72. Bench to Bedside - Can we develop Tolerance to stimulants? with Dr. James Waxmonsky

Does our brain adapt to stimulant medication over time, develop tolerance, so that we require higher doses to achieve the same effect?

When patients tell us their stimulant doesn't seem as helpful (after working well for a while), could this be tolerance? ... or could it be something else? 

To answer these questions, Dr. Elise Fallucco chats with Dr. James Waxmonsky, co-PI for NIMH-funded study: Examining Tolerance to CNS Stimulants in ADHD. 

00:00 Introduction of Dr. James Waxmonsky

01:26 What Is Tolerance?

02:10 Clinical Evidence for Tolerance

02:57 Longer-term Tolerance to stimulants

03:40 "The Brain Moves Its Targets"

04:16 Clinical Considerations in evaluating when "meds not as helpful": Changing Life Demands or true tolerance?

06:30 Management of Stimulant Tolerance

06:56 Clinical Pearl: Ask about increases in executive functioning and life demands

07:40 Taking a break from stimulant medication

08:14 Waxmonsky Longitudinal Study

09:00 Weekend Holiday Design

09:32 Recap - Do weekend holidays matter and reduce the need for higher doses?

11:46 Quicker dose escalation in continuous vs. holiday groups

14:00 Weekend Dosing Tradeoffs

15:45 Growth vs Dose Myth and Mg/Kg Dosing

17:35 Recap of how to Manage Tolerance

17:57 Toolbox for Recapturing Effect

18:37 Closing Thoughts

19:04 Final Recap

Dr. James Waxmonsky is the Division Chief of Child Adolescent Psychiatry at the Hershey Medical Center, the University Chair in Child Psychiatry at Penn State and a Professor of Psychiatry at the Penn State College of Medicine. He serves as Co-PI for an NIMH-funded study, Examining Tolerance to ADHD Stimulants.

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Transcript

Dr. Elise Fallucco 0:21

Hello and welcome back to Child Mental Health for Pediatric Clinicians. I'm your host, Dr. Elise Fallucco, child psychiatrist, and Mom Today's episode is part of our new series called Bench to Bedside, where we examine the latest science in child and adolescent mental health that has the potential to change your practice. And today we're gonna be answering the question, does your brain adapt to stimulant medication over time, develop tolerance, and then require higher doses? So in other words, when we see patients back for follow ups in our office who had been doing pretty well on a stable dose of stimulants for a while, and they now tell us the meds don't seem like they're as helpful. Could this be tolerance or could it be something else? And to answer this question, I'm thrilled to be able to welcome to the pod a very new guest. He's co-PI for an NIMH funded study called Examining Tolerance to CNS Stimulants in A DHD. In addition, he's professor and chair of child psychiatry at Penn State and has devoted his career to studying A DHD. And stimulant treatment in children and teens. So without further ado, let's welcome to the pod Dr. James Waxmonsky

Dr. Jim Waxmonsky 1:38

It's a pleasure to be here. I'm excited to have a chance to talk about stuff, and Thank you for inviting me.

Dr. Elise Fallucco 1:44

Of course, and we're so happy to get into it. How would you describe the phenomenon of tolerance? How would you define it and describe it in children and teens?

Dr. Jim Waxmonsky 1:54

You know, tolerance as a concept, I think has been around for decades. Actually, the majority of this work has done in the seventies and the eighties, and then kind of went dark for a while. But tolerance is basically, I'm using the same drug and I'm getting a diminishing response over time. And the assertion is that the body, in this case, the brain is adapting to what the drug is doing and kind of undercutting

Dr. Elise Fallucco 2:17

That's an excellent, excellent way to describe it. Certainly as clinicians, we understand the concept of tolerance when it refers to addiction and, you know, substances like cocaine but we know less about it as it refers to stimulant medications. However, our A DHD meds, like some of the drugs to which people can become addicted, act on the dopamine system. And you put it really beautifully that essentially our brain adapts to these changes in the dopamine system by trying to kind of regulate and keep things steady. So theoretically it might make sense that our brain could develop tolerance to stimulant meds. But what is the clinical evidence that we have to suggest that stimulant tolerance occurs?. Let's take the case of a patient's been on the same stimulant dose for months. They're compliant. The med initially seems to work really well for the first few months, but then several months later they returned to the office saying they do not think the med is working as well. How do you interpret that and could that be an example of longer term tolerance?

