Real-World Data Deep Dive: Viloxazine ER Compared With Atomoxetine for ADHD Study

In this roundtable discussion featuring a panel of experts, Dr Gregory Mattingly, Dr Richard Price, and Dr Birgit Amann explore key findings from the real-world study comparing viloxazine ER with atomoxetine for ADHD treatment in adult and pediatric patients. The panelists discuss the study results including efficacy of viloxazine ER in managing inattention and hyperactivity/impulsivity, its response time compared to atomoxetine, and its tolerability and safety profile. This session spotlights the implications of the study findings on clinical decision-making and the potential impact on future ADHD treatment approaches, particularly for patients with combined-type ADHD.

Dr Greg Mattingly: Let's jump into your study, okay? So you and your son came up with a landmark study. And I love this study because you took patients from your clinical practice, right?

Dr Richard Price: Real world.

Dr Greg Mattingly: Real world. This wasn't a rarefied research study where we screened you and you couldn't have other stuff. These are people that were what? Coming to your clinic and you were seeing them?

Dr Richard Price: Yep. Coming in regular course of practice. Primary complaint though was ADHD, so they did not have other active comorbidities because that would've skewed the results. But they're real-world people, yes.

Dr Greg Mattingly: Okay. And you've been in practice, if I can ask you, how long you been doing this?

Dr Richard Price: Twenty years.

Dr Greg Mattingly: Twenty years, okay. So you've been doing it for a while. So some of these patients you probably know pretty intimately, I would guess, from having seen them…

Dr Richard Price: Mm-hmm, or their parents. And these are the children, this is the next generation, and their grandparents also, yes. I have a lot of families who come to me. So I have a rich genetic tree where I can see what works…

Dr Birgit Amann:  Mm-hmm.

Dr Richard Price: …with different families.

Dr Greg Mattingly: Yeah. So a family system approach. I think of your practice, sounds like mine. It's almost, I think of myself as a primary care mental health practice.

Dr Birgit Amann: Mm-hmm.

Dr Richard Price: Absolutely. People will call me for their primary care needs, not that I can help them, just because no one else is going to respond to the text. Who else are they going to call in the middle of the night? Call Dr. Price. He's a knowledgeable person. Maybe he can give me some guidance. So yes, very much so.

Dr Greg Mattingly: Yeah. So that being with people throughout the journey, being part of their journey as they develop all these different conditions…

Dr Richard Price: And also all their successes.

Dr Greg Mattingly: Yeah, a hundred percent. So lead us to what gave you that spark? There's always that creative spark that comes to research. So great inventions are born with a spark, right?

Dr Richard Price: Well, necessity is the mother of invention.

Dr Greg Mattingly: Ok <laugh>. So you had a spark, though, that caused you to want to do a study and say, okay, I want to take a look at this new agent viloxazine extended-release, and I want to compare it to atomoxetine in patients in my clinic. What made you think about that comparison in that study?

Dr Richard Price: So here's the journey. So to go back, we have our long-acting stimulants, we have the short-acting stimulants, excellent for focusing for people who need them, rapidly effective, obviously long-acting more preferable to short-acting. Okay. So then you have the nonstimulants, the alpha-2s, outstanding for impulsivity and hyperactivity, outstanding when you don't want that hyperfocus. And then we have the longer-acting agents. Terrific. We have Strattera, atomoxetine, okay, smile, kind of treats the spectrum but not robust. But if you're tight, if you're short, it might be a last line for you because this combo approach wasn't working out. Then we hear about this new thing on the market, right? New agent comes, nonstimulant, it's like, well, there's certainly a need here, so let's give it a try. Insurance wasn't going to pay for it, it's too new. So I had my rep load me up with samples. It was a couple of years ago, and I tried it out and I paid very close attention to how my patients were doing.

