A Digital Therapeutic (CT-152) as Adjunct To Antidepressant Medication: A Phase 3 Randomized Controlled Trial (the Mirai study)

Sponsored by Otsuka Pharmaceutical Development & Commercialization Inc., and hosts are paid consultants of Psychiatric Times and Otsuka Pharmaceutical Development & Commercialization Inc.

Dr. John Docherty: Hello and welcome to today's program. My name is Dr. John Docherty. I'm an Adjunct Professor of Psychiatry at Weill Cornell Medical College in New York. It's my pleasure to discuss the background and results of the trial published in an article titled,’ A digital therapeutic (CT-152) as adjunct to antidepressant medication: A phase 3 randomized control trial, the Mirai study’. I'm very pleased to be joined today by Desiree Matthews, a psychiatric mental health nurse practitioner who is the clinical director of Different Mental Health Practice based in Charlotte, North Carolina. This program is sponsored by Otsuka Pharmaceutical Development & Commercialization Inc., and hosts are paid consultants of Psychiatric Times and Otsuka Pharmaceutical Development & Commercialization Inc.

Dr. John Docherty: Let's begin today by discussing the current treatment landscape of major depressive disorder as well as reviewing two major persistent unmet needs in effectively treating patients who are suffering from major depressive disorder. One is access to care. The other is efficacy of treatment. Evidence-based psychotherapies and cognitive training can be used to successfully treat depression. However, use of these treatments are limited due to the cost of treatment, the lack of adequately trained therapists, and scheduling difficulties.

So Desiree, we still have a big problem with treating depressed patients. We have at least two major unmet needs, it seems to be. One is that people can't get access to care, and even if they can get the care, our care today is still imperfect. We're not getting people well enough.

Desiree Matthews: Absolutely. I think in my own clinical practice, this is what we see every day. There's not enough of me and there's not necessarily the standardization across the board for major depressive treatment in United States.

Dr. John Docherty: So if we take up an issue of access to care. First, it's a real problem. We have about a third, I think 160 million Americans, who are living in what are officially designated as mental health provider shortage areas. You just can't get a provider to provide treatment. And I was wondering if you see this come up in your own practice or hear about this from other clinicians as well.

Desiree Matthews: Absolutely. In my clinical practice, I would say a good majority of individuals that come to us, they see us via telehealth. And they are absolutely in areas where there is not access to a mental health care specialist. Many of them are being treated maybe by primary care. And if you think about even in my own geographic location in North Carolina, you're actually more likely to be forced to use an out-of-network provider if you're trying to seek out mental health care because of just the lack of specialists available that is covered under their health insurance. So it's a really big problem, not only for my geographic location, but really across the nation.

Dr. John Docherty: There are additional barriers to the evidence-based psychotherapies that we just mentioned. Even when treatment is available, access to these evidence-based psychotherapies remains limited. These therapies have significantly improved treatment outcomes for depression, but their delivery requires specialized training and strict adherence to therapeutic protocols. This further constrains the availability of qualified providers and limits the scalability of effective care.

So I was wondering if that's a problem as well, that you hear from people who are trying to get CBT or IPT or other specialized treatment who can't find a provider.

Desiree Matthews: Absolutely. I think even with the expansion and utilization now of telemedicine or telehealth, there's still not physically enough trained providers to be able to deliver the therapies that so many millions of Americans need. And then even thinking about, well, if there is somebody, are they in network? Can they afford the deductible, their copays every week? So it really adds to the burden of the client in terms of financial costs, the timely access of how much does it take in terms of time from the onset of symptoms to actually getting into the door with a specialist? There's so many confounding factors that I'm not surprised and I hear many patients have spent years since their symptoms have been occurring, but it's just taken so long to get in the door with access as well as stigma. They don't want to be seen going into the mental health center. They don't want to be seen going to the therapist's office in their community.

Dr. John Docherty: So it sounds like with our current model, we have a supply-demand mismatch that we’re just never going to solve. We really do need something more innovative.

Dr. John Docherty: Now, the other big challenge that we've got, even if we can get people to treatment, is that our treatments are imperfect still. Looking at the data we have available, it appears that with an initial antidepressant treatment with an SSRI type antidepressant, that under half of people have even a 50% reduction in their symptoms and only about a third reach remission. So the single antidepressant is not the answer, because it leaves us with a lot of people who are still quite symptomatic.

