The last time we did an entire issue on ADHD was in September of 2006. In this brief article, we’ll bring you up to date on some recent developments.

1. Vyvanse (lisdexamfetamine) was approved for the treatment of ADHD in 6-12 year olds in 2007, and more recently was approved for ADHD in adults. It is essentially a 12 hour form of amphetamine, and because it requires contact with the GI tract to become activated, it does not provide a recreational high when snorted. But does it pose any advantages over the many other long-acting stimulants available, including Adderall XR, Concerta, Ritalin LA, Focalin XR, the two generic candidates, dexedrine spansules and methylphenidate SR? The anecdotal word on the streets among high prescribing psychiatrists is that it seems to provide more consistent coverage, and a smoother onset than some of its competitors. Indeed, Shire’s data shows that Vyvanse’s metabolism is less variable from patient to patient than Adderall XR (Biederman J et al., Biol Psychiatry 2007;62:970-976). Its 12 hour duration of action may be more reliable than others. The drug is now available in the following doses: 20mg, 30mg, 40mg, 50mg, 60mg, 70mg.

Bottom Line: Vyvanse’s metabolism may be the most predictable of the long-acting stimulants.

2. Strattera (atomoxetine). Strattera has the advantages of not being a controlled substance, and of lasting 24 hours a day, but clinicians have been skeptical about its efficacy for core ADHD symptoms. Now there’s solid proof that it’s a dud. In an earlier double blind study of children, Strattera (dosed up to 1.2 mg/kg) was found to be only about half as effective as Adderall XR (dosed up to 30 mg/day) (Wigal SB et al., J Attention Disorders 2005;9: 275-289). The latest study, funded by Eli Lilly, compared Strattera with Concerta. The researchers randomly assigned 516 children (mean age, about 10 years old) to Strattera (up to 1.8 mg/kg, average dose 53 mg/day), Concerta (up to 54 mg/day, average dose 39.9 mg/day) or placebo. After six weeks of treatment, Concerta’s response rate was 56%, statistically higher than either Strattera’s (45%) and placebo (24%). Concerta’s superiority is particularly surprising considering that Lilly-sponsored researchers made sure to use a small dose of Concerta, and an unusually high dose of Strattera. If the dosing had been comparable, Strattera would very likely have done even more poorly. As with other studies pitting Strattera vs. stimulants, Concerta caused more insomnia while Strattera caused more sedation. Appetite loss occurred in both conditions but more prominently for Concerta (Newcorn J et al., Am J Psychiatry 2008;165:721-730). Well, at least Strattera was more effective than placebo!

Bottom Line: Now it’s official: Strattera is significantly less effective than stimulants.

3. Provigil for ADHD? Yes, it does work, but at doses higher than typically used for fatigue (the FDA-recommeded dose is 200 mg/day). In one large nine week study, researchers assigned 248 children and adolescents to either Provigil or placebo. The Provigil dose ranged from 175 mg/day to 425 mg/day (a special formulation was devised for the study to allow such dosing); the mean dose was 368.5 mg/day. Provigil improved ADHD symptoms more than placebo, and the response rate based on the CGI scale was 48% for Provigil and 17% for placebo. Insomnia, headache, and decreased appetite were common side effects (Biederman J et al., Pediatrics 2005;116;e777-e784.) What about for adults? In one small double blind study of adults with ADHD, Provigil (mean 206.8 mg/day) was as effective as dextroamphetamine (mean 21.8 mg/day) and both were better than placebo (Taylor FB and Russo J, J Child Adolesc Psychopharmacol 2000;10:311-20). If Provigil is so effective, why hasn’t it been approved for this indication? Cephalon tried, and while the FDA was impressed with the efficacy data, one child developed a dangerous rash during the clinical trials. The FDA was so concerned that they required Cephalon to conduct larger studies to determine if this is a common Provigil side effect, and the company chose not to pursue these studies. So if you use it, it will be “off label.”

Bottom Line: Provigil works for ADHD, but dosing is higher than for approved uses.

4. Daytrana: methylphenidate in a patch. When we last reviewed Daytrana (see TCPR September 2006) we gave it a rather lackluster review. Since then, however, the product appears to have filled a small niche in ADHD treatment. Children often will not take an oral agent for ADHD, either because they hate pills or because they get nauseated. In these cases, it is reasonable to try the Daytrana. One unique advantage of the patch is that you can manipulate its pharmacokinetics in ways that are impossible to do with an oral stimulant – you can remove the patch earlier or later than the official nine hour wear time, depending on whether you want a longer or shorter duration of action. According to Shire, the stimulant effects last three hours after the patch is removed, but this post-removal period varies from patient to patient, and in some may be much less than three hours. Counsel parents to experiment with the patch to time its effects in their child. Of course, the longer the patch is left on, the higher the risk of insomnia.

Bottom line: Daytrana has developed its niche, especially in kids who hate taking meds.

5. Alpha-2 Agonists: Do they work? Stimulants don’t work for all patients, and child psychiatrists have long used alpha-2 agonists, such as clonidine (either orally or as the Catapres patch) or guanfacine, to treat some children, either alone or in combination with stimulants. Neither of these drugs are approved for ADHD, but rather for the treatment of hypertension. In a 2002 study, clonidine was shown to be more effective than placebo for children with combined ADHD and Tourette’s Syndrome (Tourette’s Syndrome Study Group, Neurology 2002;58:527-536) In a recent placebo-controlled trial (not funded by industry), clonidine was compared with methylphenidate in children with pure ADHD. In this study, 122 children were randomized to one of four conditions: clonidine (mean dose, 0.24 mg/day), methylphenidate (mean dose, 30.2 mg/day), combination of clonidine and methylphenidate, or placebo. At the 16 week endpoint of the study, clonidine alone was no more effective than placebo on the teacher’s rating, but it did surpass placebo on some secondary measures, including a parent’s rating. The combination of the two drugs was also more effective than placebo. Clonidine produced more bradycardia and more sedation than methylphenidate. The researchers speculate that parents rated clonidine more highly than teachers because they appreciate the sedative side effects at home, whereas teachers may find this side effect problematic in the classroom ( Palumbo DR et al., JAACAP 2008;47:180-188).