Current Status and Future Directions in the Development of Digital Therapeutic Interventions for Neurodevelopmental Disorders

Abstract

Innovations in digital technologies have emerged digital therapeutics (DTx) as a novel therapeutic intervention. DTx hold potential as novel theragnostics for disorders with broad diagnostic spectra, including neurodevelopmental diseases (NDDs). In this review, we highlight challenging factors in the successful development and deployment of DTx for NDDs with respect to patients, medical professionals, and manufacturers. We also discuss the implications of these factors and future directions for revitalizing DTx development for NDDs.

NEURODEVELOPMENTAL DISEASES

The etiological heterogeneity of neurodevelopmental diseases (NDDs), including autism spectrum disorder (ASD), attention‐deficit hyperactivity disorder (ADHD), intellectual disability (ID), and schizophrenia, contributes to variability in clinical phenotypes (i.e., brain structure, intellectual ability, and psychiatric status). The most prevalent NDDs are ASD and ADHD, which share several genetic risk factors. In addition, 50% to 70% of patients with ASD have comorbid ADHD. ¹ Nonetheless, ASD and ADHD have distinct differences in pathological symptoms, brain features, and therapeutic interventions.

ADHD is characterized by persistent patterns of inattention, hyperactivity, and impulsivity that interfere with daily functioning and development, ¹ while ASD is characterized by challenges in social communication, restricted interests, and repetitive behaviors, with a wide range of cognitive function and symptom severity across individuals. ² Compared with healthy controls, individuals with ADHD exhibit lower total brain volume and cerebellar connectivity, whereas individuals with ASD exhibit increased brain volume and amygdala overgrowth. ³ Decreased dopamine (DA) transmission contributes to the pathoprogression of ADHD, and medications improving DA signaling are the predominant pharmacological interventions for ADHD. ⁴ By contrast, there are no curative pharmaceutical treatments for ASD, although a few medications have been developed to alleviate specific symptoms. Non‐pharmacological therapies for ADHD include behavioral interventions, digital therapeutics (DTx), and cognitive training. ⁵ For ASD, non‐pharmacological interventions are the predominant therapeutic strategy and include behavioral and educational interventions, biofeedback and neuromodulation, and digital‐assisted interventions. ⁵ The broad spectra of diagnostic ranges for NDDs exemplified by ADHD and ASD pose a challenge for the development of specific therapeutic strategies.

CURRENT STATUS OF DIGITAL THERAPEUTICS FOR NEURODEVELOPMENTAL DISEASES

The advent of digital technologies such as artificial intelligence (AI) [e.g., machine learning (ML) and deep learning (DL)] and eXtended reality (XR) [e.g., virtual reality (VR), augmented reality (AR), and mixed reality (MR)] has given rise to DTx. DTx are software that provide evidence‐based therapeutic interventions for the prevention, management, or treatment of disorders as well as data‐based personalized treatment. ⁶ DTx have been integrated with conventional medication for various indications and might provide novel theragnostic (both diagnostic and therapeutic) strategies for NDDs.

From 2005 to 2022, 2,862 clinical trials for DTx were enrolled or completed in ClinicalTrials.gov, and the largest percentage of trials were for NDDs (23.72%, 679 trials). ⁷ Efforts to develop DTx for NDDs have predominantly aimed at disease treatment and/or management, with a minor focus on disease diagnosis (Table 1 ). DTx developed for NDD management target cognitive function and sociability (Table 1 ). ⁸ Diagnostic DTx include Canvas Dx® and EarliPointEvaluation®, which were approved by the United States (US) Food and Drug Administration (FDA) for the diagnosis of ASD in 2021 and 2022, respectively. ⁸

Table 1.

Representative digital therapeutics for neurodevelopmental diseases

Function	Target	Type	Indication	Product (Manufacturer)	FDA approval
Treatment	Cognitive function	Video game	ADHD	EndeavorRx® (Akili Interactive)	June 15, 2020
		Video game	ASD	AKL‐T02® (Akili Interactive)	None
		BCI	ADHD	RECOGNeyes® (University of Nottingham)	None
	Sociability	Mobile application	Schizophrenia	PEAR‐004® (Pear Therapeutics)	None
Diagnosis			ASD	Canvas Dx® (Cognoa)	July 2, 2021
			ASD	EarliPoint Evaluation® (Earli Tec)	June 10, 2022

