Pharmacological management of attention deficit hyperactivity disorder in children and adolescents

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Hi, and welcome to this Australian Prescriber Podcast. I'm Dr Justin Coleman, a GP in Inala in Brisbane. Today, we're talking about attention deficit hyperactivity disorder in children and adolescents, better known to you as ADHD. With me, I have an expert in the area who's written a superb article for Australian Prescriber, Daryl Efron. Daryl is a consultant paediatrician at the Royal Children's Hospital in Melbourne and a research fellow at the Murdoch Children's Research Institute. Welcome to this humble podcast, Daryl.

Thanks, Justin.

It's great to have you here. Rather than going into depth about what ADHD is, because I know that will be familiar to most listeners, we're talking about hyperactivity, impulsivity, and/or inattention, you started your article by suggesting that the paediatric prevalence is between 5 and 10%. And certainly, all listeners will be very familiar with the fact that this percentage has gone up and up over the last 20 years or so.

Just to start with a sidetrack, it does strike me, having been an editor of a medical journal, that authors do tend to quite understandably put a high percentage for the prevalence of the disease in question, which does include quite a few people who are sort of a bit borderline in terms of the diagnosis. And I guess those people at the borderline may not get quite the same benefit from the medications compared to those at the more severe end of the spectrum where most of the studies were done. Would that be true of ADHD, do you think?

Yeah. First of all, not every kid who is diagnosed with ADHD needs medication. It's really basically the moderate to severe. We did a study years ago of all the kids diagnosed by paediatricians with ADHD, in a large sample of Australian paediatricians across the country, and 4 out of 5 were treated with medication. So that, I guess, probably reflects your point that there's mild ADHD who might fulfil diagnostic criteria but don't necessarily need medication.

I had a case yesterday where we said, 'Look, there are some symptoms, probably ticks enough boxes, but he's functioning pretty well at school, not having major problems. Of course, there's always the risk of side effects with medication. I don't think it's justified at this point, but let's keep it under review and if next year, with increasing demand at school, things become more difficult, we might consider medication. Here's some information to read about it and let's keep talking.'

Yeah, it's interesting and you also mentioned in the article that GPs are going to be more involved in the initiation of medication.

Yes, I think GPs are already starting to become more involved. And I'm hoping that in the next decade, not just with adults, which is inevitable because there's not that many psychiatrists, but also with kids because it's so hard to get an appointment with a paediatrician in all parts of Australia, public and private at the moment. A key principle is gathering information across settings, from parents and teachers at school, to be confident that there are pervasive functionally impairing symptoms.

And your article makes it clear that that should be more than one setting. And in this age group, it's almost inevitably this school setting as well as the home setting. And of course, why are we treating? It's to enhance their cognitive, academic, and emotional development.

Let's move on to the medications now. So there's 2 classes of medication, the stimulants and non-stimulants. And you mentioned that about 6% of boys in Australia under the age of 18 and 2% of girls are prescribed one of these 2 classes. Let's talk about the stimulants first. Can you run us through those?

Yes, so the stimulants are almost always the preferred first-line medication if you're going to treat ADHD with a medication. As I said before, it needs to be at least moderate to severe, severity causing significant functional problems before you would contemplate prescribing. But unless there's a contraindication, and I'll come on to that in a moment, the stimulants should be prescribed first because they're the best by far. The effect size, how much benefit you get in symptom reduction, is much higher for the stimulants than for the non-stimulants.

Of course, kids with ADHD almost always have comorbid difficulties, such as anxieties, depression, learning difficulties, sometimes oppositional and aggressive behaviours. The stimulants don't usually help much with any of those. Sometimes they can help a little bit with aggression, but they're not really primarily designed to do that. They're designed to help with the core symptoms of ADHD, so inattention and impulsivity.

So the stimulants are very, very effective in about 80% of cases in helping with sustained attention to task and in reducing impulsivity, improving impulse control. And some kids have both of those symptom complexes, although there is a subgroup that are not particularly impulsive or hyperactive and that's called the predominantly inattentive type, and they benefit from this improved sustained attention.