And by trying to get people there too, we sometimes use adjunctive medications or change medications, and that brings its own problems. We get problems with adherence that happens, extra side effects.

Desiree Matthews: Absolutely. I think antidepressant monotherapy, especially in specialized facilities, psychiatry, but even in primary care, using a lot of adjunctive oral medication for major depressive disorder, because their monotherapy antidepressant is simply not enough. If you tell somebody, hey, I can get you just 50% better, they're probably going to walk out my door and find somebody else, because truly this is just not acceptable for most people. The residual symptoms of MDD are very impactful to clients, their families, their work lives, so absolutely we have a concern in terms of efficacy, and I think that's why people are reaching to adjunctive treatments, to taking multiple antidepressants at the time, trying to get into therapies such as cognitive behavioral therapy. Absolutely, all hands on deck, and then you mentioned remission. I think that's something we don't talk enough about in the mental health community.

Dr. John Docherty: So finding another way to supplement the delivery of psychotherapy would be very, very helpful.

Dr. John Docherty: The critical question we face now is, how can we improve treatment outcomes and expand access to effective care? An exciting approach towards addressing current unmet needs in the treatment of MDD is the development of Prescription Digital Therapeutics. These are digital mental health treatment applications that combine the therapeutic advances in evidence-based psychotherapies and cognitive training, and the technological advances in digital applications. Unlike unregulated mental health apps that have flooded app stores, Prescription Digital Therapeutics are clinically tested, evidence-based, and cleared for medical use by the FDA, providing a new, scalable, and accessible form of evidence-based treatment.

Desiree Matthews: That's a great point. I think as a clinician when clients come to me, a lot of times we say, oh, Desiree I have this app, it helps with my mood, or maybe it's helping with my sleep. But it's hard for me sometimes because there's so many out there. How do I as a healthcare provider vet these when they're not maybe gone through the clinical trial process? It's hard for me to say, hey, yes, this is safe and effective. Not to mention data and privacy concerns. Where is this data going? Who can see it? So it's nice to be able to take a look at vetted applications software to deliver treatment because I'm able to critically evaluate the efficacy, safety, and of course, I'm thinking about the durability of effect. How long may this help our patients?

Dr. John Docherty: Very important to put some evidence to this treatment.

Desiree Matthews: Absolutely.

Dr. John Docherty: Prescription Digital Therapeutics may show promise as an adjunctive treatment antidepressant therapies for treatment of MDD. Their potential for remote administration may help improve treatment access. The inherent standardization of digital formats ensures fidelity to evidence-based therapy. And it offers an option for patients who would prefer to minimize pharmacological treatment and the risk for drug-related adverse events.

Desiree Matthews: I love what you mentioned, standardized. It's consistent, but it's also scalable, and even for me in specialty care, it's scalable. We can potentially get this intervention without a delay. No need for referrals, and something that is flexible and convenient for the patient. They're not having to show up in front of our door, especially thinking about my smaller communities. They don't have to show up with a psychiatrist or a therapist. They can do it in the privacy of their own home.

Dr. John Docherty: Today, we will be reviewing the data associated with CT-152, which is authorized by the FDA for the treatment of major depressive disorder symptoms in adult patients with major depressive disorder ages 22 years and older who are currently on antidepressant medication.

The FDA cleared CT-152 based on these results, but first I'll give an overview of CT-152 and its offerings.

Dr. John Docherty: So this is a treatment intervention that looks at MDD according to the model of MDD as a disorder of connectivity, functional connectivity between higher order cortical parts of the brain and underlying limbic structures, specifically between the prefrontal cortex and the amygdala. So it is consistent with the evidence that in depression, there is a weakening of that emotional regulatory control of higher order cortical functions over emotional activation.

CT-152 is a smartphone app that comprises three components, which are cognitive-emotional training with the Emotional Faces Memory Test, or EFMT; cognitive behavioral therapy or CBT-based lessons; and third, personalized text messages.

The CT-152 intervention is thought to address both neural and behavioral levels through a combination of cognitive training exercises and CBT-based psychotherapy lessons and exercises.