Dr. Jim Waxmonsky 3:18

We hear that a lot from parents originally when we started the treatment, the child was really succeeding. All of feedback was positive from the school and the work was getting turned in and, and now, you know, I gotta be on them more. You know, so we always try to understand. What is the data? How, what is it you're receiving? Is it, it is just simply lack of feedback from the school, or you're getting very specific feedback but ultimately I've gotten so many occasions where the function isn't as good and the dose is exactly the same. And for a while the function was much better. And so that makes us wonder, and again, what little we know about the science of the brain suggests that, yeah. That we should expect this. it's a very fluid fluctuate system, the dopaminergic system. And we've known early on that the brain moves its targets, when we push with a med to try to reset to where it was.

Dr. Elise Fallucco 4:01

I just wanna repeat what you said'cause I think it's really powerful, this idea that the brain is moving its targets. And while we're trying to adjust things with stimulant medication to improve alertness and persistence and ability to. Engage in a task for a longer period of time that the brain is resisting these changes in some sort of way, which is kind of scary. So this brings us to, in this type of a situation, the clinical case of meds are working for months and then you go for a while and it feels like they're not working as well or not as helpful. I, how do you respond? How would you evaluate to see whether this could be tolerance or something else?

Dr. Jim Waxmonsky 4:37

Now obviously life changes and life is complicated, and one of the things we've learned from the MTA, particularly the adult data, is this concept of you either remit or you don't, probably goes out the window. What it is is life evolves. Some parts of life are more challenging and they may ask you to do something more that you're not innately good at or haven't figured compensatory mechanisms out, and then you're more impaired by your A DH adhd. It's really just a mismatch between skills and demands of the day. Now again, in kids, you can see this coming. Ah, fifth grade, that's a much different ball game than middle school. you know, ninth grade, we know that's a different ball game than middle school. And you know, even like third grade, that's typically when the kids start to get asked to do more independently. That's an appreciably different ball game than first grade. So when the decay or the decline is from grade to grade, this is a different teacher, it's different demands. and if the dose is low or reasonable, go ahead and up it. Particularly if you, you know, the current teacher is reporting a lot of A DHD symptoms. I wouldn't tend to think of that as tolerance, but when you're within a school year and you're starting to get a lot of problems that initially cleaned up very nicely within the MET, and it's the same teacher and the demands aren't really any different, I think then I legitimately wonder about tolerance.

Dr. Elise Fallucco 5:49

So to interrupt and recap, you're pointing out that when we see a clinical presentation of a patient whose stimulant, which was previously effective isn't working as well, first, we wanna consider whether the demands at school have increased to the point that they're having trouble compensating and some clinical pearls. You highlighted that there are three major times when we'd expect to see this. So third grade transition to middle school and transition to high school. And if the case is that we're not seeing major bumps up in the demands at school and the demands seem to be fairly stable, then you might wonder about the possibility of long-term tolerance.

Dr. Jim Waxmonsky 6:26

And that's when we might just quickly probe off the med to see if we get any response.'cause if you're getting no response, then I think you really wonder, well how much of this is really a DH adhd? Do we have another comorbidity that's really taken over? But if I preserve a little bit of effect and it's just clearly not what it was, That makes me wonder more about tolerance but gives me some optimism that maybe we can do something with this class of meds and get better than where we were.

Dr. Elise Fallucco 6:51

So now we're getting into talking about management of tolerance. There's a couple different ways to approach helping kids who seem to have developed a little bit of tolerance to stimulants. How would you approach it?

Dr. Jim Waxmonsky 7:03

one option clearly is it just up the dose? and every model of tolerance would suggest that's gonna give us some short-term benefit. now it gets trickier when we're starting to get into side effects and we're getting to kind of FDA maxes. but you know, that, that's the way I try to disentangle.

Dr. Elise Fallucco 7:18

Yeah. like we wanna rule out the possibility of that the external demands have increased, and that could be why it feels like we're not as successful.

