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  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">JMIR</journal-id>
      <journal-id journal-id-type="nlm-ta">J Med Internet Res</journal-id>
      <journal-title>Journal of Medical Internet Research</journal-title>
      <issn pub-type="epub">1438-8871</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">v23i11e29742</article-id>
      <article-id pub-id-type="pmid">34842543</article-id>
      <article-id pub-id-type="doi">10.2196/29742</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>Mechanisms of Change in Digital Health Interventions for Mental Disorders in Youth: Systematic Review</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="editor">
          <name>
            <surname>Kukafka</surname>
            <given-names>Rita</given-names>
          </name>
        </contrib>
      </contrib-group>
      <contrib-group>
        <contrib contrib-type="reviewer">
          <name>
            <surname>Apolinário-Hagen</surname>
            <given-names>Jennifer</given-names>
          </name>
        </contrib>
        <contrib contrib-type="reviewer">
          <name>
            <surname>Rassenhofer</surname>
            <given-names>Miriam</given-names>
          </name>
        </contrib>
      </contrib-group>
      <contrib-group>
        <contrib id="contrib1" contrib-type="author" corresp="yes">
          <name name-style="western">
            <surname>Domhardt</surname>
            <given-names>Matthias</given-names>
          </name>
          <degrees>MSc</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <address>
            <institution>Department of Clinical Psychology and Psychotherapy</institution>
            <institution>Ulm University</institution>
            <addr-line>Lise-Meitner-Str. 16</addr-line>
            <addr-line>Ulm, D-89081</addr-line>
            <country>Germany</country>
            <phone>49 73150 32803</phone>
            <fax>49 73150 32809</fax>
            <email>matthias.domhardt@uni-ulm.de</email>
          </address>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-3243-8926</ext-link>
        </contrib>
        <contrib id="contrib2" contrib-type="author">
          <name name-style="western">
            <surname>Engler</surname>
            <given-names>Sophie</given-names>
          </name>
          <degrees>BSc</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0001-5867-9552</ext-link>
        </contrib>
        <contrib id="contrib3" contrib-type="author">
          <name name-style="western">
            <surname>Nowak</surname>
            <given-names>Hannah</given-names>
          </name>
          <degrees>MSc</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-1017-697X</ext-link>
        </contrib>
        <contrib id="contrib4" contrib-type="author">
          <name name-style="western">
            <surname>Lutsch</surname>
            <given-names>Arne</given-names>
          </name>
          <degrees>BSc</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-9432-6620</ext-link>
        </contrib>
        <contrib id="contrib5" contrib-type="author">
          <name name-style="western">
            <surname>Baumel</surname>
            <given-names>Amit</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff2" ref-type="aff">2</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-7043-8898</ext-link>
        </contrib>
        <contrib id="contrib6" contrib-type="author">
          <name name-style="western">
            <surname>Baumeister</surname>
            <given-names>Harald</given-names>
          </name>
          <degrees>PhD</degrees>
          <xref rid="aff1" ref-type="aff">1</xref>
          <ext-link ext-link-type="orcid">https://orcid.org/0000-0002-2040-661X</ext-link>
        </contrib>
      </contrib-group>
      <aff id="aff1">
        <label>1</label>
        <institution>Department of Clinical Psychology and Psychotherapy</institution>
        <institution>Ulm University</institution>
        <addr-line>Ulm</addr-line>
        <country>Germany</country>
      </aff>
      <aff id="aff2">
        <label>2</label>
        <institution>Department of Community Mental Health</institution>
        <institution>University of Haifa</institution>
        <addr-line>Haifa</addr-line>
        <country>Israel</country>
      </aff>
      <author-notes>
        <corresp>Corresponding Author: Matthias Domhardt <email>matthias.domhardt@uni-ulm.de</email></corresp>
      </author-notes>
      <pub-date pub-type="collection">
        <month>11</month>
        <year>2021</year>
      </pub-date>
      <pub-date pub-type="epub">
        <day>26</day>
        <month>11</month>
        <year>2021</year>
      </pub-date>
      <volume>23</volume>
      <issue>11</issue>
      <elocation-id>e29742</elocation-id>
      <history>
        <date date-type="received">
          <day>20</day>
          <month>4</month>
          <year>2021</year>
        </date>
        <date date-type="rev-request">
          <day>21</day>
          <month>5</month>
          <year>2021</year>
        </date>
        <date date-type="rev-recd">
          <day>14</day>
          <month>7</month>
          <year>2021</year>
        </date>
        <date date-type="accepted">
          <day>27</day>
          <month>7</month>
          <year>2021</year>
        </date>
      </history>
      <copyright-statement>©Matthias Domhardt, Sophie Engler, Hannah Nowak, Arne Lutsch, Amit Baumel, Harald Baumeister. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.11.2021.</copyright-statement>
      <copyright-year>2021</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 the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.</p>
      </license>
      <self-uri xlink:href="https://www.jmir.org/2021/11/e29742" xlink:type="simple"/>
      <abstract>
        <sec sec-type="background">
          <title>Background</title>
          <p>Digital health interventions (DHIs) are efficacious for several mental disorders in youth; however, integrated, evidence-based knowledge about the mechanisms of change in these interventions is lacking.</p>
        </sec>
        <sec sec-type="objective">
          <title>Objective</title>
          <p>This systematic review aims to comprehensively evaluate studies on mediators and mechanisms of change in different DHIs for common mental disorders in children and adolescents.</p>
        </sec>
        <sec sec-type="methods">
          <title>Methods</title>
          <p>A systematic literature search of the electronic databases Cochrane Central Register of Controlled Trials, Embase, MEDLINE, and PsycINFO was conducted, complemented by backward and forward searches. Two independent reviewers selected studies for inclusion, extracted the data, and rated the methodological quality of eligible studies (ie, risk of bias and 8 quality criteria for process research).</p>
        </sec>
        <sec sec-type="results">
          <title>Results</title>
          <p>A total of 25 studies that have evaluated 39 potential mediators were included in this review. Cognitive mediators were the largest group of examined intervening variables, followed by a broad range of emotional and affective, interpersonal, parenting behavior, and other mediators. The mediator categories with the highest percentages of significant intervening variables were the groups of affective mediators (4/4, 100%) and combined cognitive mediators (13/19, 68%). Although more than three-quarters of the eligible studies met 5 or more quality criteria, causal conclusions have been widely precluded.</p>
        </sec>
        <sec sec-type="conclusions">
          <title>Conclusions</title>
          <p>The findings of this review might guide the empirically informed advancement of DHIs, contributing to improved intervention outcomes, and the discussion of methodological recommendations for process research might facilitate mediation studies with more pertinent designs, allowing for conclusions with higher causal certainty in the future.</p>
        </sec>
      </abstract>
      <kwd-group>
        <kwd>children and adolescents</kwd>
        <kwd>mental disorders</kwd>
        <kwd>mediator</kwd>
        <kwd>mechanisms of change</kwd>
        <kwd>digital health intervention</kwd>
        <kwd>psychotherapy</kwd>
        <kwd>mobile phone</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec sec-type="introduction">
      <title>Introduction</title>
      <sec>
        <title>Background</title>
        <p>Mental disorders in children and adolescents are common, with prevalence rates ranging from 10% to 20% worldwide [<xref ref-type="bibr" rid="ref1">1</xref>]. These disorders contribute substantially to the global burden of disease in youth [<xref ref-type="bibr" rid="ref2">2</xref>], and about half of all mental disorders across the life span have their onset in adolescence [<xref ref-type="bibr" rid="ref3">3</xref>]. Hence, early psychotherapeutic interventions are essential to counteract the risk of chronification and prevent possible negative long-term effects [<xref ref-type="bibr" rid="ref1">1</xref>]. However, a substantial proportion of children and adolescents with mental disorders do not receive adequate psychotherapeutic or psychosocial care [<xref ref-type="bibr" rid="ref4">4</xref>-<xref ref-type="bibr" rid="ref6">6</xref>] owing to different individual and structural barriers to treatment uptake [<xref ref-type="bibr" rid="ref7">7</xref>]. Furthermore, the availability of mental health care is often insufficient to adequately meet treatment demands, particularly in rural regions [<xref ref-type="bibr" rid="ref8">8</xref>] and low-income countries [<xref ref-type="bibr" rid="ref9">9</xref>].</p>