The key point on that is that kids with ADHD, like anybody else, can focus well on things that are interesting to them, if it's Lego for some kids or music or computer games or whatever it is. The challenge is harnessing the mental effort for something that's intrinsically of low interest, which might be a maths worksheet or reading or whatever it is for individual kids. So that's what the stimulants can really help with, the kids can use their brains more efficiently and attend to low-interest tasks for longer, and the effects are remarkable.

I often say of all the things we do in paediatrics, there's very few things that are really as satisfying as treating a child with ADHD with stimulants, because most of the time there's a really big effect. You can see at the review appointment on the parent's face before they've even opened their mouth that there's a huge difference.

We should at this point, before we move on, name the 3 stimulants and just briefly any significant pharmacological differences.

Yeah, so there's 2 stimulants available now and they each have short and long-acting forms, so methylphenidate and dexamfetamine. Methylphenidate comes in 3 forms in Australia currently. There are short-acting tablets. The main trade name for that is Ritalin, although there are others. And they last between 2 and a half and 4 hours per dose. We normally start with a short-acting, so we can start really low and gradually build up and titrate. Maybe start with just a morning dose, then add in a lunchtime dose, and then sometimes a third dose after school. And just to see how it works, try and find the optimal dose for that child and an optimal timing in the day.

You can't really predict the dose based on weight like you can with most paediatric drugs. It's like caffeine. Some people are very sensitive to small amounts and other people can tolerate larger amounts. So you basically just start very low and gradually build up according to tolerance and benefit. And when you reach a dose that's really helpful and it's well tolerated, then that's the optimal dose. You don't need to keep pushing it.

And if the child responds well to short-acting, then there's the option of switching at some point to a long-acting preparation, which they only take in the morning before school. And most kids and families prefer to switch to the long-acting form, although not all. Some say, 'Look, multiple dose of short-acting is working fine. The school's having no problems giving the lunchtime dose, the child's not embarrassed or stigmatised by it. I'd rather not rock the boat.' But more often than not, they do want to switch to one of the long-acting forms.

With methylphenidate, there are 2 long-acting forms, Ritalin LA, which stands for long-acting, but it's kind of a medium-acting one, which is a capsule that contains methylphenidate in 2 types of tiny beads. Half of them are immediate release and half are delayed release. So it's supposed to replicate the dose of the short-acting in the morning and a second dose of the short-acting at lunchtime. And the drug company says that product lasts about 8 hours because each short-acting dose is supposed to last 4 hours. In practice, Ritalin LA tends to last about 5 or 6 hours most of the time. If you're lucky, it might last longer. It varies quite a lot between different kids.

Most of the kids that switch from short-acting Ritalin to Ritalin LA continue to get pretty much equivalent benefits, but not all. There's a proportion that, for reasons that don't make pharmacological sense, it just doesn't work as well for them. And the parents prefer to go back to short-acting or maybe try the longest-acting form of methylphenidate, which is called Concerta, which is a complicated delivery system. It's called an osmotic delivery system. It's a very slow-release preparation that delivers a drip of methylphenidate through a laser-drilled hole in the top of this tablet right through the day. And it lasts, again, the drug company says 12 hours. In practice, it lasts between 6 and 12 hours. Some kids, it just doesn't seem to last as long.

Thank you, Daryl. I should point out at this stage that you have declared no pharmaceutical conflicts of interest. We are dropping brand names a bit, but part of the issue is that there are different formulations and the brands have genuinely different release times. Let's talk about dexamfetamine.

So dexamfetamine's the alternate stimulant. And some kids will tolerate methylphenidate better and some kids will tolerate dexamfetamine better, and we've got no way of knowing. Some prescribers prefer one or the other, but there's no rational reason to choose one or the other. There's been historical fashions. For some reason, adults are more likely to have been treated with dexamfetamine in this country. It's varied depending on PBS [Pharmaceutical Benefits Scheme] listing and so on. But essentially, they're more or less equivalent.