CHALLENGES FOR DEVELOPING DIGITAL THERAPEUTICS FOR NEURODEVELOPMENTAL DISEASES

The development of DTx for NDDs, including ASD and ADHD, presents a distinctive set of challenges due to the intrinsic complexity and variability of these conditions. These disorders require highly personalized, adaptive interventions that are tailored to the specific symptoms exhibited by each individual, which can vary considerably. Furthermore, it is important to maintain user engagement, particularly among younger users, who may experience difficulties in motivation or attention. Rigorous clinical validation to ensure efficacy is of the utmost importance. At present, three DTx products have been approved by the FDA for use with patients: EndeavorRx®, Canvas Dx®, and EarliPoint Evaluation®. Despite the novel approach these DTx represent for the treatment of disease symptoms, the ratio of prescriptions to actual use remains low. As reported by Kelders and colleagues, the adherence or completion rate of web‐based interventions is as low as 10%; the average is 50%. ⁹ While Kelders et al.'s results do not specifically indicate the engagement rate for NDD interventions, it is reasonable to hypothesize that these rates will be similar for DTx for NDDs. To understand the challenges in effective DTx development for NDDs, we examine factors pertaining to medical professionals and manufacturers (policies, regulations, reimbursement, clinical protocols, and chronic clinical efficacy) and patients (engagement) that warrant consideration. We then present implications and future directions for revitalizing DTx development for NDDs.

Limitations of FDA regulations for the accessibility of digital therapeutics

Existing FDA regulations for DTx are not closely aligned with the rapid and dynamic nature of software evolution, underscoring the need for effective regulation and compliance by the FDA and various stakeholders. ¹⁰ A regulatory system that ensures the safety and superior quality of DTx is required. In particular, the process from prescription to implementation needs to be further streamlined for prescription digital therapeutics (PDTs), ¹¹ which are FDA‐approved software‐based interventions used to treat psychiatric diseases with reduced costs. Following the approval of its PDT EndeavorRx, Akili Interactive released EndeavorOTC, an over‐the‐counter (OTC) version that improves accessibility for users. ¹² Because EndeavorOTC does not require a prescription from healthcare providers, it offers relatively unrestricted access compared to EndeavorRx. Regulators are often reluctant to approve PDTs due to their cautious stance toward this emerging technology. The greatest barrier to DTx adoption is healthcare professionals' lack of knowledge regarding the prescription and integration of digital health apps into clinical practice. In addition, there is a gap between the actual efficacy of DTx and their practical implementation, and this disparity must be understood to enable clinical populations to effectively utilize these technologies. In the US, DTx have not yet been widely adopted in medical practice due to the implementation of insurance coverage as a form of policy support. ¹³ Wider insurance coverage would reduce costs and enhance convenience compared with the current fragmented reimbursement policies. Insurance systems must evolve alongside new technological developments, but most European countries have not shown an active interest in integrating DTx into their insurance systems. ¹⁴ In summary, the establishment of a unified model among diverse stakeholders and the implementation of standardized procedures and prescriptions through confirmatory clinical studies are necessary to enhance the accessibility of DTx. ¹⁰ , ¹³

Limitations of FDA regulations for prescribing digital therapeutics

Digital therapeutics (DTx) are a novel noninvasive treatment paradigm, and robust prescription regulations are needed to minimize adverse effects and ensure appropriate therapeutic interventions. Currently, DTx are regulated as software as a medical device (SaMD) and classified by the FDA into risk‐based categories: Class I (low risk), Class II (moderate risk), and Class III (high risk). ¹⁵ Class I and II DTx are typically reviewed through the 510(k) pathway (90‐day review time) or the de novo premarket notification pathway (150‐day review time), while Class III devices require premarket approval (PMA), a more rigorous process with a 180‐day review period. ¹⁵ Despite these classifications, the FDA's regulatory framework for DTx remains incomplete, creating gaps that affect the balance between DTx pipeline development and market surveillance. This lack of comprehensive guidelines has hindered the successful clinical integration of DTx. For instance, while DTx outcomes, such as cognitive improvements, are central to their therapeutic value, these outcomes are often subjective and difficult to standardize across diverse populations. ¹⁶ This contrasts with traditional pharmaceuticals, for which dosing and effects are typically measurable through biochemical markers.

