is a lecturer at Yale School of Management, and Harvard Business School, codirector for the Yale Center for Digital Health, and Chief Medical Information Officer at ICON Ltd.

Gregory P. Licholai, MD, MBA

 (DTx) are evidenced-based behavioral treatments that have demonstrated their “ability to prevent or manage a disease or disorder.”

 While their rapid evolution and often confounds efforts to precisely define the role of DTx in healthcare, they are generally used to perform or enhance several key functions. These include delivering health information, providing cognitive or motivational support, supplementing and enhancing treatment with drugs or other medical technologies, and data capture.

In just the past decade, DTx products have demonstrated significant benefits in the management of patients with many complex and challenging diseases, especially in the area of mental health. There were more than 500 DTx clinical trials conducted between January 2010 and December 2019, including about 180 interventional clinical trials. More than 

 were in areas broadly defined as mental health, including psychiatry, addiction, neurology, and sleep medicine.

Beginning in the earliest stages of the digital age, researchers worked to assess the different ways that advances in digital technology could be applied to areas of human health. During the last quarter of the 20th century, pioneers in digital innovation developed the earliest software programs engineered to support wellness and the treatment of different diseases and conditions. 

By the turn of the century, advances in technology coupled with the growth of the internet began to unlock the potential for DTx to improve care and deliver strong commercial opportunities. Investment in the sector increased, rapidly leading to the establishment of the first companies dedicated to clinical research and new product development in this sector, including 

 in the United States. This growth led to the first efforts by regulatory bodies to oversee the field. 

During the past 2 decades, several companies successfully advanced DTx clinical development programs to the final stages of regulatory review and approval. In 2010, WellDoc® won its first US Food and Drug Administration (FDA) clearance for the BlueStar® diabetes management system. In 2012, Proteus Digital Health earned its first clearance for an ingestible sensor. By 2017, the reSET® program from Pear Therapeutics was approved by the FDA for the treatment of substance abuse disorder and Otsuku Pharmaceutical’s Abilify MyCite® was approved for the treatment of schizophrenia, bipolar disorder, and depression. While a 

 estimated that the market for DTx would grow from $1.8 billion in 2018 to $7.1 billion in 2025,

 now estimates that the sector could reach more than $25 billion by 2025.

 are generally delivered via smartphones or computers/tablets, offering significant levels of convenience and privacy. They can also be available in multiple languages. As a result, they have the potential to 

, especially for underserved populations.

 The fact that many are available only via prescription also positions the provider to play an active role in administering DTx therapies and in patient monitoring and outcomes assessments.

Among the earliest advances in the DTx space were several for the treatment of mental health and substance abuse conditions. Thus far, these have focused on a variety of established needs in treatment, including technologies to provide information and guidance to patients, support needs in monitoring and behavior modification, expand access to motivational support, and deliver real-time assessments of cognitive function. They can also significantly enhance the range of available data from individual patients and entire patient populations that can, in turn, support more rapid and effective modifications to treatment regimens and approaches. 

DTx are also shown to present opportunities

 for benefits in other areas, including the ability for patients to better manage the pace of their treatment and monitor their own progress, reduced costs, less need for in-person interventions, and enhanced privacy.

In the treatment of substance use disorders (SUDs) specifically, research has led to DTx options administered via computer-based and mobile technologies that are designed to complement or replace a broad range of established medical or psychological approaches to treatment. Among the first approved therapies were reSET for the treatment of nonopioid use disorders and reSET-O for the treatment of opioid use disorders. Both products are interactive-based therapies that SUD patients can use at home in conjunction with supervised therapist sessions to treat drug addiction and abuse.

The approval of reSET was an example of the rigorous standards in clinical research applied to many DTx products. FDA approval for reSET came after a 12-week clinical trial of 399 patients in 10 outpatient addiction treatment programs. The study found that use of the reSET app in conjunction with in-person counseling improved treatment retention rates and abstinence rates. Of the patients using the reSET app, 40.3% were abstinent by the end of the study, compared to 17.6% in a control group that did not use the app. In the clinical research to support 

, 82% of patients treated with buprenorphine in conjunction with reSET-O remained in treatment at 12 weeks compared to 68% treated with buprenorphine alone.