        <p>Digital health interventions (DHIs), such as internet- and mobile-based interventions with a psychotherapeutic focus (DHI<sub>PSY</sub>), offer the possibility of addressing some barriers to treatment uptake and might contribute to extending mental health care, given their various presumed advantages, such as possible cost- and time-efficient use, independence from spatial and temporal circumstances, potential anonymity, high degrees of flexibility, and autonomy for users. These assets may be especially important during the COVID-19 pandemic and allow for continued mental health care despite contact restrictions and physical distancing [<xref ref-type="bibr" rid="ref10">10</xref>]. Furthermore, in view of the fact that youth are particular familiar with digital devices (so-called <italic>digital natives</italic>; Children in a digital world [<xref ref-type="bibr" rid="ref11">11</xref>]), the use of DHIs might be especially appealing to this younger age group [<xref ref-type="bibr" rid="ref12">12</xref>]. DHIs can be distinguished and characterized based on their theoretical basis, the type of technical implementation, the area of application, and the extent of accompanying human support [<xref ref-type="bibr" rid="ref13">13</xref>,<xref ref-type="bibr" rid="ref14">14</xref>]. The type and the intensity of <italic>guidance</italic> in DHIs can vary on the continuum from (1) pure self-help interventions without any human support (so-called <italic>unguided interventions</italic>) to (2) interventions with some support (<italic>guided interventions</italic>), to (3) videoconference-based psychotherapy with the internet as the sole communication medium between therapists and patients [<xref ref-type="bibr" rid="ref15">15</xref>].</p>
        <p>The efficacy of DHI<sub>PSY</sub> for some common mental disorders in children and adolescents has been established using meta-analyses [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref16">16</xref>-<xref ref-type="bibr" rid="ref19">19</xref>]. For example, Vigerland et al [<xref ref-type="bibr" rid="ref19">19</xref>] evaluated the efficacy of internet-based cognitive behavioral therapy for a range of mental disorders, including anxiety, depression, behavioral problems, obsessive-compulsive disorder, and some somatic disorders such as chronic pain and insomnia. This meta-analysis revealed a moderate, aggregated effect size favoring internet-based cognitive behavioral therapy over waitlist (g=0.62, 95% CI 0.41-0.84; <italic>P</italic>&#60;.001). In contrast, Hollis et al [<xref ref-type="bibr" rid="ref20">20</xref>] appraised the evidence on the efficacy of DHI<sub>PSY</sub> for other mental disorders, including attention-deficit/hyperactivity disorder, autism, psychotic disorders, and eating disorders in their review as uncertain and necessitating future research regarding moderators of intervention effects. Current empirical knowledge suggests that older children and adolescents benefit more from DHI<sub>PSY</sub> than younger children [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref20">20</xref>]. In addition, the well-established finding that guided interventions are more efficacious than unguided interventions in adults [<xref ref-type="bibr" rid="ref21">21</xref>,<xref ref-type="bibr" rid="ref22">22</xref>] also seems to apply for DHI<sub>PSY</sub> in youth [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref20">20</xref>]. Complementing the evidence base and representing another major area of application, DHIs with a focus on health promotion (DHI<sub>HP</sub>), for example, on alcohol consumption or other lifestyle and health behaviors, revealed a considerably smaller effect size (Cohen <italic>d</italic>=0.14, 95% CI 0.00-0.27) [<xref ref-type="bibr" rid="ref23">23</xref>] when compared with DHI<sub>PSY</sub> with a genuine psychotherapeutic foundation such as cognitive behavioral therapy (g=0.72, 95% CI 0.55-0.90; <italic>P</italic>&#60;.001) [<xref ref-type="bibr" rid="ref16">16</xref>].</p>
        <p>Given this rather heterogeneous body of research regarding the efficacy and effectiveness of DHIs, comprising various interventions with different theoretical orientations, foci, and delivery modes, for mental health issues in children and adolescents, it seems both timely and worthwhile to investigate the presumed working mechanisms in these technology-delivered interventions. This is because evidence-based knowledge on the mediators and mechanisms of change (specific for different approaches of DHI<sub>PSY</sub> and DHI<sub>HP</sub>) can inform intervention development and mental health care practices, illustrating pathways to more powerful intervention packages and improved outcomes [<xref ref-type="bibr" rid="ref24">24</xref>-<xref ref-type="bibr" rid="ref26">26</xref>]. The first step in understanding the underlying processes in DHIs is to analyze the mediators. A mediator is an intervening variable that can explain the statistical relationship between an independent variable (eg, a DHI) and a dependent variable (eg, a symptom change) [<xref ref-type="bibr" rid="ref25">25</xref>], and can thereby potentially point to a mechanism through which an intervention achieves its effects. Although various methods for statistical mediation analysis are available (eg, MacKinnon et al [<xref ref-type="bibr" rid="ref27">27</xref>]), comprising different approaches such as latent growth curve modeling [<xref ref-type="bibr" rid="ref28">28</xref>] or structural equation modeling [<xref ref-type="bibr" rid="ref29">29</xref>], the seminal approach of Baron and Kenny [<xref ref-type="bibr" rid="ref30">30</xref>] is still one of the most applied procedures to evaluate the intervening variable effect of a potential mediator, despite having received criticism with regard to some limitations, such as low statistical power, difficulties in the assessment of multiple mediators, or quantification of the mediation effect magnitude [<xref ref-type="bibr" rid="ref24">24</xref>]. Although statistical mediation may be established either with the so-called causal-steps approach by Baron and Kenny [<xref ref-type="bibr" rid="ref30">30</xref>] or by more recent methods correcting some of its limitations (eg, Kraemer et al [<xref ref-type="bibr" rid="ref31">31</xref>]), it is important to consider that mediators might be identical to a mechanism of change (ie, the actual process responsible for change), but might also be a proxy for 1 or more other variables that do not explain the hypothesized mechanism [<xref ref-type="bibr" rid="ref25">25</xref>]. Thus, to determine the degree of validity that a mediator is actually representative of for being considered a true change mechanism, Kazdin proposed several quality criteria for psychotherapy process research [<xref ref-type="bibr" rid="ref25">25</xref>] that can be consulted when assessing the scope and justification of causal inferences: (1) Strong association (among treatment, mediator, and outcome), (2) specificity (a mediator accounts for the indirect effect of treatment on outcome), (3) consistency (the association must be replicable), (4) experimental manipulation (use of either a randomized controlled trial [RCT] design where the intervention variable is manipulated or an experimental design where the mediator itself is directly manipulated), (5) timeline or temporality (the intervention must lead to changes in the mediator, which must temporally precede changes in the outcome), (6) gradient (ie, a dose-response relationship: greater activation of the mediator is associated with greater change in the outcome), and (7) plausibility or coherence (the proposed mediator must be embedded in a plausible theoretical framework).</p>
        <p>The evidence base for the mediators and mechanisms of change in conventional face-to-face psychotherapies for children and adolescents is scarce, and only a few studies have been designed to investigate the therapeutic processes in these interventions [<xref ref-type="bibr" rid="ref32">32</xref>]. For example, 2 systematic reviews dedicated to evaluating the mechanisms of change found that only a small number of eligible primary studies actually conducted mediation analyses, with only 9% (6/67) [<xref ref-type="bibr" rid="ref33">33</xref>] and 17% (8/46) of included clinical trials [<xref ref-type="bibr" rid="ref34">34</xref>] attempting to evaluate mediation effects. In addition, Schmidt and Schimmelmann [<xref ref-type="bibr" rid="ref35">35</xref>] reviewed the empirical literature on mediators in psychotherapeutic interventions for common mental disorders in youth and concluded that most eligible studies evaluated mediators referring to the parent-child interaction (eg, family cohesion and parental support), next to mediators within the patient (eg, self-efficacy, motivation, coping, interpersonal skills, as well as changes in dysfunctional cognitions and negative emotions) and characteristics of the intervention (eg, duration of treatment, number of patient-therapist contacts, and application of specific intervention techniques). The included studies revealed inconsistent patterns of mediation effects related to therapist factors, such as flexibility, adherence to treatment, or therapeutic alliance [<xref ref-type="bibr" rid="ref35">35</xref>]. Moreover, as central conceptual and methodological requirements for mediation analyses were often not met by studies in this review, causal inferences were widely precluded, necessitating future process research with higher methodological rigor [<xref ref-type="bibr" rid="ref35">35</xref>].</p>
      </sec>
      <sec>
        <title>Objectives</title>
        <p>Although research on DHIs is a fast growing field [<xref ref-type="bibr" rid="ref36">36</xref>] and might also offer intriguing opportunities for psychotherapeutic process research [<xref ref-type="bibr" rid="ref24">24</xref>,<xref ref-type="bibr" rid="ref37">37</xref>], we are not aware of any systematic review of the mediators and mechanisms of change in DHI<sub>PSY</sub> and DHI<sub>HP</sub> for common mental disorders in youth published to this point. Therefore, this study aimed to: (1) systematically review the current state of research on mediators and mechanisms of change in various DHIs for mental disorders in children and adolescents, (2) identify mediators and potential mechanisms of change in these interventions, and (3) evaluate the methodological quality of eligible mediation studies according to the quality criteria for process research mentioned above.</p>
      </sec>
    </sec>
    <sec sec-type="methods">
      <title>Methods</title>
      <p>This systematic review was reported in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [<xref ref-type="bibr" rid="ref38">38</xref>] and was a priori registered with the Open Science Framework [<xref ref-type="bibr" rid="ref39">39</xref>].</p>
      <sec>
        <title>Eligibility Criteria</title>