Kids that don't tolerate whichever one you try first, which might be about 20%, have a high chance of doing well on the alternate. So if they don't respond or don't tolerate the first stimulant you try, then it's recommended that you then try the other stimulant. And about two-thirds of those that don't tolerate methylphenidate will tolerate dexamfetamine and vice versa.

Dexamfetamine comes in 2 forms in Australia. There are tablets which is just little white crash tablets, generic dexamfetamine tablets, 5 mg. They last a little bit longer than the short-acting Ritalin. Short-acting Ritalin, as I said, is 2 and a half to 4 hours. Short-acting dex is between 3 and 6, usually at least 4 hours. And sometimes you can get through the whole school day, particularly in younger kids with just a morning dose for short-acting dex, which wouldn't happen with short-acting Ritalin.

So it's quite a good option, particularly for younger kids where most of the key learning is in the mornings. The long-acting form of dexamfetamine is called Vyvanse, which is lisdexamfetamine, L-I-S dexamfetamine. It's a prodrug. It has a lysine amino acid attached to the dexamfetamine. And the lysine's not cleaved off until after the drug's absorbed. So that is the mechanism by which it has a very long action. So again, the drug company says 12 or 13 hours, but it's variable, so between about 6 and 12.

Let me fire a couple of questions at you which I get asked often enough by parents who perhaps aren't seeing the paediatrician for another few months. First of all, if they want to give it a break on weekends and school holidays, how do you see that?

Yeah. We always discuss that right at the start. So if the difficulties are mostly at school, then they only need to take it on school days and not on weekends and school holidays. But equally, if they've got difficulties at home, they can take it 365 days of the year or somewhere in between. It's not uncommon that parents decide to give kids medication every school day. I think they should have it every school day, so the child feels the same every day at school. And they can use it variably on weekends. They might use it for soccer on Sunday morning or on occasion if there's a birthday party or a family gathering or something like that. So it can be used flexibly.

Thank you. Second question, when the child comes back to see me and the parent says, 'I think they're doing okay, is there anything we need to look out for?' I do know enough that I should be taking the heart rate, blood pressure, weight and height. So what are we looking out for in terms of possible adverse effects?

There are very few true contraindications to stimulants. The only potential harm you can really do is if children have certain serious underlying cardiac conditions such as hypertrophic cardiomyopathy, arrhythmias, hypertension, and so on. So we should take a personal and family history of palpitations, syncope, and examine the child for a murmur, sudden unexpected death at an early age in the family. If any of those things are present, the child should see a cardiologist before starting stimulants. In the absence of those things, they don't need an ECG [electrocardiogram] or anything else.

The other relative contraindication is severe Tourette syndrome. I use the word severe intentionally there because many kids with ADHD have tics, and that's common and not a contraindication of stimulants. Stimulants can make tics worse, but they don't always. In fact, sometimes the tics improve. And can try it and see. If it does make the tics worse, then you stop.

The other one I'll just mention again to dismiss is anxiety. Anxiety is a very, very common problem for kids with ADHD. It's true that stimulants like caffeine can make people more anxious, of course, but again, they don't always. Some kids are less anxious. So again, anxiety, even quite significant anxiety is not a contraindication.

Thanks, Daryl. So meanwhile, I'm patiently sitting on my heart rate, blood pressure, and BMI [body mass index]. What am I doing with those numbers?

So stimulants at a population level, they increase the heart rate on average by 2 or 3 beats per minute and the blood pressure on average by 2 or 3 millimetres of mercury [mmHg]. So outliers, the most important group are teenagers with a family history of primary hypertension, you can tip them over into hypertension. So we should, and all the guidelines say, you should measure heart rate and blood pressure in all kids on stimulants at least every 6 months, which is true, but it's particularly important for teenagers. And you would treat that like you would monitor within the normal reference ranges for anybody else. If it's high, repeat it. And if it's still high, 24-hour ambulatory blood pressure monitoring is what I'd normally do and then get a nephrologist or a cardiologist involved. That's the cardiovascular stuff.

