David W. Goodman, MD

Rakesh, how about other emerging studies in both pediatric and adult ADHD [attention-deficit/hyperactivity disorder] treatments? What are you most excited about?

 The world of adult ADHD researchers and clinicians has been more empowered in the last decade or so. If our excitement is being shared by our colleagues listening to us, that’s great, but be ready for even more. In fact, 3 of us—Dr Andrew Cutler, Dr Mattingly, and myself—published a paper in 

 in 2020. I encourage people to check it out. The title of that very paper is “Current and Future Nonstimulants in the Treatment of ADHD.” There are a number of them. Obviously, viloxazine is 1 we have our eyes on. Centanafadine is another compound that shows great promise, with a very different mechanism of action. There are a number of other molecules in development. Our goal is to be very excited, but let’s not forget that what we have today is pretty powerful. We should focus on our accurate identification, matching the patient with the right treatment option, and using measurement-based tools. We remain very excited for what the future holds for us.

 I would add, as David also said, there are other stimulants in development. A variety of nonstimulants are in development. The 1 that’s probably going to get approval soon is viloxazine, but there are others in development. There’s a whole group of digital therapeutics in development. In these digital therapeutics, we use the world around us—digital video games, cognitive enhancers—to strengthen pathways in the brain of adults with ADHD. I have 3 trials going on of digital interventions for adults with ADHD. That’s a really promising and interesting area of the future.

Thanks to all of you for this very rich and informative discussion with my friends. Before we conclude, I’d like to get final thoughts from each of you. Are there any messages you’d like to send to our audience? I also want to thank them for caring about ADHD patients and being with us. Dr Mattingly?

 Thank you, everybody, for joining us. Thank you for the discussion. Most important, ADHD is there. We all see it. When you treat it, you make a big difference. These are the patients who walk in and they’re thankful. They’ll tell you the difference you’ve made in their job, in their family, in their marriage, at their school. Treatment makes a difference. It’s rewarding. Once you get used to this, you’ll be thankful that you dove into this field.

 I echo everything that everyone has said. What’s most important and unique about ADHD is that if you treat depression, you bring the person back to where they were. When you treat anxiety disorder, you bring them back to where they were. When you treat ADHD, you transform this person’s psychological state into a state of mind they’ve never experienced. This is an inflexion point on the trajectory of the success of their life. That’s what is unique about treating ADHD compared with some of the other psychiatric disorders.

 I’ll reflect similarly. It can be such a bittersweet story when they come in and haven’t had treatment or have been only partially treated. We watch them gain confidence and self-esteem and flourish in so many aspects of their lives. It’s rewarding for them and for me. I’ll echo what my colleagues said. Thank you all for having me.

 Here is a good way to look at it. It’s the best of times, and it’s the best of times. There’s nothing negative to talk about in terms of adult ADHD. We have so many treatment options. We have so many pathways we can take to help these individuals. I want to thank our colleagues who are listening. In many ways, you could choose to ignore adult ADHD. You might say, “I’m busy enough. I’ve got so many other disorders to take care.” But let me share this with you. If you’ve identified and treated an adult with ADHD, the transformative power of clinical intervention is 1 of the greatest I’ve seen in my 32-year career in medicine, so I encourage you to be empowered in identifying and treating as optimally as you possibly can. It’s getting more possible with the passage of time. Before I wrap up. Teresa, I want to hear your thoughts. What are you most excited about in the world of ADHD?

First, thank you all for being part of this panel. It’s much appreciated. Thank you to our viewing audience for participating. I want to emphasize that, as all of you have said, there’s so much to look forward to in this field. When I started as an ADHD specialist 20 years ago, we had very few options for treatment. We had very little understanding that there even was adult ADHD. I’ve been thrilled to be part of the process and the evolution in our understanding. I’m very excited to know that there’s much more to come.

 discussion to be useful and informative. We look forward to seeing you in the future. Thank you, everyone.

Videos

Drs Rakesh Jain, Greg Mattingly, David W. Goodman, Birgit H. Amann, and Theresa R. Cerulli, discuss emerging agents in the pipeline for the management of pediatric and adult ADHD.

Novel Agents for the Management of Pediatric and Adult ADHD

We’ve been talking about more treatment of viloxazine in children. My understanding is that the adult studies are not only completed but in the hands of the FDA with regard to treating adult ADHD [attention-deficit/hyperactivity disorder] with viloxazine. Birgit and David, perhaps you’d like to weigh in on the treatment of adults with this compound. What are your thoughts?