The cognitive-emotional training intervention is called the Emotional Faces Memory Test. It is designed to restore and strengthen cortical control of amygdala activation by using a working memory task that links activation of the amygdala with the prefrontal cortex.

The patient is shown a sequence of faces expressing one of four emotions: happiness, sadness, surprise, and disgust. The patient is asked to determine whether the emotion depicted is the same or different from an emotional face shown N times back in the past of increasing difficulty; that is, having to remember further and further back.

Thus the EFMT is designed to advance cognitive control over emotional information processing.

The idea is that you are by doing this simultaneously activating emotion. And you are also activating through the working memory test, which is the executive function, we're activating the higher order prefrontal cortex. So it's a very cool way of forcing that connection. We reinforce that.

Dr. John Docherty: The CBT based intervention is offered through 18 animated video sessions that are each two to five minutes long, which are reinforced through additional written lessons and out-of-app activities. These lessons include behavioral activation, goal setting, cognitive restructuring, distress tolerance, and relapse prevention. The CBT-based lessons are designed to help patients to learn to better control emotions and behavior and to rework negative thought and behavior patterns. The EFMT and CBT-based lessons are both thought to influence emotional regulation through neural and behavioral modifications. Together, these modalities may alter the neural connectivity between higher order cortical areas and limbic structures, which are compromised with MDD. Finally, personalized texts, which are the third component of CT-152, send reminders and reinforcements to patients to help support the lessons and engagement.

Desiree Matthews: Thank you so much for that overview. When I think about this all together, it's really a nice package for individuals potentially looking to help treat their major depressive disorder symptoms along with their oral antidepressant. But we are getting it to them really probably in a more timely manner and also in a way that they can engage at home on their own schedule. Because I think with any treatment, patients have to be willing to engage with it. And I think a lot of our patients, they tend to be very busy. Maybe they don't want to necessarily take other medications. So I think for a lot of my clients, this can be a really meaningful way to engage with another formative adjunctive therapy really on their own time.

Dr. John Docherty: Now that we have a basic understanding of CT-152, Desiree Matthews will introduce the Mirai trial.

Desiree Matthews: Thanks for that overview on CT-152, Dr. Docherty.

The Mirai trial, a Phase 3 study, investigated the effectiveness and safety of CT-152 and was multi centered, randomized, blinded, and sham controlled. The trial was conducted remotely and lasted a maximum of 13 weeks. It's comprised a screening period of up to three weeks in duration, a six-week treatment period, and a four-week extension period.

So let's take a look at some of the screening criteria. So this was some important inclusion criteria. So these are all adults, 22 to 64, they had to be diagnosed with major depressive disorder, and they had to have an inadequate response to a six-week course of a single antidepressant medication.

Inadequate response was defined as less than a 50% decrease in depression symptom severity following administration of an antidepressant at a minimum therapeutic dose over six weeks or more. Patients also had to be fluent in English, possess a smartphone, and successfully complete a training module.

These patients were required to have a score of 18 or greater on the 17-item Hamilton rating scale for depression

Key exclusion criteria included patients who had experienced an inadequate response to more than one antidepressant within the current episode, previous psychopharmacological augmentation therapy for depression, psychotherapy within the past 90 days, and a lifetime diagnosis of schizophrenia or bipolar disorder.

The treatment period involved engagement with CT-152, which included the components previously described or a sham app that used Shapes Memory Task, or SMT, which was a working memory task intended to invoke neutral emotions matched for the time and attention to EFMT; and which also included personalized text messaging. The extension period explored the durability of effect by giving participants in the CT-152 group access to previous CBT-based lessons, and both groups continued to receive supportive text messages. During this time, participants could not access EFMT or SMT.

Desiree Matthews: But let's talk about the primary endpoint. So this was in total maximum of 13 week trial. It was done remotely, and the primary endpoint was the change in the MADRS score from baseline to week six. But there was also a lot of other endpoints that were collected, including the change in CGIS, the PHQ-9, which I think clinically, especially for me, is really helpful because we use the PHQ-9 in clinical practice. MADRS tends to be more in research studies, so I was happy to see the PHQ-9 data included. Also the GAD-7, that's something clinically we use a lot as well as the WHODAS, the EQ5D-5L, and we also look at the MADRS change in terms of partial response, full response, and then remission rates at week six.