Moreover, the FDA does not provide explicit pediatric‐centric dosage frameworks for DTx, leaving developers to independently determine age‐appropriate usage parameters. This oversight is particularly critical for pediatric populations and neurodevelopmental use cases. As an example of how regulatory surveillance impacts DTx accessibility and uptake, when Akili Interactive Inc. transitioned EndeavorRx®, the first FDA‐approved DTx for ADHD, from a PDT to OTC, it did not include specific provisions for pediatric and neurodevelopmental use cases, leaving critical gaps in addressing the unique needs of these populations. Another significant challenge for DTx is ensuring patient adherence to prescribed usage, which is more difficult than enforcing compliance with traditional medications. This issue is particularly pronounced in pediatric populations with NDDs, for whom caregivers play an essential role in facilitating and monitoring therapeutic engagement. These challenges highlight the need for a more comprehensive regulatory framework to support the safe, effective, and equitable adoption of DTx across all populations.

Reimbursement for digital therapeutics

Reimbursement for DTx is a complex and evolving issue that is influenced by various factors, such as evidence of effectiveness, regulatory pathways, and stakeholder attitudes. A significant hurdle in DTx reimbursement is that regulatory requirements vary by country, which may negatively impact the global market utilization of a DTx. Another major issue for DTx reimbursement is the need for robust evidence of a device's effectiveness as a prerequisite for coverage. For instance, the early experience of the Massachusetts Medicaid program with prescription DTx demonstrated that efficacy and safety are critical criteria to secure reimbursement, thereby suggesting a roadmap for evaluations of the value of DTx by payers and policymakers. ¹⁷ In Germany, DTx care apps for conditions such as nonspecific low back pain (LBP) are reimbursed by statutory health insurance, as analyses have shown that these apps are more cost‐effective than traditional treatments, despite higher initial costs and high attrition rates. ¹⁸ Collectively, these reports indicate that long‐term outcomes and attrition rates are critical factors in reimbursement decisions.

Necessity for clear clinical protocols to validate digital therapeutics' efficacy

The development of DTx has progressed significantly over the past decade, positioning DTx as promising treatments for a wide range of diseases, including NDDs, neurodegenerative diseases, psychiatric diseases, and metabolic syndrome. Clinical evidence of therapeutic efficacy is essential for DTx development, and thus well‐developed clinical protocols are needed to certify DTx as reliable therapeutic devices. First, clinical trials for DTx should consider how patient adherence and data collection methods can influence outcomes. Critical considerations for data accrual/assessment include the Hawthorne effect, biases from repeated assessments, and disease progression over time, and statistical regression to the mean should be controlled. ¹⁹ Second, clinical protocols for DTx should clearly outline safety assurance. Primary safety issues for mobile apps include inaccurate or misleading information, erroneous clinical calculations, and diagnostic errors. ²⁰ These risks underscore the necessity of proper regulatory oversight to mitigate patient safety concerns. Finally, clinical protocols for DTx should consider the delivery method and design of training content. The clinical efficacy outcomes of cognitive behavioral training (CBT) have been shown to vary depending on the delivery method. Specifically, two types of digital CBT (telephone‐delivered CBT (TCBT) and web‐based CBT (WCBT)) lead to significantly greater improvements in primary and secondary outcomes compared with face‐to‐face CBT. ²¹ However, the primary outcomes also differ significantly between TCBT and WCBT, indicating that selecting an appropriate delivery mechanism based on therapeutic context is critical for clinical efficacy. ²¹ In sum, comprehensive clinical protocols for DTx are essential for optimal validation of DTx efficacy and demonstrating that DTx are innovative and reliable therapeutic tools.

Promoting patient engagement with digital therapeutics

For conventional medications, pharmacological target engagement (i.e., the drug delivery system) is the predominant aspect of therapeutic efficacy for patients. However, the sustained use of DTx depends on the user experience offered by the device, and thus technical engagement and behavioral engagement are factors that must be considered for successful treatment. With respect to technical engagement, therapeutic serious games (TSGs), which integrate learning/informative strategies and entertainment elements, are regarded as an engaging way to rehabilitate patients with NDDs. ²² Specifically, TSGs and exergames (TSGs incorporating physical exercise) have been shown to improve cognitive, social, and motor skill functions in adolescent patients with ASD, ADHD, Down syndrome, or fragile X syndrome. ²² However, TSGs may have adverse effects on eyesight and addictive potential. In terms of patient behavioral engagement, self‐reported feedback (user satisfaction) can provide information on adherence, and effectiveness should be validated by clinical data (e.g., ECG, EEG, electrode activity, etc.). Overall, user experience is an essential factor for developing DTx that can overcome the patient engagement barrier and provide therapeutic efficacy.

