Psychostimulants and ADHD: An Update

Psychostimulants and ADHD: An UpdateSince our last issue on ADHD in April of 2005, two new psychostimulant formulations have been approved (Daytrana [the Ritalin patch] and Focalin XR), and one older medication received a new indication (Adderall XR is now indicated for adult ADHD).

The bigger news over the past year, however, was that two safety warnings were added to the product labeling of ADHD meds – a sudden cardiac death warning for stimulants and a suicidal ideation warning for Strattera.

In February of 2006, an FDA Advisory Committee voted 8 to7 to recommend that all stimulant makers add a warning about the cardiovascular risks of these drugs. The action was based on data from the Adverse Event Reporting System showing 25 cases of sudden death, mostly in children who had used either methylphenidate or amphetamine preparations.

This decision got plenty of flak from academic psychiatrists, who took issue with some of the statistics used and who worried that the warning, in the words of the Journal of Clinical Psychopharmacology’s Richard Shader, M.D., would make it “more difficult to convince parents to allow children with ADHD to try these agents” (J Clin Psychopharmacol 2006;26(3):223-224). In fact, this was exactly the FDA’s intention, since it was dismayed by a report that 10% of 10-yearold boys in the United States are on stimulants, and that a total of 2.5 million children are taking these drugs.

If you peruse Adderall XR’s updated insert, the actual warning is only a one-liner tucked underneath the drug abuse warning that these inserts have contained for years, and the controversial sentence reads: “Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events.” It’s interesting that the companies got away with specifying “misuse,” because the FDA’s sudden death data gave no indication that the deaths were due to anything other than normal use.

At any rate, the death risk, if it truly exists, is miniscule, about 0.2–0.5 deaths per 100,000 patient years of exposure, which should be compared with the estimated baseline rate of 4.6 deaths per 100,000 person years in children (see J Clin Psychopharmacol article cited above for references).

The Strattera story is similar to the recent requirement that all antidepressants must warn about an increased risk of suicidal ideation. Like antidepressants, the Strattera adverse events database revealed a very small number of children with suicidal ideation (five cases out of 1357 patients), but no actual suicides (see

Aside from these safety considerations, there’s not much new to say about how to choose stimulants. There are two major decision points: first, methylphenidate vs. amphetamine; and second, longer-acting vs. shorter-acting. Because methylphenidate preparations cause somewhat less insomnia and irritability than amphetamines (Pediatrics 1997;100(4):662-666), most clinicians will start with methylphenidate. Then, all you have to do is to choose among the thirteen versions of methylphenidate crowding the market.

For kids who hate swallowing pills, there are now three methylphenidate options: Methylin CT (chewable tablet), Methylin Oral Solution, and the new Ritalin patch, Daytrana, which is officially known as the methylphenidate transdermal system, or MTS.

Focalin is simply the dextro-isomer of methylphenidate. It is no more effective than Ritalin, though it lasts a little longer (J Am Acad Child Adolesc Psychiatry 2004;43(11):1406-1444). A long-acting version of Focalin, Focalin XR, was just approved for both pediatric and adult ADHD, but there is no evidence of any advantages over current meds.

Intermediate-acting methylphenidate comes in three versions. Ritalin SR was the original and is available generically. Metadate ER is the branded generic of methylphenidate SR and is essentially identical to Ritalin SR; they are both methylphenidate molecules mixed into a wax matrix. Methylin ER, also a branded generic, offers methylphenidate mixed into a hydrophilic polymer, which, according to the manufacturer, may yield an advantage in terms of being more continuously released than its competitors – but who really knows?

The long-acting versions of methylphenidate are dominated these days by Concerta, which appears to last longer than either Metadate CD or Ritalin LA.

Metadate CD, Ritalin LA, and the new Focalin XR are capsules filled with beads, so they can be sprinkled over food for kids. They contain anywhere from 30% (Metadate CD) to 50% (Ritalin LA and Focalin XR) of their beads in immediate-release form, providing an extra stimulant punch in the morning, if that’s what your patient needs.

If methylphenidate doesn’t work or isn’t tolerated, you’ll move on to the amphetamine preparations. In this category, you have dextroamphetamine and its branded generics, such as Dexedrine and Dextrostat. Desoxyn (methamphetamine) is the prescription version of crystal meth, so most clinicians avoid it because of its particularly high abuse potential.

For intermediate and long-acting coverage, Shire’s Adderall (available in both IR and XR forms) is heavily promoted, but may be no better than dirt-cheap Dexedrine SR in many patients.

TCR VERDICT: Formulations are fancy, but it’s basically Ritalin vs. Dexedrine.

Psychostimulants and ADHD: An Update

This article originally appeared in:

The Carlat Psychiatry Report
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This article was published in print 9/2006 in Volume:Issue 4:9.