Desiree Matthews: For the purpose of today’s discussion, we will focus on the key depression outcomes. 386 patients met eligibility criteria and were randomized 1:1 to receive either CT-152 or the sham app as adjunctive treatment. The primary efficacy was assessed in the modified intent-to-treat group, comprising the 354 participants who have received one or more treatment sessions, plus a MADRS assessment at baseline and at least one MADRS assessment following baseline.

177 patients met the mITT criteria in both the CT-152 and sham app groups. In supportive analysis, the intent-to-treat sample included 386 randomized participants.

The demographics of the CT-152 and sham app groups were similar across both the ITT and mITT analysis sets, with groups being majority female, over 85%, and mostly white, 78%. The mean age of the participants was 42.6 in the ITT group and 42.4 in the mITT group. Similarly, the average baseline scores were similar across treatment groups and analysis settings, with a MADRS total score around 28.5, a PHQ-9 score around 15.3, a CGI-S score of 4.3, and a HAM-D17 around 22.6.

So if you look at the baseline psychiatric evaluation scores, these patients were across the board what we would consider moderately depressed. So this really looks a lot like the type of depression that I see in practice.

Now, Dr. Docherty will review the efficacy outcomes.

Dr. John Docherty: Well, the results were really very reassuring actually with this study. If you look at the study from the combined outcomes, I think there's a consistency of support for the superiority of CT-152 in terms of the various measures that we use.

Findings from the primary endpoint in the modified intent-to-treat sample showed the mean MADRS score change from baseline to week six was -9.03 in the CT-152 group compared to -7.25 in the sham group, with a difference between the groups of -1.78. The p-value was equal to 0.0568.Supportive analysis of that endpoint in the intent-to-treat sample showed that between group differences in MADRS score at week six to be -2.12 in favor of CT-152 with a nominal P-value equal to 0.0211.The slight difference between the modified intent-to-treat and intent-to-treat results were likely due to the greater statistical power to detect a significant difference allowed by the 10% larger size of the intent-to-treat group.Additionally, overall, a greater percentage of patients in the CT-152 group experienced a partial or full MADRS response at week six than those in the sham group, at 48.3% versus 37.5%, respectively. I would also like to note that these improvements from baseline showed durability of effect with continued improvement in MADRS total score during the extension phase. At week 10, the mean MADRS score change was -10.96 for the CT-152 group and -9.93 for the sham group, with a difference between groups of -1.03.

Dr. John Docherty: Now, in looking at both patient and clinician-reported outcomes, similar improvements were observed with the change from baseline to week six in the PHQ-9 and the CGI-S scores.Participants in the CT-152 group showed greater improvement from baseline than sham at six weeks on the PHQ-9 score, with the CT-152 group improving by 6.68 points, compared to 5.10 points in the sham app group, and had a nominal p-value equal to 0.0029.

For clinician-rated outcomes measured by the CGI-S score, the CT-152 group also demonstrated greater improvements at week six compared to the sham app group, with the reduction of 1.06 versus 0.8 respectively, with a nominal p-value equal to 0.0098. Now that we've covered the effectiveness data, let's move on to the safety data.

Desiree Matthews: Throughout the study, there were no severe TEAEs, no discontinuations due to TEAE, and no deaths. One serious TEAE, a transient ischemic attack, occurred in the CT-152 group during the extension phase, but was deemed unrelated to CT-152. Overall, TEAEs were experienced by 20.6% of patients during the treatment period and 10.5% of patients during the extension period. Notably, TEAE incidence was numerically lower in the CT-152 group. The most common TEAEs during the treatment period were upper respiratory tract infection, nasopharyngitis, and headache. None of the TEAEs that occurred throughout the study were assessed as being associated with CT-152.

Dr. John Docherty: That's terrific. Those safety findings are really important because there are a lot of people who are afraid of taking another antidepressant because they're worried about side effects. So the safety profile is really very, very important because of really reassuring results.