        <p>Studies were eligible for inclusion if they fulfilled the following criteria: (1) participants were children (0-13 years) or adolescents (14-21 years) diagnosed with a mental disorder or exhibited clinically relevant symptoms of a mental disorder; (2) in the case of mixed samples with adolescents and young adults, the mean age of the sample was not above 21 years; (3) the interventions were designed for children or adolescents, or for parents of children or adolescents fulfilling the first criterion; (4) the diagnosis of mental disorders was based on the diagnostic and statistical manual of mental disorders, or the International Classification of Diseases criteria and was assessed with a validated and standardized clinical interview, or a standardized self-report instrument, or standardized ratings by significant others (eg, parents, teachers, clinicians); (5) samples of mixed or comorbid mental disorders were included; (6) studies with different recruitment strategies were eligible; (7) interventions with different theoretical orientations were eligible; (8) the intervention was predominantly delivered through the internet (eg, via web browsers or mobile or smartphone apps); (9) interventions with different degrees of human guidance and completely self-guided interventions were eligible for inclusion; (10) different active and passive control groups (CGs) were included; (11) changes in the symptoms and (12) mediators were reported; (13) at least one mediation analysis was performed; (14) studies were RCTs or secondary analyses of RCTs published in a peer reviewed journal in English language.</p>
      </sec>
      <sec>
        <title>Systematic Literature Search and Study Selection</title>
        <p>The search strategy was 3-fold. First, systematic literature searches were conducted in the Cochrane Central Register of Controlled Trials, Embase, MEDLINE (ie, Ovid MEDLINE, Ovid MEDLINE Epub Ahead of Print, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily Update), and PsycINFO databases from database inception until May 30, 2020. The search strings were built on established prior search strings [<xref ref-type="bibr" rid="ref24">24</xref>,<xref ref-type="bibr" rid="ref40">40</xref>] further adapted to specifically meet the research questions at hand and modified for each database in Ovid (for details on all search strings, see <xref ref-type="supplementary-material" rid="app1">Multimedia Appendix 1</xref>). Second, the reference lists of all eligible studies and other relevant reviews were manually searched to identify further studies that met our inclusion criteria (ie, backward searches). Third, a citation-search (ie, forward search) was conducted in the Web of Science database.</p>
        <p>Study selection was conducted with the support of a software tool for systematic reviews [<xref ref-type="bibr" rid="ref41">41</xref>]. Duplicates were detected automatically by the software or were manually removed. First, 1 reviewer (SE) screened titles and abstracts of all the remaining studies and discarded irrelevant articles. Second, the full texts of all potentially relevant articles were screened in terms of the aforementioned eligibility criteria independently by 2 reviewers (SE and HN). Disagreements were resolved by consultation with a third reviewer (MD). The full process of the systematic literature search and study selection is displayed in the PRISMA flowchart of <xref rid="figure1" ref-type="fig">Figure 1</xref>.</p>
        <fig id="figure1" position="float">
          <label>Figure 1</label>
          <caption>
            <p>PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart.</p>
          </caption>
          <graphic xlink:href="jmir_v23i11e29742_fig1.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
        </fig>
      </sec>
      <sec>
        <title>Data Extraction</title>
        <p>Two independent reviewers (SE and HN) extracted the following data: study information items (name of first author, country, and year), sample information (sample size and age), intervention characteristics (theoretical orientation, number of modules, and duration of intervention), information about control conditions, and information about outcomes (mediator type, instrument, and statistical analysis of mediation). Authors were contacted via email in case of missing information essential for decisions on study selection and the application of the systematic review.</p>
      </sec>
      <sec>
        <title>Categorization of Studies</title>
        <p>The included studies were divided into 2 categories: studies evaluating interventions with a psychotherapeutic focus (ie, DHI<sub>PSY</sub>) and studies evaluating interventions with a focus on health promotion (comprising interventions targeting health behavior, lifestyle, and behavior change interventions for the purpose of primary and secondary prevention; ie, DHI<sub>HP</sub>). Of note, interventions with rehabilitation or tertiary prevention focus were not included.</p>
      </sec>
      <sec>
        <title>Quality Assessment</title>
        <sec>
          <title>Risk-of-Bias Assessment</title>
          <p>The methodological quality of the included studies was assessed independently by 2 reviewers (SE and HN) using the Cochrane risk-of-bias (RoB) tool for randomized trials (version 2, RoB2; [<xref ref-type="bibr" rid="ref42">42</xref>]) on 5 domains: (1) bias arising from the randomization process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in measurement of the outcomes, and (5) bias in selection of the reported result. The included studies were rated as having <italic>low</italic>, <italic>unclear</italic>, or <italic>high RoB</italic> in each domain [<xref ref-type="bibr" rid="ref42">42</xref>]. Interrater reliability was calculated using the Cohen κ in RStudio (version 1.2.1335; [<xref ref-type="bibr" rid="ref43">43</xref>]).</p>
        </sec>
        <sec>
          <title>Quality Criteria for Process Research and Approximating Causality</title>
          <p>The included studies were rated by 2 independent reviewers (SE and HN). The rating system was based on Kazdin’s [<xref ref-type="bibr" rid="ref25">25</xref>] initial criteria to approach causality, modified by Domhardt et al [<xref ref-type="bibr" rid="ref24">24</xref>] and Lemmens et al [<xref ref-type="bibr" rid="ref44">44</xref>]. To meet the respective criteria, studies had to: (1) use an appropriate RCT design, (2) include a CG, (3) report a theoretical foundation for mediators, (4) have a minimum sample size of 40 participants per group, (5) examine multiple mediators within 1 study, (6) assess temporality (3 or more assessments of the mediator variables and outcomes), (7) experimentally manipulate the mediator, and (8) reveal a strong statistical association among intervention, mediator, and outcome (operationalized as statistical significance of <italic>P</italic>&#60;.05, as suggested by Moreno-Peral et al [<xref ref-type="bibr" rid="ref45">45</xref>]). All criteria were rated as fulfilled or not fulfilled. In accordance with prior research [<xref ref-type="bibr" rid="ref24">24</xref>,<xref ref-type="bibr" rid="ref44">44</xref>], criteria specificity, consistency, and gradient were not assessed, as they are not meaningfully applicable in single studies (consistency) or are too exclusive for some therapeutic processes (gradient and specificity).</p>
        </sec>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Results</title>
      <sec>
        <title>Study Characteristics</title>
        <p>Altogether, data from 25 (<italic>k</italic>=25) publications were analyzed [<xref ref-type="bibr" rid="ref46">46</xref>-<xref ref-type="bibr" rid="ref70">70</xref>]. Specifically, 52% (13/25) of the studies [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref47">47</xref>,<xref ref-type="bibr" rid="ref49">49</xref>,<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref58">58</xref>-<xref ref-type="bibr" rid="ref60">60</xref>,<xref ref-type="bibr" rid="ref64">64</xref>-<xref ref-type="bibr" rid="ref67">67</xref>,<xref ref-type="bibr" rid="ref69">69</xref>] evaluated DHI<sub>PSY</sub> and 48% (12/25) of the studies evaluated DHI<sub>HP</sub> [<xref ref-type="bibr" rid="ref48">48</xref>,<xref ref-type="bibr" rid="ref50">50</xref>-<xref ref-type="bibr" rid="ref53">53</xref>,<xref ref-type="bibr" rid="ref55">55</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref61">61</xref>-<xref ref-type="bibr" rid="ref63">63</xref>,<xref ref-type="bibr" rid="ref68">68</xref>,<xref ref-type="bibr" rid="ref70">70</xref>]. In the studies, a total of 4884 participants were randomized. Studies on DHI<sub>PSY</sub> accounted for 43.2% (2110/4884) of participants, and studies on DHI<sub>HP</sub> accounted for 56.8% (2774/4884) of participants. The overall sample sizes varied from 51 [<xref ref-type="bibr" rid="ref59">59</xref>] to 818 [<xref ref-type="bibr" rid="ref63">63</xref>]. The median publication year was 2014 (2002 [<xref ref-type="bibr" rid="ref48">48</xref>] to 2020 [<xref ref-type="bibr" rid="ref49">49</xref>]). Most studies were conducted in the United States (17/25, 68%), and most of the study participants were female (2985/4884, 61.18%). In 1 study, no information was provided regarding the distribution of sex [<xref ref-type="bibr" rid="ref54">54</xref>]. The mean age of participants was 18.49 (SD 2.01) years. The lowest mean age was 5.4 (SD 2.2) years [<xref ref-type="bibr" rid="ref67">67</xref>], and the highest was 21.02 (SD 2.16) years [<xref ref-type="bibr" rid="ref70">70</xref>]. Participants were younger in studies evaluating DHI<sub>PSY</sub> compared with participants in studies evaluating DHI<sub>HP</sub> (17.11 vs 19.67 years). The exact information on the average age of the final sample was not provided in 4 studies [<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref56">56</xref>,<xref ref-type="bibr" rid="ref63">63</xref>,<xref ref-type="bibr" rid="ref68">68</xref>]. Most interventions took place without parental involvement and were directed at the youth themselves (20/25, 80%). In 20% (5/25) of the studies, interventions for children [<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref67">67</xref>] as well as interventions for both children and adolescents [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref65">65</xref>] and for adolescents only [<xref ref-type="bibr" rid="ref64">64</xref>] were evaluated with the involvement of parents (including intervention components for parents or parent training). Demographic information about the parents who participated was provided in 16% (4/25) of the studies [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref54">54</xref>,<xref ref-type="bibr" rid="ref65">65</xref>,<xref ref-type="bibr" rid="ref67">67</xref>]. Study participants were recruited predominantly from educational or health-related settings (15/25, 60%). In 32% (8/25) of the studies, participants were made aware of the study through both web-based advertising (including social media and websites) and conventional advertising (including letters and flyers). To identify potential participants, one study (1/25, 4%) used data from a mass web-based survey [<xref ref-type="bibr" rid="ref59">59</xref>]. Information on recruitment strategy could not be identified in 4% (1/25) of the studies [<xref ref-type="bibr" rid="ref68">68</xref>]. Across studies, the average study dropout rate accounted for 18% (range 0% [<xref ref-type="bibr" rid="ref62">62</xref>] to 39.3% [<xref ref-type="bibr" rid="ref54">54</xref>]). In 4% (1/25) of the studies, the dropout rate was not reported [<xref ref-type="bibr" rid="ref46">46</xref>].</p>
