          <source>Comput Hum Behav</source>
          <year>2016</year>
          <volume>63</volume>
          <fpage>321</fpage>
          <lpage>33</lpage>
          <pub-id pub-id-type="doi">10.1016/j.chb.2016.05.005</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref50">
        <label>50</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Wijnhoven</surname>
              <given-names>LA</given-names>
            </name>
            <name name-style="western">
              <surname>Creemers</surname>
              <given-names>DH</given-names>
            </name>
            <name name-style="western">
              <surname>Vermulst</surname>
              <given-names>AA</given-names>
            </name>
            <name name-style="western">
              <surname>Lindauer</surname>
              <given-names>RJ</given-names>
            </name>
            <name name-style="western">
              <surname>Otten</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Engels</surname>
              <given-names>RC</given-names>
            </name>
            <name name-style="western">
              <surname>Granic</surname>
              <given-names>I</given-names>
            </name>
          </person-group>
          <article-title>Effects of the video game 'Mindlight' on anxiety of children with an autism spectrum disorder: a randomized controlled trial</article-title>
          <source>J Behav Ther Exp Psychiatry</source>
          <year>2020</year>
          <volume>68</volume>
          <fpage>101548</fpage>
          <pub-id pub-id-type="doi">10.1016/j.jbtep.2020.101548</pub-id>
          <pub-id pub-id-type="medline">32155470</pub-id>
          <pub-id pub-id-type="pii">S0005-7916(18)30277-5</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref51">
        <label>51</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Scholten</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Malmberg</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Lobel</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Engels</surname>
              <given-names>RC</given-names>
            </name>
            <name name-style="western">
              <surname>Granic</surname>
              <given-names>I</given-names>
            </name>
          </person-group>
          <article-title>A randomized controlled trial to test the effectiveness of an immersive 3D video game for anxiety prevention among adolescents</article-title>
          <source>PLoS One</source>
          <year>2016</year>
          <volume>11</volume>
          <issue>1</issue>
          <fpage>e0147763</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://dx.plos.org/10.1371/journal.pone.0147763"/>
          </comment>
          <pub-id pub-id-type="doi">10.1371/journal.pone.0147763</pub-id>
          <pub-id pub-id-type="medline">26816292</pub-id>
          <pub-id pub-id-type="pii">PONE-D-15-29519</pub-id>
          <pub-id pub-id-type="pmcid">PMC4729475</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref52">
        <label>52</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Marechal</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Berthiller</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Tosetti</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Cogniat</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Desombres</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Bouvet</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Kassai</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Chassard</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>de Queiroz Siqueira</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title>Children and parental anxiolysis in paediatric ambulatory surgery: a randomized controlled study comparing 0.3 mg kg-1 midazolam to tablet computer based interactive distraction</article-title>
          <source>Br J Anaesth</source>
          <year>2017</year>
          <volume>118</volume>
          <issue>2</issue>
          <fpage>247</fpage>
          <lpage>53</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://linkinghub.elsevier.com/retrieve/pii/S0007-0912(17)30086-7"/>
          </comment>
          <pub-id pub-id-type="doi">10.1093/bja/aew436</pub-id>
          <pub-id pub-id-type="medline">28100529</pub-id>
          <pub-id pub-id-type="pii">S0007-0912(17)30086-7</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref53">
        <label>53</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Sakızcı Uyar</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Polat</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Bolat</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Donmez</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <article-title>Which is good for pre-operative anxiety? Midazolam, video games or teaching with cartoons: a randomised trial</article-title>
          <source>Eur J Anaesthesiol</source>
          <year>2021</year>
          <volume>38</volume>
          <issue>7</issue>
          <fpage>744</fpage>
          <lpage>50</lpage>
          <pub-id pub-id-type="doi">10.1097/EJA.0000000000001384</pub-id>
          <pub-id pub-id-type="medline">33186304</pub-id>
          <pub-id pub-id-type="pii">00003643-202107000-00008</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref54">
        <label>54</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Liu</surname>
              <given-names>KY</given-names>
            </name>
            <name name-style="western">
              <surname>Ninan</surname>
              <given-names>SJ</given-names>
            </name>
            <name name-style="western">
              <surname>Laitman</surname>
              <given-names>BM</given-names>
            </name>
            <name name-style="western">
              <surname>Goldrich</surname>
              <given-names>DY</given-names>
            </name>
            <name name-style="western">
              <surname>Iloreta</surname>
              <given-names>AM</given-names>
            </name>
            <name name-style="western">
              <surname>Londino 3rd</surname>
              <given-names>AV</given-names>
            </name>
          </person-group>
          <article-title>Virtual reality as distraction analgesia and anxiolysis for pediatric otolaryngology procedures</article-title>
          <source>Laryngoscope</source>
          <year>2021</year>
          <volume>131</volume>
          <issue>5</issue>
          <fpage>E1714</fpage>
          <lpage>21</lpage>
          <pub-id pub-id-type="doi">10.1002/lary.29148</pub-id>
          <pub-id pub-id-type="medline">33017065</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref55">
        <label>55</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Butler</surname>
              <given-names>O</given-names>
            </name>
            <name name-style="western">
              <surname>Herr</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Willmund</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Gallinat</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Kühn</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Zimmermann</surname>
              <given-names>P</given-names>
            </name>
          </person-group>
          <article-title>Trauma, treatment and Tetris: video gaming increases hippocampal volume in male patients with combat-related posttraumatic stress disorder</article-title>
          <source>J Psychiatry Neurosci</source>
          <year>2020</year>
