Efficacy and Safety of Treatment Options Utilized in Adult ADHD


Stephen Faraone, PhD; Theresa Cerulli, MD; Craig Chepke, MD, FAPA; and Andrew J. Cutler, MD, discuss efficacy and safety of treatment options in adults with ADHD.

Stephen Faraone, PhD: Dr. Cutler. Could you give us the big picture from 50,000 feet of the efficacy and safety of each of the current classes of medications that are used for adult ADHD?

Andrew Cutler, MD: Yes, I'd be happy to, trying to be brief here we could certainly talk for a long time about this. But let's look at big picture. First of all, we divide the treatments for ADHD into stimulants and non-stimulants, within the stimulant class as Greg said, there's very few molecules there's basically amphetamines and methylphenidates. Within the non-stimulant class, we have alpha 2 agonists, we have norepinephrine reuptake inhibitors, basically. Let's first look at the stimulants, the stimulants have great similarities as far as efficacy, the effect sizes are quite high, we're talking in the 0.9 to 1.2 range, very effective across a range of symptoms. Now, there are certain issues with safety and tolerability of course we're all aware of some of the adverse effects like insomnia, irritability, decreased appetite, certainly in kids, we worry about growth suppression. The cardiovascular risks that we know, the possibility of worsening psychiatric conditions psychosis and mania. Now, there are some differences between amphetamines and methylphenidates in how they work, they both block the re-uptake of norepinephrine and dopamine, but there are some other differences. And it is interesting that there are some patients who do better with one than the other either they have a better response, or they tolerate one better than the other. One of the points I always like to make to clinicians is if you've been using methylphenidate and methylphenidate and the patient and they're not doing well, please switch over to the amphetamine, always make sure you've tried both before you give up on them. Of course, the other issue is they are controlled substances, and there's all the issues around that, they're very liable to abuse. They all have boxed warnings about the possibility of abuse, when we talk about abuse, misuse, and diversion those 3 issues. The non-stimulants are not controlled substances, at least the ones that are currently available, they can be very effective, but they are not as universally effective, their effect sizes tend to be more in the 0.5 to 0.6 range. And they don't work for everybody obviously, but they have a lot less of some of the baggage of the stimulants. If we're talking about the norepinephrine reuptake inhibitors, we do have issues with blood pressure there, they also have bolded warnings about suicidality, there are warnings around somnolence sedation as well, and you do have to worry about activation and the possibility of mania. The alpha 2 agonists are interesting, they have sort of the opposite profile, those are medications that are also effective to treat hypertension. We worry about lowering blood pressure, not increasing blood pressure, and when used by themselves, they can be quite sedating, but and they are only FDA approved for kids. I want to be clear that 2 norepinephrine reuptake inhibitors are the only two non-stimulants approved for adults. That's one big overview, the other thing to say about this stimulant is besides being divided into amphetamine and methylphenidate, within the universe we divide them into various formulations, as Craig mentioned, that gives us different pharmacokinetic characteristics as far as how fast they start working, and the duration of how long they were.

Theresa Cerulli, MD: If I may add to that, this short acting versus long acting in terms of what I mentioned as a comorbidity and the risks with substance abuse there. These are all the stimulants that are all C2s they all carry the black box warning for abuse and dependence, but in terms of the street value on the short acting, there seems to be those are the ones we worry the most with regard to diversion, which is the most common form of abuse, and certainly in my college students. I try when I'm both practicing clinically, talking with my patients and educating my patients, but also in teaching with the residents through Beth Israel Deaconess Medical Center, that you want to consider the long acting stimulants and not be. They were afraid sometimes that what if I have an adverse effect and it's going to last me all day? True, but in terms of the risk with abuse and dependence, looking at long-acting formulations has value before we talk about the short acting formulations being standard.

Andrew Cutler, MD: Yes, we would all agree the standard of care is the extended-release stimulant, and I the benefit clearly outweighs any downside there. It's interesting, we do need to mention - I forgot to mention there is one stimulant, at least one part of one stimulant that is a C4 the others are all C2, there is a new pro drug of methylphenidate and of D methylphenidate called., that if it was available by itself would be a C4. It showed a lower liability for abuse, but it is currently available only in combination with immediate released dexmethylphenidate, so that makes it a C2.

Craig Chepke, MD, FAPA: One thing I'd like to throw in there about the instant versus extended-release discussion. I'm very much in favor of using extended-release formulations, but they're not all created equal, extended doesn't always mean extended. What was extended release 20 years ago, is not what we'd consider extended today. If someone did have a problem, where one extended-release formulation was too long acting for them, well we can switch them to a shorter acting, extended release formulation and vice versa. If it's too short of a short acting, don't need to necessarily add a booster of an instant release as has been common in the past, we can switch to a long-acting stimulant that is extra-long acting.

Andrew Cutler, MD: You know Craig you mentioned this, while we have a very small number or dearth of molecules, we have a surfeit or a cornucopia of formulations which really allows you to tailor it, doesn't it to the patient?

Theresa Cerulli, MD: I've certainly seen evolve over time, is you can take the same molecule, and when you change the delivery system as we have done, and seen in the last 20 years, many times. It does feel different for the patients where they describe the exact same active ingredient in a long acting versus short acting formulation can feel quite different to the individual taking it.

Craig Chepke, MD, FAPA: Absolutely, I've had many patients that have put on long-acting stimulants that they swear that they're not taking anything at all, they don't feel anything, but everyone around them notices a difference, their performance levels, their quality of life. It's noticeable that they're having benefit, but they don't feel anything, and some patients will want to go back to an instant release because they can tell when it's working, and what I have to tell them is that's not a good thing, that's a buzz, that's not a therapeutic effect you're feeling, you don't need that to have efficacy.

Transcript edited for clarity

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