        <p>The interventions were directed toward a broad range of mental health problems, including risky drinking behavior (including risky or heavy drinking and binge drinking; 11/25, 44%), depressive disorders (5/25, 20%), anxiety disorders (including separation anxiety, generalized anxiety disorder, social phobia, and specific phobia; 3/25, 12%), behavioral problems (2/25, 8%), and insomnia (1/25, 4%). Furthermore, 12% (3/25) of the studies evaluated interventions that addressed multiple disorders simultaneously (ie, transdiagnostic interventions). De Bruin et al [<xref ref-type="bibr" rid="ref47">47</xref>] addressed transdiagnostic <italic>psychopathological abnormalities</italic> (including affective, anxiety, and somatic problems; problems concerning attention-deficit/hyperactivity disorder; oppositional defiant behavior; and conduct problems). Levin et al [<xref ref-type="bibr" rid="ref60">60</xref>] addressed <italic>psychological problems</italic> such as depressive disorders, generalized anxiety disorder, social phobia, alcohol consumption, academic worries, worries concerning eating, hostility, and negative stress. Another intervention addressed depression, anxiety, and stress [<xref ref-type="bibr" rid="ref56">56</xref>]. Of note, there were 2 interventions evaluated and applied in more than 1 study (the <italic>e-CHUG</italic> interventions in 4 studies; and the <italic>BRAVE</italic> interventions in 2 studies), but the investigated mediators differed in all studies; thus, these publications were regarded as distinct entities and single studies (see <xref ref-type="supplementary-material" rid="app2">Multimedia Appendix 2</xref> [<xref ref-type="bibr" rid="ref46">46</xref>-<xref ref-type="bibr" rid="ref70">70</xref>] for details).</p>
        <p>Internet-based interventions were evaluated in 92% (12/13) of the studies on DHI<sub>PSY</sub>. Most interventions were based on the components of cognitive behavioral therapy [<xref ref-type="bibr" rid="ref46">46</xref>,<xref ref-type="bibr" rid="ref47">47</xref>,<xref ref-type="bibr" rid="ref49">49</xref>,<xref ref-type="bibr" rid="ref59">59</xref>,<xref ref-type="bibr" rid="ref66">66</xref>]. In addition, relaxation strategies, such as progressive muscle relaxation and autogenic training [<xref ref-type="bibr" rid="ref49">49</xref>], and elements of social learning theory [<xref ref-type="bibr" rid="ref54">54</xref>] were deployed. Further interventions were based on the acceptance and commitment therapy [<xref ref-type="bibr" rid="ref60">60</xref>], components of systemic family therapy, problem solving and communication training, cognitive restructuring, and alternative family roles [<xref ref-type="bibr" rid="ref64">64</xref>]. One intervention [<xref ref-type="bibr" rid="ref56">56</xref>] was based on the <italic>temporal model of control</italic>. In 23% (3/13) of the studies, precise information on the theoretical orientation and background of the intervention was not available [<xref ref-type="bibr" rid="ref58">58</xref>,<xref ref-type="bibr" rid="ref67">67</xref>,<xref ref-type="bibr" rid="ref69">69</xref>]. Moreover, 7% (1/13) of the studies evaluated a mobile-based intervention based on a self-monitoring program [<xref ref-type="bibr" rid="ref58">58</xref>].</p>
        <p>All DHI<sub>HP</sub> studies were internet-based and included a feedback component (12/12, 100%). The so-called <italic>e-CHUG</italic> tool was evaluated in 33% (4/12) of the studies [<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref57">57</xref>,<xref ref-type="bibr" rid="ref62">62</xref>,<xref ref-type="bibr" rid="ref68">68</xref>]. Feedback was provided via email [<xref ref-type="bibr" rid="ref48">48</xref>,<xref ref-type="bibr" rid="ref53">53</xref>] or in person using a motivational interviewing approach [<xref ref-type="bibr" rid="ref51">51</xref>,<xref ref-type="bibr" rid="ref52">52</xref>]. In addition to the feedback components, cognitive components such as expressive writing [<xref ref-type="bibr" rid="ref70">70</xref>] and retrieval of remembered information from feedback were evaluated [<xref ref-type="bibr" rid="ref57">57</xref>]. A detailed overview of the study characteristics is provided in <xref ref-type="supplementary-material" rid="app2">Multimedia Appendix 2</xref>.</p>
      </sec>
      <sec>
        <title>Mediators</title>
        <p>An overview of the classification of mediators and their empirical support is provided in <xref ref-type="table" rid="table1">Table 1</xref>. A total of 39 potential mediators were investigated in the included RCTs. Among these, more than half of the mediators were evaluated as significant (21/39, 54%). With 48% (19/39) intervening variables, the largest group of all examined intervening variables was of a cognitive nature. A total of 13 cognitive mediators were evaluated as significant in the primary studies (13/19, 68%). We further divided the group of cognitive mediators into the <italic>assessment</italic> (examined: 8/39, 20%; significant: 5/8), <italic>motivation</italic> (examined: 1/39, 2%; significant: 0/1, 0%) and <italic>cognitive processes</italic> subcategories (examined: 10/39, 25%; significant: 8/10, 80%). Further evenly investigated mediator categories were emotional/affective (examined: 4/39, 10%; significant: 4/4, 100%), interpersonal (examined: 4/39, 10%; significant: 1/4, 25%), and parenting behavior mediators (examined: 4/39, 10%; significant: 0/4, 0%). The second largest group of mediators was not clearly classifiable into one of the aforementioned categories and was thus subsumed into a separate <italic>other</italic> mediator category (examined: 8/39, 20%; significant: 3/8, 38%). Of note, a Wilcoxon rank-sum test revealed no difference in the sample sizes between studies that found at least one significant mediator and studies that found no significant mediator (W {19,6}=59; <italic>P</italic>=.93).</p>
        <table-wrap position="float" id="table1">
          <label>Table 1</label>
          <caption>
            <p>Classification of mediators.</p>
          </caption>
          <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
            <col width="30"/>
            <col width="30"/>
            <col width="100"/>
            <col width="0"/>
            <col width="100"/>
            <col width="0"/>
            <col width="140"/>
            <col width="0"/>
            <col width="130"/>
            <col width="0"/>
            <col width="150"/>
            <col width="0"/>
            <col width="110"/>
            <col width="0"/>
            <col width="120"/>
            <col width="0"/>
            <col width="90"/>
            <thead>
              <tr valign="top">
                <td colspan="4">Mediators</td>
                <td colspan="2">Studies, n (%) (n=25)</td>
                <td colspan="2">Age (years), range<sup>a</sup></td>
                <td colspan="2">Guidance</td>
                <td colspan="2">Disorder</td>
                <td colspan="2">Effect size<sup>b</sup></td>
                <td colspan="2">Significance</td>
                <td>Criteria met ≥5</td>
              </tr>
            </thead>
            <tbody>
              <tr valign="top">
                <td colspan="17">
                  <bold>Emotional and affective mediators</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Emotional self-perception</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">14-22</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Depression</td>
                <td colspan="2">Partially standardized ES<sup>c</sup>=−1.049 (95% CI −1.35 to −0.755)</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)<sup>d</sup></td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Fear</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">16-24</td>
                <td colspan="2">Internet-based psychotherapy</td>
                <td colspan="2">Depression</td>
                <td colspan="2">Between groups ES=0.49 (95% CI 0.24 to 0.75)</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Hopelessness</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">&#62;18</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Depression</td>
                <td colspan="2">Cohen <italic>d</italic>=1.13 (between groups follow-up)</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Thought-related distress</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Undergraduate students</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Generalized anxiety disorder</td>
                <td colspan="2">Cohen <italic>d</italic>=0.526 (between groups follow-up)</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td colspan="17">
                  <bold>Interpersonal mediators</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Parent-Youth conflict</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">12-19</td>
                <td colspan="2">Internet-based psychotherapy</td>
                <td colspan="2">Depression</td>
                <td colspan="2">—<sup>e</sup></td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Family conflicts related to diabetes management</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">12-19</td>
                <td colspan="2">Internet-based psychotherapy</td>
                <td colspan="2">Depression</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Failed help or negative social support</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">12-19</td>
                <td colspan="2">Internet-based psychotherapy</td>
                <td colspan="2">Depression</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Social skills</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">8-17</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Social phobia</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td colspan="17">