The growth aspects are interesting. So in terms of linear growth, height, the current consensus is that the stimulants, if you take them over a number of years, may reduce your final adult height by up to 2 or even 3 cm on average. Now, we always tell parents about that before we start. And in my experience, they're almost never concerned. You often get a response like, 'Oh, we're all tall in our family, so a centimetre or 2 won't make any difference,' or 'We're all short in our family, so a centimetre or 2 won't make any difference.' They're virtually never concerned about that, but it's important that we monitor it.

And I have seen kids over the years, a small number that have had growth arrest, and I've referred them to endocrinologists, but that's unusual. That's the reason for monitoring height.

Weight is more commonly a problem. The stimulants almost always suppress appetite. That's the commonest side effect by far. So naturally, growth can be a challenge for kids, particularly those that start out a bit on the slim side. So we need to give advice in advance about healthy nutrition, snack foods through the day and so on.

Often, kids on stimulants don't have much lunch. But usually, over 24 hours, the overall caloric intake can be maintained at an adequate level, but the timing of meals is often a bit different. So they'll have hopefully a reasonable breakfast, not much through the day, maybe a couple of muesli bars or half a sandwich. And then after school, they're usually hungry. 4 pm, they might have a large snack or a small meal and commonly another meal at 6 pm or something like that, so that in total they get enough calories to maintain growth.

Thank you, Daryl. Let's move on to the non-stimulants, which, as you pointed out, aren't quite as efficacious as the stimulants but still have a place. What medications are we talking about?

There's 3 main ones. First on the market was atomoxetine, which is marketed as Strattera. The other one is clonidine, which is a drug that GPs are familiar with for a wide range of indications. And then there's guanfacine, marketed as Intuniv. Clonidine and guanfacine are both centrally-acting alpha agonist drugs, but guanfacine is long acting.

And these 3 drugs have all been shown to be better than placebo in treating core ADHD symptoms. However, the effect size is only about half that, currently half that of the stimulants, so they're not powerful.

But they all have their own individual advantages. They're mostly considered or prescribed either if a child doesn't tolerate either of the stimulants, which happens sometimes. If there's a true contraindication to the stimulants, which is unusual. Or probably the most common reason they're prescribed is in conjunction with a stimulant. So if a child tolerates a stimulant, for example, up to a certain dose, but beyond that dose has side effects, we see that quite often. Then you might use the highest tolerated dose of stimulant, and adding a dose of a non-stimulant is a complementary concomitant medication. And that's quite common practice. So for example, you might use methylphenidate with atomoxetine, both in moderate doses.

Just on the mechanism of atomoxetine, it's noradrenergic, fairly selective. It's called SNRI, which is a bit of a confusing term. It's a selective noradrenaline reuptake inhibitor, so it doesn't have much serotonin effect. It's predominantly a noradrenergic agent.

The stimulants are mostly dopaminergic agents. They prevent dopamine reuptake. Dopamine's probably the most important neurotransmitter in ADHD. I think that's the main reason why the stimulants are best, is the dopamine. Atomoxetine boosts noradrenaline in the synaptic cleft and that's helpful.

It's a pretty gentle drug, atomoxetine, doesn't have many side effects. Does not suppress appetite, in contrast to the stimulants. Can have a mild anti-anxiety effect in contrast to the stimulants. And has a mild anti-tic effect, in contrast to the stimulants. So for all those reasons, it's quite a nice drug to use in a relatively low dose in combination with stimulants in some kids.

Clonidine is a very flexible drug, which can be really helpful in kids with a range of developmental disorders. It's good for core ADHD symptoms, similar effect size to atomoxetine. It's also very good for episodic explosive behaviour. And while it can be sedating, it's important we try not to sedate kids. But it's got an anxiolytic action that can be really helpful for some kids. And it's also the sedative properties we use sometimes intentionally with a nighttime dose. So sometimes we'll have kids on a dose in the morning to help with ADHD and anxiety, and another dose at nighttime to help with sleep. And sometimes you need 3 doses a day because it can only last a few hours in some kids, which is pretty annoying, but it can be a very, very helpful drug.