          <volume>45</volume>
          <issue>4</issue>
          <fpage>279</fpage>
          <lpage>87</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.jpn.ca/lookup/pmidlookup?view=long&#38;pmid=32293830"/>
          </comment>
          <pub-id pub-id-type="doi">10.1503/jpn.190027</pub-id>
          <pub-id pub-id-type="medline">32293830</pub-id>
          <pub-id pub-id-type="pmcid">PMC7828932</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref56">
        <label>56</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Bove</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Rowles</surname>
              <given-names>W</given-names>
            </name>
            <name name-style="western">
              <surname>Zhao</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Anderson</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Friedman</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Langdon</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Alexander</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Sacco</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Henry</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Gazzaley</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Feinstein</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Anguera</surname>
              <given-names>JA</given-names>
            </name>
          </person-group>
          <article-title>A novel in-home digital treatment to improve processing speed in people with multiple sclerosis: a pilot study</article-title>
          <source>Mult Scler</source>
          <year>2021</year>
          <volume>27</volume>
          <issue>5</issue>
          <fpage>778</fpage>
          <lpage>89</lpage>
          <pub-id pub-id-type="doi">10.1177/1352458520930371</pub-id>
          <pub-id pub-id-type="medline">32584155</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref57">
        <label>57</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Sanchez</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Brown</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Kocher</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>DeRosier</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title>Improving children's mental health with a digital social skills development game: a randomized controlled efficacy trial of adventures aboard the S.S. GRIN</article-title>
          <source>Games Health J</source>
          <year>2017</year>
          <volume>6</volume>
          <issue>1</issue>
          <fpage>19</fpage>
          <lpage>27</lpage>
          <pub-id pub-id-type="doi">10.1089/g4h.2015.0108</pub-id>
          <pub-id pub-id-type="medline">28051877</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref58">
        <label>58</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Beidel</surname>
              <given-names>DC</given-names>
            </name>
            <name name-style="western">
              <surname>Tuerk</surname>
              <given-names>PW</given-names>
            </name>
            <name name-style="western">
              <surname>Spitalnick</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Bowers</surname>
              <given-names>CA</given-names>
            </name>
            <name name-style="western">
              <surname>Morrison</surname>
              <given-names>K</given-names>
            </name>
          </person-group>
          <article-title>Treating childhood social anxiety disorder with virtual environments and serious games: a randomized trial</article-title>
          <source>Behav Ther</source>
          <year>2021</year>
          <volume>52</volume>
          <issue>6</issue>
          <fpage>1351</fpage>
          <lpage>63</lpage>
          <pub-id pub-id-type="doi">10.1016/j.beth.2021.03.003</pub-id>
          <pub-id pub-id-type="medline">34656191</pub-id>
          <pub-id pub-id-type="pii">S0005-7894(21)00047-2</pub-id>
          <pub-id pub-id-type="pmcid">PMC8531536</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref59">
        <label>59</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Haberkamp</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Walter</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Althaus</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Schmuck</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Rief</surname>
              <given-names>W</given-names>
            </name>
            <name name-style="western">
              <surname>Schmidt</surname>
              <given-names>F</given-names>
            </name>
          </person-group>
          <article-title>Testing a gamified Spider App to reduce spider fear and avoidance</article-title>
          <source>J Anxiety Disord</source>
          <year>2021</year>
          <volume>77</volume>
          <fpage>102331</fpage>
          <pub-id pub-id-type="doi">10.1016/j.janxdis.2020.102331</pub-id>
          <pub-id pub-id-type="medline">33166870</pub-id>
          <pub-id pub-id-type="pii">S0887-6185(20)30145-6</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref60">
        <label>60</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Litvin</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Saunders</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Maier</surname>
              <given-names>MA</given-names>
            </name>
            <name name-style="western">
              <surname>Lüttke</surname>
              <given-names>S</given-names>
            </name>
          </person-group>
          <article-title>Gamification as an approach to improve resilience and reduce attrition in mobile mental health interventions: a randomized controlled trial</article-title>
          <source>PLoS One</source>
          <year>2020</year>
          <volume>15</volume>
          <issue>9</issue>
          <fpage>e0237220</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://dx.plos.org/10.1371/journal.pone.0237220"/>
          </comment>
          <pub-id pub-id-type="doi">10.1371/journal.pone.0237220</pub-id>
          <pub-id pub-id-type="medline">32877425</pub-id>
          <pub-id pub-id-type="pii">PONE-D-19-35191</pub-id>
          <pub-id pub-id-type="pmcid">PMC7467300</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref61">
        <label>61</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Steinman</surname>
              <given-names>SA</given-names>
            </name>
            <name name-style="western">
              <surname>Teachman</surname>
              <given-names>BA</given-names>
            </name>
          </person-group>
          <article-title>Cognitive processing and acrophobia: validating the Heights Interpretation Questionnaire</article-title>
          <source>J Anxiety Disord</source>
          <year>2011</year>
          <volume>25</volume>
          <issue>7</issue>
          <fpage>896</fpage>
          <lpage>902</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://europepmc.org/abstract/MED/21641766"/>
          </comment>
          <pub-id pub-id-type="doi">10.1016/j.janxdis.2011.05.001</pub-id>
          <pub-id pub-id-type="medline">21641766</pub-id>
          <pub-id pub-id-type="pii">S0887-6185(11)00091-0</pub-id>
          <pub-id pub-id-type="pmcid">PMC3152668</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref62">
