PsychEd4Peds: child mental health podcast for pediatric clinicians

32. Meds for ADHD and/or anxiety

• Elise Fallucco, Jeffrey Strawn • Season 2 • Episode 32

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Is there a go-to medication to treat a child with both ADHD and anxiety?  Join us as we continue the conversation with Dr. Jeffrey Strawn from Cincinnati Children's Medical Center to discuss how to approach medication treatment for a child with ADHD and anxiety.  

We talk about which stimulants are better tolerated, when to use alpha 2 agonists (like clonidine and guanfacine), and finally what to know about the norepinephrine reuptake inhibitors, Viloxazine (Qelbree) and atomoxetine (Strattera). 

Key Points:

1 – treat ADHD first, then address residual anxiety (unless anxiety is Severe)

2 – When treating ADHD, start with stimulants;  Methylphenidate (MPH) stimulants are less likely to cause mood/anxiety sxs than mixed-amphetamine salts; MPH stimulants also have  ½ incidence of appetite suppression relative to the mixed-amphetamine salts

3 – When to use alpha 2-agonists

o   Clonidine is “a little messier” – hits multiple receptors (alpha 2a, 2b, 2c; hits imidazoline receptor), more likely to affect BP, sedation; best for problems initiating sleep 

o   Guanfacine – “much more selective for alpha 2 A receptor”,

o   Guanfacine XR can be dosed once daily (vs. clonidine xr which is still BID) 

o   Dosing and titration of Guanfacine XR stay below 6mg, 0.1 mg/kg/day

o   Guanfacine XR considered as adjunctive med in addition to SSRI for anxiety

o   Good to help w/ impulsivity

4 – Viloxazine/Qelbree (NRI) “what’s hype vs. what’s clinically relevant pharmacology?”

o   Works more rapidly than atomoxetine: Even within first couple of weeks, noticing improvement in symptoms

o   Little 2D6 metabolism, but not affected by 2D6 metabolizer status like atomoxetine (did you know fda recommends different dosing/titration based on metabolizer status in atomoxetine)

o   Potent CYP 1A2 inhibitor (which metabolizes caffeine/energy drinks)  increase caffeine exposure (blood level over time) six fold 

** ADR2A genetic polymorphism means 2/3 people do NOT experience anxiety when they consume caffeine

Dr. Jeff Strawn is a Professor of Psychiatry and Behavioral Neuroscience at the University of Cincinnati College of Medicine.  Dr. Strawn directs the Anxiety Disorders Research Program and conducts clinical trials and neuroimaging studies in patients with anxiety and related disorders.  He is an internationally recognized expert int he field of child and adolescent anxiety disorders.

Check out our website PsychEd4Peds.com for more resources.
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Dr. Elise Fallucco:

Welcome back to PsychEd4Peds the child mental health podcast for pediatric clinicians, helping you help kids. I'm your host, Dr. Elise Fallucco, child psychiatrist and mom. This week, we're continuing the conversation with Dr. Jeff Strawn about medication treatment for ADHD and anxiety. We'll start by talking about stimulant medication. Then we'll switch and talk about non-stimulant options. Like alpha agonists. As well as the norepinephrine re-uptake inhibitors viloxazine and Atomoxetine. So let's jump back into the conversation. With Dr. Jeff Strawn. is there a go to stimulant that you would use for a child with ADHD and a positive family history of anxiety to try to minimize the likelihood of worsening anxiety?

Dr. Jeffrey Strawn:

Now, this is where the guidelines probably don't help us as much as they could because these guidelines, which are a bit old at this point, actually recommend treating the primary disorder. But if we actually look at the evidence, except in some rare circumstances, the evidence actually suggests treating the ADHD first, and then seeing, what we're left with in terms of those residual anxiety symptoms again, situation where we had severe anxiety and ADHD. We might approach this a little bit differently, but all other things being equal, our data really suggests that we should treat the ADHD first. So now to your question about treatment, which should we go with? So in terms of now we're talking about treating ADHD, and so I think really the evidence that we have is for stimulants and within that stimulant family, I tend to use the methylphenidate based medications. And I think that's, somewhat based on some of the tolerability meta analyses that suggests that they may not worsen anxiety symptoms. In fact, there's actually some evidence they improve anxiety symptoms. We can talk a little bit about that, but I tend to avoid the mixed amphetamine salts in the pediatric population, at least as a first line medication, just because there is some evidence that they can cause more irritability and some other symptoms, at least from meta analyses.