                  <bold>Parenting behavior mediators</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Appropriate education</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">10-13</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Behavioral problems</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Skill in setting clear boundaries</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">10-13</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Behavioral problems</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Severity and inconsistent education</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">10-13</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Behavioral problems</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Change in parenting behavior</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">3-9</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Behavioral problems</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(−)<sup>f</sup></td>
              </tr>
              <tr valign="top">
                <td colspan="17">
                  <bold>Cognitive mediators</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="16">
                  <bold>Assessment</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Assessment of discrepancy<sup>g</sup></td>
                <td colspan="2">2<sup>g</sup> (8)</td>
                <td colspan="2">College students; College students</td>
                <td colspan="2">Guided self-help; guided self-help</td>
                <td colspan="2">Risky drinking behavior</td>
                <td colspan="2">—; —</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Assessment of peer drinking behavior<sup>g</sup></td>
                <td colspan="2">2<sup>g</sup> (8)</td>
                <td colspan="2">18-24; 18-24</td>
                <td colspan="2">Guided self-help; guided self-help</td>
                <td colspan="2">Risky drinking behavior</td>
                <td colspan="2">—; —</td>
                <td colspan="2">Yes</td>
                <td colspan="2">Different result</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Perceived norm<sup>g</sup></td>
                <td colspan="2">4<sup>g</sup> (16)</td>
                <td colspan="2">18-25; Students; First semester students; 18-26</td>
                <td colspan="2">Guided self-help; unguided; guided self-help; unguided</td>
                <td colspan="2">Risky drinking behavior</td>
                <td colspan="2">—; Cohen <italic>d</italic>=−0.2 (ES Biannual); —; —</td>
                <td colspan="2">Different results<sup>h</sup></td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="16">
                  <bold>Motivation</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Motivation to change drinking behavior</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">College students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Risky drinking behavior</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="16">
                  <bold>Cognitive</bold>
                  <bold>processes</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Alcohol-related expectations</td>
                <td colspan="2">—</td>
                <td colspan="2">Students</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Risky drinking behavior</td>
                <td colspan="2">—</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Remembered information</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Students</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Risky drinking behavior</td>
                <td colspan="2">—</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Mastering</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">16-25</td>
                <td colspan="2">Internet-based psychotherapy</td>
                <td colspan="2">Depression</td>
                <td colspan="2">Between groups ES=0.94 (95% CI 0.64 to 1.23)</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Willingness to cope</td>
                <td colspan="2">—</td>
                <td colspan="2">Students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Depression</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(−)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Cognitive arousal before falling asleep</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Insomnia</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Sleep-related cognition</td>
                <td colspan="2">—</td>
                <td colspan="2">Students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Insomnia</td>
                <td colspan="2">—</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Postevent processing</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">8-17</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Social phobia</td>
                <td colspan="2">—</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Mindful acceptance</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Students</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Transdiagnostic<sup>i</sup></td>
                <td colspan="2">Proportion mediated ES=range 16.05% to 28.57%</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(−)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Obstruction of appreciation of life</td>
                <td colspan="2">—</td>
                <td colspan="2">Students</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Transdiagnostic<sup>i</sup></td>
                <td colspan="2">Proportion mediated ES=range 29.18% to 57.94%</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(−)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td>
                  <break/>
                </td>
                <td>Perceived control</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">18-21</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Transdiagnostic<sup>i</sup></td>
                <td colspan="2">Cohen <italic>d</italic>=0.07; Cohen <italic>d</italic>=0.59; Cohen <italic>d</italic>=0.66 (between groups follow-up)</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td colspan="17">
                  <bold>Other</bold>
                </td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Alcohol consumption as coping behavior</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">18-21</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Risky drinking behavior</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Therapy adherence</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">7-18</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Anxiety disorder</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(−)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Eating disorder</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">18-25</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Depression</td>
                <td colspan="2">—</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Overall sleep quality</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Insomnia</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Chronotypical</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Insomnia</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Physical arousal before falling asleep</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Insomnia</td>
                <td colspan="2">—</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Trauma-related sleeping disorder</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">Students</td>
                <td colspan="2">Unguided</td>
                <td colspan="2">Insomnia</td>
                <td colspan="2">—</td>
                <td colspan="2">No</td>
                <td colspan="2">(+)</td>
              </tr>
              <tr valign="top">
                <td>
                  <break/>
                </td>
                <td colspan="2">Insomnia</td>
                <td colspan="2">1 (4)</td>
                <td colspan="2">12-19</td>
                <td colspan="2">Guided self-help</td>
                <td colspan="2">Transdiagnostic<sup>i</sup></td>
                <td colspan="2">—</td>
                <td colspan="2">Yes</td>
                <td colspan="2">(+)</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="table1fn1">
              <p><sup>a</sup>If age range was not reported, participant group labels were used.</p>
            </fn>
            <fn id="table1fn2">
              <p><sup>b</sup>Effect size measures differed across studies.</p>
            </fn>
            <fn id="table1fn3">
              <p><sup>c</sup>ES: effect size</p>
            </fn>
            <fn id="table1fn4">
              <p><sup>d</sup>Met 5 or more criteria.</p>
            </fn>
            <fn id="table1fn5">
              <p><sup>e</sup>Not available.</p>
            </fn>
            <fn id="table1fn6">
              <p><sup>f</sup>Met fewer than 5 criteria.</p>
            </fn>
            <fn id="table1fn7">
              <p><sup>g</sup>If mediator was assessed in more than 1 study, data and results were separated with “;”.</p>
            </fn>
            <fn id="table1fn8">
              <p><sup>h</sup>The only mediator nonsex-specific perceived norm was not significant.</p>
            </fn>
            <fn id="table1fn9">
              <p><sup>i</sup>Transdiagnostic intervention targets more than one disorder.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>A broad range of different approaches to mediation analyses was deployed, with some studies relying on several strategies at once. Bootstrapping (eg, Preacher and Hayes [<xref ref-type="bibr" rid="ref71">71</xref>]) was used in almost half of the studies (11/25, 44%). In 32% (8/25) of the studies, the mediation analysis was based on the approach of Baron and Kenny [<xref ref-type="bibr" rid="ref30">30</xref>], and in addition, 8% (2/25) performed a Sobel test. Furthermore, 32% (8/25) of the mediation analyses were performed using structural equation modeling (7/25, 28% using the MPlus software). Moreover, 4% (1/25) of the studies performed multiple regression analysis according to the Judd and colleagues paradigm [<xref ref-type="bibr" rid="ref72">72</xref>], and another study did not provide any information on the statistical analysis.</p>
      </sec>
      <sec>
        <title>Quality Assessment of Included Studies</title>
        <sec>
          <title>Risk-of-Bias Assessment</title>