Dr Richard Price: Either those who were stimulant-naive or those who were currently on stimulants or those who were on alpha-2s and stimulants. They wouldn't be on Strattera as well, but they could be on all the above. And I just was getting empirical data at that point, just seeing how is this working out. And what I was finding is that within a couple of weeks, I was able to taper the alpha-2s first and then get those off perhaps, and then at least get the stimulants down, perhaps off, and they were ending up on viloxazine ER monotherapy. Wow, this is really cool. Then my rep disappeared and I had no more samples, and at that point it was too new on the market to really get it approved. And then some time passed, and then I got a new rep and I said, I'm so glad you're here. I need to do a study because I need to prove to insurers, I need to prove to the clinicians, I need to prove to academia, I need to prove to seasoned psychiatrists who are set in their ways and they're looking at the data and they're looking at effect size, that this does something very special, that this could really upend the field, disrupt the field in a positive way.

Dr Greg Mattingly: So let me ask you, so when you looked at viloxazine and you had that spark, it was seeing your patients, right?

Dr Richard Price: Listening to the patients…

Dr Greg Mattingly: Listening to patients…

Dr Richard Price: …and the parents, and the parents of the patients, what they're telling you.

Dr Greg Mattingly: And seeing something that you hadn't seen before with some of the other agents. Was that…

Dr Richard Price: Or it would've been a complicated cocktail to achieve that with side effects, right?

Dr Birgit Amann: Mm-hmm.

Dr Greg Mattingly: Was that based on mechanism of action in your thinking or was it based on clinical response or a little bit of both?

Dr Richard Price: So at that point in time, the mechanism of action was not well understood. It was classed as another NRI, a norepinephrine retake inhibitor, which actually was discouraging because we thought about Strattera and it was like, oh, okay, if that's what it is, it's just a me-too branded Strattera for a pharmaceutical company, that's not so exciting. So at that point, there wasn't so much literature out on investigating how this might be working. That came out subsequently. Now that we have more data on how it may be theorized to work beyond just norepinephrine uptake inhibiting, that makes a lot of sense when you pair it with the clinical response that you see now. So now it gets really exciting, and most people have no clue how it works. Or we have some clue, but we haven't shared that yet publicly in a way that people understand how this is not just an NRI.

Dr Greg Mattingly: So Birgit, I love it in that his research was started not because of mechanism of action or something fancy…

Dr Richard Price: That’s discouraging.

Dr Greg Mattingly: …but it was based on what he was seeing with his patients.

Dr Birgit Amann: Right.

Dr Greg Mattingly: A new agent that he was using with people because he had some unmet needs, people not doing well, and all of a sudden he saw people doing better. He saw people being able to be titrated off of some of their other comorbid medications, right? And just saw some better outcomes that seemed a little bit different to you. Did you think it was different? Did you think it was just a little faster? What was your gut hunch when you first started seeing those results with patients?

Dr Richard Price: Well what was most impressive was the impact on comorbidities.

Dr Greg Mattingly: Okay.

Dr Richard Price: And not exacerbating comorbidities but actually ameliorating comorbidities. Because it's unusual to see someone unless they're in a research trial and they're sterilized, scrubbed patients, that they have ADD inattentive type and nothing else, just ADHD and nothing else. And in the real world, people have history thereof of depression, of anxiety, of borderline personality disorder with impulsivity, of Alzheimer's, of mood swings that are not bipolar mood swings but they're just irritable, OCD. You don't want to exacerbate those conditions potentially with other agents. This was not only favorably impacting on the core ADHD symptoms, this was favorably impacting on their life, which is not always captured in an ADHD rating scale score when you're looking at effect sizes. Also, it didn't take away their personality.

Dr Birgit Amann: Right.

Dr Richard Price: It wasn't making them laser focused, like maybe they would get a better score on a rating scale. They were properly focused, not hyper-focused and not under focused, and they were able to, signal-to-noise ratio was nicely balanced. That inverted U-shaped curve, norepinephrine. It was just right. Goldilocks – just right.

Dr Greg Mattingly: It's interesting when we do research, research is designed for different purposes. So when I do clinical trials to get something approved by the FDA, the FDA sets certain criteria, you have to prove that it beats placebo. We're the only country in the world that typically still has to do that, but we have to do that with compounds. So we're proving that this compound beats placebo, but I don't know a clinician out there that really cares if this beats placebo. The other part of clinical trials, and Birgit, I know you've done a number of these in the past, is it tends to be that pure patient that has nothing else.