        <label>62</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Abd-Alrazaq</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Al-Jafar</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Alajlani</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Toro</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Alhuwail</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Ahmed</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Reagu</surname>
              <given-names>SM</given-names>
            </name>
            <name name-style="western">
              <surname>Al-Shorbaji</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Househ</surname>
              <given-names>M</given-names>
            </name>
          </person-group>
          <article-title>The effectiveness of serious games for alleviating depression: systematic review and meta-analysis</article-title>
          <source>JMIR Serious Games</source>
          <year>2022</year>
          <volume>10</volume>
          <issue>1</issue>
          <fpage>e32331</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://games.jmir.org/2022/1/e32331/"/>
          </comment>
          <pub-id pub-id-type="doi">10.2196/32331</pub-id>
          <pub-id pub-id-type="medline">35029530</pub-id>
          <pub-id pub-id-type="pii">v10i1e32331</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref63">
        <label>63</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Adelman</surname>
              <given-names>CB</given-names>
            </name>
            <name name-style="western">
              <surname>Panza</surname>
              <given-names>KE</given-names>
            </name>
            <name name-style="western">
              <surname>Bartley</surname>
              <given-names>CA</given-names>
            </name>
            <name name-style="western">
              <surname>Bontempo</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Bloch</surname>
              <given-names>MH</given-names>
            </name>
          </person-group>
          <article-title>A meta-analysis of computerized cognitive-behavioral therapy for the treatment of DSM-5 anxiety disorders</article-title>
          <source>J Clin Psychiatry</source>
          <year>2014</year>
          <volume>75</volume>
          <issue>7</issue>
          <fpage>e695</fpage>
          <lpage>704</lpage>
          <pub-id pub-id-type="doi">10.4088/JCP.13r08894</pub-id>
          <pub-id pub-id-type="medline">25093485</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref64">
        <label>64</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Christ</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Schouten</surname>
              <given-names>MJ</given-names>
            </name>
            <name name-style="western">
              <surname>Blankers</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>van Schaik</surname>
              <given-names>DJ</given-names>
            </name>
            <name name-style="western">
              <surname>Beekman</surname>
              <given-names>AT</given-names>
            </name>
            <name name-style="western">
              <surname>Wisman</surname>
              <given-names>MA</given-names>
            </name>
            <name name-style="western">
              <surname>Stikkelbroek</surname>
              <given-names>YA</given-names>
            </name>
            <name name-style="western">
              <surname>Dekker</surname>
              <given-names>JJ</given-names>
            </name>
          </person-group>
          <article-title>Internet and computer-based cognitive behavioral therapy for anxiety and depression in adolescents and young adults: systematic review and meta-analysis</article-title>
          <source>J Med Internet Res</source>
          <year>2020</year>
          <volume>22</volume>
          <issue>9</issue>
          <fpage>e17831</fpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.jmir.org/2020/9/e17831/"/>
          </comment>
          <pub-id pub-id-type="doi">10.2196/17831</pub-id>
          <pub-id pub-id-type="medline">32673212</pub-id>
          <pub-id pub-id-type="pii">v22i9e17831</pub-id>
          <pub-id pub-id-type="pmcid">PMC7547394</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref65">
        <label>65</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Newby</surname>
              <given-names>JM</given-names>
            </name>
            <name name-style="western">
              <surname>Twomey</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Yuan Li</surname>
              <given-names>SS</given-names>
            </name>
            <name name-style="western">
              <surname>Andrews</surname>
              <given-names>G</given-names>
            </name>
          </person-group>
          <article-title>Transdiagnostic computerised cognitive behavioural therapy for depression and anxiety: a systematic review and meta-analysis</article-title>
          <source>J Affect Disord</source>
          <year>2016</year>
          <volume>199</volume>
          <fpage>30</fpage>
          <lpage>41</lpage>
          <pub-id pub-id-type="doi">10.1016/j.jad.2016.03.018</pub-id>
          <pub-id pub-id-type="medline">27060430</pub-id>
          <pub-id pub-id-type="pii">S0165-0327(16)30050-7</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref66">
        <label>66</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Rooksby</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Elouafkaoui</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Humphris</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Clarkson</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Freeman</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
          <article-title>Internet-assisted delivery of cognitive behavioural therapy (CBT) for childhood anxiety: systematic review and meta-analysis</article-title>
          <source>J Anxiety Disord</source>
          <year>2015</year>
          <volume>29</volume>
          <fpage>83</fpage>
          <lpage>92</lpage>
          <pub-id pub-id-type="doi">10.1016/j.janxdis.2014.11.006</pub-id>
          <pub-id pub-id-type="medline">25527900</pub-id>
          <pub-id pub-id-type="pii">S0887-6185(14)00172-8</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref67">
        <label>67</label>
        <nlm-citation citation-type="book">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Bhattacherjee</surname>
              <given-names>A</given-names>
            </name>
          </person-group>
          <source>Social science research: principles, methods, and practices</source>
          <year>2012</year>
          <publisher-loc>Tampa</publisher-loc>
          <publisher-name>USF Tampa Library Textbooks Collection</publisher-name>
        </nlm-citation>
      </ref>
      <ref id="ref68">
        <label>68</label>
        <nlm-citation citation-type="web">
          <article-title>Mobile statistics report, 2021-2025</article-title>
          <source>The Radicati Group</source>
          <year>2021</year>
          <access-date>2022-02-08</access-date>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="https://www.radicati.com/wp/wp-content/uploads/2021/Mobile_Statistics_Report,_2021-2025_Executive_Summary.pdf">https://www.radicati.com/wp/wp-content/uploads/2021/Mobile_Statistics_Report,_2021-2025_Executive_Summary.pdf</ext-link>
          </comment>
        </nlm-citation>
      </ref>
      <ref id="ref69">
        <label>69</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Murray</surname>
              <given-names>CJ</given-names>
            </name>
            <name name-style="western">