Dr. Jim Waxmonsky 7:27

Yeah. And maybe yes, depending on what the demand is, maybe having a higher blood level of the medicine would be helpful because it requires more mental effort or there's less supports within the classroom because you're expected to be more independent when you're older, because the demands have changed. So we wouldn't, shouldn't be surprised if the function has changed because the expectations have changed. But if the expectations are exactly the same and we used to meet them and now we're not meeting them, then one wonders did is something going on with the drug. And I think tolerance is a reasonable thing to explore. and that either means you go up on the dose or you come off the med.

Dr. Elise Fallucco 8:01

Just to elaborate on what you're saying, some of the literature suggests that if you stop a stimulant and give your body a little bit of a break, whether it's in terms of days or weeks, that during that time, the brain readjusts so that it loses some of its tolerance, and then you can restart the medication. And recapture some of the original efficacy.

Dr. Jim Waxmonsky 8:22

most people don't want to come off the meds in the busy, in the middle of a demanding school year. Right. But when you start to get to kind of cornered by the dose or side effects, you're like, all right, well, it, it is a consideration. And, and that got us to this study,

Dr. Elise Fallucco 8:35

tell us about your study.

Dr. Jim Waxmonsky 8:37

Sure. We took kids that come to one of our therapeutic summer camps, started by Bill Palm way back when, The kids would come in, we would work with these kids for eight weeks. We would know them very well. We would adjust the medicine as part of their summer camp experience with all this wonderful direct observational data as to how they're doing. But in the best way that we could, we picked what dose worked literally while we were watching the kids in the camp. And the camp has a school component. It's not as demanding as school, but it has school component, and we've seen in studies that predicts the dose that works in school. So we find the dose. They're fairly low doses. We wanted to use Concerta to be consistent. So, 90% of the kids, anybody who could swallow a pill was on Concerta dose ranges is,, these are seven to 12-year-old, 11-year-old kids, so very low, 18, 27, 36. so then you come into the school year, 250 kids, run over four different annual cohorts. So we would take 50 kids a year in the summer, and then we track'em for the, for school year. And they're randomly assigned then, to take the med on the weekend or not And we blinded the weekend med because, we wanted to try to compensate for parental perception. The theory was then over the course of the year, would the dose change less? If you were unmedicated on the weekends, then if you were medicated on the weekends.

Dr. Elise Fallucco 9:53

what you're saying is you were intentionally giving some of the kids a weekend drug holiday where they were off meds, and then the rest of the group would just continue to take meds seven days a week, and you were trying to see if the kids that get these two day breaks from meds over the weekends, if they ultimately require lower doses in long the long term compared to those kids who are taking the same dose seven days a week.

Dr. Jim Waxmonsky 10:21

Now apriori, we have no idea if a weekend holiday is a good idea or not. If there is tolerance, if that's the best way to do it. But it's, it's practical. Mm-hmm. We know families do it. Uh, we've done other studies with weekend holidays looking at effects on weight gain and growth. And so we've done that before in studies and people don't quit on us. Um, and we gave them the med, so the med was free, but it also meant we knew exactly how much med we were dispensing and we would track them, we would track it weekly with them, whether they were giving the med So at the end of the year, the question was, did the dose differ if you were assigned to seven day a week dosing versus if you were assigned to five day a week dosing?

Dr. Elise Fallucco 10:56

This is a beautifully designed study. and, and I just wanna summarize for our listeners. So not only do you have this set up, this kind of like summer camp slash summer school situation where you have teachers doing monthly ratings and evaluations of the kids in the classroom

Dr. Jim Waxmonsky 11:14

We actually rate the kids every 15 minutes across the day. So you walk out of there with probably 50 ratings across an average day. it's a very precision estimate. So I would think of it as a special ed camp meets a partial hospitalization program with a focus on evaluating A DHD.

Dr. Elise Fallucco 11:31

So a lot of systematically collected observations from the teachers throughout the day over time to really get at what are their symptoms like, and then that drives what their meds, medication dose is gonna be. And the theory being that, Like going back to the issue of tolerance, the thought is that if your body sees the same dose of medication every day, seven days a week, that it's more likely to become tolerant and to eventually require a higher dose than if you're only on it five days a week and then you have your weekend holiday off meds.

Dr. Jim Waxmonsky 12:01

Right the goal was to let's create an interrupted break and see if that associates with dose at all.

Dr. Elise Fallucco 12:07

And what did you find? Can you tell us?