Guanfacine, it's the most recent of these drugs on the market. It's probably in Australia for about 10 years now. It's a once-day drug. The side effects are the same as clonidine, that is sedation and postural hypotension. It's unpredictable. For some kids, it works really well. For some kids, it doesn't.

When I use it, I normally prescribe it in the morning. But if they're sedated during the day, then we switch to giving it at night. There are some kids where even if you give it at night, because of sedation during the day, they're still sedated the next morning and they just can't tolerate it. It comes in 4 strengths, 1, 2, 3, and 4 mg, and we always start with the lowest dose.

Daryl, we might finish with where pharmacological management itself finishes, which is stopping the treatment or duration. When is it time to stop? And can we stop these things straight away? What do you recommend?

Yeah, so anytime a child is on any psychotropic medication, I think an important principle is that every review, we look for opportunities to reduce the dose or discontinue. Not that I'm terribly worried about long-term effects, but if a child can get by with less meds, obviously that's better.

When should we look for opportunities? Well, what I normally tell parents at the start is that once we've made a decision collectively to commence a medication, if they have a good response, they're likely to be on it for at least a couple of years.

Then how long they stay on it after that depends on their rate of natural maturity. All kids improve developmentally in their capacity to sustain attention, in the capacity to control impulses and so on. But the rate of improvement is unpredictable. And it's kind of a race between the child's natural maturity and the increasing demands imposed by the environment.

There's a number of factors involved, but essentially if there's a good period of stability, that the child's functioning really well for, say, 12 months, then we might say, 'Hmm, do you think he still needs that medication?' And sometimes the parents say, 'I don't know, because we never miss a dose. I don't know what he's like without it.' And in that situation I say, 'Well, how would you feel about trying for a week without medication? Not the first week of term or last week of term because they're likely to be a bit all over the place, but just a regular school week. And you can decide whether you tell the teacher or not, but you definitely need feedback from the teacher and see how it goes. What do you think?'

And I'm encouraging parents to do that, and they do. And they might come back to the next appointment and say, 'Look, after 3 days it was obvious it was a disaster. The teacher actually called me and he just couldn't cope, so he's back on the medication.' Or they might say, 'Actually, he was no different and he's off and we're really happy.'

The other scenario is that from time to time that do forget a dose, which is actually the more common scenario, and that's the best way the parents and the child understand the effects is when they have days without medication. And that's a common thing parents will say at an appointment is, 'A couple of weeks ago I ran out and for 2 days he didn't have it and he was all over the place. He definitely still needs it.'

Is there any withdrawal or rebound effect? So if the parent says they started playing up 3 days after they stopped taking it, is that just likely to be lack of medication rather than the withdrawal of medication?

No. No, there's not. And we know that because a lot of kids don't take it on weekends. It's just like caffeine. If you're used to having coffee every day, you don't have it, you might feel a bit funny in the head or whatever. But no, there's no behavioural withdrawal syndrome with the stimulants.

Again, tell families right at the start if they don't like the effect it's having on their child, if, for example, it changes their personality, which it occasionally does do, and obviously we don't want that, if you think, 'I don't like what this is doing to my child,' just stop. No problems.

Well, talk of a coffee reminds me that it's probably time for you and I to get a coffee and perhaps listeners as well. Daryl Efron, it's been an education listening to you. I encourage listeners to read your article, Pharmacological management of attention deficit hyperactivity disorder in children and adolescents, in Australian Prescriber. Thanks so much for sharing that with us today, Daryl.

My pleasure Justin, nice to chat.

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The views of the hosts and the guests on this podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Daryl Efron was a member of the guideline development group for the 2022 Australian Evidence-Based Clinical Practice Guideline for ADHD.