              <surname>Vos</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Lozano</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Naghavi</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Flaxman</surname>
              <given-names>AD</given-names>
            </name>
            <name name-style="western">
              <surname>Michaud</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Ezzati</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Shibuya</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Salomon</surname>
              <given-names>JA</given-names>
            </name>
            <name name-style="western">
              <surname>Abdalla</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Aboyans</surname>
              <given-names>V</given-names>
            </name>
            <name name-style="western">
              <surname>Abraham</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Ackerman</surname>
              <given-names>I</given-names>
            </name>
            <name name-style="western">
              <surname>Aggarwal</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Ahn</surname>
              <given-names>SY</given-names>
            </name>
            <name name-style="western">
              <surname>Ali</surname>
              <given-names>MK</given-names>
            </name>
            <name name-style="western">
              <surname>Alvarado</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Anderson</surname>
              <given-names>HR</given-names>
            </name>
            <name name-style="western">
              <surname>Anderson</surname>
              <given-names>LM</given-names>
            </name>
            <name name-style="western">
              <surname>Andrews</surname>
              <given-names>KG</given-names>
            </name>
            <name name-style="western">
              <surname>Atkinson</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Baddour</surname>
              <given-names>LM</given-names>
            </name>
            <name name-style="western">
              <surname>Bahalim</surname>
              <given-names>AN</given-names>
            </name>
            <name name-style="western">
              <surname>Barker-Collo</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Barrero</surname>
              <given-names>LH</given-names>
            </name>
            <name name-style="western">
              <surname>Bartels</surname>
              <given-names>DH</given-names>
            </name>
            <name name-style="western">
              <surname>Basáñez</surname>
              <given-names>MG</given-names>
            </name>
            <name name-style="western">
              <surname>Baxter</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Bell</surname>
              <given-names>ML</given-names>
            </name>
            <name name-style="western">
              <surname>Benjamin</surname>
              <given-names>EJ</given-names>
            </name>
            <name name-style="western">
              <surname>Bennett</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Bernabé</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Bhalla</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Bhandari</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Bikbov</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Bin Abdulhak</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Birbeck</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Black</surname>
              <given-names>JA</given-names>
            </name>
            <name name-style="western">
              <surname>Blencowe</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Blore</surname>
              <given-names>JD</given-names>
            </name>
            <name name-style="western">
              <surname>Blyth</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Bolliger</surname>
              <given-names>I</given-names>
            </name>
            <name name-style="western">
              <surname>Bonaventure</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Boufous</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Bourne</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Boussinesq</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Braithwaite</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Brayne</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Bridgett</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Brooker</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Brooks</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Brugha</surname>
              <given-names>TS</given-names>
            </name>
            <name name-style="western">
              <surname>Bryan-Hancock</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Bucello</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Buchbinder</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Buckle</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Budke</surname>
              <given-names>CM</given-names>
            </name>
            <name name-style="western">
              <surname>Burch</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Burney</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Burstein</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Calabria</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Campbell</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Canter</surname>
              <given-names>CE</given-names>
            </name>
            <name name-style="western">
              <surname>Carabin</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Carapetis</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Carmona</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Cella</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Charlson</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Chen</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Cheng</surname>
              <given-names>AT</given-names>
            </name>
            <name name-style="western">
              <surname>Chou</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Chugh</surname>
              <given-names>SS</given-names>
            </name>
            <name name-style="western">
              <surname>Coffeng</surname>
              <given-names>LE</given-names>
            </name>
            <name name-style="western">
              <surname>Colan</surname>
              <given-names>SD</given-names>
            </name>
            <name name-style="western">
              <surname>Colquhoun</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Colson</surname>
              <given-names>KE</given-names>
            </name>
            <name name-style="western">
              <surname>Condon</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Connor</surname>
              <given-names>MD</given-names>
            </name>
            <name name-style="western">
              <surname>Cooper</surname>
              <given-names>LT</given-names>
            </name>
            <name name-style="western">
              <surname>Corriere</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Cortinovis</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>de Vaccaro</surname>
              <given-names>KC</given-names>
            </name>
            <name name-style="western">
              <surname>Couser</surname>
              <given-names>W</given-names>
