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Dr. Rakesh Jain on Nonstimulant Treatment Options for Pediatric ADHD

February 18, 2021

In this video, Psych Congress Steering Committee member Rakesh Jain, MD, MPH, discusses an article he cowrote on nonstimulant treatment options for pediatric attention-deficit/hyperactivity disorder (ADHD). The paper, which summarizes both currently available treatments and those under development, was recently published in CNS Spectrums.

Read the transcript:

Hello, dear colleagues, this is Rakesh Jain, clinical professor at Department of Psychiatry at Texas Tech University School of Medicine, in private practice in Austin, Texas, and a proud member of the Psych Congress Steering Committee.

Earlier this year in 2021, me and several other colleagues published an article in the CNS Spectrums. I'm looking forward to telling you more about it. The title of this paper is “Current and Future Nonstimulants in the Treatment of Pediatric ADHD: Monoamine Reuptake Inhibitors, Receptor Modulators, and Multimodal Agents.”

Four of us cowrote the article: Andy Cutler, Greg Mattingly, myself, and Welton O'Neal. If you wish to read this paper for yourself, it is available as a free download by going to this website. You can enter either this citation or the DOI number I have put on the screen for you.

As we look at the abstract of the paper, we clearly and quickly establish that ADHD is the single most common neuropsychiatric disorder. While we do have 30 classic Schedule II stimulant preparations for the treatment of this condition, we only have 3 nonstimulant medications available so far.

We also appreciate that the heterogeneity and the complex nature of ADHD in most patients does require even more treatment options. We therefore examined the pipeline for ADHD medications, particularly those in relatively advanced development so that we can provide clinicians an update on what might be coming soon.

A Summary of ADHD Treatment Options (2:06)

While I and my coauthors certainly hope you have a chance to read the full article, this chart summarizes admirably, in terms of what we already have and what might be coming.

Atomoxetine, a norepinephrine reuptake inhibitor, is already available and approved. Dasotraline, which is a dopamine and norepinephrine inhibitor, did have positive studies, but it did run into some challenges with FDA approval. We do not expect it to come to clinical practice.

Centanafadine sustained‑release, which is a norepinephrine, dopamine, and serotonin transporter inhibitor, has had successful phase 3 trials. We are hoping very much to see it in clinical practice in time. There's, of course, another molecule that is also a monoamine inhibitor called OPC‑64005 that also appears to be a triple reuptake inhibitor, but we don't know much about it.

In terms of receptor modulators, we have 2 medications, clonidine extended‑release and guanfacine extended‑release, that are both approved by the FDA for the treatment of children who are 6 years of age or older.

Then, we have multimodal agents. Vortioxetine, which has already been approved in the United States for major depression, has been studied in ADHD, but the results have been somewhat challenging. Our belief is it most likely will not come to fruition.

Then, there's, of course, mazindol controlled‑release, which has, as you can see, a pretty significant multimodal range of activities. We anxiously await the arrival of more data.

Finally, we have viloxazine extended‑release, which is a norepinephrine inhibitor, though a weak one, and has direct activities on several serotonin receptors, as you can see, including a modulator of 2 of the norepinephrine receptor family. This has indeed completed phase 3 trials in pediatric patients with ADHD, and we expect to see this medication potentially as an option for our children with ADHD.

This chart hopefully gives you a good picture of what we already have and what we anticipate might be coming down the pipeline in due course.

Chemical Structure of Nonstimulant Medications (5:04)

We, the coauthors, thought that you might also like looking at the chemical structures of these various nonstimulant medications. You have had a chance to look at their receptor pharmacology, which demonstrates they are very different from each other. But also, structurally, there are major differences.

We encourage you to look at the structural differences amongst the monoamine reuptake transporter inhibitors—the atomoxetine, dasotraline, and centanafadine class. Same is true for clonidine, guanfacine in the receptor modulator class.

Finally, in the multimodal agent class, vortioxetine, mazindol, and viloxazine, all three nonapproved medications, are structurally very different.

We, the coauthors, thought these structural differences will end up being potentially clinically useful, because different mechanisms of action could only mean that we could serve a greater percentage of our patients who might be either underserved by their current treatment or may be having side effect challenges. We believe that diversity is a significant positive.

In this paper, we very importantly address the issue of “Why do we need more options to Schedule II stimulant medications in the treatment of ADHD?” Obviously, these stimulant medications are highly effective. There's no question about that. But even with their great effectiveness, they only, at best, serve the needs of about 70 percent of our patients. What about the rest?

Additionally, there are side effect issues many of these patients have. What about them? Also, what if patients have worries about diversion, addiction, insomnia, weight challenges, mood difficulties, anxiety, tics, just to name a few?

We thought even though stimulants are surprisingly and thankfully very effective, there is a very clear need to have more treatment options besides the stimulant medications for the treatment of ADHD.

Therefore, we offered this paper with a strong desire to offer you a lay of the land as to what is currently available in the world of nonstimulants and what we hope and expect will be available in the near future.

We, the coauthors, thank you very much for your interest on the topic of current and future nonstimulants in the treatment of ADHD. This is Rakesh Jain wishing you and your patients the very best. Goodbye.


Cutler AJ, Mattingly GW, Jain R, O'Neal W. Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents. CNS Spectrums. 2020:1-9.

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