Drs Cerulli and Cutler discuss factors guiding treatment selection in ADHD.
Theresa R. Cerulli, MD: Andy, what factors guide diet-treatment selection in ADHD [attention-deficit/hyperactivity disorder]? That’s a broad question. Sorry to throw that 1 your way, but I know you can handle it.
Andrew Cutler, MD: It’s a broad question, but let me start with some of the general principles and concepts, and then we can get into some of the details. First, overall, Mike did a great job talking about some of the various aspects of life that ADHD can affect, especially self-esteem issues. I want to remind people, as we always say, “Pills don’t teach skills.” I don’t throw pills at people to fix problems. We have to remember that the appropriate treatment of ADHD is multimodal and, ideally, multidisciplinary. It’s not just the medication, the pharmacology. We need to pay attention to all these other aspects that we’re talking about, whether that’s therapy, or coaching or skills training, things like that. All these things need to be considered.
Let’s say we’re talking about the medication. The first general concept that we have to decide is whether we’re talking about a stimulant or a nonstimulant. As we know, the data suggest that the stimulants are more effective. They’re more effective universally, and they’re more effective as far as the effect size and the magnitude of effect. In general, start with a stimulant, unless there’s some reason not to, out of the gate. That could be various things. Whether that’s contraindication or comorbid conditions that don’t respond well, it could get worse with a stimulant or patient or family preference.
Within the stimulants, we subdivide between the methylphenidates and the amphetamines. Even though they’re both stimulants, they have some important differences in their mechanisms of action. Both are inhibiting the reuptake of norepinephrine and dopamine, but the amphetamines in a dose-related fashion also start to flip the transporter around and pump out dopamine and norepinephrine. They have a little more kick. They’re a little more potent. Sometimes that’s important for someone to respond, but sometimes that makes tolerability a little more of a challenge.
It’s very important to realize that there’s a 30% to 40% preferential response rate, meaning that someone might do better from an efficacy point of view or tolerate 1 better than the other. If you’ve tried a couple and you’re not getting a good response, try an amphetamine. The next level of decision-making is the duration of action that I’m trying to achieve. Younger kids may not need as long a duration of action. Older adolescents and adults need as long a duration as we can get away with. The key to that is the formulation. Over the past 20 years, there haven’t been any new stimulants introduced. We’re still talking about methylphenidates and amphetamine. The real progress and real revolution has been in the technology of the formulation. Methylphenidate and amphetamine on their own have relatively short half-lives, so we have to develop different formulations to extend the release, or the absorption, or the duration of action to try to get longer duration. Those are some of the main things I’m thinking about.
Another 1 is the actual PK [pharmacokinetic] curve. What we know for stimulants is that unlike some of our other medicines, there’s a very tight correlation between pharmacokinetics, like the blood level, and pharmacodynamics, which is the clinical effect. More and more, we’re looking at and thinking about the PK profiles of these drugs, how fast the blood level rises, and how fast we can expect the effect to begin. How long does it last, and what’s the shape? Is it a very sharp, up and down? In which case, I worry about adverse effects on the peak blood level and a crash or a rebound on the back end. Do I go up and stay a little more smooth and come down more gradually? That’s the so-called softer landing.
When we’re thinking about nonstimulants, there are 4 that are FDA approved: atomoxetine, extended-release guanfacine, extended-release clonidine, and viloxazine extended release. Of those 4, only 2 are approved for adults—atomoxetine and viloxazine XR, which was approved recently for adults. Also, there are certain differences in these medications as far as mechanism of action—tolerability, safety profiles, and so on—that helped guide us in which of these we’re going to choose.
Theresa Cerulli, MD: Impressive, Dr Cutler.
Andrew Cutler, MD: Thank you.
Theresa Cerulli, MD: I can’t resist throwing in—
Andrew Cutler, MD: Can I say 1 more thing? I’m sorry, Theresa. There’s 1 thing I forgot to mention. There’s 1 final thing we need to talk about, that some people either aren’t able to swallow pills or don’t want to, so we have various formulations available, such as liquids, oral dissolving tablets, chewables, and even patches. As a matter of fact, a new amphetamine patch was recently approved. It’s the equivalent of the methylphenidate patch that we’ve had available for many years.
Theresa Cerulli, MD: I can’t resist throwing in a visual—as I do with patients—to try to explain some of the differences of mechanisms with methylphenidates vs amphetamines. I use the “How do you fill your bathtub?” discussion—don’t laugh. Our methylphenidates block reuptake with neurotransmitters, dopamine, and norepinephrine. You’re blocking the drain of the tub, and you get more water in your tub if you’re blocking the drain. It’s not getting pulled out when you block the neurotransmitter reuptake—you get more neurotransmitters in the synapse. That’s for methylphenidates.