            </name>
            <name name-style="western">
              <surname>Cowie</surname>
              <given-names>BC</given-names>
            </name>
            <name name-style="western">
              <surname>Criqui</surname>
              <given-names>MH</given-names>
            </name>
            <name name-style="western">
              <surname>Cross</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Dabhadkar</surname>
              <given-names>KC</given-names>
            </name>
            <name name-style="western">
              <surname>Dahiya</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Dahodwala</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Damsere-Derry</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Danaei</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Davis</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>De Leo</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Degenhardt</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Dellavalle</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Delossantos</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Denenberg</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Derrett</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Des Jarlais</surname>
              <given-names>DC</given-names>
            </name>
            <name name-style="western">
              <surname>Dharmaratne</surname>
              <given-names>SD</given-names>
            </name>
            <name name-style="western">
              <surname>Dherani</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Diaz-Torne</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Dolk</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Dorsey</surname>
              <given-names>ER</given-names>
            </name>
            <name name-style="western">
              <surname>Driscoll</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Duber</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Ebel</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Edmond</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Elbaz</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Ali</surname>
              <given-names>SE</given-names>
            </name>
            <name name-style="western">
              <surname>Erskine</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Erwin</surname>
              <given-names>PJ</given-names>
            </name>
            <name name-style="western">
              <surname>Espindola</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Ewoigbokhan</surname>
              <given-names>SE</given-names>
            </name>
            <name name-style="western">
              <surname>Farzadfar</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Feigin</surname>
              <given-names>V</given-names>
            </name>
            <name name-style="western">
              <surname>Felson</surname>
              <given-names>DT</given-names>
            </name>
            <name name-style="western">
              <surname>Ferrari</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Ferri</surname>
              <given-names>CP</given-names>
            </name>
            <name name-style="western">
              <surname>Fèvre</surname>
              <given-names>EM</given-names>
            </name>
            <name name-style="western">
              <surname>Finucane</surname>
              <given-names>MM</given-names>
            </name>
            <name name-style="western">
              <surname>Flaxman</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Flood</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Foreman</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Forouzanfar</surname>
              <given-names>MH</given-names>
            </name>
            <name name-style="western">
              <surname>Fowkes</surname>
              <given-names>FG</given-names>
            </name>
            <name name-style="western">
              <surname>Fransen</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Freeman</surname>
              <given-names>MK</given-names>
            </name>
            <name name-style="western">
              <surname>Gabbe</surname>
              <given-names>BJ</given-names>
            </name>
            <name name-style="western">
              <surname>Gabriel</surname>
              <given-names>SE</given-names>
            </name>
            <name name-style="western">
              <surname>Gakidou</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Ganatra</surname>
              <given-names>HA</given-names>
            </name>
            <name name-style="western">
              <surname>Garcia</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Gaspari</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Gillum</surname>
              <given-names>RF</given-names>
            </name>
            <name name-style="western">
              <surname>Gmel</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Gonzalez-Medina</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Gosselin</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Grainger</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Grant</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Groeger</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Guillemin</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Gunnell</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Gupta</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Haagsma</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Hagan</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Halasa</surname>
              <given-names>YA</given-names>
            </name>
            <name name-style="western">
              <surname>Hall</surname>
              <given-names>W</given-names>
            </name>
            <name name-style="western">
              <surname>Haring</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Haro</surname>
              <given-names>JM</given-names>
            </name>
            <name name-style="western">
              <surname>Harrison</surname>
              <given-names>JE</given-names>
            </name>
            <name name-style="western">
              <surname>Havmoeller</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Hay</surname>
              <given-names>RJ</given-names>
            </name>
            <name name-style="western">
              <surname>Higashi</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Hill</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Hoen</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Hoffman</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Hotez</surname>
              <given-names>PJ</given-names>
            </name>
            <name name-style="western">
              <surname>Hoy</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Huang</surname>
              <given-names>JJ</given-names>
            </name>
            <name name-style="western">
              <surname>Ibeanusi</surname>
              <given-names>SE</given-names>
            </name>
            <name name-style="western">
              <surname>Jacobsen</surname>
              <given-names>KH</given-names>
            </name>
            <name name-style="western">
              <surname>James</surname>
              <given-names>SL</given-names>
            </name>
            <name name-style="western">
