Large Effect from Methylphenidate, Medium Effect from Atomoxetine in ADHD Trial

Marlene Busko

June 19, 2008

June 19, 2008 — In a large, placebo-controlled, head-to-head, 6-week trial, the response rate for osmotic-release oral system (OROS) methylphenidate (Concerta, McNeil Consumer & Specialty Pharmaceuticals) (56%) was statistically superior to that for atomoxetine (Strattera, Eli Lilly) (45%), and both were superior to placebo (24%), in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

Following the parallel-group study, a subsequent 6-week crossover study from methylphenidate to atomoxetine found that a third of patients responded to only 1 of the drugs. Each medication was well tolerated.

The study, by the Atomoxetine/Methylphenidate Comparative Study Group, with lead author, Jeffrey H. Newcorn, MD, from Mount Sinai Medical Center, in New York, New York, is published in the June issue of the American Journal of Psychiatry.

"Both treatments produced robust improvement, with a statistically significant difference in response favoring osmotically released methylphenidate," the authors summarize. The preliminary finding of a differential response in the crossover part of the study "is consistent with practice guidelines that recommend change to a different class of medication if there is a poor response to or tolerance of the first agent used," they note.

"This study provides data on the efficacy and tolerability of atomoxetine in the context of a well-established, highly effective stimulant comparator," Dr. Newcorn told Medscape Psychiatry.

How Does Atomoxetine Compare With Stimulants?

Atomoxetine, a nonstimulant norepinephrine-specific reuptake inhibitor that was approved in the United States in November 2002 for the treatment of ADHD, had not been directly compared with stimulants such as methylphenidate, which provide well-established, highly effective interventions for ADHD, the group writes.

The current trial was designed to compare the acute treatment response of children and adolescents with ADHD to atomoxetine and to OROS methylphenidate, the most frequently used and longest-acting methylphenidate formulation at the time of the study. Following the acute comparison trial, subjects initially treated with OROS methylphenidate were crossed over to receive atomoxetine under double-blind conditions.

The study, conducted at 20 sites in the United States, enrolled children and adolescents aged 6 to 16 years who met Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) criteria for ADHD. The subjects had a mean age of about 10 years, and about three-quarters were boys.

The primary efficacy outcome was a "response to treatment," which was defined an ADHD Rating Scale total score that was at least 40% lower at week 6 compared with baseline. The child's ADHD symptoms were rated by a clinician using this scale, following an interview with the child's parent. This definition of response was used since it corresponds to a clinically meaningful response to atomoxetine, according to previous studies.

After 2 assessment visits, 516 study participants were randomized in a 3:3:1 fashion to receive 1 of 3 treatments:

  • Atomoxetine (0.8 to 1.8 mg/kg per day, administered as a twice-daily dose; n = 222).

  • OROS methylphenidate (18 to 54 mg/day, administered as a single morning dose; n = 220).

  • Placebo (n = 74).

All patients received 3 capsules in the morning and 2 capsules at night (in a double-dummy design) for 6 weeks.

Solid Response With Both Drugs, But Greater Response with Stimulant

In the head-to-head comparison, the response to OROS methylphenidate (56%) was superior to that for atomoxetine (45%), and the response rates for both drugs were superior to that for placebo (24%). Methylphenidate had a larger effect size (d = 0.8) compared with thatfor atomoxetine (d = 0.6).

In the crossover study, 178 patients were switched from OROS methylphenidate to atomoxetine for 6 weeks. A total of 44% responded to both treatments, 22% did not respond to either treatment, and 34% responded to only one treatment.

Overall, both drugs were safe and well tolerated. Atomoxetine was more likely to be accompanied by somnolence, while methylphenidate was more often associated with insomnia. Both drugs decreased appetite, but weight loss was greater with methylphenidate. Both drugs increased diastolic blood pressure, but atomoxetine increased heart rate also.

"While atomoxetine did not perform as well as osmotically released methylphenidate overall, response to atomoxetine was nevertheless solid, with an effect size within 0.2 of that achieved for methylphenidate," the group summarizes. In addition, the crossover study "provides at least some empirical support for clinical guidelines that recommend using a second medication class if treatment with the first agent is unsatisfactory," they note.

Editorial: "Study Conclusively Confirms Stimulant Superiority"

The report by Newcorn and colleagues indicates that while both drugs were better than placebo, methylphenidate is more effective than atomoxetine in decreasing ADHD symptoms, Benedetto Vitiello, MD, from the National Institute of Mental Health, in Bethesda, Maryland, writes in an accompanying editorial.

"Methylphenidate had a large effect size (d = 0.8) with a highly favorable number needed to treat [NNT] of 3, and atomoxetine had a medium effect size (d = 0.6) with a higher, less favorable but still very acceptable NNT of 5," he notes.

"The study conclusively confirms previous, methodologically less rigorous reports of stimulant superiority over atomoxetine in the treatment of children and adolescents with ADHD, and it provides support to the current treatment guidelines," he adds.

Limitations in the current study include the short treatment duration (too short to determine growth suppression) and the fact that only patients in the methylphenidate group were included in the crossover part of the study, he adds.

"Despite these limitations, the data provide support for the presence of preferential treatment response. . . . This preferential treatment response is likely to be genetically determined," he writes, adding that there is a need to further investigate individual variations in treatment response and to elucidate the underlying mechanisms for this.

The study was supported by Eli Lilly. Dr. Newcorn receives grant support from Eli Lilly and McNeil; is a consultant and/or advisor for Eli Lilly, McNeil, Shire, Novartis, and Sanofi-Aventis; and is a member of speakers' bureaus for Eli Lilly and Novartis. The financial disclosures of the other authors are listed in the paper. Dr. Vitiello reports no competing interests. The opinions expressed in his editorial are his private views.

Am J Psychiatry. 2008;165:721-730 Abstract, 666-667. Abstract

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