Dr. James Waxmonsky 12:10

When you look at the actual results we got between the two randomized groups overall, the mean change in dose over the school year was about 16 milligrams, and the difference in the amount of dose escalation between the two groups was about two milligrams between holiday and continuous dosing. Well, the actual two milligram difference at the end of the year wasn't statistically significant, and we did see that the trajectory or the rate of change over the course of the year did differ significantly based on which group you were randomized to. And what we saw is that in the beginning, third of the year, the kids assigned to continuous dosing seven days a week, escalated their dose faster, and then for the remainder of the year, that difference persisted, but it really didn't change, uh, didn't increase further or didn't really shrink. And then overall, the results do suggest that the dosing schedule or how frequently you give the dose does impact how fast the dose escalates over the course of the year, and possibly the timing as to when it escalates. And interestingly, we also noticed that how much medication you had received before the study also impacted the shape of the dose trajectory, or how the dose changed over the course of the school year within the study.

Dr. Elise Fallucco 13:22

So that's interesting. It sounds like over the course of a year, the difference between the group that didn't take meds on weekends and the group that took meds seven days a week was not statistically significant and it was really small, like about two milligrams. However, The group that took meds seven days a week overall tend to escalate their dose more quickly than the group that stopped meds on weekends. But the differences between the two groups over the course of the year was still pretty small.

Dr. Jim Waxmonsky 13:52

it's not enough to make me think you should change your standard prescribing practices for the first year of medication that a child uses over a school year.

Dr. Elise Fallucco 14:01

Mm-hmm.

Dr. Jim Waxmonsky 14:01

Um, if the med helps on the weekend, use the med on the weekend. But I does, I do think it gets back to the question if we just give the med, because we give the med all the time and there's not really any benefit from it. First of all, we know there's some impact on weight gain and in terms of that first year of use by skipping weekends. Secondly, yeah, maybe you're preserving the effect a little bit longer, going into year two or year three, by having those built-in breaks. I think it puts the emphasis on figuring out if the weekends matter. If they matter, two milligrams is small, don't worry about it. But if it's really not that much of a difference, and if schools while you're doing this, you might actually be preserving some of the effect for future school years by, Preserve by interrupting the medicine.

Dr. Elise Fallucco 14:47

What I'm hearing is sort of a really thoughtful discussion about whether it makes sense to continue stimulant medication over the weekend versus not. Obviously the most important thing we're looking at is. What does the child need to do over the weekend? Mm-hmm. Is it really critical for them to Right. Be on stimulant medication for the household to run smoothly for them to be able mm-hmm. Socialize well with their peers Right. And have a good time. And if so, you continue over the weekend. But what I'm also hearing certainly for kids who are not driving, and who don't have high demand over the weekend, that stopping the stimulant medication over the weekend may not be bad. it potentially may help, prevent slash minimize or mitigate the potential of tolerance by, you know, requiring increasing doses over time. And you mentioned the weight effect too, that if it's their first year of treatment for A DHD with stimulants and we're concerned that they're underweight, let's say that by not taking the medication on the weekend, that would help, you know, address potential appetite suppression.

Dr. Jim Waxmonsky 15:48

Yeah, that we know. Us and other people have done enough of these studies which says that, we don't seem to screw up the tolerability during the week by skipping the weekend meds. And there's no evidence that we screw up the efficacy during the week by skipping the weekend meds. So what you're risking is the weekend, and the parents are the very good judge of that. They're the ones who have to live with it. And yes, you'll probably, you'll help weight gain if that's relevant. And our data suggests that yeah, you'll probably come out, you know, with a technically potentially smaller, slightly lower dose. Now obviously you can't dose conservative two milligrams, so they're probably clinically that's not very impactful. Right. But, you know, for those kids that maybe it's a little bit more robust, so you might be one dose different. and, and over the course of years that could matter.

Dr. Elise Fallucco 16:32

one last question before I let you go. You mentioned in one of the studies, it's like seven to 12, seven to 11-year-old, the, you know, the current study. We know that during that time, you know, a lot of natural growth occurs and especially if, as kids are going through puberty, to what extent is the need for a higher dose better explained by just normal growth? Like should we expect as children develop and gain weight that they would naturally require a higher dose?