Dr Birgit Amann: Right, not…

Dr Greg Mattingly: It has to just be the condition you're studying. It can't be ADHD with depression, anxiety, all those comorbid things that we said that 80% of our patients with ADHD has. We're looking for those pure ADHD patients that don't really reflect the real-world evidence. There's a whole new trend these days in research, and the WHO, the World Health Organization, is a big fan of this, and it's called real-world clinical data. So we look at patients coming into clinics like ours that aren't the real research-pure patient. They're the complicated patients. They're patients that we see in our clinical practice that have all of those comorbid conditions. And then we say, is this treatment safe there? Does it move the needle there? Does it help with maybe some of the other comorbid conditions there? So I just did this for a large depression trial, an international trial. We put a thousand people in the trial looking at complex, complicated, real-world patients saying how does treatment with depression with different agents make a difference in a complicated group of patients? But you had the insight to do that in your clinic.  Give us real-world data from a real-world clinic about, let's look at a novel agent and say, what do I see that's different there? Now, you've mentioned this, but for the audience, you said, listen, I can't just sample everybody in my practice with viloxazine for the rest of their life, so I'm probably going to have to prove to insurance and everybody else that there's something different between atomoxetine versus viloxazine, right? So your gut hunch what you were seeing with patients, you said, I want to research that in my clinical population with complex patients and say, does that really hold true? So walk the audience through how you kind of designed that study and how you thought about, how do I prove this to insurers, to patients? How do I prove my hunch that it really is there?

Dr Richard Price: Right. So about half the patients were already on stimulants, and when you're building in a nonstimulant, you're not going to just abruptly rip off the stimulant because you'll have withdrawal effects that you'll then attribute to the nonstimulant as effects or side effects. So anybody who was on stimulants was allowed to stay on stable doses of their stimulants throughout the study.

Dr Greg Mattingly: Did you care which one?

Dr Richard Price: They were on every stimulant, long-acting, short-acting, that you could think of.

Dr Greg Mattingly: So whatever you thought was their best agent at the time.

Dr Richard Price: That’s what they were on. That’s what they were on.

Dr Greg Mattingly: So once again, real-world patients, real-world, if it was methylphenidate, if it was amphetamine, if it was immediate-release, if it was pro-drug, whatever it was, right?

Dr Richard Price: Whatever was the best they could do on what they were on.

Dr Greg Mattingly: With existing options.

Dr Richard Price: And that was where they started, and yet their baseline scores were still pretty bad, but it was better than nothing. So they were staying on that. Then the other group that was included were people who either had taken medication in the past or hadn't taken anything yet. So really treatment-naive from the standpoint of starting a study.

Dr Greg Mattingly: Okay, so you're answering a couple different questions already.

Dr Richard Price: Mm-hmm, yeah.

Dr. Greg Mattingly: That group already on treatment but having some breakthrough symptoms, and that group that's coming in looking for other options or a new option, they've never tried anything.

Dr Richard Price: Right.

Dr Greg Mattingly: Okay. How did you structure, why did you try atomoxetine first and not viloxazine?

Dr Richard Price: Because at that time, insurance mandated a 4-week adequate trial, as they deem adequate, of adequate dose and titration, prior to covering viloxazine ER. It was a forced study upon me that must have been done.

Dr Greg Mattingly: So you decided...

Dr Richard Price: Had to do it. Game on.

Dr Greg Mattingly: So how did you start with the atomoxetine?

Dr Richard Price: So they were titrated as per FDA guidelines and according to tolerability.

Dr Greg Mattingly: And you left them on their stimulant when you first did that?

