Table 3.

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