Centanafadine For Comorbid ADHD and Anxiety: Talking New Data With John Kraus, MD, PhD

Centanafadine (Simtriyo), a first-in-class norepinephrine, dopamine, serotonin reuptake inhibitor and central nervous system stimulant, was approved by the US Food and Drug Administration (FDA) for treatment of attention-deficit/hyperactivity disorder (ADHD).¹ Because ADHD carries substantial rates of comorbid anxiety disorders, particularly among young adults, a phase 3b trial evaluated centanafadine in 315 adults with ADHD and comorbid generalized or social anxiety disorder.² The trial met its primary endpoint, with centanafadine producing a 5.87-point treatment difference over placebo on the Adult ADHD Investigator Symptom Rating Scale, and its key secondary endpoint, with a 1.92-point treatment difference on the Hamilton Anxiety Rating Scale.^3,4 Centanafadine's serotonergic activity, in addition to its dopaminergic and noradrenergic effects is thought to offer an alternative to traditional stimulants. John Kraus, MD, PhD, discussed these findings and their implications with Psychiatric Times as the new data is shared.

Psychiatric Times: What do clinicians need to know about the phase 3b data on centanafadine (Simtriyo) for comorbid ADHD and anxiety?

John Kraus, MD, PhD: Centanafadine was recently approved by FDA as a first in class norepinephrine, dopamine, serotonin, reuptake inhibitor and central nervous system (CNS) stimulant for the treatment of ADHD. What we do know in thinking about unmet needs in this population, particularly in the young adult population, is there are substantial comorbidities with this disease, including anxiety disorders.

So we sought to assess whether patients, adult patients with ADHD and comorbid anxiety disorder, either generalized anxiety or social anxiety disorder, could, number 1, obtain benefit in their ADHD symptoms from centanafadine (Simtriyo). And number 2, whether there could be an impact on their anxiety symptoms, given the novel mechanism of this drug, as compared to a traditional CNS stimulants for example. That was the primary impetus for this, to see if we can meet the unmet need, not just of the ADHD symptoms, but with the comorbid anxiety symptoms.

What we did see in the study, not unexpectedly, was that the ADHD symptoms, and this is measured by a score called the AISRS (the Adult ADHD Investigator Symptom Rating Scale). We've used this in our other adult studies of centanafadine and have found a good effect. In this study, we also saw a positive primary endpoint with a difference between drug and placebo: a fairly good effect size of minus 5.87 points.

So very highly significant from a statistical standpoint, but more importantly, clinically meaningful. We had a key secondary endpoint in this study, and this was the Hamilton Anxiety Rating Scale (HAM-A), which has a list of a number of symptoms associated with anxiety disorders.And in that assessment, we also found a statistically significant and clinically meaningful treatment difference of 1.92 points in this patient population. So not only did ADHD have efficacy, but we had efficacy in terms of improvement of anxiety symptoms in these adults with ADHD. And that's important because certain stimulants, for example, the traditional amphetamine-based stimulants, and even, you know, if you're treating anxiety disorders themselves, certain SSRIs can actually, at least initially worsen anxiety symptoms. So we were very pleased to see in this population an improvement in both symptoms.

PT: If you were to highlight 1 or 2 items from the most recent data for the practicing clinician, what things should be keeping in mind as they're watching the development of this research?

Kraus: I think the first point is that we really need to think about mental health disorders, psychiatric disorders as having comorbidities. And this reflects a more real world population of patients with ADHD, with comorbid anxiety.

But we also know, particularly as persons with ADHD age and their lives become more complex, relationships become more complex, certain symptoms also become more important. One of these is executive function. This is kind of the ability to plan, organize, have a sense of trying to ensure that your kind of path and plans are going forward, that can be disrupted in ADHD. And we saw in this study, as we have in other ones, positive effects on executive function as compared to placebo. Additionally, there's something called emotional control, so you can have some emotional liability, you know, quick to have certain moods and emotions that can be part of this disorder as well. We saw also positive effects in this subscale, in addition to, of course, the typical ADHD type symptoms.