Dr Richard Price: The ones who were on stimulants were allowed to stay. They stayed on stable doses, they didn't change their dose throughout the study. And the ones who weren't, remained on what they were on, nothing. And they just titrated up their atomoxetine as per FDA guidelines to the maximum tolerated dose based on their weight or age, and that was 4 weeks. So people would say, well, 4 weeks is not enough time. Give it a chance. You need to give it to 6 to 12 weeks. Well, a semester in college is 15 weeks. I can't afford, and they can't afford, to wait a semester to get better for the next semester. We have to get the show on the road, and that's one of the points. So we wanted to show also the relative speed of action between the agents. Some criticism, okay, you didn't give the atomoxetine a full 6-to-12-week chance. Well, I gave an adequate dose, but I had to cut it at 4 weeks because that's what insurance says was an adequate trial. And I can't expect ADHD patients, or really any patients, to wait much longer than that, or parents who were dealing with their kids, much longer than that when we have another agent we want to start potentially thereafter.

Dr Greg Mattingly: Well, and I always say people vote with their feet. You can say, hey, stay on this, but if they're not doing well...

Dr Birgit Amann: They're not going to.

Dr Greg Mattingly: They drift away, right? They drift away from your practice or from that treatment, or they find a reason why they don't want to stay on that treatment. So 4 weeks of atomoxetine, titrated to therapeutic dose, either with or without a stimulant, so they could come in either way they wanted to, whatever was their best treatment option. And it didn't matter which stimulant they'd been on. It was what you thought was their best treatment option at that point.

Dr Richard Price: At that point, yeah.

Dr Greg Mattingly: Okay. So how did you measure outcomes? So I know you wanted to quantify it for us and actually say, because people would've said, ah, you're just making this up.

Dr Richard Price: Right, exactly.

Dr Greg Mattingly: How'd you measure outcomes?

Dr Richard Price: So there's the ADHD rating scale 5, and the AISRS for the adults, which are validated scales in the research world. We followed the paradigm that would've been used in any large, randomized, double-bind clinical trial.

Dr Greg Mattingly: Yep. So if this was Harvard, WashU, Stanford, UCal Berkeley, this is the scales they'd been using, right?

Dr Richard Price: That's right.

Dr Greg Mattingly: Okay. So you use the ADHD-RS, for the audience that doesn't know there, that's a child/adolescent scale primarily. You can use it for adults as well, but it just measures the 18 symptoms for ADHD. None, mild, moderate, severe. Simple scale, easy to use. I like it. It's my favorite research rating scale.

Dr Richard Price: Yes.

Dr Greg Mattingly: Okay. So those 18 items, we measure them over time, 9 inattentive, 9 hyperactive, and we look at change. The AISRS, it's the exact same 18 items, it just gives you adult prompts. And so we're not saying do you get up and run around the room? Do you get restless in a meeting? Do you interrupt people? Do you have a hard time with traffic at the end of the day? Is it hard to wait in line? But it gives you prompts to ask about the adult questions there, but you're asking about the same symptoms. Okay, so what did you see with atomoxetine?

Dr Richard Price: Well, there were tolerability issues, like you mentioned. The GI side effects were the most notable. So we tried to use the lowest dose that they could tolerate, but sometimes they couldn't tolerate it. They had to stop, but we titrated up to the best that they could. And the effects were mild, mild across the spectrum. It had a signal as we would expect. So it validated what we know about atomoxetine. It wasn't like an aberrant study. It had mild effects for impulsivity and hyperactivity, and inattention, and some tolerability issues.

Dr Greg Mattingly: So I remember the graph in your article, having read your article when it first came out, and not that atomoxetine didn't have any effect.

Dr Richard Price: No, of course.

Dr Greg Mattingly: But it had a mild effect.

Dr Richard Price: Mild, yes.

Dr Greg Mattingly: A mild effect over and above what they were already taking, either stimulant or on no medicine.

Dr Richard Price: Correct. 

Dr Greg Mattingly: It improved some symptoms, but not in a robust fashion. And there were a fair amount of side effects, right?

Dr Richard Price: Mm-hmm. 

Dr Greg Mattingly: GI, other side effects. Okay. You then took those patients who had tried atomoxetine, and what did you do next with them?

Dr Richard Price: So then we did a 5-day washout, and we searched the literature just to confirm that we don't really see a withdrawal syndrome from atomoxetine, and we verified that their AISRS and their ADHD rating scale scores had reverted to their baseline. So we were now back to where we had started.

