Insights From Dr Price: Extended-Release Viloxazine Compared With Atomoxetine for Attention-Deficit/Hyperactivity Disorder (ADHD)

 

Join us for this insightful interview with Dr Price as he shares his expertise and insights into the study comparing the effectiveness and tolerability of viloxazine extended-release (ER) to atomoxetine in the treatment of pediatric and adult ADHD. Learn about the key takeaways of this study as Dr Price delves into the benefits of viloxazine ER, including demonstrated rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability in pediatric and adult ADHD patients, and the beneficial implications of the study results for individuals diagnosed with ADHD.

Rabbi Richard Louis Price, MD: Hello, my name is Dr Richard Louis Price. I'm a professor of psychiatry at Weill Cornell Medical College in New York. And today we'll be discussing my findings regarding the extended-release viloxazine compared with atomoxetine for attention-deficit/hyperactivity disorder.

So the question was: Can you elaborate on the rationale for reserving psychostimulants predominantly for inattentive ADHD and using extended-release alpha-2 agonists for hyperactivity/impulsivity? And how does this align with your clinical approach and experience? So, psychostimulants have been around for many years. They're highly, highly effective. They're rapidly acting. So for someone, a child or an adult, who just needs to focus for a time-limited period, and not necessarily even every day, and doesn't want to take something every day, psychostimulant might be appropriate, assuming there's no risk for abuse and tolerance and diversion and things that we encounter with psychostimulants—very effective on that sort of as-needed basis. If you have to study for a test, if you have to prepare for a project, and you need that focus and you're diagnosed with ADHD, might be the treatment of choice.

Then you have children, let's say, who are highly impulsive and hyperactive, and when they can sit and they can be patient, they do pretty well, and they need coverage throughout the day or throughout the week. And for them, psychostimulants might be helpful during the hours during which they work, but before they work in the morning could be a nightmare. And when they wear off, especially hard on the family, such that the family may feel they're not even working at all because they're only seeing the kids in the morning and they're only seeing the kids when they come home. And the school's very satisfied and the parents can't deal with this. And same thing with adults who may have very, very long days, may have to get up early, may have to work late at night. So you don't want them popping stimulants throughout the day. So if they are primarily hyperactive and impulsive, even as adults, behavioral stimulants probably won't cover it. Not the treatment of choice. Problem is, is that the alpha-2 agonists are not very good for focusing compared to stimulants. So what one lacks the other picks up, what the other picks up the other one lacks. And tailoring your clinical approach and experience to these different patient profiles for kids and adults within the spectrum of ADHD symptoms can be very helpful to select the appropriate treatment.

Stimulants can work within half an hour, an hour. So when we think about rapid control, traditionally we've always thought of stimulants as the way to go. The nonstimulants tend to take a longer time, like we spoke about, the alpha-2 agonists are not particularly good for focusing. And the other nonstimulant, which was really the only one that addressed the full spectrum prior to viloxazine was Strattera, could take several weeks to work. Not even days but weeks, perhaps 4, 6, even 12 weeks to work, titrating the doses, having to adjust for people's metabolism. So that didn't really give us a great option for someone who needed rapid response. Now, when viloxazine ER came along, we had something that for children could work within a week and adults could be working within 2 weeks, which was pretty fast for a nonstimulant compared to what we were used to with Strattera.

So this has changed the game because we often don't have time to wait up to 12 weeks. I mean, the semester in college is 15 weeks, so you're saying you're going to lose most of the semester waiting for this nonstimulant to work? So now that you have something that could work within 1 week or 2 weeks, this is not a long time, for a chronic condition, to take effect. And this has changed the game because now we have something that's rapidly acting, that's a nonstimulant that could help inattentiveness, hyperactivity, impulsivity. And that, in that sense, and in many other senses which we'll go through, is a game changer, I believe, in the field of the treatment of ADHD.

When we have adults with combined ADHD and children combined-type ADHD, so the state of the field before viloxazine came along was maybe we give a stimulant for the focus and we give a nonstimulant for the behavior. And then sometimes we have to give medications to mitigate the side effects from the stimulants, such as insomnia and poor appetite. So you could see kids and adults on a whole cocktail of medications to treat one condition. So then you have Strattera, but Strattera on its own never really held up very well as a monotherapy in terms of being particularly effective, in terms of attentiveness, hyperactivity, and impulsivity, compared to the benefits of the alpha-2 agonists for the behavior and the stimulants for the focus.

So then viloxazine comes along, and now we have something which is highly effective, rapidly acting, and could potentially obviate the need for stimulants entirely or alpha-2 agonists as a monotherapy. So this a game changer, again.

