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Analysis of the Status and Future Direction for Digital Therapeutics in Children and Adolescent Psychiatry
J Korean Acad Child Adolesc Psychiatry 2023; 34(4): 192-203
Published online October 1, 2023
© 2023 Korean Academy of Child and Adolescent Psychiatry.

Haemi Choi1*, Bora Kim1,2*, Insoo Kim3, Jae-Gu Kang1, Yoonjae Lee1, Hyowon Lee1, and Min-Hyeon Park1

1Department of Psychiatry, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
2Department of Literature and Art Therapy, Konkuk University, Seoul, Korea
3Department of Novel, Chung-Ang University Graduate School of Arts Short Course, Seoul, Korea
Correspondence to: Min-Hyeon Park, Department of Psychiatry, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 1021 Tongil-ro, Eunpyeong-gu, Seoul 03312, Korea
Tel: +82-2-2030-2722, Fax: +82-2-2030-2720, E-mail: neominnie00@hanmail.net
*These authors contributed equally to this work.
Received July 11, 2023; Revised September 6, 2023; Accepted September 8, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Digital therapeutics based on software, such as artificial intelligence, virtual reality, games, and smartphone applications, are in the spotlight as new therapeutic alternatives in child and adolescent psychiatry. It draws attention to overcoming conventional therapeutics’ limitations, such as toxicity, cost, and accessibility, and encourages patients to participate in the treatment attractively. The growth potential of the digital therapeutics market for psychiatric disorders in children and adolescents in Korea and abroad has been highlighted. Clinical studies and Food and Drug Administration approvals for digital therapeutics have increased, and cases approved by the Ministry of Food and Drug Safety have emerged in Korea. As seen above, digital transformation in child and adolescent psychiatry will change treatment paradigms significantly. Therefore, as this new field has just begun to emerge, it is necessary to verify the effectiveness and scope of the application of digital therapeutics and consider preparing a compensation system and institutional arrangements. Accordingly, this study analyzed the development trends and application status of digital therapeutics in children and adolescents and presented limitations and development directions from the perspective of application in healthcare. Further, the study is expected to identify the utility and limitations of digital therapeutics for children and adolescents and establish effective application measures.
Keywords : Healthcare; Telemedicine; Mental health; Digital technology; Mobile health
INTRODUCTION

Digital therapeutics (DTx), based on digital technology, have begun to attract attention as a third therapeutic option to overcome the limitations of conventional therapeutics, such as toxicity, side effects, manufacturing and purchasing costs, and accessibility [1,2]. In particular, as the non-face-to-face medical system was activated owing to the coronavirus disease 2019 (COVID-19) pandemic, the need for and demand for pharmaceutical and medical services through technology- based approaches, such as telemedicine, have rapidly increased. Moreover, the U.S. Food and Drug Administration (FDA) accelerated the adoption of digital solutions, allowing DTx to temporarily approve psychiatric treatment during the COVID-19 pandemic [3]. Moreover, DTx is expected to play a vital role in future healthcare services, showing direct effects on disease prevention, management, and treatment beyond simple health management (monitoring) [4,5].

DTx refers to evidence-based software products directly applied to patients for disease prevention, management, and treatment based on digital technology [6], forming an axis of non-face-to-face medical care and telemedicine [7]. According to the Ministry of Food and Drug Safety of Republic of Korea (MFDS) licensing system, they are classified as medical devices. Notwithstanding, they can also be considered close to medicine when they provide treatment functions similar to conventional medicines by utilizing software [8]. DTx has the advantages of significantly reducing the time and cost of development compared to conventional therapeutics, performing treatment functions through evidence-based treatment methods such as cognitive behavioral therapy, having less toxicity and side effects, and increasing accessibility to data-based individualized treatment [9]. Moreover, because a variety of digital technologies can converge, including artificial intelligence (AI), big data, virtual reality (VR), augmented reality (AR), metaverse, games, and applications, the scope for developing and utilizing therapeutics is broad.

DTx, which provides continuous and personalized treatment with this attractive approach, is emerging as a new treatment method for psychiatric disorders in children and adolescents. In child and adolescent psychiatry, treatment effectiveness can be substantially improved through behavioral interventions, a field in which existing pharmaceutical companies repeatedly fail to develop novel drugs [10]. Hence, products psychiatric disorders account for most DTx products currently being developed [11,12]. Additionally, since child and adolescent psychiatry often requires long-term treatment and a lot of labor and costs in treatment [7,13], the development and demand for DTx that can be used for an extended period at a relatively low cost is expected to continue [7]. Furthermore, by utilizing the functions of DTx, Personal Health Records, including psychiatric data that are classified as sensitive information under the Personal Information Protection Act and cannot be computerized, can be digitized to easily collect, track, and monitor patient data, thereby overcoming the fragmentation of treatment linkage due to the nature of pediatric psychiatry, which requires various treatment linkages and has the advantage of being able to provide more effective medical services [14,15]. Moreover, modern children and adolescents have high access to digital devices because they are a generation that has grown under the influence of the digital society since infancy. Thus, treatment utilizing attractive digital technologies such as games effectively reduces resistance to treatment among children and adolescents and improves their immersion, thereby enhancing the treatment’s sustainability, usefulness, and effectiveness.