Amphetamines do that but also turn up the faucet. When you use the word potent, Dr Cutler, the amphetamines block the drain—block the reuptake—and you get more neurotransmitters accumulating in the synapse or filling the bathtub. You also turn up the faucet by releasing more neurotransmitter from the axon terminal. It’s like turning up the faucet and blocking the drain of the bathtub; you get more water. That’s the analogy talking to patients when I’m trying to describe differences in the mechanism.
Andrew Cutler, MD: Very nice. That increased potency can translate into better efficacy for certain patients. But amphetamines have a little more liability for appetite suppression, insomnia, and irritability, and that could be a challenge for tolerability.
Theresa Cerulli, MD: Hopefully it gives the idea that we’re not just randomly selecting. It’s not trial and error. We have some ideas of what direction we’re going with medications. People respond differently for reasons, such as the mechanism of action.
Andrew Cutler, MD: Yes.
Birgit Amann, MD, PLLC: I do that too. That goes a long way with the families and the patients we’re treating because sometimes they’re fearful or hesitant. I use analogies like Tylenol and Motrin. This is before they’ve taking a single pill or capsule. It’s just to give them a basic lay of the land. Then they feel they have a sense of where we might go with things down the road too, so it’s important to put it in terms like that or give them a visual. It helps.
Theresa Cerulli, MD: It does. Some patients get a little nervous when I say to visualize taking a bath, visualize your bathtub.
Michael Feld, MD: I do something a little different. Can I add 1 final thing?
Theresa Cerulli, MD: Yes, absolutely, Dr Feld.
Michael Feld, MD: We also have to watch how much caffeine our patients drink.
Andrew Cutler, MD: Excellent.
Theresa Cerulli, MD: Very good point.
Michael Feld, MD: There’s a similar adverse effect profile. When you work a lot with adults or kids—I’m a patient with ADHD, so I’ve experienced this—you think of amphetamines. That includes short amphetamines and maybe some older delivery systems, like the beta-delivery system, which is like doing espresso shots. When you get into some of the newer delivery systems, you’re moving from a latte to a nice, slow drip of French roast coffee. The difference with methylphenidate would be going from Dunkin’ Donuts to McDonald’s. It’s a milder feel, and it concerns a lot of people because they realize, “Maybe this is like caffeine.”
Theresa Cerulli, MD: That’s really good point. I had 1 patient make a check list of what they’re doing, in terms of supplements they might be taking and other medications over the counter. I always ask about caffeine.
Andrew Cutler, MD: Yes.
Theresa Cerulli, MD: The person wrote 3. I said, “Are you drinking 3 cups of coffee a day?” They said, “No.” It was 3 pots.
Michael Feld, MD: Three pots.
Theresa Cerulli, MD: Of coffee—3 pots of coffee.
Andrew Cutler, MD: I’ve had that too.
Theresa Cerulli, MD: My bad—OK. It shows that you do have to ask. There are some medications, like viloxazine and the mechanism of viloxazine. It’s a blocker of CYP1A2, and caffeine is a substrate of CYP1A2. If you happen to be mixing caffeine with your viloxazine you’re raising the levels of caffeine and perhaps leading to more insomnia. Those are things we have to know and talk to patients about.
Andrew Cutler, MD: I was just at a meeting, and I saw a poster on that exact topic. This introduces another layer of complexity, which is the pharmacokinetics and drug-drug interactions. This poster showed that for viloxazine extended release, the most common adverse effect in kids was somnolence, or sedation. For adults, it was insomnia, which was hard to figure out. It turns out, in those trials, we didn’t control for caffeine use. What happens is that by blocking the metabolism, you’re not increasing the Cmax [peak plasma concentration]. You’re increasing the duration of the action, the so-called area under the curve. You’re spreading it out. What’s happening is that a lot of adults will drink caffeine in the afternoon and then viloxazine XR will make it so that it’s extending into the evening and cause more insomnia.
The other thing is that amphetamines are predominantly metabolized by CYP2D6, as is atomoxetine. There are a lot of drugs that can interfere with CYP2D6, and a certain percentage of the population are slow metabolizers or poor metabolizers at 2D6. Methylphenidates are metabolized by 1 enzyme called CES1, carboxylesterase 1. There’s some genetic variability in that enzyme. There aren’t a lot of drugs that interfere with it. These things need to be taken into consideration.
Theresa Cerulli, MD: To translate that into the clinical world, it means that there are people who will tolerate some stimulants and not others.
Andrew Cutler, MD: Yes.
Theresa Cerulli, MD: Even though we don’t have all the data for that patient, we have some ability to test genetically. But at least know that it’s the reason why and that it’s worth continuing to pursue treatment options and not a 1-size-fits-all approach.
Andrew Cutler, MD: Yes. Another point is that the alpha-2 agonists—guanfacine and clonidine—have established a 1-mg/kg dosing, but none of the others have. We need to feel comfortable using the whole range of doses. For instance, I have some little kids on high doses of stimulants and some big kids on low doses. I’m sure we all do.
Transcript edited for clarity