              <surname>Jarvis</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Jasrasaria</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Jayaraman</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Johns</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Jonas</surname>
              <given-names>JB</given-names>
            </name>
            <name name-style="western">
              <surname>Karthikeyan</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Kassebaum</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Kawakami</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Keren</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Khoo</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>King</surname>
              <given-names>CH</given-names>
            </name>
            <name name-style="western">
              <surname>Knowlton</surname>
              <given-names>LM</given-names>
            </name>
            <name name-style="western">
              <surname>Kobusingye</surname>
              <given-names>O</given-names>
            </name>
            <name name-style="western">
              <surname>Koranteng</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Krishnamurthi</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Laden</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Lalloo</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Laslett</surname>
              <given-names>LL</given-names>
            </name>
            <name name-style="western">
              <surname>Lathlean</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Leasher</surname>
              <given-names>JL</given-names>
            </name>
            <name name-style="western">
              <surname>Lee</surname>
              <given-names>YY</given-names>
            </name>
            <name name-style="western">
              <surname>Leigh</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Levinson</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Lim</surname>
              <given-names>SS</given-names>
            </name>
            <name name-style="western">
              <surname>Limb</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Lin</surname>
              <given-names>JK</given-names>
            </name>
            <name name-style="western">
              <surname>Lipnick</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Lipshultz</surname>
              <given-names>SE</given-names>
            </name>
            <name name-style="western">
              <surname>Liu</surname>
              <given-names>W</given-names>
            </name>
            <name name-style="western">
              <surname>Loane</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Ohno</surname>
              <given-names>SL</given-names>
            </name>
            <name name-style="western">
              <surname>Lyons</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Mabweijano</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>MacIntyre</surname>
              <given-names>MF</given-names>
            </name>
            <name name-style="western">
              <surname>Malekzadeh</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Mallinger</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Manivannan</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Marcenes</surname>
              <given-names>W</given-names>
            </name>
            <name name-style="western">
              <surname>March</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Margolis</surname>
              <given-names>DJ</given-names>
            </name>
            <name name-style="western">
              <surname>Marks</surname>
              <given-names>GB</given-names>
            </name>
            <name name-style="western">
              <surname>Marks</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Matsumori</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Matzopoulos</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Mayosi</surname>
              <given-names>BM</given-names>
            </name>
            <name name-style="western">
              <surname>McAnulty</surname>
              <given-names>JH</given-names>
            </name>
            <name name-style="western">
              <surname>McDermott</surname>
              <given-names>MM</given-names>
            </name>
            <name name-style="western">
              <surname>McGill</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>McGrath</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Medina-Mora</surname>
              <given-names>ME</given-names>
            </name>
            <name name-style="western">
              <surname>Meltzer</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Mensah</surname>
              <given-names>GA</given-names>
            </name>
            <name name-style="western">
              <surname>Merriman</surname>
              <given-names>TR</given-names>
            </name>
            <name name-style="western">
              <surname>Meyer</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Miglioli</surname>
              <given-names>V</given-names>
            </name>
            <name name-style="western">
              <surname>Miller</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Miller</surname>
              <given-names>TR</given-names>
            </name>
            <name name-style="western">
              <surname>Mitchell</surname>
              <given-names>PB</given-names>
            </name>
            <name name-style="western">
              <surname>Mock</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Mocumbi</surname>
              <given-names>AO</given-names>
            </name>
            <name name-style="western">
              <surname>Moffitt</surname>
              <given-names>TE</given-names>
            </name>
            <name name-style="western">
              <surname>Mokdad</surname>
              <given-names>AA</given-names>
            </name>
            <name name-style="western">
              <surname>Monasta</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Montico</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Moradi-Lakeh</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Moran</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Morawska</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Mori</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Murdoch</surname>
              <given-names>ME</given-names>
            </name>
            <name name-style="western">
              <surname>Mwaniki</surname>
              <given-names>MK</given-names>
            </name>
            <name name-style="western">
              <surname>Naidoo</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Nair</surname>
              <given-names>MN</given-names>
            </name>
            <name name-style="western">
              <surname>Naldi</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Narayan</surname>
              <given-names>KM</given-names>
            </name>
            <name name-style="western">
              <surname>Nelson</surname>
              <given-names>PK</given-names>
            </name>
            <name name-style="western">
              <surname>Nelson</surname>
              <given-names>RG</given-names>
            </name>
            <name name-style="western">
              <surname>Nevitt</surname>
              <given-names>MC</given-names>
            </name>