Notably, DTx for psychiatric disorders in children and adolescents is being developed. Currently, products released with proven effectiveness in children and adolescents include EndeavorRX (Akili Interactive), ATENTIVmynd (ATENTIV), SparkRx (Limbix), and Canvas Dx (Cognoa). EndeavorRX is a DTx approved by the FDA in 2020 to treat children aged 8 to 12 years with attention deficit hyperactivity disorder (ADHD) through immersive video game experiences on smartphones and tablet devices. Additionally, ATENTIVmynd has been developed to improve attention in ADHD, SparkRx to improve symptoms of adolescent depressive disorder, and Canvas Dx to assist in the early diagnosis of autism spectrum disorder (ASD) are being developed. Furthermore, studies and clinical trial results on DTx for various psychiatric disorders in children and adolescents are continuously accumulated to build a foundation. As digital transformation in child and adolescent psychiatry accelerates, the development of DTx for psychiatric disorders in children and adolescents is expected to begin earnestly, resulting in significant changes in the treatment paradigm. The growth potential of DTx for psychiatric disorders in children and adolescents is substantial, and the scope of application of digital technology is expanding. Thus, it is necessary to verify the effectiveness and scope of the application of therapeutics.

Therefore, this study aimed to analyze the development trends and application status of DTx in child and adolescent psychiatry in Korea and abroad. Further, it aimed to present the limitations, development directions, and future tasks of DTx from the perspective of application in healthcare. This study is expected to identify the utility and limitations of DTx in child and adolescent psychiatry and establish effective application measures for DTx in the future.

DEVELOPMENT TRENDS OF DTx IN CHILD AND ADOLESCENT PSYCHIATRY

The Digital Therapeutics Alliance (DTA), launched in 2017, is a nonprofit trade association of industries that developed DTx in 17 countries, including the United States and Europe. Approximately 100 companies participated, including global pharmaceutical companies such as Novartis and Otsuka and companies specializing in DTx, such as Akili Interactive, Big Health, Cognoa, Limbix, and Pear Therapeutics [16]. Furthermore, 13 Korean companies, including AIMMED, MiNDCAFE, and WELT (a spin-off company of Samsung), are also members of DTA [16,17]. DTA divides DTx into three categories depending on its main purpose: disease prevention and health function improvement, disease management, and disease treatment (Table 1) [18]. Additionally, DTx is classified into standalone, augmented, and complementary types depending on the kind that affects disease treatment (Table 2) [19]. Table 3 shows representative DTx in the child and adolescent psychiatry fields approved or provisionally approved overseas [20-54].

Classification of digital therapeutics by purposes

Classification Disease prevention and health function improvement Disease management Disease treatment
Regulatory oversight The extent of regulation depends on local regulatory systems Validation of efficacy and safety claims is conducted by a national regulatory organization or its equivalent Validation of efficacy and safety claims is conducted by a national regulatory organization or its equivalent
Level of medical claims Low to medium-risk claims Medium to high-risk claims Medium to high-risk claims
Clinical evidence Clinical trials and ongoing evidence generation are required Clinical trials and ongoing evidence generation are required Clinical trials and ongoing evidence generation are required
Patient access Nonprescription or Prescription Nonprescription or Prescription Prescription
Clinical endpoints Delivering a therapeutic intervention while supporting product claims with clinical endpoints Delivering a therapeutic intervention while supporting product claims with clinical endpoints Delivering a therapeutic intervention while supporting product claims with clinical endpoints

Adapted from Digital Therapeutics Alliance [18], under the permission of Digital Therapeutics Alliance



Types of digital therapeutics

Type Content
Standalone Designed for independent disease treatment, it can be used either as a replacement for conventional medications or in conjunction with other treatments. This type is prevalent in the field mental health, where mobile apps can deliver cognitive behavioral therapy digitally
Augmented Designed for use alongside prescribed pharmacological interventions to augment their effectiveness, typically supporting the existing treatment of chronic diseases such as diabetes
Complementary Designed to complement existing treatments and improve the self-management of health conditions alongside therapeutic medications. This type is prevalent in managing behavioral patterns and lifestyles related to obesity, hypertension, and other important disease factors