Dr. Jim Waxmonsky 16:58

Right. And I've, that, that's been out there because we live in milligram per kilo dosing. Right. but I've always been a little surprised by that because I could never really think of a mechanism why your body weight would impact How much of a, how much fluctuations in dopamine impact your cognitive function? it probably got my, I'm guessing more to do with developmental maturation timing within the brain than it does body weight. and when you look at the amount, you look at this as a predictor'cause it's easy to measure weight and the kids who simply gain a lot of weight are not the kids who tend to up their dose much. We do it, but I think it's a proxy of life getting harder. That's, you know, you go a grade level up, so you gain 20 pounds when you really look at it across a large group of kids and break down how much the weight has changed versus how much the dose has changed. It doesn't appear to be a predictor. I think it has some capacity to predict tolerability. I've not seen any real good data that makes me feel that it predicts. Efficacy. So to me it's irrelevant. And when you look at the adult doses, I mean the adult doses aren't that much. They're not any different than the kid doses. Barely the optimal doses for things like list dexamphetamine are not that different at adults versus adolescents versus kids, even though we've tripled body weight and you can argue about metabolism rates and all that, but they're not really that relevant for most stimulants. So I just don't think the data is there. The data we've gotten doesn't really suggest it. So I feel no compulsion at all to up dose based on body size.

Dr. Elise Fallucco 18:22

That is super helpful. in terms of treatment of tolerance, what you're saying is, let's say you have a child whose dose is escalated to the point that they're at the FDA max or near the FDA max and it feels like it's not as effective as it was and at that point. Something to consider is to take a break, give the brain some rest from that medication, see if, you know, some sort of adaptation occurs before restarting the med.

Dr. Jim Waxmonsky 18:44

Jim Swanson has really been behind this for years. He's the one who dragged me down this pathway, and he has a recent article in psychiatric times, that has some very specific suggestions. And he's even wondering if just shortening the stimulant duration to like, going back to one dose of immediate release, methylphenidate gives enough break over the course of the day, could you actually recover some of this effect? But again, that's all speculative. but I think it puts a tool in the toolbox that, hey, if you temporarily interrupt the dosing. Might you be able to recapture lost effect. And, and I think now it's worth a discussion is what I would say the data has led us to.

Dr. Elise Fallucco 19:23

Great way to close it. thank you so much, Dr. Wax Monki, for sharing this cutting edge research and most importantly, for sharing, clinical relevance. Like what do we do with this information and the data that's been emerging over time about tolerance? How does that affect our clinical practice with kids and with families? So this was an awesome discussion. I really appreciate getting this opportunity to talk with you. And thank you so much for sharing your experience, your research, your expertise with our listeners.

Dr. Jim Waxmonsky 19:50

Oh, my pleasure. Thank you for inviting me.

Dr. Elise Fallucco 19:52

And now for our listeners, I wanted to recap some highlights from today's episode. In this discussion about stimulant tolerance, Dr. Wax Monki and I talked about how our brain can adapt to stimulant medication over time in small, subtle ways and my takeaways from this discussion were One, I think we need to reconsider weekends instead of just defaulting to seven days a week dosing for stimulants. Make sure to have a good discussion with families about what are the demands over the weekends, and if it makes sense to continue the meds, to help meet those demands, or to just take weekend drug holidays. And that's such a funny word. I think we need better ways to describe not taking stimulants on the weekend, but this is what we have anyway. Benefits of potential drug holidays are decreasing the risk for long-term tolerance and also decreasing the risk for appetite suppression associated with stimulants. The second takeaway that I had from this discussion is to take a systematic approach when you see patients who are doing well on a certain dose of medication and then after a certain amount of time report that they don't think it's working as well. To not only consider the context, which we always do, checking to see if the demands that are being placed on the patient have changed and especially looking out for those big developmental transitions such as during third grade or the transition of middle school and high school. If the demands are increasing, it is reasonable to bump up the dose to see if that's more helpful. It's important to always remember that we do have evidence for some very subtle, longer term tolerance, and to be aware that that could be playing a role. Lots of things to think about. I hope you learned something. From this episode and that you liked our new Bench to Bedside series where we take the latest science in child, adolescent mental health that has the potential to change your practice. As always, please feel free to share your comments and questions, either on your podcast app, in the comment section, or check us out at our website, psyched the number four peds.com or on Instagram at psyched for peds. Thanks for listening. See you next time.