          <p>As illustrated in the <italic>RoB2 Graph</italic> (<xref rid="figure2" ref-type="fig">Figure 2</xref>), approximately three-quarters (19/25, 76%) of the included studies were rated as having a <italic>high</italic> RoB. In more than half of the studies (14/25, 56%), the <italic>bias due to deviation from the intended intervention</italic> was rated as <italic>high</italic>. The RoB on this domain was more often evaluated to be <italic>high</italic> in studies on DHI<sub>HP</sub> (10/25, 40%) when compared with studies on DHI<sub>PSY</sub> (4/25, 16%). Both the randomization procedure and the process of reporting results were predominantly rated with <italic>some concern</italic> across studies (19/25, 76% and 22/25, 88%). Interrater reliability varied across domains from Cohen κ=0.76 to Cohen κ=0.93. According to Landis and Koch [<xref ref-type="bibr" rid="ref73">73</xref>], these agreements can be rated as <italic>substantial</italic> to <italic>almost perfect</italic>. A summary of the RoB2 assessments is shown in <xref rid="figure3" ref-type="fig">Figure 3</xref>.</p>
          <fig id="figure2" position="float">
            <label>Figure 2</label>
            <caption>
              <p>Risk-of-bias graph.</p>
            </caption>
            <graphic xlink:href="jmir_v23i11e29742_fig2.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
          <fig id="figure3" position="float">
            <label>Figure 3</label>
            <caption>
              <p>Risk-of-bias summary.</p>
            </caption>
            <graphic xlink:href="jmir_v23i11e29742_fig3.png" alt-version="no" mimetype="image" position="float" xlink:type="simple"/>
          </fig>
        </sec>
        <sec>
          <title>Evaluation of the Quality Criteria for Process Research and Approximating Causality</title>
          <p>The evaluation of the included studies with regard to the methodological quality of process research revealed that in both the DHI<sub>PSY</sub> and the DHI<sub>HP</sub> groups, most studies (DHI<sub>PSY</sub>: 9/13, 69% vs DHI<sub>HP</sub>: 11/12, 92%) fulfilled 5 or more out of the 8 criteria. Owing to the eligibility criteria used in this review, almost all studies met the requirement of an RCT design (24/25, 96%) and a CG (24/25, 96%). In the publication by Anderson et al [<xref ref-type="bibr" rid="ref46">46</xref>], the results from 8% (2/25) of the studies were jointly reported, with only the second study evaluating a DHI<sub>PSY</sub> without a direct comparison with the CG, although this criterion was fulfilled in the first study. Even if mediators were collected at more than 2 measurement time points in more than half of the studies (15/25, 60%; including follow-up), an evaluation of the chronology of changes in the mediator variable or variables and outcomes was conducted in only 4% (1/25; de Bruin et al [<xref ref-type="bibr" rid="ref47">47</xref>]) of the studies. Furthermore, 8% (2/25) of the studies, Hintz et al [<xref ref-type="bibr" rid="ref56">56</xref>] and Jouriles et al [<xref ref-type="bibr" rid="ref57">57</xref>] implemented direct experimental manipulation of mediators. A detailed overview of the evaluation of the methodological quality criteria for process research and the approximation of causality are outlined in <xref ref-type="table" rid="table2">Tables 2</xref> and <xref ref-type="table" rid="table3">3</xref>, as well as in <xref ref-type="supplementary-material" rid="app3">Multimedia Appendix 3</xref>.</p>
          <table-wrap position="float" id="table2">
            <label>Table 2</label>
            <caption>
              <p>Quality criteria for process research and approximation of causality (n=25).</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="30"/>
              <col width="130"/>
              <col width="120"/>
              <col width="60"/>
              <col width="80-"/>
              <col width="80"/>
              <col width="120"/>
              <col width="90"/>
              <col width="120"/>
              <col width="90"/>
              <col width="80"/>
              <thead>
                <tr valign="top">
                  <td colspan="2">Studies</td>
                  <td>Randomized controlled trial</td>
                  <td>CG<sup>a</sup></td>
                  <td>Theoretical foundation</td>
                  <td>n≥40<break/>(Each CG and EG<sup>b</sup>)</td>
                  <td>Various mediators</td>
                  <td>Time sequence</td>
                  <td>Manipulation</td>
                  <td><italic>P</italic> value (&#60;.05)<sup>c</sup></td>
                  <td>∑ (Yes)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td colspan="11">
                    <bold>DHI<sub>PSY</sub> <sup>d</sup>
                    </bold>
                  </td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Anderson, 2012 [<xref ref-type="bibr" rid="ref46">46</xref>]<sup>e</sup></td>
                  <td>No<sup>f</sup></td>
                  <td>No</td>
                  <td>Yes<sup>g</sup></td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>2</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>de Bruin et al [<xref ref-type="bibr" rid="ref47">47</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Denis et al [<xref ref-type="bibr" rid="ref49">49</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Ghaderi et al [<xref ref-type="bibr" rid="ref54">54</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes<sup>i</sup></td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>6</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Hintz, 2014 [<xref ref-type="bibr" rid="ref56">56</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>6</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Kauer et al [<xref ref-type="bibr" rid="ref58">58</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>LaFreniere, and Newman [<xref ref-type="bibr" rid="ref59">59</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>4</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Levin et al [<xref ref-type="bibr" rid="ref60">60</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>4</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Riley et al [<xref ref-type="bibr" rid="ref64">64</xref>]</td>
                  <td>Yes<sup>j</sup></td>
                  <td>Yes<sup>j</sup></td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>6</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Spence et al [<xref ref-type="bibr" rid="ref65">65</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>No<sup>h,</sup><sup>k</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Zanden et al, 2014 [<xref ref-type="bibr" rid="ref66">66</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>6</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Wade et al [<xref ref-type="bibr" rid="ref67">67</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No<sup>i</sup></td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>4</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Wilksch, O’Shea, and Wade [<xref ref-type="bibr" rid="ref69">69</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td colspan="11">
                    <bold>DHI<sub>HP</sub><sup>l</sup>
                    </bold>
                  </td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Collins, Carey, and Sliwinski [<xref ref-type="bibr" rid="ref48">48</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Doumas, McKinley, and Book [<xref ref-type="bibr" rid="ref50">50</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>4</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Doumas et al [<xref ref-type="bibr" rid="ref51">51</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Dunn, 2019 [<xref ref-type="bibr" rid="ref52">52</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Geisner, Neighbors, and Larimer [<xref ref-type="bibr" rid="ref53">53</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>6</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Gilmore and Bountress [<xref ref-type="bibr" rid="ref55">55</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Jouriles et al [<xref ref-type="bibr" rid="ref57">57</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Lewis et al [<xref ref-type="bibr" rid="ref61">61</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Murphy, 2010 [<xref ref-type="bibr" rid="ref62">62</xref>]<sup>h</sup></td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>6</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Neighbors et al [<xref ref-type="bibr" rid="ref63">63</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>6</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Walters, Vader, and Harris [<xref ref-type="bibr" rid="ref68">68</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes<sup>m</sup></td>
                  <td>No</td>
                  <td>No<sup>h</sup></td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
                <tr valign="top">
                  <td>
                    <break/>
                  </td>
                  <td>Young and Neighbors [<xref ref-type="bibr" rid="ref70">70</xref>]</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>Yes</td>
                  <td>No</td>
                  <td>No</td>
                  <td>No</td>
                  <td>Yes</td>
                  <td>5</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table2fn1">
                <p><sup>a</sup>CG: control group.</p>
              </fn>
              <fn id="table2fn2">
                <p><sup>b</sup>EG: experimental group.</p>
              </fn>
              <fn id="table2fn3">
                <p><sup>c</sup>Overall significance level <italic>P</italic>&#60;.05; only data from study 2 taken into account.</p>
              </fn>
              <fn id="table2fn4">
                <p><sup>d</sup>DHI<sub>PSY</sub>: digital health interventions with a psychotherapeutic focus.</p>
              </fn>
              <fn id="table2fn5">
                <p><sup>e</sup>Only data from study 2 are taken into account.</p>
              </fn>
              <fn id="table2fn6">
                <p><sup>f</sup><italic>No</italic> indicates criteria not met.</p>
              </fn>
              <fn id="table2fn7">
                <p><sup>g</sup><italic>Yes</italic> indicates criteria met.</p>
              </fn>
              <fn id="table2fn8">
                <p><sup>h</sup>More than 2 measurements (including follow-up) reported, but no evaluation of time sequence.</p>
              </fn>
              <fn id="table2fn9">
                <p><sup>i</sup>Subscales have no theoretical foundations.</p>
              </fn>
              <fn id="table2fn10">
