BackgroundNumerous studies have revealed that adolescents with chronic physical or mental conditions (CPMCs) are at an increased risk for depression and anxiety, with serious direct and indirect negative effects on treatment adherence, family functioning, and health-related quality of life. As game-based approaches are effective interventions in treating anxiety and depression, we propose to explore the use of a multiplayer role-playing game (RPG) as a potential intervention for social isolation, anxiety, and depression.ObjectiveThe objectives of this study were to (1) determine the feasibility of using Masks, a multiplayer RPG, as an intervention for social isolation, anxiety, and depression in adolescents with CPMCs; (2) evaluate the viability of the research process; and (3) gauge participation in and engagement with RPG-based interventions.MethodsThis study is a remote synchronous game-based intervention for adolescents with CPMCs aged 14-19 years. Eligible participants completed a web-based baseline survey to assess anxiety, depression, and social isolation and to identify their gaming habits. After completing the baseline survey, they participated in 5 moderated Masks game sessions. In Masks, players assume the roles of young superheroes; select their character types, superpowers; and perform actions determined by the game’s rule system and dice rolls. All game sessions were played using Discord, a communication platform commonly used by gaming communities. Games were led and moderated by game masters (GMs). After each game session, participants completed surveys to assess changes in anxiety, depression, and social isolation, and their attitude toward the game and the user experience. The participants also completed an exit survey after all 5 game sessions (modified version of the Patient Health Questionnaire and the Generalized Anxiety Disorder Questionnaire, and 17 open-ended questions). The GMs rated each game session and reported on gameplay, player behavior, comfort, and engagement levels of the players.ResultsAs of March 2020, six participants were recruited for the pilot study to participate in moderated web-based game sessions of Masks; 3 completed all game sessions and all required assessments. Although the number of participants was too low to draw generalizable conclusions, self-reported clinical outcomes did seem to indicate a positive change in depression, anxiety, and social isolation symptoms. Qualitative analysis of postgame survey data from participants and GMs indicated high levels of engagement and enjoyment. Furthermore, the participants provided feedback about improved mood and engagement related to weekly participation in Masks. Lastly, responses to the exit survey showed interest in future RPG-related studies.ConclusionsWe established a workflow for gameplay and evaluated a research protocol for evaluating the impact of RPG participation on isolation, anxiety, and depression symptoms in adolescents with CPMCs. Preliminary data collected from the pilot study support the validity of the research protocol and the use of RPG-based interventions in larger clinical studies.International Registered Report Identifier (IRRID)RR1-10.2196/43987