Dr Greg Mattingly: So wash out the atomoxetine, so we're not worried about theoretical issues, about more combinations. Kept them on their stimulant If they're on a stimulant?

Dr Richard Price: They stayed on that same stimulant throughout.

Dr Greg Mattingly: Okay, so we're not changing that variable, we're just getting rid of atomoxetine, washing it out. What did you start next?

Dr Richard Price: So then we titrated up the viloxatine ER, and for the children 6 to 11 as per FDA guidelines be 100 mg for a week and then reassess. They were assessed every week, and if they were happy with that, they would stay on that. If they felt like it was somewhat of a response but could be better, next week we would go to 200, and the maximum would be 400, titrating weekly. And for the adolescents we would start 200 milligrams for a week, reassess, they're happy with that, we'll stay with that. If they felt could be better, we'll go to 2 200 milligram capsules, that's 400, keep them on that. For the adults, 200, 400, 600 week to week as tolerated, depending on how they respond. And I think one of the misconceptions in the field, and I think it comes from Strattera, with the slow titration with Strattera, is that you need to do a very slow titration with viloxazine ER, and that's not the case. It's the opposite. You can get the show on the road, boom, boom, boom, 1 week, 2 week. 1 week, 2 week, 3 week perhaps for adults. And that's how we did it.

Dr Greg Mattingly: So it's important for clinicians who haven't gotten to use viloxazine.

Dr. Richard Price: Correct. 

Dr Greg Mattingly: Having been in those studies,

Dr Richard Price: They’re underdosed.

Dr Greg Mattingly: Yep. So pediatric, we start with 100, but the average pediatric dose in the trials would’ve been around 300 milligrams. Adolescents, we start right away with 200, and the average adolescent's going to wind up usually 300 to 400. For adults, we get a little bigger dose, we start at 200, we can go as high as 600, and the average adult in the trials wound up at around 400 in the clinical trials. So the biggest mistake you make is you're hesitant to go fast because of what you’ve gotten burned by in the past, and you hang at a subtherapeutic dose, right?

Dr Richard Price: And you also don't have to wait to titrate. You can get the show on the road.

Dr Greg Mattingly: Okay, so you titrated and did both of these according to their package inserts?

Dr Richard Price: Yes.

Dr Greg Mattingly: Both atomoxetine and viloxazine. You use the therapeutic doses of both. You had a 5-day washout between atomoxetine and viloxazine. What did we see with viloxazine? So what were the results you saw?

Dr Richard Price: I'll say in two words, it kicked butt. <laughing> It's remarkable. So within a week you start seeing a signal in the kids, in about 2 weeks you start seeing a signal in the adolescents and the adults, and then it just gets better and better through let's say the next 4 weeks.

Dr Greg Mattingly:  So it's interesting listening to you, you're echoing back what we saw in the larger trials, right? Kids, within about a week, you start to see something, adolescents and adults, about 2 weeks, you could start to see something and then gradually improving the longer they stayed on it, but pretty quick onset for a nonstimulant.

Dr Richard Price: Yes.

Dr Greg Mattingly: Yeah. Quicker than what we're used to thinking about, right?

Dr Richard Price: That’s what I tell my patients and their parents, I say, give me 2 weeks, and I'll show you the world. Just give me 2 weeks. It's a chronic condition. It's not that long. It's not going to be 30 minutes. It's not going to be a 30-minute-onset stimulant. Give me 2 weeks, trust me, give me 2 weeks.

Dr Greg Mattingly: Yeah. So I love that setting the expectation. It's not tomorrow you wake up and it's already working. It's a week or 2, give me 2 weeks. I like that. Setting the expectation. I love your dataset though, for 2 reasons. One is it gives us data about viloxazine along with a stimulant if you need a stimulant, right? Because some patients that will be coming from that stimulant as they come to viloxazine, I don't want to just stop the stimulant, then they're going to call me 2 days later saying, oh, my medicine's gone.

Dr Birgit Amann: Mm-hmm.

Dr Greg Mattingly: So you overlapped it. I think that was a very elegant, smart thing to do where they could stay on that as you introduce this new agent.