The content has been summarized from S3 Connected Health [19]



Representative digital therapeutics in children adolescent psychiatry approved or provisionally approved abroad

Device Applicant Target disease Features Target age FDA approval
reSET [20,21] Pear Therapeutics Substance use disorder (except opioid) A mobile application designed to address addiction and dependency issues related to stimulants, alcohol, cannabis, and cocaine. A 12-week (90 days) CBT program prescribed for use in conjunction with an existing therapy program. Its goal is to increase abstinence from substances and improve retention in outpatient therapy. This is the first FDA-cleared DTx for disease treatment 18 years and older September 14, 2017
reSET-O [22] Pear Therapeutics Opioid use disorder A mobile application designed for treating addiction and dependency on opioids. A 12-week (84 days) CBT program prescribed and used as an adjunct outpatient treatment alongside transmucosal buprenorphine and contingency management. Its aim is to enhance retention in outpatient treatment using buprenorphine 18 years and older December 10, 2018
Somryst [23] Pear Therapeutics Chronic insomnia A mobile application designed to enhance sleep quality. A 9-week CBT program available by prescription only. It comprises six treatment modules focused on CBT concepts, including sleep restriction and consolidation, stimulus control, and cognitive reconstruction. It leads to significant and enduring improvements in insomnia symptoms. It serves as a complement to current therapy 22 years and older March 26, 2020
SparkRx [24-26] Limbix Depression A mobile application designed to alleviate depression symptoms. It provides a neurobehavioral intervention (CBT–behavioral activation) as an adjunct treatment for depression symptoms. This intervention spans five levels, aiding users in understanding depression and acquiring coping skills to manage their symptoms 13-22 yrs Not cleared or approved (under the FDA’s enforcement policy, a prescription is not required)
EndeavorRx [27,28,29] Akili Interactive ADHD An action video game designed to improve attention function in children primarily diagnosed with inattentive or combined-type ADHD. It digitally assesses sustained and selective attention and provides a treatment program that challenges a child’s attention control during gameplay. This requires concentration and the ability to multitask. It represents the first and the only FDA-authorized prescription 8-12 yrs June 15, 2020
AKL-T02 [30] Akili Interactive ASD An action video game designed to address cognitive dysfunction, attention-related functions, and associated symptoms in children with ASD. This game has been adapted for use with ASD, incorporating specific and simultaneous sensory and motor stimuli to those found in EndeavorRx. It has demonstrated high acceptability and engagement as a treatment, along with improvements in attention-related measures 9-13 yrs Not cleared or approved
AKL-T03 [31] Akili Interactive MDD A video game aimed at enhancing cognitive function in patients with MDD when used in conjunction with antidepressant medication. It utilizes a multitasking interface, presenting two simultaneous tasks that players must complete. It is specifically designed to offer interference management training with a flexible and personalized level of difficulty, achieved through the application of proprietary algorithms similar to those used in EndeavorRx. It has shown significant improvements in sustained attention 22-55 yrs Not cleared or approved
ATENTIVmynd [32] ATENTIV ADHD A brain-computer interface therapy combines a headband with mounted dry EEG sensors and a tablet-based game. This consists of a series of virtual world adventures spanning 4 to 8 weeks. During the game, patients face multiple challenges aimed at teaching cognitive skills related to attention and impulse inhibition. The therapy has led to a sustained and significant reduction in the primary symptoms of ADHD, along with a significant improvement in academic performance 6-12 yrs Not cleared or approved
REThink [33] Babes-Bolyai University Emotion regulation An application designed for tablets, adapted as a prevention tool for children and adolescents to acquire emotion regulation skills. Its purpose is to build psychological resilience by teaching healthy strategies to cope with dysfunctional negative emotions. This is based on the principles of Rational-Emotive Behavior Therapy and Education intervention 10-16 yrs Not cleared or approved
MindLight [34] Play Nice Institute Anxiety and depression A game that employs three evidence-based strategies to reduce anxiety in children and adolescents. These strategies include neurofeedback training, exposure training, and attention bias modification. The game offers 8-12 weeks of CBT in as little as 5.5 hours of gameplay, with real-time relaxation states measured by the EEG headset 10-16 yrs Not cleared or approved
Mightier [35] Boston Children’s Hospital and Harvard Medical School Emotion regulation A game application designed to facilitate the learning emotional regulation and the practice of calming skills. Users wear a heart rate sensor while playing games. This game demands relaxation while engaging executive functions to complete short reaction tasks, expanding the typical biofeedback paradigm. The program is grounded in CBT, aiming to reduce the need for psychiatric medication and assist in developing emotional control 6-14 yrs Not cleared or approved