Dr. Elise Fallucco:

I completely agree. I also start with the methylphenidate products. I clinically, I find them, the kids tend to tolerate them better. And then if they don't work, then we'll think about mixed amphetamine salts., but I've had a lot of kids where you start on mixed amphetamine salts and they'll get irritability or increased anxiety. And so they're not my first choice,

Dr. Jeffrey Strawn:

right? And also, I think, just in terms of tolerability. We roughly have almost half the incidence of appetite suppression and some of these other side effects that we think of outside of just the emotional or neurobehavioral side effects of stimulants with the methylphenidate based medicines relative to the mixed amphetamine salts.

Dr. Elise Fallucco:

Backing up, sometimes when we're starting treatment for ADHD, you can use family history to guide you, if you One of the parents is doing or one of the siblings is doing really well on a certain medicine. You might think about trying that one for the child, but without any of that information, the go to medicine would be something in the methylphenidate class.

Dr. Jeffrey Strawn:

That would certainly be my approach. It sounds like it's yours

Dr. Elise Fallucco:

as well. Yes. Shifting gears from talking about the stimulant medications. Let's talk about the non-stimulant medications for ADHD. So, of course, we've got the. Older ones, the alpha two agonists, like guanfacine and Clonidine. And in addition, we have the nor epinephrin re-uptake inhibitors like Atomoxetine which is Strattera and the newer one. Viloxazine or Qelbree. There's a lot of buzz, about non stimulant medications for ADHD. Are there any cases of kids with ADHD where you would start ADHD monotherapy treatment with a non stimulant as opposed to a stimulant?

Dr. Jeffrey Strawn:

There are probably a few. The one may be in an older adolescent who has a history of perhaps stimulant misuse. Now, again, I think, even in those situations, that doesn't necessarily rule out my using a stimulant because, many of these kids may have used it more as a Self-help medication, but I think other situations, would be where we've had significant side effects with a stimulant. I think you laid out some of the options in terms of the alpha two agonists and also in terms of Viloxazine and atomoxetine. With regard to the alpha two agonists. Really what we have here are clonidine and guanfacine and a couple of things that I'd say first of all, while they're both alpha 2 agonists, they differ a little bit in their pharmacology and that's something that does give rise to differences in terms of tolerability. So when we're thinking about clonidine, we're thinking about something that's a little messier. So it's going to hit alpha, 2A, 2B and 2C. It's also going to hit the imidazoline receptor, which may give rise to more of the blood pressure related side effects, as well as probably some sedation as well. But it's a little bit of a dirtier medication relative to guanfacine, which is going to be much more selective for that alpha 2a. I tend to, for that reason, as well as just in terms of ease of dose, because if I'm using the extended release form, I can do once a day with guanfacine, whereas I still have to do twice a day with the extended release Clonidine. But I do tend to probably use guanfacine a little bit more than clonidine.

Dr. Elise Fallucco:

Personally for kids with ADHD. I really would just use clonidine for sleep. I rarely use it during the day to control impulsivity or ADHD symptoms. More often I would, like you, I would use the guanfacine or particularly guanfacine XR. We used to think about guanfazine XR or Intuniv as 1,2,3, and 4 milligrams. But maybe about 5 to 10 years ago, I started hearing about, being able to titrate up to 5, 6, or 7., do you have a ceiling when you use guanfacine

Dr. Jeffrey Strawn:

XR? I do. I generally stay below six milligrams, but I think the dosing is really important in terms of guanfacine because if we look at the ADHD studies, it's really not until you get to 0. 08 milligrams per kilogram with the extended release guanfacine that you really get the big effect. And if you want to make the math easier, it's actually 0. 08 to 0. 12, so I sometimes will just go by 0. 1 because I tend to not like math and that way I can just divide in terms of the patient's weight in kilograms,

Dr. Elise Fallucco:

that's really helpful. Obviously we're going to start at the lowest dose and even though guanfacin is not as messy as clonidine, we still have the potential for blood pressure side effects. But the idea would be to titrate knowing that. In clinical studies, getting a getting close to 0. 1 milligrams per kilogram per day dose is going to be where you're going to see the effect.