IMPLICATIONS FOR REVITALIZING THE DEVELOPMENT OF DIGITAL THERAPEUTICS FOR NEURODEVELOPMENTAL DISEASES

Metrics for DTx efficacy of NDDs are predominantly related to noninvasive behavioral biomarkers, including cognitive function and social function, and specific invasive metrics for NDDs have not been identified. For example, imbalanced dopamine (DA) signaling is a predominant symptom of ADHD, and hyper‐ and hypo‐insulinism have been linked to the pathogenesis of schizophrenia, leading to the development of pharmacological interventions regulating/targeting DA or insulin signaling, respectively. However, the dosage and frequency of administration of these medications must be optimized to avoid disrupting DA and insulin homeostasis, which are critical for various intracellular signaling pathways. Furthermore, these medications alone may not sufficiently regulate the primary and secondary symptoms of ADHD. Combination therapies comprising pharmacological interventions and DTx might be a strategic solution to this gap. However, the modes of action and primary endpoint outcomes of these two interventions must be compared to optimize their combination.

Comparative efficacy of digital therapeutics and conventional drugs for NDDs

There are distinct differences in mode of action and primary endpoint outcomes between pharmacological treatments and DTx. Specifically, conventional drugs activate or inhibit their specific on‐targets, leading to changes in related intracellular signaling cascades and therapeutic effects, whereas DTx target specific symptoms of chronic diseases via evidence‐based software. ⁶ , ²³ Primary endpoint outcomes for DTx mainly focus on clinical outcomes (e.g., primary symptoms, including behavioral and phycological indicators), patients' reported outcomes (adherence/compliance, engagement), and technical outcomes (accuracy and stability of DTx). By contrast, outcomes for traditional pharmacological interventions prioritize non‐invasive behavioral symptoms and invasive biochemical markers. ¹⁶ Despite their differential therapeutic efficacies, both DTx and conventional interventions aim to improve an individual's health outcomes, and combinations of DTx and pharmacological drugs might exhibit synergistic efficacy. DTx might enhance or complement conventional treatments, ultimately resulting in more effective treatments for NDDs.

Combination therapies of digital therapeutics and conventional drugs for NDD

The primary advantages of DTx include their accessibility, minimal side effects, and capability of continuous patient monitoring. In addition, DTx offer personalized therapeutic interventions tailored to an individual's condition and can augment patient‐centered care when integrated with conventional treatments. Combining DTx with existing pharmacological therapies has been shown to enhance clinical efficacy, improve safety profiles, and increase patient adherence to treatment regimens. For instance, combining medication and AKL‐T01, a DTx for inattention in ADHD, resulted in greater improvements in academic outcomes for patients with ADHD compared to medication alone. ²⁴ Consequently, combining DTx and conventional drugs might be the most effective way to ameliorate invasive biomarkers and noninvasive behavioral impairments in patients with NDDs. Conventional drugs with different targets often exhibit synergistic therapeutic effects when administered together, and it is possible that combination therapies comprising a conventional drug that targets invasive pathological factors and a DTx that selectively regulates noninvasive symptoms will achieve significant synergism.

CONCLUSIONS

The digital transformation (i.e., AI and XR) of therapeutics may pave the way for DTx as a novel theragnostic strategy for NDDs. DTx can provide new diagnostic and therapeutic strategies for data‐driven and personalized care of patients with NDDs. The design of DTx should be user‐centric, and efficacy must be validated based on clear clinical protocols. Furthermore, clear guidelines regarding the prescription and reimbursement of DTx are required for the active deployment of DTx in the global market. DTx for NDDs will be most successful if they are developed for use in conjunction with conventional drugs to achieve synergistic therapeutic efficacy and minimize adverse effects (Figure 1 ).

Figure 1.

Summary illustration of challenging factors in the development of digital therapeutics for neurodevelopmental diseases.

FUNDING

This work was supported by the Korea Brain Research Institute (KBRI) basic research program through KBRI funded by the Ministry of Science, ICT & Future Planning (grant numbers 24‐BR‐02‐03, 24‐BR‐04‐02 and 24‐BR‐03‐05, H.S.H.) and the National Research Foundation of Korea (grant number RS‐2024‐00357857, H.J.L.). This work was also supported by the Korea Ministry of Science and ICT's Special Account for Regional Balanced Development for Commercialization supervised by the NIPA (National IT Industry Promotion Agency) to support AI‐based digital medical devices for neurodevelopmental disorders (H0301‐24‐1001).

CONFLICTS OF INTEREST

The authors declared no competing interests for this work.