RECOGNeyes [36] University of Nottingham ADHD A computer game played using the eyes as the game controller. The interactive game incorporates eye-tracking technology, which appears to enhance the visual attention system 8-15 yrs Not cleared or approved
Abilify MyCite [42] Otsuka Pharmaceutical Co. and Proteus Digital Health Schizophrenia A prescription smart pill equipped with built-in technology. The aripiprazole tablets, embedded with sensors, send signals to a wearable Bluetooth patch that connects to a smartphone, enabling the viewing of daily data. This can be used for the treatment of schizophrenia, the acute treatment of manic and mixed episodes associated with bipolar I disorder and an add-on treatment for depression 24 years and older November 13, 2017
Feel Therapeutics solution [12,43,44] Feel Therapeutics MDD, GAD A remote mental health support program designed to improve emotional awareness and self-regulating skills. This program deploys the Feel Emotion Sensor, Feel Mobile App, and Feel Mental Health Biomarkers platform. It combines evidence-based approaches, including CBT, with psychophysiological data, specifically focusing on emotion-related information from the autonomic nervous system 18years and older Not cleared or approved
Canvas Dx [45, 46] Cognoa ASD A diagnostic solution designed to assist healthcare providers to diagnose or rule out autism in children. It collects parent or caregiver questionnaires, videos of the child’s interactions, and clinician questionnaires, and then provides clinical judgements through algorithm evaluation. This marks the first FDA-approved digital therapeutics for children with ASD 18-72 months July 2, 2021
EarliPoint Evaluation [47] EarliTec ASD Utilizing the significant of looking behavior as an indicator of neurodevelopmental vulnerability. It tracks and evaluates children’s gaze while they watch videos, comparing it to typical behavior. It offers caregivers and healthcare providers information regarding potential developmental vulnerabilities to aid in the diagnosis and assessment of ASD 16-30 months June 10, 2022
Sleepio [48] Big Health Insomnia A mobile and web-based digital sleep improvement program, clinically proven to relaxation and enhance sleep quality. Comprising six sessions, each averaging 20 minutes, the program can be completed in weeks, alongside a daily sleep diary that takes under 5 minutes to complete. This program helps reduce the need for GP appointments and prescription costs by offering immediate access to CBT for insomnia in situations where face to face CBT is unavailable. It does not replace the care of a medical provider or the patient’s prescribed medication 18 years and older Not cleared or approved (USA: under the FDA’s enforcement policy, a prescription is not required; UK: Class I CE mark)
Daylight [49] Big Health GAD A mobile and web-based digital anxiety management program, based on CBT. It only requires 10 minutes per day. By offering instance access to CBT for insomnia in cases where in-person CBT is not available, it helps reduce the need for GP appointments and prescription costs. It is not a substitute for the care of a medical provider or the patient’s prescribed medication 18 years and older Not cleared or approved (USA: under the FDA’s enforcement policy, a prescription is not required; UK: Class I CE mark)
Deprexis [50] GAIA Depression An internet-based software platform accessible 24/7 on any device, designed to enhance depression symptoms when used as an adjunctive therapy. It offers a 12-week program with CBT-based support. The platform employs AI to facilitate interaction with a therapist and provide personalized feedback and strategies for managing depressive symptoms 18 years and older Not cleared or approved (USA: under the FDA’s enforcement policy, a prescription is not required; Germany & Switzerland: Class I CE mark)
FreeSpira [51] Palo Alto Health Sciences PTSD, panic disorder, panic attack A digital panic attack program incorporated proprietary sensors, physiological feedback displays, and coaching to synchronize breathing and normalize CO2 and respiratory rates over a 28-day course. It aims to reduce symptoms and emergency medical care needs. Patients receive training from clinicians or Freespira coaches and follow a home-based protocol with two 17-minute breathing sessions daily for one month, including four weekly virtual coaching sessions 22 years and older August 23, 2018
Nightware Kit [52] Nightware PTSD A prescription digital therapeutic system designed to reduce sleep disturbances related to nightmare disorder or nightmares stemming from PTSD. When a nightmare is detected, the device delivers brief vibrations to interrupt the nightmare without fully waking the patient. It is the first FDA-cleared prescription DTx designed to enhance sleep 22 years and older November 6, 2020
Vorvida [53] GAIA Alcohol abuse A web-based software program spanning 180 days, accessible 24/7 on any device. It utilizes AI to interact with a therapist, providing personalized feedback and strategies for managing drinking behaviors. The program has shown a significant reduction in average daily alcohol consumption at 3 and 6 months 18 years and older Not cleared or approved (under the FDA’s enforcement policy, a prescription is not required)
PEAR-004 [54] Pear Therapeutics Schizophrenia A mobile application-based program designed to improve the symptoms and functioning of individuals with schizophrenia. It deploys a combination of social skills training, CBT for psychosis, and helping in the management of drug treatment 18 years and older Not cleared or approved (under the FDA’s enforcement policy, a prescription is not required)