Dr. Jeffrey Strawn:

Absolutely. And in the one study that we have, that's a placebo controlled study. In terms of disclosure, this was one of our studies, but it was not designed to be an efficacy study. We actually did go higher than that four milligrams in terms of treating kids with anxiety. Now, this is a population without ADHD, but kids with generalized separation or social anxiety disorder, treating them with Guanfacine.

Dr. Elise Fallucco:

I'm so glad you brought up that study because I wanted to talk about it. It's the one that was published in 2017. You were first author and you guys looked at, as you said, guanfacine in kids with different types of anxiety, the generalized separation social anxiety who did not have ADHD. And so at the time we're thinking, Oh, this isn't ADHD med, but they're looking at it in kids with anxiety. And then you find out it's well tolerated, it's feasible. And in fact, the kids showed some improvement in their clinical global impression. on the medication. And so could this be an adjunctive medication for anxiety? So how do you use guanfacine in, let's say a kid does not have ADHD. Do you consider guanfacine for anxiety treatment?

Dr. Jeffrey Strawn:

I do, but I think we generally have better treatments as first or second line. As you alluded to, I often use it adjunctively uh, in those patients, perhaps that I've not gotten a full response in terms of my SSRI. Or there's been some tolerability concern, et cetera.

Dr. Elise Fallucco:

What I would teach some of the pediatricians around here is obviously start First line treatment for anxieties, SSRIs, but if you're close, but we're not quite there, the child may or may not have ADHD, it's reasonable to consider adding on guanfacine to see if it can help with some of the anxiety symptoms Shifting gears a little bit from the alpha two agonists, I wanted to talk about the new hot drug on the market. That's not actually that new and maybe not that hot, it's called viloxazine or Qelbree or sometimes I call it Quelbree because I have no idea how to say it. I think they say

Dr. Jeffrey Strawn:

Qelbree, but I've heard both. So I add

Dr. Elise Fallucco:

a U in there. It seems like all of my Scrabble intuition tells me that Qs have to be followed by Us. But moving on, so for which cases, do you think that Viloxazine or Qelbree is a good option?

Dr. Jeffrey Strawn:

So maybe taking a step back in terms of Viloxazine and talking a little bit about it. So you know when this originally came out, it was really presented to me as something like atomoxetine and certainly reading through things, I looked at it as another norepinephrine reuptake inhibitor. It does do a bit more, but again, it's always hard to figure out what's height versus what's actually clinically relevant pharmacology. I'm sure your experience is similar to mine in terms of atomoxetine. We started. We titrate, we wait. Are you better? Are you a little bit better? You a little bit better? Let's wait some more. And for me, that's often something that's very frustrating because, during that time, you may still be getting side effects but you're not necessarily seeing the efficacy. And that for me is probably one of the biggest drawbacks to atomoxetine. And so when I started using Viloxazine I was expecting. A similar profile in terms of just that temporal course of response and what patients started telling me was even within those first couple of weeks, they had a much earlier response. They were noticing some improvement in symptoms. And so I think it probably is very different relative to atomoxetine. The other issue is that we don't have as much of an issue in terms of variation in metabolism. We have a little bit of 2D6 with filoxazine, but obviously with atomoxetine, we have major differences in terms of how folks metabolize the medicine. And the FDA even recommends different titrations and different dosing based on Whether a patient is a slow or faster metabolizer for cytochrome 2D6. Back to Viloxazine, a couple things that are probably also relevant certainly I do see improvement beyond what I historically have seen even with an alpha 2 uh, or with atomoxetine. But the other thing that I've noticed a couple of times, especially when I forgot to mention it, is it's a pretty potent inhibitor of cytochrome 1A2. And so a lot of my patients, like me, drink energy drinks and coffee, and they've actually In coming back and as I asked about the medicine mentioned some tremulousness and as we started really unpacking that what we learned was that it was directly related their caffeine intake. Viloxazine will actually increase your caffeine exposure. So blood level over time SIX FOLD. Whoa. Substantially. So my cup of coffee that I'm drinking right now becomes six cups of coffee. So that's probably very clinically significant.

