FDA-Approved Medications for ADHD

Andrew J. Cutler, MD: The American Academy of Pediatrics has published treatment guidelines for children and adolescents from the ages of 6 to 18 for ADHD [attention-deficit/hyperactivity disorder]. The class of medications that is recommended as first-line therapy is stimulants. Stimulants have the most extensive and best evidence for efficacy, with some of the highest effect sizes or measures of efficacy of any treatment we have in clinical medicine. The guidelines don’t specify which of the stimulants to start with, and the stimulants are divided into 2 categories. There are methylphenidates and amphetamines.

It’s interesting that there are some patients who preferentially respond to or tolerate 1 of them better than the other. We think as many as 30% of patients will respond better to a methylphenidate or an amphetamine or tolerate 1 better than the other, so it’s important to be comfortable prescribing both of these categories of medication.

There are also some nonstimulant medications that are FDA approved, and the treatment guidelines do recommend FDA-approved medications as first-line treatment. Currently, only 3 nonstimulant medications are FDA approved. One is called atomoxetine, and the other 2 are extended-release versions of alpha-2 agonists. These bind to alpha-2 norepinephrine receptors and stimulate them, whereas atomoxetine is a norepinephrine reuptake inhibitor.

As far as the pros and cons, stimulants are very effective, but there are issues with certain warnings and precautions. For instance, there’s a warning about the potential for abuse and diversion and dependence. There is a warning about cardiovascular risk. There’s a warning about the precipitation of psychosis or mania. There’s a warning about vasoconstriction and Raynaud disease. Also, not everybody can tolerate a stimulant. There are some negative attitudes out there about stimulants, and some people are hesitant to prescribe stimulants. Some people are hesitant to accept a stimulant as a choice for their child.

Also, the problem with stimulants is they only work for a certain portion of the day. When you take them in the morning, there’s a delay until they kick in and start working. Of course, they wear off at some point. They have to wear off at some point. They can’t last around the clock or the child would never sleep. There is a problem with what we call the “bookend” times in the morning and evening.

There are also some practical issues with stimulants, such as prescribing regulations and restrictions that can make it more difficult to prescribe stimulants. We also have to keep track of our records. We often have to check prescribing databases to make sure the patient is not abusing the medication.

As far as the nonstimulants, their efficacy may not be as robust, but when they work, they can certainly work. With atomoxetine there are issues with titration. You have to titrate the medicine, which is slower in onset of efficacy. There are some warnings, particularly around hepatic or liver function. There are some adverse effects that we can see, including things like nausea, fatigue, urinary retention, constipation.

The predominant problem with alpha-2 agonists is sedation, so when used by themselves they can be quite sedating. There’s also a risk of some other adverse effects, but they can be effective, and they do cover more around the clock. They are approved for monotherapy, but I also commonly use them in combination with a stimulant, which is how they’re also FDA approved.

One of the other problems with the nonstimulants, besides the fact that there can be a little lag—you have to titrate them and there’s a little lag in the onset of efficacy—is that you have to be able to swallow a pill, a tablet, or a capsule. There’s not a way to open the package and sprinkle the treatment into a liquid or onto food. There’s not a dissolvable form or a chewable form. That’s certainly an unmet medical need.

As far as efficacy and safety of the various FDA-approved medications to treat ADHD, the best evidence we have for efficacy is with the stimulants. Stimulants have effect sizes in the range of 0.8 to 1.0, which is very high, very strong, and these are some of the highest effect sizes we have in clinical medicine. They work best for some of the core symptoms of ADHD, particularly some of the inattentive symptoms. However, they don’t completely address all the symptoms. They might not always address some of the executive function issues. They may induce anxiety or agitation, and may worsen dysphoria in some patients. There are also adverse effects such as irritability, decreased appetite, and insomnia. Those are some of the most common adverse effects. They may not be tolerated or appropriate for every patient.

As far as the nonstimulants, the effect sizes for the nonstimulants have ranged from about 0.4 to 0.6, which we consider medium-effect sizes. These are certainly very good and effective. What we find, though, is they may not be as universally effective for as many patients. Stimulants seem to work in up to 80% to 90% of patients, whereas nonstimulants may not be quite as effective for as many patients. They also have been shown to work on the core inattentive and hyperactive impulsive symptoms. They may not be as prone to inducing anxiety, agitation, or irritability. They’re less likely to decrease appetite, and they’re less likely to induce insomnia.

Transcript Edited for Clarity