                <p><sup>j</sup>Initial study had a randomized controlled trial design; in secondary analysis, both groups were taken together.</p>
              </fn>
              <fn id="table2fn11">
                <p><sup>k</sup>Due to missing follow-up data in the waitlist condition, mediation analysis was conducted only with data from baseline and after 12 weeks (at least 3 sessions were completed).</p>
              </fn>
              <fn id="table2fn12">
                <p><sup>l</sup>DHI<sub>HP</sub>: digital health interventions with a focus on health promotion.</p>
              </fn>
              <fn id="table2fn13">
                <p><sup>m</sup>Information was given after contacting authors.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <table-wrap position="float" id="table3">
            <label>Table 3</label>
            <caption>
              <p>Number of studies meeting each single quality criterion for process research (n=25).</p>
            </caption>
            <table width="1000" cellpadding="5" cellspacing="0" border="1" rules="groups" frame="hsides">
              <col width="420"/>
              <col width="190"/>
              <col width="190"/>
              <col width="200"/>
              <thead>
                <tr valign="top">
                  <td>Criterion</td>
                  <td>DHI<sub>PSY</sub><sup>a</sup>, n (%)</td>
                  <td>DHI<sub>HP</sub><sup>b</sup>, n (%)</td>
                  <td>Overall, n (%)</td>
                </tr>
              </thead>
              <tbody>
                <tr valign="top">
                  <td>Randomized controlled trial</td>
                  <td>12 (48)</td>
                  <td>12 (48)</td>
                  <td>24 (96)</td>
                </tr>
                <tr valign="top">
                  <td>CG<sup>c</sup></td>
                  <td>12 (48)</td>
                  <td>12 (48)</td>
                  <td>24 (96)</td>
                </tr>
                <tr valign="top">
                  <td>Theoretical foundation</td>
                  <td>11 (44)</td>
                  <td>12 (48)</td>
                  <td>23 (92)</td>
                </tr>
                <tr valign="top">
                  <td>n≥40 (for CG and EG<sup>d</sup> each)</td>
                  <td>7 (28)</td>
                  <td>10 (40)</td>
                  <td>17 (68)</td>
                </tr>
                <tr valign="top">
                  <td>Evaluation of various mediators</td>
                  <td>6 (24)</td>
                  <td>3 (12)</td>
                  <td>9 (36)</td>
                </tr>
                <tr valign="top">
                  <td>Time sequence or temporality</td>
                  <td>1 (4)</td>
                  <td>0 (0)</td>
                  <td>1 (4)</td>
                </tr>
                <tr valign="top">
                  <td>Manipulation of mediators</td>
                  <td>2 (8)</td>
                  <td>0 (0)</td>
                  <td>2 (8)</td>
                </tr>
                <tr valign="top">
                  <td><italic>P</italic>&#60;.05</td>
                  <td>13 (52)</td>
                  <td>12 (48)</td>
                  <td>25 (100)</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="table3fn1">
                <p><sup>a</sup>DHI<sub>PSY</sub>: digital health interventions with a psychotherapeutic focus.</p>
              </fn>
              <fn id="table3fn2">
                <p><sup>b</sup>DHI<sub>HP</sub>: digital health interventions with a focus on health promotion.</p>
              </fn>
              <fn id="table3fn3">
                <p><sup>c</sup>CG: control group.</p>
              </fn>
              <fn id="table3fn4">
                <p><sup>d</sup>EG: experimental group.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
      </sec>
    </sec>
    <sec sec-type="discussion">
      <title>Discussion</title>
      <sec>
        <title>Principal Findings</title>
        <p>This systematic review, to the knowledge of the authors the first of its kind, comprehensively evaluated research on mediators and mechanisms of change in DHIs for common mental disorders in youth. Altogether, 25 studies were included in the review, that have examined 39 distinct mediators. Cognitive variables were found to be the most often investigated mediators, followed by a broad range of other mediators. Even though our eligibility criteria were not limited to a specific mental health condition in youth, only a rather low number of studies were identified by our systematic literature searches, a finding that corresponds to the limited evidence base of research on mechanisms of change in psychotherapy in general [<xref ref-type="bibr" rid="ref37">37</xref>,<xref ref-type="bibr" rid="ref74">74</xref>], and for children and adolescents in specific [<xref ref-type="bibr" rid="ref24">24</xref>,<xref ref-type="bibr" rid="ref35">35</xref>,<xref ref-type="bibr" rid="ref37">37</xref>], necessitating further high-quality research efforts to improve interventions and mental health care practices for this younger age group.</p>
        <p>Remarkably, our findings indicate that the mediator category with the highest percentage of significant intervening variables was the affective or emotional mediator group (4/4, 100%). The proportions of significance in other mediator categories were by far less high and included combined cognitive (13/19, 68%), other (3/8, 37%), interpersonal (1/4, 25%), and parenting behavior–related mediators (0/4, 0%). The consistent nonsignificant findings on parenting behavior–related intervening variables are astonishing, as parenting behavior is otherwise thought to be of paramount importance in the treatment of behavioral problems in youth, both in conventional interventions delivered face-to-face [<xref ref-type="bibr" rid="ref75">75</xref>] and in digital parent training alike [<xref ref-type="bibr" rid="ref76">76</xref>,<xref ref-type="bibr" rid="ref77">77</xref>]. Therefore, the findings of our study are in contrast to those of a systematic review [<xref ref-type="bibr" rid="ref75">75</xref>], which revealed that in 45% (39/86) of the included studies on face-to-face parent training programs, parenting behavior served as a mediator for the association between the intervention and symptom change in children. Furthermore, the importance of emotion regulation might be underestimated in (digital) psychotherapeutic interventions for children and adolescents, considering the consistent pattern of significant findings across studies in our review, as well as by allowing for comprehensive earlier research highlighting the overall importance of emotion regulation competencies for mental health in childhood and adolescence [<xref ref-type="bibr" rid="ref78">78</xref>]. However, given the rather small number of mediation studies per category in our review, these findings need to be interpreted with caution and must be considered as preliminary. This is also owing to the rather heterogeneous evidence base, where included studies varied broadly in terms of the theoretical foundations of the intervention as well as the simultaneous consideration of various mental disorders, which may further restrict the comparability between studies. Nevertheless, a Wilcoxon rank-sum test revealed no differences in the sample sizes between studies that found at least one significant mediator and studies that found no significant mediator, suggesting that there is no effect of sample size on the evaluation of intervening variables, strengthening the robustness and validity of the findings on the mediators in this regard.</p>
        <p>Importantly, participants were most often adolescents, with only 16% (4/25) of eligible studies evaluating interventions for children, suggesting an additional research gap for this younger age group. Here, all interventions for children were conducted with the involvement of parents, suggesting a crucial role of the accompanying human support in DHIs for younger children, which must be corroborated and further specified by forthcoming research [<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref79">79</xref>]. In studies evaluating DHI<sub>HP</sub>, only cognitive mediators (perceived norm and alcohol-related expectation) were investigated. This finding is consistent with prior research, where the cognitive mediator, perceived norm, was established as one of the most evaluated mediators in interventions for problematic drinking behaviors in adolescents and young adults delivered on site [<xref ref-type="bibr" rid="ref80">80</xref>]. However, this result rather highlights the researcher’s presumptions than the evidence base of the superior relevance of cognitive mediators over other, not yet well examined, affective and behavioral mediators.</p>
        <p>The results of the RoB assessment indicated a rather limited overall study quality, with 76% (19/25) of the included studies rated with a <italic>high RoB,</italic> a finding that aligns with the review by Christ et al [<xref ref-type="bibr" rid="ref81">81</xref>], in which 92% (22/24) included studies on DHIs for adolescents and young adults were assessed with a <italic>high RoB</italic>. These findings on RoB2 might be largely due to the specifics of psychotherapy research [<xref ref-type="bibr" rid="ref82">82</xref>], where masking of therapists or personnel and participants is difficult to achieve, as well as the more conservative novel RoB2 algorithm [<xref ref-type="bibr" rid="ref83">83</xref>]. Of note, in our review, the mean study dropout rate was 18%. Therefore, only a fraction of the included studies fulfilled the RoB2 criterion that 95% of randomized participants’ data should be available for data analysis. Although the current mean dropout rate in this review is rather small compared with other high dropout rates found in DHIs, the well-known issue of limited engagement still warrants future research to further investigate approaches to remedy (study and intervention) attrition [<xref ref-type="bibr" rid="ref84">84</xref>,<xref ref-type="bibr" rid="ref85">85</xref>]. In this particular field, primary studies in the review at hand may offer guidance and direction to more effective engagement in youth (<xref ref-type="supplementary-material" rid="app2">Multimedia Appendix 2</xref>), such as interactive intervention components and age-appropriate content presentation in the form of puzzles, videos, or cartoons [<xref ref-type="bibr" rid="ref12">12</xref>].</p>