So I think this population is probably closer to what you might see in the real world with comorbid anxiety. But we also looked at those symptoms that can be quite disruptive, particularly as your life gets more complicated as you age. So we are pleased to see we were able to reproduce those results as well in this population.

PT: Thinking about how centanafadine works biologically, how is it thought to function in addressing both the anxiety and the ADHD?

Kraus: That's a very good question, and it'll be speculative. We have a mechanism of action that is unique. It'll be the first compound, norepinephrine, dopamine, serotonin reuptake inhibitor approved, although these have been studied for many years.
And I think the kind of novelty in how we approach centanafadine was to assess it in a population where these types of drugs have not been evaluated. And we do know that dopamine reuptake inhibition, for example, can be quite effective in core ADHD symptoms.

Same with norepinephrine. But the serotonin component may actually contribute to some of the findings we're seeing here today in terms of the anxiety, as well as in terms of the other symptoms that I spoke about, including emotional dyscontrol. However, I have to stress that's speculative, because when we talk about mechanism of action, We talk about what we measure approximately, which is the reuptake inhibition of these various neurotransmitters. But what happens is important in terms of over time and in those circuits where those neurotransmitters are involved. So I wouldn't claim to say that centanafadine does X and therefore we improve these symptoms. But it does make sense based on what we know about these classes of medicines individually that the combination, at least in this population, shows enhanced efficacy.

PT: How would expanded use of centanafadine help support a unique population with these comorbidities?

Kraus: Even with a disease like ADHD, where there are a number of options that have been available for years, and indeed many patients benefit from their current options available, there's still substantial unmet need in this disorder, particularly around targeting those comorbidities, as well as those symptoms of ADHD that may not be as well treated.

So ideally, what we do when we develop any drug at Otsuka is really identify that there is still significant medical unmet need. Do we have a different or novel approach that may meet that unmet need—something unique that we can contribute? And that led to the investigation of centanadadine. I look at this as the ability to give clinicians and patients more choice for their treatment of ADHD.

Potentially a broader population may benefit, including those with comorbidities, maybe helping simplify their medical treatments over time. And again, I highlighted a bit that in late adolescent to early adulthood, where life gets more complicated (starting new work, school, etc), it's a lot different than when everything may have been handled by someone else when you're younger. Having an option for those adults is important. It is also important that there are options that aren't necessarily traditional stimulants, like amphetamines, because some patients do want to avoid those and some parents want to avoid those as well. So the bottom line is we are trying to address the unmet need by having an approach that is novel and providing more choices for clinicians and patients.

And I want to emphasize that it's not a small subset of ADHD that has these comorbidities. It's actually a large subset of patients that suffer from this. And again, one medicine doesn't work for every patient every time, but having those choices available is incredibly important. I believe Simtriyo (centanafadine) will represent a great option for the right patients in consultation with their prescribers.

Dr Kraus is executive vice president, chief medical officer at Otsuka Pharmaceutical Companies.

References

1. Walters J. FDA approves centanafadine for ADHD in children, adolescents, and adults. Psychiatric Times. July 24, 2026. https://www.psychiatrictimes.com/view/fda-approves-centanafadine-for-adhd-in-children-adolescents-and-adults

2. Walters J. Positive phase 3 data for centanafadine to treat comorbid ADHD and anxiety. Psychiatric Times. July 1, 2026. https://www.psychiatrictimes.com/view/positive-phase-3-data-for-centanafadine-to-treat-comorbid-adhd-and-anxiety

3. Strawn JR, Hebert C, Childress AC, et al. Executive function and behavioral regulation in adults with ADHD and comorbid anxiety disorders treated with centanafadine: results from a phase 3b trial. Poster presented at: Psych Congress 2026 Annual Meeting; September 15-19; New Orleans, LA. Accessed September 18, 2026.

4. Hebert C, Childress AC, Strawn JR, et al. Efficacy and safety of centanafadine in adults with ADHD and comorbid anxiety disorders: a randomized, double-blind, placebo-controlled trial. Poster presented at: Psych Congress 2026 Annual Meeting; September 15-19; New Orleans, LA. Accessed September 18, 2026.