In terms of the differential response to viloxazine in adults versus kids, so many adults come in and they're asking for Adderall by name. Either they've taken it, they've gotten it from friends, they were prescribed earlier in their life, or that's just what they want. That's all they know. They know it's rapidly effective. Unfortunately, it has a lot of liabilities in terms of not necessarily covering the day, wear off, irritability, insomnia, abuse, misuse, diversion, and shortages. So I'll say it to the adults: Look, I'll give you a reasonable dose of Adderall if you will take viloxazine with it. And what you will find is as you build up the viloxazine over a couple of weeks, you'll be less and less dependent on the Adderall. And that's a sell that I can get most adults to get around. Same thing with the kids. The parents generally don't want their kids on stimulants. Once you explain how stimulants work and stimulant side effects, they're thrilled if there's an effective nonstimulant option that can cover the entire day. And if they happen to already be on stimulants, getting them on viloxazine, in my experience, has helped them taper their stimulant.

In terms of dosing, for the young kids under, 6 to 11, they're going to start on 100 milligrams. They can build up week to week, 200 up to a maximum of 400. For the older kids, adolescents, they'll start with 200, they'll go to 400 week to week. And for the adults, they start with 200, go right to 400, go right to 600 as needed, week to week.

In terms of the time of day, for the kids there’s a little bit of sedation potentially on viloxazine, which can help the kids at night because many of the kids with ADHD at night can’t settle down, a little bit hyper, and then they can't get up in the morning. So having the little bit of sedation of the viloxazine at night is a welcome effect to help them settle down, go to sleep.

For the adults, it’s the opposite. They may have trouble with insomnia with viloxazine, so they'll start it in the morning, and there's an interaction between caffeine and viloxazine because of the 1A2 pathway that it will prolong the activity of caffeine. So they'll start it in the morning. And again, dose, timing of doses can be adjusted based on their response. So this is how children and adults could be treated differently, very effectively with viloxazine, but in a different approach.

The thinking has been that the stimulant is the foundation of the treatment, and then we layer on a nonstimulant, like an alpha-2 agonist or a Strattera, to kind of cover where the stimulant lacks. I propose we look at it the opposite way, the same way we think about treatment of anxiety. So if someone comes in with anxiety, of course they want their benzos, something acute, but we really want them on an SSRI/SNRI to treat the underlying anxiety throughout the day and then reduce their dependency on the benzodiazepine. So the same way, if someone comes in with ADHD that generally affects their entire day, start them on viloxazine first, and once that kicks in, they may not need a stimulant. If they do need a supplemental stimulant just to help top it off on certain high-stress, high-need, high-demand days, fine, but they won't be as dependent on it because the viloxazine is covering the entire day, not just for behavior, but for focusing. And for people who are already on stimulants, introducing the viloxazine, in my experience, can help reduce their dependency and their need for stimulants, which is a very welcome thing for many adults who have to function throughout the day and not just for a time-limited period.

So ADHD is a condition that can affect multiple areas of your life beyond just having difficulty with focus. So you think about women who may have to manage a job and domestic responsibilities around the clock. So having a short-acting stimulant might help for one of those settings, but won't necessarily help first thing in the morning, won't help by the end of the day, won't help by the evening. And if you're relying on stimulants, you're popping stimulants throughout the day, which is really no way to live with highs and lows and highs and lows and crashes and efficacy, and all these things, and dependency. So that's one group where viloxazine could really cover the whole day and the full spectrum.

Same thing with the elderly. Viloxazine was studied up to the age of 65 in terms of safety, and it's approved for adult ADHD, including seniors, and also proven to be effective for executive functioning. So there are many people who are elderly and struggle with executive functioning. And if you do a thorough history, you'll find that they may have had a childhood history of ADHD, and now that's being compounded by their aging process, and treating that could make a world of difference in terms of helping them with their overall functioning throughout the day without giving them stimulants that could have cardiac toxicity and appetite and irritability and insomnia, which elderly people may suffer from anyway.

And then in terms of other working people, generally it's not limited to a 9-to-5 day anymore. People if they work, they're working multiple jobs, they're working long hours, and they need help throughout the day to attend to their responsibilities, both interpersonal ones as well as professional ones. And for kids also, kids’ days don't end with the end of school. They still have activities after school. They still have to get along with their family members and with their peers. So ADHD is a broad diagnosis that affects many aspects of life where stimulants might help very well in that focusing period for a limited period of time but will not address necessarily the full spectrum of symptoms across the lifespan.

So the study really came out of the real world, where I practice and thousands of people practice and millions of people live. So it wasn't set up to be a sterile placebo-controlled double-blinded. It's really from the real world, and in the real world, back when the study started, insurance companies, they didn't really hear of viloxazine, and as far as they were concerned, it was just another norepinephrine reuptake inhibitor similar to Strattera. So, you have to go through Strattera first. What they would think of was the generic equivalent. So all the patients had to take Strattera anyway. So I decided to track their progress and their side effects in clinical practice on Strattera and then say, Hey, this is where we're up to now after 4 weeks, would you like to try another medication? See how that works for you? And universally, they all said yes, we would definitely like to try something else, either because of side effects or because of lack of efficacy. And then they switched over, and this is what I've been doing all the time.

