Transforming MDD Symptom Management with a Digital Therapeutic

The intended audience for this program is healthcare professionals involved in the treatment of patients with Major Depressive Disorder.

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‍What are Digital Therapeutics (DTx)?

Digital therapeutics deliver evidence-based therapeutic interventions through software programs that prevent, manage, or treat medical conditions. Unlike wellness apps, DTx are designed to be clinically validated and are evaluated and authorized for marketing by the FDA. They can function as standalone treatments or complement conventional therapeutics such as medications.¹

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These interventions include smartphone applications, web-based platforms, and interactive programs designed for specific therapeutic purposes. For mental health conditions, digital therapeutics provide targeted interventions through technology patients already use daily. For example, patients can access therapeutic content between clinical appointments, potentially enhancing treatment continuity and engagement.¹

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‍Rejoyn®: The First and Only FDA-Authorized Prescription Digital Therapeutic for the Treatment of MDD Symptoms

Rejoyn is the first prescription digital therapeutic authorized by the FDA to treat the symptoms of MDD.^2,3 Rejoyn is indicated for adult patients with MDD age 22+ who are on antidepressant medication.² Unlike wellness apps, Rejoyn is a regulated medical device that has undergone FDA review.³

The Neurobiology Behind the Intervention

Depression may involve disrupted connectivity between brain regions responsible for cognitive control and emotional regulation. Hypoactivity in the prefrontal cortex, the brain region involved in working memory and cognition, coupled with hyperactivity in the amygdala—which is responsible for emotional processing—may account for the emotional and cognitive symptoms of MDD. This dysregulated corticolimbic circuit provides a specific target for intervention.^4,5
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From Neural Circuit Theory to Digital Therapeutic Using Cognitive-Emotional Training (CET)

Researchers developed the Cognitive-Emotional Training (CET) approach to simultaneously engage the prefrontal cortex and amygdala—the key nodes in the disrupted corticolimbic circuit. This training activates the amygdala by having patients recognize emotional expressions while engaging the prefrontal cortex through a memory task requiring recall of previously shown faces.^4,6 Dr. Jain offers a compelling analogy: "It's like going to the gym, but it's your brain going to the gym by activating both of these brain regions." This cognitive-emotional "workout" is thought to strengthen neural pathways through repeated activation, much like physical exercise strengthens muscles.
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Functional MRI (fMRI) studies support this mechanism, showing that six weeks of CET led to increased connectivity from the right prefrontal cortex to the amygdala. These neurobiological changes correlated with depression symptom reduction, providing mechanistic evidence for the intervention's effects.^7
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Based on this foundation, Rejoyn was developed as a comprehensive digital therapeutic integrating:

• Cognitive-emotional training (CET)²
• CBT-based video lessons²
• Supportive text messages²
  
  
  

Mirai Trial: Methodologies and Design

The Mirai trial (Mirai means "future" in Japanese) evaluated Rejoyn in 386 adult patients with MDD who reported inadequate response to antidepressant monotherapy.² Researchers employed several key features:

• Randomized controlled design: Patients were randomized 1:1 to either Rejoyn or a sham control (cognitive training without emotional processing), with both groups continuing their antidepressant therapy.^2,8

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• Active control comparison: The trial used a sham digital therapeutic with supportive text messages rather than waitlist controls.^2,8
• Standardized outcome measures: Researchers used both clinician-rated (MADRS, CGI-S) and patient-reported (PHQ-9) validated assessments.^2,8
• Dose-response analysis: Examined the relationship between adherence and clinical outcomes.²

Clinical Evidence: Mirai Trial Results

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Primary Efficacy Endpoint: Change in MADRS Total Score From Baseline to Week 6:

• mITT Population (primary analysis): MADRS total score decreased by 9.03 points in the Rejoyn group vs. 7.25 points in the sham group (p=0.0568).²
• ITT Population (supportive analysis): MADRS total score decreased by 8.78 points in the Rejoyn group vs. 6.66 points in the sham group (p=0.0211).²

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Other Endpoints:

• Durability of effect: Benefits persisted through the 4-week extension period (weeks 7-10) with a trend favoring continued improvement.^{2
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• PHQ-9 improvement: Patients using Rejoyn improved from "moderately severe" to "mild" depression—crossing two clinical categories. In the sham group, there was also a categorical improvement from “moderately severe” to “moderate”.^{2
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• Response rates (≥30% reduction in MADRS total score from baseline to week 6): 48.3% in the Rejoyn group vs. 37.5% in the sham group in the mITT analysis (p=0.0485).^{2
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• MADRS Anxious Subgroup: Among patients with moderate or higher anxiety symptoms (GAD-7 ≥10), Rejoyn produced a 9.01-point MADRS reduction vs. 5.39 points in the sham group (p=0.0099).^{2
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• Adherence impact: 88.1% completed at least 12 of 18 sessions.^{2
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• Safety profile: No treatment-emergent adverse events were assessed as related to Rejoyn. Most common TEAEs were upper respiratory tract infection, nasopharyngitis, and headache.²

Clinical Implementation of Rejoyn For Your Patients

Patient Education Before Prescription

Before starting treatment, patients can download the Rejoyn app from the Apple or Google Play store to access educational resources.⁹ Within the app, patients can view videos explaining how Rejoyn is thought to work, its intended benefits, and what to expect during the 6-week treatment plan.