ADHD, attention deficit hyperactivity disorder; AI, artificial intelligence; ASD, autism spectrum disorder; CBT, cognitive behavioral therapy; CO2, carbon dioxide; DTx, digital therapeutics; EEG, electroencephalography; FDA, Food and Drug Administration; GAD, generalized anxiety disorder; GP, general practitioner; MDD, major depressive disorder; PTSD, post-traumatic stress disorder



The most representative example of a standalone DTx is the reSET, developed by Pear Therapeutics in the United States. The reSET, the world’s first DTx approved by the FDA in 2017, is an application for treating addiction to various substances and drugs, such as alcohol, marijuana, and cocaine, in adolescents and adults over 18 years old. It is a program prescribed and used for 12 weeks with existing treatment programs that provide cognitive behavioral therapy through various content. These include text and animation when patients install it on their smartphones and enter information about their condition and drug use [20,21]. In addition to the effectiveness of the therapy itself, it also supports patients in completing existing treatment programs better [21]. Pear Therapeutics has also received marketing approval for reSET-O, an addiction treatment application for narcotic analgesics, and Somryst, a therapeutic for insomnia. It has developed a digital application of cognitive behavioral therapy to treat psychiatric disorders in adolescents and adults [22,23]. Another representative standalone DTx for children and adolescents is SparkRx. SparkRx is a DTx that provides cognitive behavioral therapy to children and adolescents aged 13–22 years with depressive symptoms. Although SparkRx has not been licensed or approved by the FDA, it has received emergency use authorization per the FDA’s enforcement policy for DTx to treat psychiatric disorders during the public health emergency called COVID-19. It can be used free of charge without a prescription [24,25]. A treatment program combining cognitive behavioral therapy and behavioral activation protocols was provided for five weeks, and a significant reduction in depressive symptoms was reported in a clinical trial [26].

In addition to smartphone applications, standalone therapeutics provide highly immersive cognitive behavioral therapy in various forms, such as games and VR or AR, for pediatric and adolescent patients. For example, Akili Interactive’s EndeavorRx, approved by the FDA in 2020, was the first game to be used as a therapeutic agent for ADHD. EndeavorRx showed improvements in spatial working memory in both children and adolescents with ADHD and typical development aged 8–12 years, indicating that the more severe the ADHD symptoms, the greater the degree of improvement [27,28]. It has been reported that the activity of midline frontal theta, a brain wave related to attention and cognitive control ability, increases while playing the game and is associated with decreased inattention symptoms [29]. In addition to EndeaverRx, game-type DTx for children and adolescents, such as ATENTIVmynd, REThink, MindLight, Mightier, and RECOGNeyes, are either under development or have been developed [32-36]. However, to recognize the effectiveness of game-type therapeutics, the transfer effect should be evaluated and compared before and after the intervention [37-39]. The transfer effect can be determined by improving cognitive functions other than the trained cognitive function and the sustainability of the treatment effect after the end of training [39]. Currently, transfer effects are classified into two distinct categories, namely, near transfer effects and far transfer effects. In particular, when only cognitive functions similar to the directly trained cognitive functions are improved, and as a far transfer effect, cognitive functions that are not closely related are improved [39]. To date, no reported cases of the far-transfer effect exceed the neartransfer effect in game-type DTx [40,41]. As such, there is insufficient evidence to report transfer effects to improvements in cognitive functions other than those trained or whether the effectiveness of DTx is maintained long-term after training is completed.

An example of an augmented DTx is the Abilify MyCite of Otsuka. It is a method of recording and managing whether and when to take a drug by inserting a sensor into Abilify (Apriqizole), a therapeutic for schizophrenia [42]. This system manages a patient’s medication status by sharing it with the patient, parents or caregivers, and physicians. Moreover, the Feel Therapeutics solution of Feel Therapeutics, classified as an augmented type of medication management, is a DTx managing stress using biomarkers [12]. Data was obtained via a wearable band with an integrated sensor measuring heart rate, mood, sleep, and cognitive function. Based on the data, the mobile application connected to the band provides personalized coaching and biological indicators to assist users in improving their emotional stability [43,44].