 The data haven’t been published. I don’t want to overpromise and underdeliver. That was the shortcoming that happened with atomoxetine. Clinicians ought to keep in mind that there’s a place for nonstimulants. We’ll see what the adult studies show. Obviously, they were submitted, so they’re going to be positive. I’ll highlight that the history has been effect-sized for nonstimulants as well as stimulants as higher in children and adolescents than it is in adults. I anticipate a similar outcome in regard to comparative effect sizes. We’ll see.

The drug interactions are a consideration much more in adults because adults are on polypharmacy and other medications. Caffeine is very important. If you assume that your elevated tachycardia or blood pressure is a function of medication and not elevations in caffeine levels as a result of A12 inhibition, you’re going to be diagnostically misdirected in stopping the viloxazine. We’ll wait and see. For the adverse-effect profile, we’ll have to see. It’s often different in adults from children. Children are more sensitive to some of the adverse effects, and adults are less sensitive but may have other adverse effects. We’ll see. I’m optimistic. I’m glad to have more options. There are 15% of patients who aren’t responding adequately to what we have available with the stimulant medication, so we need more options.

The other option for adults that was recently approved is an amphetamine extended-release tablet. We can spend a moment talking about that. They have adult trials. They’re approved for adults. This is amphetamine racemic mixture; it’s a tablet, long-acting, and chewable. They have a study in adults that’s out to 13 hours that showed improvement in the PERMP [Permanent Product Measure of Performance] score, which is a test of mathematics and how many math problems you can do in a period of time. They had an onset at 30 minutes and extended at 13 hours. If we come back to the other stimulant medications, with a thoughtful process of what compound are you going to choose, what delivery system are you going to choose? How you are going to develop a combination? There isn’t a lot of combination therapy with stimulants and nonstimulants, and I hope that develops because the atomoxetine stimulant trials were very useful for clinicians treating patients who aren’t responding adequately to 1 treatment or another.

Birgit, I believe I heard you say that you have had some experience clinically using viloxazine in adult patients with ADHD. Any thoughts to add?

 I have. It’s been limited because we’ve been met with difficulties with the insurance companies letting it go through, so I’ve been having to sample them. I’m hopeful, fingers and toes crossed. It won’t be difficult to begin to use in adults, no different from use in the child and adolescent population.

I’d like to share 1 of the few adult patient stories that I’ve heard in using viloxazine in my own practice. As you said, for a few patients the coverage has been challenging because we don’t have the approvals. The feedback from this patient was just so powerful. By the way, I often ask that question to patients: what does it feel like to take this medication? That’s a question that doesn’t get captured in the data but that we very much care about in our day-to-day practices. This patient responded to me. She’s in her mid-30s and definitely not a simple ADHD case. It’s a complex case, with multiple comorbidities. At least 2 come to mind. She hadn’t been comfortable taking stimulants previously because of her complex situation. On her first visit after she started on Qelbree, her words were, “Instead of walking through an old home with cobwebs hanging from the ceiling, it felt like those cobwebs parted, and there was a very clear path for me to think.”

That was the description she gave me. I wanted to share that because this isn’t something you’re going to see reported in the studies. But that’s what it sounded like. Rakesh Jain, as you were saying, each patient ADHD is a patient with ADHD, and that’s it. Everyone is unique, but that was my experience. It’s worth taking a look at. At this point, what I’m hearing sounds different from what I’ve heard on other medications, whether we’re talking about stimulants or nonstimulant medications.

David W. Goodman, MD, leads a discussion on the use of viloxazine for the treatment of adults with ADHD.

Role of Viloxazine in Adult ADHD Treatment

Are there some strategies you are using in dosing and titration with regard to adverse events perhaps when you have used viloxazine [Qelbree] in kids and adolescents?

 Absolutely. I tell the patients it’s approved to take once a day, so as long as you’re taking it once a day. I tend to have them start it in the evening but if they prefer to start it in the morning, that’s fine. I just let them know that if they do struggle with fatigue or somnolence, tiredness, I don’t want them to not be able to function obviously during the day, but they can modify that timing. So, once a day, anytime a day, I tell them, and I ask them to start with 1 of the bookends more commonly for me in the evening and then adjust accordingly if they need to.