Now that the study's out, and it's very clear, at least to me, that viloxazine is superior in terms of rapid onset of action, in terms of tolerability, in terms of efficacy for both inattentive and hyperactivity and impulsivity, I can't in good conscience ethically make people suffer 4 weeks on Strattera or just waste time. So I think the study is important because it gives a basis for practitioners, patients, and perhaps insurers to realize that these two are not the same. And if you dig into some of the preclinical studies that have been done on mechanism of action, the norepinephrine reuptake inhibition aspect of viloxazine is a very minor effect. There are a couple receptors where it's an antagonist to serotonin, which can help release the GABA break, which holds up the system in terms of glutamate, in terms of serotonin. It's also working as a partial agonist at another serotonin receptor, which can directly stimulate dopamine and norepinephrine release. So you have norepinephrine, dopamine, and serotonin being increased prefrontal cortex without necessarily waiting that time for reuptake inhibition because it's directly affecting receptors. And I think you see that clinically. So, there's preclinical studies that were done post-FDA approval I feel are now backed up in the real world because you can see the translation between the basic science and what your patients are reporting. And this is nothing like a traditional NRI, like Strattera, in what you see clinically and what I've just explained very briefly in the pharmacodynamics, you could see it in the patient results.

So the key takeaways are number one, this is not Strattera. That was how it was branded out in the world when it was first released a couple years ago. More effective, more rapidly effective, better tolerated. Number two, we have to change our mindset about how we think about ADHD. Rather than starting with a stimulant, particularly for kids, why don't you start with an effective nonstimulant? Why don't you start with viloxazine first and see what that does for a week or two? Give it a week or two. The kid is markedly better. You've spared their brain from ever having to taste a stimulant, which I think is a great thing. And let's say it's pretty effective, but they need a little bit of a stimulant added on top. Okay, so maybe you'll use the stimulant on school days but not non-school days. And for adults, it's very hard to wrestle them away from their stimulant of choice, but you can propose to them: Look, let's get the viloxazine on board together with the stimulant. In fact, I won't even give it to you without viloxazine because I'm not going to have you dependent on stimulants, and let's try it out, see how it goes. And wouldn't it be nice if you didn't have to take your stimulant 3 times a day, maybe only once a day, maybe not even every day, and you weren't crashing in between? And this could be working for you very nicely for your overall picture in life. So I think these are some of the key takeaways. It's the paradigm shift of how we're looking at ADHD treatment for children, for adults, and like I said, also for seniors for whom they need that cognitive enhancement in ADHD, but we don't want the stimulant side effects, particularly in elderly patients.

Well, I think that these findings have a lot of implications for ADHD plus other comorbidities. So for instance, let's say you have patients who really are legitimately addicted to their stimulants. They have physiologic withdrawal, they have dependency, they have craving. Titrating them up on viloxazine for their ADHD, as I've shown, can help taper their use of stimulants; that might be relevant in a substance abusing population. Because right now we're using bupropion – bupropion, it's very weak in terms of norepinephrine, dopamine reuptake inhibition. It also can drive up anxiety. Viloxazine generally not because of its serotonin effects, tends to be pretty calming.

Next is comorbid ADHD and depression. Viloxazine was around 30 years in Europe 3 times a day as an antidepressant, brought to this country, made into an extended-release novel molecule here once a day for ADHD. So it stands to reason that viloxazine certainly shouldn't exacerbate depression in someone who has unipolar depression. It might even be helpful; however, it appears to be it's much more helpful for the ADHD than even the depression, but it might help that as well.

Comorbid anxiety, ADHD and anxiety, stimulants notorious, just like caffeine and other stimulants, to drive up anxiety, or when they wear off to increase anxiety. Viloxazine is smooth, so ADHD and anxiety. ADHD and insomnia, many adults, many kids, they can't settle down at night. So because viloxazine can have a little bit of sedation on it, and if it's given at night, it'd be helpful for that.

ADHD and Alzheimer's: study just released in JAMA that patients who had childhood history of ADHD had increased risk of Alzheimer's, and that treating the ADHD in adults help mitigate some of the horrible effects of Alzheimer's. So again, we think about stimulants, stimulants for elderly. What about nonstimulants? Well, nonstimulants, up until viloxazine didn't work that well. I think viloxazine might have a role there as well. ADHD plus Alzheimer's. And finally, recent study came out, there's not much we can do pharmacologically for the core symptoms of ADHD plus borderline personality disorder. But many of the reasons why patients with borderline get into trouble is because of impulsive acts. The impulsive acts tend to predispose them to self-harm, harm to others, getting into accidents, things like that. So if you can treat the underlying ADHD, well I don't think you would want them on stimulants. They're not going to cover the day. And the nonstimulants, again, good for behavior. But what about the focusing? What about the executive functioning? What about getting overwhelmed, being flooded with emotions? So if someone has underlying ADHD, you aggressively treat that ADHD with something like viloxazine nonstimulant, you might favorably impact on some of the dangerous and impulsive behaviors that you could see in borderline personality disorder. So there's a world of potential for this new product in many of these comorbidities. And they would all be on-label because every one of them I mentioned, we're talking about treating the ADHD, but for most patients it's always ADHD plus some other aspect. And viloxazine could potentially pick up some of those comorbidities as well. Treating on-label, though, for ADHD in children and adults.