        <p>The results of the methodological quality assessment for process research revealed that most studies adhered to certain quality criteria satisfactorily (ie, using an RCT design and CG, evaluation of a strong statistical association, describing a theoretical foundation for mediators and sample size per trial group). However, in contrast, most primary studies did not experimentally manipulate the potential mediators, did not assess several mediators simultaneously, and did not evaluate the time sequence or temporal ordering of changes in mediators and outcomes. However, this latter criterion is considered to be of utmost importance for causal inferences and is sometimes referred to as the <italic>fifth step</italic> of mediation analysis [<xref ref-type="bibr" rid="ref86">86</xref>]. Even though mediators and outcomes were assessed more than twice in 60% (15/25) of the included studies, only 4% (1/25) of the studies [<xref ref-type="bibr" rid="ref47">47</xref>] actually conducted a statistical evaluation of the time sequence of cause and effect. Taken together, the findings of our review seem to be in line with those of other research [<xref ref-type="bibr" rid="ref24">24</xref>,<xref ref-type="bibr" rid="ref44">44</xref>,<xref ref-type="bibr" rid="ref45">45</xref>,<xref ref-type="bibr" rid="ref83">83</xref>], pointing to important methodological shortcomings of mediation studies, which should be amended by future research. At this point, 1 high-quality RCT [<xref ref-type="bibr" rid="ref58">58</xref>] sets an example, fulfilling 6 out of 8 quality criteria.</p>
      </sec>
      <sec>
        <title>Strengths and Limitations</title>
        <p>This systematic review offers several strengths, including a comprehensive literature search, as well as the broad consideration of common mental disorders and theoretical orientations, resulting in an extensive overview of the research on mediators and mechanisms of change for DHIs in children and adolescents conducted so far. Furthermore, with the differential consideration of the 2 categories of DHI<sub>PSY</sub> and DHI<sub>HP</sub>, we intended to provide specific evidence-based information that might be valuable for digital psychotherapeutic and health promotion interventions alike. However, some limitations must be considered when interpreting the findings of this review. First, the number of eligible studies is rather small; the generalizability of the findings might be reduced as most studies were conducted in Western countries; these studies evaluated internet-based interventions; participants were predominantly female; and these studies relied on older participants. Second, only English language papers were included, and we did not incorporate gray literature in our study as recent findings indicated a negligible relevance of gray literature in systematic reviews [<xref ref-type="bibr" rid="ref87">87</xref>]; further, publication bias cannot be ruled out. Third, although we only included RCT studies in our review (which might have led to an overestimation of the study quality in general, omitting other design studies with potentially lower methodological rigor), the RoB assessment indicated substantial shortcomings in the included studies. However, this finding should be weighed against the typical constraints of research on psychological interventions.</p>
      </sec>
      <sec>
        <title>Future Directions</title>
        <p>The following recommendations might be helpful for future mediation studies, aiming to advance our understanding of the working mechanisms of DHIs for youth. First, it is essential to avoid the methodological shortcomings outlined in the assessment of quality criteria for process research, especially with regard to the temporality of changes and experimental manipulation of mediators, both of which are key for the justification of causal inferences. Furthermore, future studies should resort to more sophisticated and current methods of mediation analysis (eg, Grimm et al [<xref ref-type="bibr" rid="ref88">88</xref>] and Hofmann et al [<xref ref-type="bibr" rid="ref89">89</xref>]), ideally capable of clarifying temporal precedence and illustrating the actual pattern of change [<xref ref-type="bibr" rid="ref24">24</xref>]. Second, the therapeutic or working alliance (ie, the professional relationship between therapists and patients; eg, Grawe et al [<xref ref-type="bibr" rid="ref90">90</xref>]) was not evaluated as a mediator in any of the included studies. However, the recent development of the working alliance inventory for digital interventions [<xref ref-type="bibr" rid="ref91">91</xref>] may contribute to future process research, informing the evidence base of the effects of a <italic>digital</italic> therapeutic alliance in DHIs for youth [<xref ref-type="bibr" rid="ref37">37</xref>,<xref ref-type="bibr" rid="ref92">92</xref>]. Furthermore, mediators that have not been investigated so far, such as behavioral and biological variables, should be evaluated in future studies. At this point, the possibilities of novel technological methods in process research seem not to be fully exploited in this research field [<xref ref-type="bibr" rid="ref37">37</xref>]. Passive sensing methodologies and digital phenotyping approaches with smartphones [<xref ref-type="bibr" rid="ref93">93</xref>] might generate insights on behavioral and biological mechanisms in real life, in addition to the predominant information on cognitive variables derived from self-reports identified in the current review. Third, although worldwide about 90% of youth live in countries with low or medium income, 90% of RCTs investigating mental disorders in children and adolescents are conducted in high-income countries [<xref ref-type="bibr" rid="ref1">1</xref>], mirroring the findings of the review at hand. In contrast, the presumed advantages of DHIs may be especially relevant in structurally weak and low-income countries. To overcome this contradiction, replication studies should aim to include and reach populations from low-income countries as well. Finally, our review revealed that mediators focusing on emotional and cognitive processes might be of paramount importance as potential mechanisms of change in DHIs for youth. However, the processes covered by these mediators varied to some extent. Thus, future studies focusing on both emotional and cognitive processes in a systematic way within one framework could be of great importance for the field.</p>
      </sec>
      <sec>
        <title>Conclusions</title>
        <p>This systematic review is the first to comprehensively investigate the mechanisms of change in different DHIs for youth. The key findings indicate that the largest group of examined mediators are cognitive variables, followed by an array of other mediator variables, including interpersonal, parenting behavior, and affective mediator categories. Of note, emotional and affective mediators consistently reached statistical significance across studies, whereas parenting-related mediators were evaluated constantly as nonsignificant. However, these findings must be considered cautiously, as we detected only a limited number of primary studies, despite including a broad range of mental disorders and interventions. Future studies should aim to lessen this research gap, ideally adhering to the quality criteria for process research and recent methods of mediation analyses, enabling more causally robust findings. These forthcoming studies might contribute to disentangling the therapeutic processes in DHIs, providing evidence-based knowledge to inform intervention development and augmented mental health care practices worldwide.</p>
      </sec>
    </sec>
  </body>
  <back>
    <app-group>
      <supplementary-material id="app1">
        <label>Multimedia Appendix 1</label>
        <p>Search strings for Cochrane Central Register of Controlled Trials, Embase, MEDLINE, and PsycINFO in Ovid.</p>
        <media xlink:href="jmir_v23i11e29742_app1.docx" xlink:title="DOCX File , 64 KB"/>
      </supplementary-material>
      <supplementary-material id="app2">
        <label>Multimedia Appendix 2</label>
        <p>Study characteristics.</p>
        <media xlink:href="jmir_v23i11e29742_app2.docx" xlink:title="DOCX File , 113 KB"/>
      </supplementary-material>
      <supplementary-material id="app3">
        <label>Multimedia Appendix 3</label>
        <p>Studies with number of criteria met.</p>
        <media xlink:href="jmir_v23i11e29742_app3.docx" xlink:title="DOCX File , 68 KB"/>
      </supplementary-material>
    </app-group>
    <glossary>
      <title>Abbreviations</title>
      <def-list>
        <def-item>
          <term id="abb1">CG</term>
          <def>
            <p>control group</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb2">DHI</term>
          <def>
            <p>digital health intervention</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb3">DHIHP</term>
          <def>
            <p>digital health intervention with a focus on health promotion</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb4">DHIPSY</term>
          <def>
            <p>digital health intervention with a psychotherapeutic focus</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb5">RCT</term>
          <def>
            <p>randomized controlled trial</p>
          </def>
        </def-item>
        <def-item>
          <term id="abb6">RoB</term>
          <def>
            <p>risk of bias</p>
          </def>
        </def-item>
      </def-list>
    </glossary>
    <ack>
      <p>This work was supported by the German Federal Ministry of Education and Research (grant identification FKZ01KG1802). The funding source, the Federal Ministry of Education and Research, had no role in the study design, collection, analysis, or interpretation of the data, writing of the manuscript, or the decision to submit this paper for publication.</p>
    </ack>
    <fn-group>
      <fn fn-type="con">
        <p>MD, SE, and HB developed the study design. SE and HN conducted the systematic literature searches, extracted the data, and rated the risk of bias and methodological quality criteria of included studies under the supervision of MD. MD wrote the first draft of the manuscript. All authors (MD, SE, HN, AL, AB, and HB) have contributed to the writing of the manuscript and have approved the final manuscript.</p>
      </fn>
      <fn fn-type="conflict">
        <p>AB has received payment for consulting from Pro-Change Behavior Systems. All other authors (MD, SE, HN, AL, and HB) stated no conflicts of interest.</p>
      </fn>
    </fn-group>
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