Marking Progress, Promise of Prescription Digital Therapeutics for Mental Health: Interview with Shaheen Lakhan, MD, PhD

CLINICAL CONVERSATIONS

The investigational prescription digital therapeutic (PDT), CT-155, codeveloped by Click Therapeutics and Boehringer Ingelheim (BI) for treatment of negative symptoms in schizophrenia is in phase 3 clinical testing, after receiving Breakthrough Device designation from the US Food and Drug Administration (FDA) in 2024. Also in 2024, CT-152 (Rejoyn), a PDT codeveloped by Click and Otsuka Pharmaceutical, was cleared by the FDA to augment treatment of major depressive disorder.

Psychiatric Times discussed the state of PDT development and how these apps can advance treatment of mental illness with Shaheen Lakhan, MD, PhD, chief medical officer of Click Therapeutics. The interview was conducted May 25, 2025, and has been abridged for publication.

Psychiatric Times: Could you speak to the processes and challenges of conducting clinical trials with PDTs for mental health; particularly with the CT-155 product in phase 3 trials for negative symptoms of schizophrenia?
Shaheen Lakhan, MD, PhD: It was maybe just a few months into the collaboration, in early 2021, when the Global Head of CNS for BI, Vikas Sharma, and I kind of shared a stage and established some of the pillars of this working relationship; and the common goal was “precision psychiatry.”

I will tell you, a lot of pursuits of precision psychiatry actually neglect the patient entirely. Sometimes it is your genetics or your neuroimaging findings that dictate what treatment you get. We uniquely have the availability of something that patients already use, and they use on a regular basis. And in fact, we have published studies with 95% of people with this disease of interest—negative symptoms of schizophrenia—already having access to smart phones that carry this technology.

We wanted to flip the switch. We could design the clinical investigations and trials to use engagement metrics to keep people on task, engage with the therapy, engage with the assessments, to carry out inventories.

We decided against a full site-based recruitment approach and actually did this hybrid-type mode. Yes, there are sites, and there are principal investigators who are psychiatrists and have a good cadre of patients with negative symptoms of schizophrenia. But we lowered the lift and burden because of the digital modality and created a lot of virtual visits in what we call a hybrid design.

Now, we did not cut any corners on the robustness of trial designs. I will be the first to admit that a lot of the early-stage digital therapeutic investigations were not methodologically sound. There are many that did not have controls and were open label. When they had a control, it was not a real sham control, it was waitlist control or usual care controls, which I do not consider valid controls, particularly from a drug development lens.

If you look at our study design and pivotal trial designs, they are built to mirror contemporary drug development trials. We are talking double blinds, even triple blind designs, and hundreds of patients to ensure adequate power. The endpoints are not just about coping with the disease, they are about quality of life and disease management.

Everything that a drug company would target will become our primary endpoints: all the data safety monitoring boards and the central ratings of the primary assessment. We set ironclad, class 1 evidence generation for our phase 3 program.

We did a follow up phase 3, in which we extended and gave every patient access to a second course of therapy. With that, you ascertain durability and whether there are benefits with a second course of treatment. Additionally, we do not have to wait for post marketing.

Our partners at BI are the primary sponsors of the real-world evidence, and more pragmatic, prospective study with more self reported outcomes in less of a controlled environment. You are getting this robust evidence package that happens simultaneously, which normally in drug development gets protracted.

PT: While the efficacy of PDTs for depression can be measured in reduction of symptoms and possibly hastening of recovery, what were the measures of a PDT for the more intractable condition of schizophrenia?

Lakhan: We really wanted to design a solution that affects the majority of patients living with this element of the disease—negative symptoms. There are no approved therapeutics, be it drug, biologic, or device that targets negative symptoms in their label or in study. We would be the first if we really accomplish this.

We are targeting experiential negative symptoms. Those are the lack of motivation, leisure, and sociality that these patients exhibit. The classical positive symptoms are things that you have unfortunately gained such as hallucinations, paranoia, and disorganized thoughts. The negative symptoms are things that are lost, and current therapies do not adequately address them. It is the negative symptoms that are responsible for the majority of disability, the lack of integration to society, the inability to return to school or work, and the difficulty sustaining healthy, functional relationships.

Those are the exact targets that our mechanisms of action restore over the course of the therapy. We have finished 2 early phase studies with sizable populations, close to 100 participants each, and showed that, before we moved those endpoints, we were able to establish a bond, a rapport, a relationship that we call the digital working alliance (DWA).

There is a validated instrument for the DWA, and in the first 3 weeks, we were able to establish that. From weeks 3 to 7 in our early phase studies, we were able to maintain that. Then we were able to move our primary endpoint on the Clinical Assessment Interview for Negative Symptoms-Motivation and Pleasure (CAINS-MAP) subscale—the latest generation of inventories that holistically takes into account all the patient’s negative symptoms.

PT: Can you describe the process of individualizing the patient-PDT interface?

Lakhan: We have AI-built technology that individualizes and personalizes the daily missions, levels of difficulty, engagements, time of engagement, and the sentiment or tones in which the platform sends personalized messaging to the patients. Everything is built on that AI platform that makes it unique to that patient. Frankly, I think that is the secret sauce, because it is not like a generic app that someone just opens once and finds that it is not relevant to them. With those kinds of apps, you do not have that therapeutic alliance, bond, or rapport, and people fail to use them. Therefore, you get no positive outcomes.

What we did was capture feedback from 4 peer support specialists who have lived experience with schizophrenia, and then we assembled a 15-patient panel from individuals with a diagnosis of schizophrenia. This is before we wrote a single line of code. We tried to understand unmet needs, current usage of traditional therapies, and digital therapies. We then created a kind of a therapeutic scaffolding that led to what we are calling now a randomized controlled trial version of CT-155.

PT: Do you anticipate new roles for the clinicians prescribing PDTs, with the patient-app interface or perhaps accessing and reviewing stored data or receiving alerts from the app?
Lakhan: We are assessing what the market wants and what the prescriber wants, and those could become enhancements or commercial accessories. The current version is self contained, titrated, and dosed for the patient, provided they are diagnosed with negative symptoms of schizophrenia and attain a prescription for this PDT. It is self-enclosed for the duration of the experience, which is currently 16 weeks. However, that is why we have done repeated dosing studies. It could be represcribed, because schizophrenia, obviously, is a chronic condition with episodic manifestations.

That being said, I could imagine that there will be some use cases where information should flow back; whether it is to the prescriber, to case managers, to complex care coordinators, or more panels of patients.

These become very valuable therapeutic targets. Are the patients returning to school, work, or to family relationships? It is not just asking, “How is your mood? How are your delusions or hallucinations?” It could give the clinician objective level information on whether their patient is leaving the house and being productive at work or school, and with family or relationships.

PT: Along with the potential benefit in accessing the archived data, there are concerns with security of data. For individuals with schizophrenia, in particular, concerns can rise to paranoia about collecting and using personal and behavioral data. How are you addressing that?

Lakhan: Patient data privacy and protection are paramount, especially for vulnerable populations like those with schizophrenia. We know that building trust in our therapies is critical.

As part of our patient-centric approach to the design and development of our products, we implement data minimization and purpose limitation practices, ensuring we only collect and use the information essential for treatment. This reflects our holistic methodology, which integrates robust privacy and data protection directly into the design and operation of our technology systems, business practices, and applications.

PT: Thank you!

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.