Finally, a representative example of a complementary DTx is Canvas Dx, developed by Cognoa. Canvas Dx was the first DTx for children with ASD approved by the FDA in 2021 and was developed utilizing AI technology to assist in diagnosing ASD in children aged 18–72 months at risk of developmental delay [45,46]. It collects parent or caregiver questionnaires, videos of the child interacting, and clinician questionnaires, and provides diagnostic results for clinical judgment through algorithm evaluation [46]. Additionally, following Canvas Dx, the EarliPoint Evaluation of EarliTec, an ASD diagnosis-assisted DTx, was approved by the FDA in 2022. EarliPoint Evaluation tracks and assesses the gaze of children aged 16-30 months while they watch videos, comparing their behavior to typical patterns. This is based on the significance of looking behavior as an essential indicator of neurodevelopmental vulnerability. This informs parents, caregivers, and healthcare service providers about potential developmental vulnerabilities [47]. DTx has the advantage of preventing delayed diagnosis and improving prognosis by intervening during the critical period, as ASD is a disorder for which early diagnosis and intervention are crucial.

As mentioned above, the development of DTx in psychiatry, including child and adolescent psychiatric disorders, is highly active and rapidly increasing, especially in the United States and Europe. In addition to the positive evaluation of the effectiveness and marketability of DTx, support policies for DTx are being expanded in Korea, accelerating the research and development of DTx in psychiatry. The MFDS approved the AIMMED Somzz as the first DTx in Korea in 2023. Somzz is a DTx that implements cognitive behavioral therapy techniques in mobile applications to improve insomnia symptoms. This application is designed for patients with chronic insomnia, and its core principle is to improve the patient’s insomnia symptoms through a doctor’s prescription. It achieves this by providing sleep habit education, implementing behavioral interventions, and delivering real-time feedback through the Somzz application for 6–9 weeks [55]. In a clinical trial, a significant improvement was found in insomnia severity before and after using the Somzz app. The results of the safety and effectiveness evaluation of the innovative medical technology of cognitive behavioral therapy for patients with chronic insomnia using the therapeutic have been revised and announced. Thus making temporary non-reimbursable prescriptions possible for three years from June 1, 2023 [56]. Following Somzz, WELT-I obtained approval from the MFDS as the second DTx for insomnia in Korea. WELT-I is also a DTx that implements cognitive behavioral therapy for insomnia into a mobile application, which improves insomnia symptoms by providing sleep restriction therapy, sleep hygiene education, cognitive restructuring, and relaxation therapy for eight weeks depending on sleep patterns when an insomnia patient installs WLET-I prescribed by a doctor [57].

In addition to Somzz and WELT-I, which can be classified as representative standalone DTx utilizing cognitive behavioral therapy techniques in Korea, clinical trials of DTx in psychiatry for children, adolescents, and adults are in progress. These preparations encompass various stages, including game-based improvement of attention deficits in pediatric patients with ADHD and ameliorating depression in patients with depressive disorder using VR or AR technology (Table 4) [58]. Most DTx currently in clinical trials with official approval in Korea are cognitive therapy software. Further, their scope of use is expanding, including the improvement of alcohol addiction disorder, nicotine addiction, improvement of symptoms of mild cognitive impairment, and attention function in ADHD.

Digital therapeutics in child and adolescent psychiatry approved clinical trials from MFDS*

Device Applicant Target disease Clinical trial phase MFDS approval
Minds.NAVI MINDsAI MDD Pivotal study November 3, 2021
CHEEU.Forest MINDsAI MDD Pivotal study December 23, 2021
Anxeilax HAII GAD Confirmatory clinical study December 30, 2021
D-kit/EF1 DoBrain Mild intellectual disorder, borderline intellectual functioning Pivotal study October 20, 2022
ALCO-THERA Medimind Alcohol abuse Confirmatory clinical study October 20, 2022
OMNFIT DTx MDD Omni C&S MDD Confirmatory clinical study November 29, 2022
Neuro-World WOORI SOFT ADHD Pivotal study December 1, 2022
AttnKare-D Hippo T&C ADHD Confirmatory clinical study January 6, 2023
No official name (CBT-based) WELT Eating disorder Confirmatory clinical study January 17, 2023
NDTx-01 Neudive ASD or SCD Pivotal study February 22, 2023
No official name (metaverse-based) DoBrain High-functioning ASD Pivotal study March 23, 2023
NICO-THERA Medimind Nicotin abuse Confirmatory clinical study April 10, 2023
BlueKare-T Hippo T&C Depression Confirmatory clinical study June 8, 2023

*these cases are referenced from data retrieved between 2021 Sep 1 and 2023 Jul 7 from MFDS [58]. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CBT, cognitive behavioral therapy; GAD, generalized anxiety disorder; MDD, major depressive disorder; MFDS, Ministry of Food and Drug Safety of Republic of Korea; SCD, social communication disorder