Dr. Elise Fallucco:

Six times exposure. So basically like it's The equivalent of ordering a tall at Starbucks and getting three Venti's instead of getting exposure to three Venti's. Yes.

Dr. Jeffrey Strawn:

and then we also back to our topic today have that complex relationship between caffeine and anxiety, which again, I think we're all taught in residency and actually, quite frankly, in medical school that caffeine causes anxiety. The reality is that it doesn't for about two thirds of individuals. So there's a genetic polymorphism in the ADR2A gene uh, that makes some people really not experience any of those symptoms with caffeine.

Dr. Elise Fallucco:

This makes sense. I'll see somebody having a caffeinated beverage at five or at 6 PM and I'm thinking, Are you kidding? If I had that, I would be up all night and they swear it doesn't affect them that they still can sleep and they're probably right. ADR2A polymorphism. It explains it all now. back to Qelbree. This is really promising that in your clinical experience, it tends to be more effective than atomoxetine or stratera. Certainly it works more rapidly that we don't have to worry as much about the 2d6 polymorphisms that can affect dosing depending upon whether you're slow or rapid metabolizer. And that the main thing to look out for would be that it's gonna increase your exposure to any caffeine that you're drinking. And so we have to be careful about that.

Dr. Jeffrey Strawn:

I think that was an excellent summary. So the other thing that probably is important to mention with regard to Viloxazine, is that some of it is metabolized by 2D6. And so what we'll see is about a 20 percent bump in drug levels of Viloxazine in patients that are 2D6 poor metabolizers. Now, in general, that's not thought to really be clinically significant.

Dr. Elise Fallucco:

so there are some 2D6 effects, but unlike with atomoxetine, we don't have to be dose adjusting significantly in response

Dr. Jeffrey Strawn:

I think that's very well put.. And we wouldn't necessarily check 2D6 metabolizer status at baseline or pharmacogenetics for VIloxazine, whereas we would want to with Atomoxetine. I think that's also a very fair statement.

Dr. Elise Fallucco:

Wow. We've covered so much in just a short period of time. So I want you to do a quick recap before shifting gears. Dr Strawn. You would recommend that in somebody with ADHD and anxiety, we treat ADHD first and then address residual anxiety. Unless the anxiety itself happens to be incredibly severe. And as far as treatment for ADHD, you would start with the methylphenidate stimulant products instead of the mixed amphetamine salts, because they seem to be better tolerated. We talked about the role of alpha two agonists and that Clonidine is a little bit messier, alpha, two agonists that hits multiple receptors and is more likely to cause the blood pressure changes and sedation. Whereas guanfacine is much more selective for the alpha two, a receptor and the XR version can be dosed once daily. With a target dose of 0.1 milligrams per kilogram, per day. To help with impulsivity. And also to help manage some of the side effects with stimulant medication. And finally we discussed the norepinephrine re-uptake inhibitors and it sounds like you're a big fan of Viloxazine which works more rapidly than Atomoxetine I mean, is not effected by two D six metabolizer status like Atomoxetine is, but that we just have to be careful about Viloxazine because it's a potent 1A2 inhibitor which can increase caffeine exposure over time. Six fold. We are not done talking about ADHD and anxiety with Dr. Strawn. So we hope you'll join us next week. As we do some rapid fire Q and a. Talk about an amazing resource available for all pediatric clinicians. And finally discuss why medication for ADHD and anxiety is like peanut butter and jelly. Thanks for joining hope to see you next week.