And is somnolence 1 of the more common adverse events you are seeing, and if so, what else might you know from both the data and your clinical practice to warn clinicians to watch for?

 Somnolence, fatigue, decreased appetite—those are the top 3, I believe. But the discontinuation rates in the studies were low, quite low. I believe it was 3% on the Qelbree treated patients as compared to 1% on those on placebo. I have to say in my office utilizing Qelbree it’s not often I have had to stop due to fatigue, and what I have done if they, for example, let’s say an adolescent did 200 mg for a week and then went to 400 mg and then he had difficulty with somnolence, then I have reverted them back to 300 mg. I don’t have samples for that but thankfully at the pharmacy I can get them the 2 150 mg [doses]. So we have been able to do those half stuffs to help them. Very commonly if they do have difficulty with somnolence or fatigue, it does resolve after a short time, 7 to 10 days. So if they are able to work through that we don’t need to make any adjustments.

 If I could offer some guidance for maybe some of the clinicians that haven’t got the chance to use viloxazine. There are a couple of unique things about it that you want to keep in mind when you’re using this product. First of all, it’s the first non-stimulant that can be sprinkled. None of our other non-stimulants have that as an availability, so you have patients that don’t like swallowing capsules, that you want to titrate the dose by being able to sprinkle the dose, you can sprinkle it, you take it once daily, any time of day, as Dr Amann had just said. Viloxazine itself is metabolized through [CYP]2D6 [cytochrome P450 CYP2D6] in the liver, so it’s metabolized through 2D6. So, if you have people on 2D6 medicine, remember that’s going to raise your viloxazine dose somewhat. And then viloxazine itself speeds up the metabolism, changes the metabolism of 1A2. So 1A2 you are going to slow medicines that go through 1A2 and 2 common medicines that go through CYP1A2 [cytochrome P450 1A2] that viloxazine will slow their metabolism is both melatonin and caffeine. Those are things you may want to think about. When you’re using viloxazine tell your patients, “Hey, you may not need as much melatonin. You may try to want to go to sleep without melatonin tonight and see how you do. If you are big caffeine drinker, why don’t you cut back on your caffeine a little bit when we first start the viloxazine because it’s going to raise your caffeine levels a little bit if you’re using it along with caffeine.”

So, once daily, you can sprinkle it. It’s metabolized through the liver, and then once again many of you guys have seen a video of 1 of my patients who is in the long-term pediatric trial. It’s a medicine that in this young man’s experience, he came in and he told us at the end of the study, I said, “Tell me what you have seen with this.” And he said, “Dr Mattingly, I used to be the kid in the family that nobody wanted to be around because I would agitate and frustrate everybody, and I was always all over the place and scattered.” And then he gave me a big smile and he goes, “I think what I am proud of stuff now is I think I am a good big brother.” You could see the self-confidence has changed, you can see the self-image changed, and that’s because his ADHD [attention deficit hyperactivity disorder] was getting good and adequately controlled.

You can’t think of a better outcome, Greg, than having someone’s self-esteem improving with a medication, not that we can attribute it to any 1 medication, but in general it’s been what’s so rewarding and working in the field of ADHD that my experience is that it’s a very treatable condition both with pharmacologic and non-pharmacologic interventions and to see lives change with our assistance and all of the folks listening on the line today has just been so rewarding.

Birgit H. Amann, MD, and Greg Mattingly, MD, share strategies for mitigating adverse events with viloxazine in ADHD and its effect on metabolism of drugs.

Managing Patients with ADHD on Viloxazine

 I’ve heard Rakesh and maybe this is a place for you to jump in but you’ve talked a lot about the many faces of ADHD [attention deficit hyperactivity disorder]. We have 18 symptoms that kind of co-aggregate with each other. They can have very different presentations. Somebody who’s really hyperactive, somebody who’s very frustrated, somebody who’s impulsive, somebody has a lot of executive function cognitive difficulties. But then the multitude of other presentations: the anxious patient with ADHD, the overwhelmed patient, the depressed, the irritable. Why don’t you talk to us about where you think about some of these newer treatment options and where they may fit and that multitude of patients we take care of?