Cognitive behavioral therapy mechanisms are widely used in psychiatry in Korea and abroad, especially in developing DTx for psychiatric disorders in children and adolescents. In clinical practice guidelines, cognitive behavioral therapy is recommended as the primary treatment. In addition, it has the advantage of treating various diseases and symptoms by delivering clinically proven cognitive behavioral therapy techniques through digital methods, such as applications and games, resulting in high accessibility and scalability. Moreover, the effectiveness of online-based cognitive behavioral therapy in improving depressive disorders and anxiety disorders in children and adolescents has been proven. Accordingly, to date, DTx for children and adolescents has mainly been developed focusing on cognitive behavioral therapy for depression, anxiety, obsessive-compulsive disorder, disruptive behavior disorder, drug abuse, eating disorders, and body image problems. However, there is insufficient evidence on the long-term effects of DTx, and the mechanism of this effect is often not elucidated, even when the treatment effects are identified. Hence, studies have been performed to elucidate treatment mechanisms and are continuously being conducted to overcome the limitations of DTx. For example, ATENTIVmynd used resting-state functional magnetic resonance imaging to measure the brain network before and after treatment. As a result, it was suggested that one treatment mechanism could improve the inattention symptom and internalizing problems in children with ADHD by reorganizing the salience network associated with focusing attention on essential stimuli [59]. Furthermore, brain maturation can be promoted by reorganizing brain networks. However, this study also has limitations because the sample size was small, and long-term follow-up is required [59]. Despite these limitations, DTx is likely to be used as a treatment tool in the future because the study results are encouraging for preventing and treating psychiatric disorders in children and adolescents.

DEVELOPMENT DIRECTIONS OF DTx

DTx in child and adolescent psychiatric disorders not only has excellent accessibility but also has the obvious advantages of low cost, low risk, and overcoming the fragmentation of child psychiatric treatment linkage. Thus, it is expected to grow in the future while overcoming physical limitations, such as medical location, time, and human resource availability. However, because we are currently in a transitional period in which rapidly developing digital technology is permeating the medical community, the direction in which digital technology will be accepted and regulated is crucial. As this new field has just begun to emerge, it is clear that there are various areas of controversy and matters to consider.

First, because objective proof of effectiveness is insufficient, there is an urgent need to verify its additional effectiveness. For instance, game-type DTx needs to be confirmed for transferability (transfer effect, persistence of treatment, and spread of effects to adjacent functions) in addition to short-term effectiveness indicators. Additionally, as a new field has recently emerged, there is still insufficient evidence on whether the effectiveness of DTx is maintained in the long term. Further, the possibility of long-term side effects from using digital technologies, such as audiovisual and electrical stimulation, should be considered. In particular, DTx is also used to rehabilitate cranial nerve disorders such as Alzheimer’s disease, Parkinson’s disease, and stroke and can induce brain neuroplasticity. Therefore, it is necessary to examine how DTx affects brain development and maturation. Moreover, DTx emphasizes personalized treatment. However, it is difficult to exclude the influence of confounding effects owing to individual characteristics that can affect treatment, even though it is challenging to differentiate and classify patients using digital technology. Therefore, high-quality, real-world evidence, clinical verification, and follow-up evaluations are required.

Second, DTx has the advantage of overcoming the limitations of accessibility as an axis of telemedicine. However, issues of accessibility and compliance with DTx should be considered. DTx is only effective when it is used. It is more valuable than medication adherence because usage records can be checked electronically. The fulfillment rate can affect product upgrades based on real-world data, real-world evidence, and value-based evaluations derived from the fulfillment rate. Specifically, the real-world fulfillment rate is essential for patients, healthcare professionals, companies, and related organizations, including improving treatment effectiveness and generating corporate profits. However, even in overseas countries where the DTx market is active, there are minor problems in the distribution process of DTx. These include application payment procedures, authentication procedures, and content access, which are difficulties using DTx. Even if children and adolescents are familiar with digital technology, there may be difficulties in accessing DTx themselves if the parents or caregiver assists in use or the actual user is not familiar with digital technology. Moreover, according to the 2022 first-quarter performance data released by Pear Therapeutics, an American DTx company considered a successful case of DTx. The total number of prescriptions for the three developed products (reSET, reSET-O, and Somryst) was more than 9200, and the fulfillment rate was 57% (percentage of completing an application to the end). Although this is a 6% increase compared to the fulfillment rate disclosed in 2021, it is still an insufficient result. Thus, as DTx is a new treatment area, measures to raise user awareness and improve accessibility to DTx within app services should be prepared. Additionally, it is necessary to put efforts such as increasing usability by improving the internal design of the app, continuously managing it, and establishing an educational model.