Another example is the digital therapeutic Vorvida for the treatment of problematic drinking. Vorvida is a web-based software program that talks directly to patients about ways to help control drinking based on individual behaviors and habits. In a randomized controlled trial involving 608 adults with problematic alcohol intake, researchers found that participants in the intervention group with Vorvida significantly reduced their daily alcohol consumption over 3 and 6 months, with significant effect sizes.

 was launched in the United States in July 2020 for the management of problematic alcohol misuse.

Approaches in the treatment of insomnia that can involve cognitive, behavioral, and educational components are especially well suited to the potential applications of DTx. In some studies, digital approaches in cognitive behavioral therapy have been shown to 

provide benefits that are similar to in-person care

 while also having a positive impact on related symptoms including anxiety, depression, fatigue, and health-related quality of life.

Somryst was launched in November 2020 as a digital treatment that has been shown to improve the symptoms of 

 In treatment over several weeks, the program provides a range of lessons and challenges, including algorithm-driven sleep restriction to train the brain and body to improve sleep. The program also provides clinicians with real-time data on patient progress.

Sleepio is an example of a DTx product that is both supported by clinical research and available as an OTC therapeutic option. In a study of the use of cognitive-behavioral therapy interventions, Sleepio was shown in a United Kingdom study to improve both sleep and mental health in individuals with insomnia and clinically significant depressive symptoms.

 In clinical studies, the use of Sleepio was found to improve insomnia by 76% and depressive symptoms by 48% compared to the control group. The researchers saw these 

Standard of care in the treatment of attention deficit hyperactivity disorder (ADHD) includes a range of pharmacological and nonpharmacological interventions, many of which present limitations and unacceptable long-term risk profiles. In these treatment protocols, DTx have the potential to represent approaches in treatment that offer improved patient access, minimal side effects, and low potential for abuse while supporting improvements in cognitive functions, such as attention. Substantial research in this area has focused on the applications of video games that can function as a form of enjoyable therapy.

In June 2020, the FDA approved EndeavorRxTM (AKL-T01) as a prescription treatment for children with ADHD. EndeavorRx was granted clearance based on data from 5 clinical studies in more than 600 children showing that treatment improved objective measures of attention in children with ADHD

 After 4 weeks of treatment, one-third of children no longer had a measurable attention deficit on at least 1 measure of objective attention. About 

half of parents saw a clinically meaningful change

 in their child’s day-to-day impairments after 1 month of treatment; this increased to 68% after a second month of treatment.

While the majority of DTx products are administered when patients are awake, the Monarch external Trigeminal Nerve Stimulation (eTNS) system highlights the versatility of DTx by working while the patient is asleep. An electronic device about the size of a cell phone, Monarch eTNS electrically stimulates the brain’s trigeminal nerve through a patch applied to the forehead before bedtime. The system targets areas of the brain involved in mood disorders, epilepsy, and attention. In a study led at the University of California, Los Angeles, children who used the system at bedtime for 4 weeks experienced significantly reduced impulsivity, hyperactivity, and inattention as measured by clinician-administered ADHD rating scales.

Both the breadth and pace of research in development of DTx products to address areas of unmet need in mental health have expanded rapidly in recent years and are positioned to grow exponentially in the years ahead. DTx products are clinically validated and often meet regulatory standards related to safety and efficacy, and this can support patient confidence, health care provider adoption, and reimbursement pathways. In addition, the rapid pace of innovation in digital technology overall can support development of therapies in an ever-expanding range of applications.

Within this promising scenario, DTx research is likely to advance many unprecedented approaches in product development that can present significant challenges based on current standards in patient and clinician education, clinical research, regulatory review, access/reimbursement, and other areas. A critical component of success will be the ability to align stakeholders—including providers in mental health, leaders in patient advocacy, payers, industry partners, and regulatory agencies—to establish the new standards in product development at every stage. This will be essential to advance these innovative research programs and guarantee the broadest levels of patient access. These efforts could involve unprecedented levels of innovation and demand entirely new standards in clinical research and adoption of new technologies. Based on results thus far, there is strong indication that successfully addressing these challenges can deliver significant benefits to a broad spectrum of patients affected by mental health disorders.

is a lecturer in psychiatry, faculty advisor of innovation and entrepreneurship, and assistant clinical professor of psychiatry at Yale University Center for Biomedical and Interventional Technology.

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