            <name name-style="western">
              <surname>Newton</surname>
              <given-names>CR</given-names>
            </name>
            <name name-style="western">
              <surname>Nolte</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Norman</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Norman</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>O'Donnell</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>O'Hanlon</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Olives</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Omer</surname>
              <given-names>SB</given-names>
            </name>
            <name name-style="western">
              <surname>Ortblad</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Osborne</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Ozgediz</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Page</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Pahari</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Pandian</surname>
              <given-names>JD</given-names>
            </name>
            <name name-style="western">
              <surname>Rivero</surname>
              <given-names>AP</given-names>
            </name>
            <name name-style="western">
              <surname>Patten</surname>
              <given-names>SB</given-names>
            </name>
            <name name-style="western">
              <surname>Pearce</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Padilla</surname>
              <given-names>RP</given-names>
            </name>
            <name name-style="western">
              <surname>Perez-Ruiz</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Perico</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Pesudovs</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Phillips</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Phillips</surname>
              <given-names>MR</given-names>
            </name>
            <name name-style="western">
              <surname>Pierce</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Pion</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Polanczyk</surname>
              <given-names>GV</given-names>
            </name>
            <name name-style="western">
              <surname>Polinder</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Pope</surname>
              <given-names>CA</given-names>
            </name>
            <name name-style="western">
              <surname>Popova</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Porrini</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Pourmalek</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Prince</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Pullan</surname>
              <given-names>RL</given-names>
            </name>
            <name name-style="western">
              <surname>Ramaiah</surname>
              <given-names>KD</given-names>
            </name>
            <name name-style="western">
              <surname>Ranganathan</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Razavi</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Regan</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Rehm</surname>
              <given-names>JT</given-names>
            </name>
            <name name-style="western">
              <surname>Rein</surname>
              <given-names>DB</given-names>
            </name>
            <name name-style="western">
              <surname>Remuzzi</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Richardson</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Rivara</surname>
              <given-names>FP</given-names>
            </name>
            <name name-style="western">
              <surname>Roberts</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Robinson</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>De Leòn</surname>
              <given-names>FR</given-names>
            </name>
            <name name-style="western">
              <surname>Ronfani</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Room</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Rosenfeld</surname>
              <given-names>LC</given-names>
            </name>
            <name name-style="western">
              <surname>Rushton</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Sacco</surname>
              <given-names>RL</given-names>
            </name>
            <name name-style="western">
              <surname>Saha</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Sampson</surname>
              <given-names>U</given-names>
            </name>
            <name name-style="western">
              <surname>Sanchez-Riera</surname>
              <given-names>L</given-names>
            </name>
            <name name-style="western">
              <surname>Sanman</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Schwebel</surname>
              <given-names>DC</given-names>
            </name>
            <name name-style="western">
              <surname>Scott</surname>
              <given-names>JG</given-names>
            </name>
            <name name-style="western">
              <surname>Segui-Gomez</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Shahraz</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Shepard</surname>
              <given-names>DS</given-names>
            </name>
            <name name-style="western">
              <surname>Shin</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Shivakoti</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Singh</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Singh</surname>
              <given-names>GM</given-names>
            </name>
            <name name-style="western">
              <surname>Singh</surname>
              <given-names>JA</given-names>
            </name>
            <name name-style="western">
              <surname>Singleton</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Sleet</surname>
              <given-names>DA</given-names>
            </name>
            <name name-style="western">
              <surname>Sliwa</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Smith</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Smith</surname>
              <given-names>JL</given-names>
            </name>
            <name name-style="western">
              <surname>Stapelberg</surname>
              <given-names>NJ</given-names>
            </name>
            <name name-style="western">
              <surname>Steer</surname>
              <given-names>A</given-names>
            </name>
            <name name-style="western">
              <surname>Steiner</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Stolk</surname>
              <given-names>WA</given-names>
            </name>
            <name name-style="western">
              <surname>Stovner</surname>
              <given-names>LJ</given-names>
            </name>
            <name name-style="western">
              <surname>Sudfeld</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Syed</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Tamburlini</surname>
              <given-names>G</given-names>
            </name>
            <name name-style="western">
              <surname>Tavakkoli</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Taylor</surname>
              <given-names>HR</given-names>
            </name>
            <name name-style="western">
              <surname>Taylor</surname>