Dr Richard Price: Well think about a benzodiazepine. Someone’s coming to you on Klonopin 3 times a day, Xanax 3 times a day, and you want to build in an SSRI. You're not going to just rip it off. You're going to build in and then taper.

Dr Greg Mattingly: Yeah. An important safety thing, and Birgit, I know we've discussed this, the clinical trials for viloxazine that we were a part of, they didn't look at that combination the way you did in your study, but they did have specific data about safety with stimulants. So what we looked at very carefully was when we added viloxazine on top of a stimulant, we didn't see any additional increases in heart rate or blood pressure. And when we used viloxazine with the stimulant, we didn't see that either one interfered with the other one's metabolism. So we saw no pharmacokinetic changes with that. So we have cardiac safety data that it didn't look unsafe to use the combination. And we have pharmacokinetic safety data that they didn't interfere with each other's blood levels. But we haven't had data about symptom response...

Dr Birgit Amann: Right.

Dr Greg Mattingly: …which is what your study gives us. So I think that's a very interesting piece of the puzzle. So you saw a significant improvement. If I remember the graph, compared the improvement they had with atomoxetine versus the improvement with viloxazine. Was it significant? Was it a little bit of improvement? What was the difference between the response?

Dr Richard Price: It was like four zeros (.00…), that level of significance. And I encourage people to check out the study. CNS Drugs, July 2023. Yeah, highly statistically significant. And that's why even in this sample of 50 patients and then the same 50 patients, so it's within subjects, so it helps statistical significance, it was a very strong signal. You didn't need hundreds and hundreds of patients to show a small reduction, and across the spectrum – inattentiveness, hyperactivity, impulsivity.

Dr Greg Mattingly: And so it's a crossover study. Not saying, am I better than nothing? It's a crossover study saying, am I better one agent to another? We don't have a lot of those in psychiatry, unfortunately.

Dr Richard Price: Right, mm-hmm.

Dr Greg Mattingly: That's not what we have. Our clinical trials are designed to show, is this better than placebo? You said, let's take a look at something that's historical. We've used it. We may have to step through it. Let's say our new treatment option with viloxazine now, does it bring something new to the table for us, right?

Dr Richard Price: And these are the same patients. These aren't like matched controls.

Dr Greg Mattingly: Love it. It's me versus me.

Dr Richard Price: That's right. 

Dr Greg Mattingly: So it's not me versus you.

Dr Richard Price: And every single one of them who was on Strattera said, I'm up for a switch. I'm not feeling so great on Strattera that I feel like I want to stay with that. Every single one of them agreed to try something else, similar class, and see what happened. In the end, there were only 2%, 4% that said, I think I would like to go back to Strattera; 96%, 98% decided that this was a better agent and I'd like to stay on this.

Dr Greg Mattingly: Okay, so let me summarize once again, for this is important. Crossover study, get to stay on whatever you're on, either stimulant or nonstimulant, no stimulant at all. We add atomoxetine, we measure the response, we take atomoxetine away for 5 days. We add viloxazine, we measure the response, and then we compare those 2 agents, and now big statistical significance, with viloxazine pulling away, right?

Dr Richard Price: Yeah.

Dr Greg Mattingly: Okay.

Dr Richard Price: And tolerability.

Dr Greg Mattingly: Yeah.

Dr Richard Price: Very well tolerated. There were only a couple patients who couldn't tolerate sedation even at the lowest dose. But that's not always a bad thing because we spoke about sleep disturbance and ADHD. So for the kids to be able to take something, we'll start it at night, we can move it to the morning for tolerability, but start it at night. And most kids finding that it helps them wind down and settle and get a good sleep without having to add additional sleep aids.

Dr Greg Mattingly: I've seen the same thing. Yeah, I was wondering what your take was there about sleep. Okay. Not just symptom improvement, but something we've all been hinting at is the speed of improvement.

Dr Birgit Amann: Mm-hmm.

Dr Greg Mattingly: There's another graph in your study that I remember and it just showed us the time course.

Dr Richard Price: The takeoff.

Dr Greg Mattingly: Yeah, it was the takeoff.