Desiree Matthews: And then so we talked about the TEAEs for the Mirai trial, but I think beyond that, thinking about patient engagement and satisfaction with CT-152, I think that's a really important thing when I'm thinking through clinically, what is the patient experience going to be? Because with most things, if individuals don't have a positive response, maybe the app is hard to use. Maybe they don't feel like it's beneficial. How likely are they going to do in terms of engagement, adherence with medication, adherence with digital therapy? Very important.

So let's take a look at what the trial showed. We see here that participants in general had a positive or extremely positive result in terms of satisfaction with treatment. They found the notifications, the push notifications to be helpful as well as the personalized daily text message, and the majority of individuals did recommend others to get the app.And on the flip side, in terms of the healthcare provider experience, also high satisfaction in terms of it's easy to install. So that's a plus, especially for people maybe not so technically inclined sometimes. Maybe that's me. So it is fairly easy to install. And then thinking about just how convenient it is to deliver this type of adjunctive treatment, most healthcare providers thought that it was convenient. So this is really nice and kind of helps support the data, not only the efficacy data, the safety data. This gives another lens in terms of the treatment experience both on the patient and the healthcare providers.

Dr. John Docherty: So the fact that you've got this level of satisfaction is very reassuring. Even this app won't work if people don't use it.

Desiree Matthews: Exactly.

Dr. John Docherty: So that is very, very reassuring.

Dr. John Docherty: That brings us to the conclusion of this study.

This is a very important study. I really do think it's a landmark study, which is transformative for the field.

To summarize, CT-152 is a prescription digital therapeutic that utilizes a complementary combination of cognitive emotional training, CBT-based lessons, and personalized text messaging. It is indicated for the adjunctive treatment of MDD symptoms in patients 22 years and older who are receiving an antidepressant medication and clinical management.

This was the first FDA cleared app for the treatment of MDD symptoms.

The Mirai trial showed that patients utilizing CT-152 in conjunction with their traditional antidepressants have a numerically greater improvement in MADRS scores than patients using a sham app while also showing greater improvement in PHQ-9 and CGI-S scores. The convergent validity of these results across scales split by independent raters, patients, and clinicians indicated the benefit of CT-152 to participants in improving depressive symptoms.

There are limitations of this study to consider, including that demographics of the participants were older and majority female.The sham app may also have limited the observed treatment impact because there was an expectation of benefit by telling participants that they would receive one of the two digital therapeutic applications. Additionally, the placebo effect caused by the use of the sham app could have been another factor.Furthermore, while this clinical trial established shorter-term effectiveness of CT-152, the longer-term use of this prescription digital therapeutic is not known.Strengths of the study include the robustness of the trial, with multiple gold standard measurements and the blinding of data due to a rigorous sham control.The remote aspect of the app was another great strength, as it allowed for a greater diversity of study participants, but also reflecting a real-world scenario in which patients utilized CT-152 independently.

Dr. John Docherty: In conclusion, CT-152 is a novel digital therapeutic that reduced depressive symptoms in adults with MDD on antidepressant medication. The safety profile is showing a lack of adverse events related to the use of CT-152, supporting its use is an adjunct to clinician-managed care for adults with MDD on antidepressant therapy. CT-152 represents a safe and convenient treatment that utilizes a unique combination of cognitive-emotional, and cognitive-behavioral exercises for use in the treatment of MDD symptoms.

Dr. John Docherty: This trial and its subsequent clearance by the FDA really ushers in a whole new type of class of therapeutics. One that I think will really be very welcomed by a patient population. It's easy to use. It's easy to get to. It doesn't require changes in your schedule. And so it has, I think, just absolutely numerous advantages. And the entirely new way that it approaches the healing of the brain is really quite exciting.I think the standard that this study, the Mirai trial, has set for the field is also very important because it helps establish this new area of therapeutics as well. We can hopefully see many new treatments also, that also fall into this range of prescription digital therapeutics. But for now, I'm very happy that we have CT-152 available to help our patients who are in a moderate or moderately severe state of distress, as you pointed out, with the baseline findings from this study. So I think it's very exciting, a very exciting new development.

Dr. John Docherty: This concludes our discussion of the article titled, "A digital therapeutic (CT-152) as adjunct to antidepressant medication: A phase 3 randomized controlled trial, the Mirai study." Thank you for joining us today for this important conversation.

January 2026 US.UNB.X.26.00005