              <given-names>JA</given-names>
            </name>
            <name name-style="western">
              <surname>Taylor</surname>
              <given-names>WJ</given-names>
            </name>
            <name name-style="western">
              <surname>Thomas</surname>
              <given-names>B</given-names>
            </name>
            <name name-style="western">
              <surname>Thomson</surname>
              <given-names>WM</given-names>
            </name>
            <name name-style="western">
              <surname>Thurston</surname>
              <given-names>GD</given-names>
            </name>
            <name name-style="western">
              <surname>Tleyjeh</surname>
              <given-names>IM</given-names>
            </name>
            <name name-style="western">
              <surname>Tonelli</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Towbin</surname>
              <given-names>JA</given-names>
            </name>
            <name name-style="western">
              <surname>Truelsen</surname>
              <given-names>T</given-names>
            </name>
            <name name-style="western">
              <surname>Tsilimbaris</surname>
              <given-names>MK</given-names>
            </name>
            <name name-style="western">
              <surname>Ubeda</surname>
              <given-names>C</given-names>
            </name>
            <name name-style="western">
              <surname>Undurraga</surname>
              <given-names>EA</given-names>
            </name>
            <name name-style="western">
              <surname>van der Werf</surname>
              <given-names>MJ</given-names>
            </name>
            <name name-style="western">
              <surname>van Os</surname>
              <given-names>J</given-names>
            </name>
            <name name-style="western">
              <surname>Vavilala</surname>
              <given-names>MS</given-names>
            </name>
            <name name-style="western">
              <surname>Venketasubramanian</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Wang</surname>
              <given-names>M</given-names>
            </name>
            <name name-style="western">
              <surname>Wang</surname>
              <given-names>W</given-names>
            </name>
            <name name-style="western">
              <surname>Watt</surname>
              <given-names>K</given-names>
            </name>
            <name name-style="western">
              <surname>Weatherall</surname>
              <given-names>DJ</given-names>
            </name>
            <name name-style="western">
              <surname>Weinstock</surname>
              <given-names>MA</given-names>
            </name>
            <name name-style="western">
              <surname>Weintraub</surname>
              <given-names>R</given-names>
            </name>
            <name name-style="western">
              <surname>Weisskopf</surname>
              <given-names>MG</given-names>
            </name>
            <name name-style="western">
              <surname>Weissman</surname>
              <given-names>MM</given-names>
            </name>
            <name name-style="western">
              <surname>White</surname>
              <given-names>RA</given-names>
            </name>
            <name name-style="western">
              <surname>Whiteford</surname>
              <given-names>H</given-names>
            </name>
            <name name-style="western">
              <surname>Wiebe</surname>
              <given-names>N</given-names>
            </name>
            <name name-style="western">
              <surname>Wiersma</surname>
              <given-names>ST</given-names>
            </name>
            <name name-style="western">
              <surname>Wilkinson</surname>
              <given-names>JD</given-names>
            </name>
            <name name-style="western">
              <surname>Williams</surname>
              <given-names>HC</given-names>
            </name>
            <name name-style="western">
              <surname>Williams</surname>
              <given-names>SR</given-names>
            </name>
            <name name-style="western">
              <surname>Witt</surname>
              <given-names>E</given-names>
            </name>
            <name name-style="western">
              <surname>Wolfe</surname>
              <given-names>F</given-names>
            </name>
            <name name-style="western">
              <surname>Woolf</surname>
              <given-names>AD</given-names>
            </name>
            <name name-style="western">
              <surname>Wulf</surname>
              <given-names>S</given-names>
            </name>
            <name name-style="western">
              <surname>Yeh</surname>
              <given-names>P</given-names>
            </name>
            <name name-style="western">
              <surname>Zaidi</surname>
              <given-names>AK</given-names>
            </name>
            <name name-style="western">
              <surname>Zheng</surname>
              <given-names>Z</given-names>
            </name>
            <name name-style="western">
              <surname>Zonies</surname>
              <given-names>D</given-names>
            </name>
            <name name-style="western">
              <surname>Lopez</surname>
              <given-names>AD</given-names>
            </name>
            <name name-style="western">
              <surname>AlMazroa</surname>
              <given-names>MA</given-names>
            </name>
            <name name-style="western">
              <surname>Memish</surname>
              <given-names>ZA</given-names>
            </name>
          </person-group>
          <article-title>Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010</article-title>
          <source>Lancet</source>
          <year>2012</year>
          <volume>380</volume>
          <issue>9859</issue>
          <fpage>2197</fpage>
          <lpage>223</lpage>
          <pub-id pub-id-type="doi">10.1016/S0140-6736(12)61689-4</pub-id>
          <pub-id pub-id-type="medline">23245608</pub-id>
          <pub-id pub-id-type="pii">S0140-6736(12)61689-4</pub-id>
        </nlm-citation>
      </ref>
      <ref id="ref70">
        <label>70</label>
        <nlm-citation citation-type="journal">
          <person-group person-group-type="author">
            <name name-style="western">
              <surname>Oladeji</surname>
              <given-names>BD</given-names>
            </name>
            <name name-style="western">
              <surname>Gureje</surname>
              <given-names>O</given-names>
            </name>
          </person-group>
          <article-title>Brain drain: a challenge to global mental health</article-title>
          <source>BJPsych Int</source>
          <year>2016</year>
          <volume>13</volume>
          <issue>3</issue>
          <fpage>61</fpage>
          <lpage>3</lpage>
          <comment>
            <ext-link ext-link-type="uri" xlink:type="simple" xlink:href="http://europepmc.org/abstract/MED/29093905"/>
          </comment>
          <pub-id pub-id-type="doi">10.1192/s2056474000001240</pub-id>
          <pub-id pub-id-type="medline">29093905</pub-id>
          <pub-id pub-id-type="pii">S2056474000001240</pub-id>
          <pub-id pub-id-type="pmcid">PMC5618877</pub-id>
        </nlm-citation>
      </ref>
    </ref-list>
  </back>
</article>