Dr Richard Price: The time to takeoff, time to launch.

Dr Greg Mattingly: And so with the atomoxetine curve, what I remember is it was a smaller improvement, but it was a lot slower improvement.

Dr Richard Price: Slogging along.

Dr Greg Mattingly: Yeah, it took a long time, which is why people get frustrated. They call you, they're not doing well. What did you see with the viloxazine, the speed of improvement?

Dr Richard Price: So when it kicks in, whether it's a week or 2, boop!

Dr Greg Mattingly: Yeah. And I would encourage the audience to go look at that article because that graph, it's one of those places where a picture's worth a thousand words, right? You see atomoxetine slow and gradual, just a little improvement. And you see viloxazine, it was just a whole different order of magnitude for speed of response.

Dr Richard Price: Well, full disclosure, I have to thank Maxwell Zachary Price, my son, medical student. He designed those graphs and of course helped instrumentally in the study, but he did all the Python programming to produce those wonderful graphs, which I agree with you. If you don't have patience, you don't have time and patience to read the whole study, look at the two graphs and it's like, mic drop.

Dr Greg Mattingly: Yeah. Well, and I think it's great for patients too.

Dr Richard Price: Sure.

Dr Greg Mattingly: Patients have a hard time with a page full of numbers, right?

Dr Richard Price: I've done that too. I've sent my study to patients or parents and they said, I don't know. I didn't hear about it, I'm not sure about this agent. It's kind of new. I read something about it. Okay, well take a look. These are your peers from the neighborhood. This is how they're doing. 

Dr Greg Mattingly: Birgit, what do you take away when you look at his study? I know you've looked at it as well.

Dr Birgit Amann: Right, right.

Dr Greg Mattingly: What was your take-home for your practice?

Dr Birgit Amann: Well, I was just thinking, now I have something I can submit with my appeal because they're rejecting my viloxazine request. And although I write all these things, now I can utilize this study to say, look, it is not just a me-too, but like you said, that's what it was initially likely considered. And I think insurance companies are still doing that. So to be able to add that to my letter could make a big difference for me and all of us clinically and for the patient to be able to access the medication. Our patients need to be compliant with our medications. And the other thing that your study helps me tell my patients is you're going to be comfortable with this medicine because you're going to tolerate it well. If you do have sleepiness, you can adjust the time that you take it. You're going to get that response. Bear with me for 2 weeks. I do that too. I think 2 weeks, in the big scheme of things, is nothing. So to be able to tolerate it, get that rapid onset, all of those things are a win-win for them, but we have to be able to access it. They have to be able to access it. So I see it as hopefully a very useful tool for us too.

Dr Greg Mattingly: Okay. The two topics I know we've covered so far: So overall bigger symptom improvement with viloxazine, highly significantly improvement, like 3 to 4 times the symptom improvement if I remember right. And then faster onset. There were two other data pieces that I really pulled out of your article. And I'll have to say, I'll share something with you. Your article sits in my top right-hand drawer of my desk in my office. It's something I think has a lot of real-world clinical evidence for our patients. And I do love those graphs. I've shown those graphs about helping people to understand the difference between these 2 agents. Patient preference – so it wasn't just symptom improvement, but patients tend to tell you, listen, I either like something or don't like something based on side effects, whatever it is, speed of onset, and just how do I feel in my life? Am I functioning well? So what was patient preference between atomoxetine versus viloxazine?

Dr Richard Price: Well, just about all of them, when they had compared the 2 agents, said I want to stick with this viloxazine ER. I don't want to go back. And the only reason why is was because maybe the sedation was a little bit too much, even at the lower dose. They just couldn't tolerate that. But that was unusual.

Dr Greg Mattingly: But if I remember the number, it was what – 96, 98%...

Dr Richard Price: Yeah, very high, yeah.

Dr Greg Mattingly: ...that preferred viloxazine? So a 96, 98% hit rate...

Dr Richard Price: Right.

Dr Greg Mattingly: ...for one agent, head-to-head versus another?