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Prescription Process

Prescribers can submit a Rejoyn prescription through their EMR directly to CaryRx pharmacy. The pharmacy contacts patients to collect payment and provides an access code.¹⁰ Patients download the app, enter their unique code, and begin their 6-week program of CET exercises and CBT videos.^2,10

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Ongoing Support

‍Rejoyn includes built-in patient support with automatic reminders and motivational messages. Patients can also opt-in to receive proactive outreach from a dedicated support team throughout their treatment. For questions about Rejoyn, providers and patients can call 1-833-Y-REJOYN (1-833-973-5696), Monday through Friday, 8 AM to 8 PM ET, excluding holidays.^11
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Identifying Appropriate Candidates for Rejoyn

Rejoyn serves as an adjunctive treatment for adults age 22+ with MDD who:
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• Are motivated and want further improvement in their MDD symptoms^{11
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• Are interested in a different type of adjunctive MDD treatment^{11
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• Have reported an inadequate response to their current antidepressant therapy (ADT)¹¹

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As Dr. Jain emphasizes, Rejoyn "doesn't replace anything; it's just another tool" in comprehensive MDD symptom management, designed to integrate with existing treatment modalities.

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INDICATION

Rejoyn is a prescription digital therapeutic for the treatment of Major Depressive Disorder (MDD) symptoms as an adjunct to clinician-managed outpatient care for adult patients with MDD age 22 years and older who are on antidepressant medication. It is intended to reduce MDD symptoms.

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SAFETY INFORMATION

Rejoyn is not intended to be used as a standalone therapy or a substitute for medication. Patients should continue their current treatment as directed.

Rejoyn does not monitor the patient’s symptoms or clinical status and cannot send or receive alerts or warnings to the prescriber. Patients should be clearly instructed that if they believe their depression is worsening or if they have feelings or thoughts of harming themselves or others, to contact a healthcare professional, dial 911 or go to the nearest emergency room immediately.

You can view the Clinician Brief Summary here: www.rejoynhcp.com. 
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References:

1. Digital Therapeutics Alliance. (2021). Digital therapeutics overview. Retrieved from https://dtxalliance.org/wp-content/uploads/2021/06/DTA_DTx-Overview_US.pdf
   
   
2. Otsuka America Pharmaceutical, Inc. (2024). Rejoyn clinician brief summary. Retrieved from https://rejoynhcp.com/CBS
   
   
3. Otsuka Pharmaceutical & Click Therapeutics. (2024, April 1). Otsuka and Click Therapeutics announce the U.S. Food and Drug Administration (FDA) clearance of Rejoyn™, the first prescription digital therapeutic authorized for the adjunctive treatment of major depressive disorder (MDD) symptoms [Press release]. Retrieved from https://otsuka-us.com/news/rejoyn-fda-authorized
   
   
4. Iacoviello, B. M., Wu, G., Alvarez, E., Huryk, K., Collins, K. A., Murrough, J. W., ... Charney, D. S. (2014). Cognitive-emotional training as an intervention for major depressive disorder. Depression and Anxiety, 31(8), 699–706. https://doi.org/10.1002/da.22266
   
   
5. Iacoviello, B. M., & Charney, D. S. (2015). Developing cognitive-emotional training exercises as interventions for mood and anxiety disorders. European Psychiatry, 30(1), 75–81. https://doi.org/10.1016/j.eurpsy.2014.09.415
   
   
6. Neta, M., & Whalen, P. J. (2011). Individual differences in neural activity during a facial expression versus identity working memory task. NeuroImage, 56(3), 1685–1692. https://doi.org/10.1016/j.neuroimage.2011.02.051
   
   
7. Hoch, M. M., Combs, T., O'Donnell, K., Holdren, A., Frazier, P. A., & D'Zurilla, T. J. (2019). The association between emotion regulation and emotional distress in college students: A meta-analysis. Chronic Stress, 3, 2470547019877880. https://doi.org/10.1177/2470547019877880
   
   
8. Rothman, B., Iacoviello, B. M., Sheehan, J., Charney, D. S., & Murrough, J. W. (2024). Evaluating the efficacy of digital cognitive-emotional training for depression: Protocol for a randomized controlled trial. JMIR Research Protocols, 13(e56960), 1–14. https://doi.org/10.2196/56960
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9. Otsuka Precision Health. (2024). Patient instructions for use: Rejoyn. Retrieved from https://www.rejoyn.com/Patient-Instructions-for-Use.pdf‍

10. Otsuka Precision Health. (2024). Prescribing Rejoyn. Retrieved from https://www.rejoynhcp.com/Prescribing-Rejoyn.pdf
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11. Otsuka Precision Health. (2024). Patient-powered adjunctive treatment for MDD symptoms. Retrieved from https://www.rejoynhcp.com/your-patients

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March 2025   20US25EBP0025