Third, DTx has been approved in Korea because of the rapid improvement in the approval system by the MFDS. Nevertheless, there are still no management mechanisms for DTx, such as determining treatment prices, calculating physicians’ prescribing fees, health insurance applications, and follow-up management. This limits its actual use and market growth. Pear Therapeutics, the first publicly traded DTx company, went bankrupt in 2023 because it failed to provide benefits in the United States national health insurance system. It has been over 5 years since Pear Therapeutics received FDA approval. However, its sales growth has inevitably been slow due to limited application to national or private insurance in the United States and limitations in profit generation.

Thus, an innovative compensation system is required at the government level. The Ministry of Health and Welfare recently reported and discussed health insurance application guidelines that would allow DTx patients to receive preliminary benefits. In particular, through an innovative medical technology assessment, track and pay a service fee to physicians who prescribe them at the relevant fee and a usage fee to companies. The bankruptcy of Pear Therapeutics, the first publicly traded DTx company, underscores the importance of promptly addressing various conditions to ensure patients can benefit from innovative treatment technologies. These conditions may include the social consensus required for prescription, the calculation of insurance fees for both prescribers and users, and the designation of control towers.

Finally, regulatory authorities may need to move away from conventional regulatory methods and realistically ease regulations to promptly introduce rapidly changing digital technologies. However, there is a need to acquire more expertise by training experts within the regulatory agencies and have the capabilities and infrastructure to verify DTx effectively. The process of developing DTx is low-cost and lowrisk. Hence, if companies without sufficient preparation or expertise use deregulation to create substandard digital therapeutic products indiscriminately, the damage will ultimately fall on patients, resulting in increased distrust of DTx. Furthermore, many companies have attempted to enter the DTx market as a blue ocean. However, this may lead to failure due to various practical limitations. As the wearable device market proliferates and declines, the DTx market may decline quickly.

CONCLUSION

The number of related clinical studies and cases receiving FDA approval in child and adolescent psychiatry increases. Thus, DTx, which treats patients using software such as AI, VR, games, and smartphone applications, is in the spotlight as a novel therapeutic alternative. Children and adolescents with psychiatric disorders often require long-term treatment, which is labor-intensive and expensive. Hence, the demand for DTx will continue to increase because it provides personalized and effective treatment at a relatively low cost. Moreover, unlike medications or injections, DTx opens up significant market opportunities for software development startups because of its scalability, as it can be distributed to millions of people simultaneously. From the perspective of existing pharmaceutical companies, investing in and partnering with DTx companies that require relatively less development time and cost, are less invasive, and can assist or enhance the effectiveness of existing drugs can be a new business opportunity. As mentioned above, the DTx market’s growth potential in psychiatry, including children and adolescents, has been substantially highlighted. Hence, it is predicted that the potential for future growth will be high, and it is possible to be used as an efficient treatment tool. This field has just begun to emerge. It will be necessary to consider the direction to accept and regulate digital technology, such as verifying the effectiveness and scope of the application of therapeutics, innovative compensation systems, and institutional preparation. Accordingly, this study examined the current status of DTx in children and adolescents in Korea and abroad and considered its limitations and development directions from the perspective of its application in healthcare. Based on this study, we believe it can be used to identify the utility and limitations of DTx in child and adolescent psychiatry from the perspective of application in healthcare settings. Further, it can be employed to establish effective application measures for DTx in the rapidly growing digital healthcare technology.

Availability of Data and Material

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors have no potential conflicts of interest to disclose.

Author Contributions

Conceptualization: Min-Hyeon Park. Data curation: Haemi Choi, Bora Kim, Insoo Kim, Jae-Gu Kang, Yoonjae Lee, Hyowon Lee. Funding acquisition: Min-Hyeon Park. Investigation: all authors. Project Administration: all authors. Supervision: Min-Hyeon Park. Visualization: Haemi Choi. Writing—original draft: Haemi Choi, Bora Kim. Writing—review & editing: Haemi Choi.

Funding Statement

This study was supported by a grant from the Game Science Forum in South Korea and by the Technology Innovation Program (grant PC20ONDI0074; AI [artificial intelligence]-Driven Global PHR [personal health record] Pediatric Developmental Disability Management/Treatment Platform) funded by the Ministry of Trade, Industry, and Energy, Korea. The funders played no role in the study design, data collection and analysis, publication decision, or manuscript preparation.

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Funding Information
  • Ministry of Trade, Industry and Energy
      10.13039/501100003052
      PC20ONDI0074
  • Game Science Forum in South Korea