 Well said, Greg and David. Thank you for reminding all of us that heterogeneity is ADHD’s middle name. It’s its calling card. If you’ve seen 1 person with ADHD, you’ve seen 1 person with ADHD. And Greg, you’re right. When you look at the constellation of possibilities of symptoms and comorbidities that can come together, it’s in the thousands. There are so many different presentations and that’s why I very loudly resonate with you David that thinking about ADHD as a dopaminergic-only disorder is fraught with difficulty and fraught with challenges. And viloxazine [Qelbree] really sets us on the right path, which is think about the patient’s individual needs and you go beyond that. So let’s look into the issue of nonpharmacologic treatment options a bit, Teresa. That’s the question you had asked.

I do think we need to appreciate that the complexity of ADHD and the heterogeneity requires broader thinking. But even amongst non-stimulants, even though we call them 1 category, there is reason to divide and conquer. There’s a reason to think about. Thank you, Birgit, for reminding us alpha-2 still matters. They might be off-label, but they still matter. Atomoxetine [Strattera]—thank you David for reminding us that even though we did run into some headwinds with it—there’s a definitive place for it. There really is. And the same, thank you, Greg, for reminding us of the data set we have. Off-label, I’ve already started using viloxazine in my adult patients, both monotherapy and combination therapy. That heterogeneity of the disorder requires me to go after it with a wide variety of treatments and I do think we should be reminded that our non-stimulant treatment options are actually fairly different from each other. So we can divide and conquer to serve our patients better.

I so agree with you, Rakesh, and it’s hard for me to even lump them into 1 category namely non-stimulant as a category because they are so different from 1 another. Even though most of my time is spent as a practicing clinician, I do still teach with the residents at Harvard Longwood. But, most of the time, I’m practicing clinically. I like to think about how each of the prescriptions I’m writing is having its effects in the brain so that I can best understand where to go next in my treatment options if what I’m doing is working or not working and perhaps why it’s working or not working.

So, thinking about what you just described, Greg, with the viloxazine multimodal mechanism of action, elevating serotonin, dopamine, and norepinephrine. And my understanding is all 3 of those are going up in the prefrontal cortex. It’s become a fast and velocity has become a fascinating choice for me as a neuropsychiatrist in treating when I’ve got combinations of cognitive and emotional disorders rather than just diagnostic categories remembering how complicated ADHD is when you’re talking about ADHD plus comorbidities and treating both. And then add to that, with viloxazine, what I found very interesting was the data originally in the IR [immediate-release] form of viloxazine, remembering that in the U.S., the viloxazine has been studied in its extended-release preparation once a day dosing. Remembering that its original version was a short-acting IR form available in Europe as an antidepressant. At first, when I think about where this may fit in in my practice, I’m taking all of those things into consideration with regard to its history and its science. And I’m curious, Dr Amann, I know you spend a lot of time practicing clinically as well. Based on the data, where do you see the viloxazine fitting into your practice?

 Well, the viloxazine has already fit into my practice in a big way since it came out. I was very excited to begin to utilize it and I’ve really seen a lot of benefit from it. I’ll just say, first and foremost in general, and obviously at first, looking at it for my ADHD patients who may have only had ADHD but not uncommonly might have been on another agent for depression or anxiety. What I really liked about it is that I see that 1 to 2 week-onset, but I like to utilize the starter kits to really help me to navigate getting them to the proper dose. We have the sample bottles as you all know that we can utilize, so what I will do is I will give them 2 or sometimes 3 weeks’ worth, sometimes I write down the kits so that I can do maybe 2 weeks of 1 dose and then go up. And then I don’t send the script until I hear from the patient. In this case, maybe the parent of the child or adolescent 2 maybe 3 days before they are due for the prescription give me some feedback on how the medication is working and how well they are tolerating it and then I go ahead and send the prescription for the next dose.

I, too, as 1 of my colleagues said have patients who are on viloxazine along with a stimulant in some cases, so thus far it has been a welcome addition. I don’t expect anything different when hopefully it gets an adult indication. I too have used it in adults sometimes by sampling them because there are some challenges if it’s not adult-approved. But when you talk about its use for patients that are comorbid with mood disorders, I mean it’s intriguing to me. I can’t say that I have yet reduced antidepressant dose because addition of viloxazine seems to have improved enough mood wise but that might be a to be continued story.

Key opinion leaders in the management of ADHD comment on where they anticipate using viloxazine and other nonstimulants in the ADHD treatment landscape.

David W. Goodman, MD

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