Dr Richard Price: And look, in real-world clinical practice, we're switching people all the time for whatever their condition is. They try one medicine. We either do a cross titration or we taper it off or we stop it and we start something else. People are switching agents all the time. I don't really have any other agents like this, and I am familiar with all the agents that are out there, that had this kind of universal appeal and preference in switching. Usually you're switching and you're switching, switching. And when you have to switch. So the people appreciating the benefits and then staying on it, and tolerability. And then you might invest some time upfront, maybe you'll have a couple visits upfront, but with stimulants, you're going to have those monthly sessions, which cost the healthcare system money. And it might just be a refill, but you have to have those sessions, make sure not abuse, diversion, it's adequate. With this, they're good to go. You need a couple of visits, and now, see you in 6 months if we're good. And come back 6 months, how's it working? Still working.

Dr Greg Mattingly: Okay, I'm going to use a sports analogy. To hit a grand slam, you've got to cover all four bases, right? You can't just get stuck at first. Can't get stuck at second. You got to get all the way around. So you showed us bigger symptom improvement. You showed us faster onset patient preference, 96, 98%. The last part of that grand slam that I thought was really interesting is you were able to pull back on the stimulant...

Dr Richard Price: See, that's fascinating.

Dr Greg Mattingly: ...in a lot of your viloxazine patients, right?

Dr Richard Price: Didn't anticipate that.

Dr Greg Mattingly: Yeah.

Dr Richard Price: We didn't set out to find that. We wanted to make things better and not make things worse, but we didn't know what would happen. So what happened was the vast majority, almost all the kids - and their parents were very happy about this, they weren't so happy about stimulants in general for their kids - were able to not just taper, but taper off. And for the adults, at the very least, they were able to taper and to decrease the burden of how many times a day they took it, what the dose was, the on/off effects. And I felt that has huge implications because many people out there either are on stimulants or they want stimulants, especially adults. You just can't pry them away from it. But you can make a deal with them. Look, we're going to build in this agent, which is in your best interest. I will give you stimulant if you agree to take this with it. It'll minimize your dependence on stimulants when the pharmacy doesn't have it, when you ran out of pills, when you didn't calculate properly, you won't be living on the clock. And this has, I think, implications for the substance abuse community, which I think we could talk about at some point.

Dr Greg Mattingly: Yeah, I think it has implications not just for the ADHD community, right? Having an agent that has a different mechanism of action that we now know that had faster onset, bigger symptom improvement, high patient preference, but allowed you to help to decrease the stimulant burden. If I remember your article, like you said, the majority of your kids came all the way off stimulants. So it was the majority, it was a large percentage, and the majority of your adults were either able to come off stimulant or decrease their dose. So that's a winning message. And I think that's the grand slam symptom improvement, faster onset, patient preference, and being able to decrease the stimulant burden.

Dr Richard Price: And when I found that, that's when I reversed the paradigm. Look, this is the foundational treatment. If it doesn't work out, it doesn't work out, but we're going to try this first. And if this is working sufficiently, you're good. It's working but maybe not quite enough, so then we'll add another agent if we need to. Maybe it won't even be every day. Maybe it'll be workdays and it won't be weekends, but you're not going to be dependent on it as your only agent. And I just think that's a much better public health message and public health need for our society and for patient wellbeing and for the family members that live with them. It's a 24/7 condition, and stimulants are not working that way.

Dr Greg Mattingly: Birgit, you're thinking over there, what's going through your mind as you hear this?

Dr Birgit Amann: Well, it just resonates for me with the challenges that I'm faced in my practice every day. And it's just such a helpful answer to a lot of the things that other medications really haven't accomplished or covered.

Dr Greg Mattingly: I think it's a holistic message. We're not saying that there's a one-size-fits-all answer for our patients. It's a holistic message. Talking about, let's start with something that's been highly successful in my practice, something that's given me good overall coverage. It's helped to minimize some of the other burdens of treatment. And a holistic message about how do we think about this journey with ADHD, not a one-size-fits-all, but how do we help to optimize your outcomes as an individual patient, a kid, an adolescent, an adult, whatever your comorbid conditions may have been in your population and all of those types of things.