WASHINGTON – Methylphenidate appears to be effective and safe for the treatment of attention-deficit hyperactivity disorder in preschool-age children, according to preliminary data presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.
The results come from the Treatment of Attention Deficit Hyperactivity Disorder in Preschool-Age Children study (PATS), sponsored by the National Institute of Mental Health.
Several studies have previously suggested that preschool-age children with ADHD would respond to and tolerate methylphenidate, and this multisite study is the first major effort aimed at directly assessing the safety and efficacy of a stimulant for the treatment of attention-deficit hyperactivity disorder in children aged 3-5 years.
“The take-home message is that 85% of the children responded to the methylphenidate,” during the 5-week crossover period to determine the optimal dosing for each of the children, said study investigator Howard B. Abikoff, Ph.D., of the New York University Child Study Center.
The optimal dose for each child was determined during a 5-week period. Over that period, all of the children were given a placebo or a dose of 1.25 mg, 2.5 mg, 5 mg, or 7.5 mg three times daily for 1 week each. Overall, 144 children completed this 5-week trial. Each week, a composite score of symptom severity was assigned based on parent and teacher responses to the Conners, Loney, and Milich (CLAM) Questionnaire and the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale.
Two blinded assessors were then asked to identify the best dose for each child. A full panel of all investigators decided upon the appropriate dose when the two assessors did not agree. Just over half (51%) of the children were referred to the full panel of investigators to determine the optimal dose.
Children also could be evaluated at a 10-mg dose if investigators agreed that there was a good chance that the child would have an even better response with a higher dose. This happened in 15 of the cases.
“First of all, we got a very significant effect per dose relative to placebo,” said Dr. Abikoff. For the 2.5-mg, 5-mg, and 7.5-mg doses, the children's composite scores were significantly lower than for placebo.
“We got small to moderate effect sizes at the intermediate doses [2.5 mg and 5 mg] and a reasonably robust effect size at the 7.5-mg dose,” Dr. Abikoff said. There was also a trend toward significantly lower scores for children in the 1.25-mg group.
After the 5-week crossover period, 113 children were randomized to receive either the optimal dose (61 children) or placebo (52 children) for 4 weeks. In the analysis of this portion of the trial, all children were included even if they left the trial early, with the last observation for that child carried through.
In the second portion of the study, a statistically significant difference was found in the composite scores–1.79 points for those in the placebo group and 1.49 points for those receiving the optimum dose of methylphenidate. “The effect sizes are linear from 1.25 mg up to 7.5 mg. … The effect size for 10 mg was somewhat lower,” said Dr. Abikoff.
Over the course of the trial there were 39 adverse events, including difficulty falling asleep, decreased appetite, emotional outbursts, and stomach discomfort, he said.
Safety was a significant concern, given the age group involved. The researchers worked closely with the Food and Drug Administration in designing the trial to ensure safety. In fact, the original study design was altered to account for the concern that children in this age group might be uniquely sensitive to stimulants and have a number of adverse events. Originally, the lowest dose of methylphenidate was planned to be 2.5 mg three times a day, but the dose was lowered to 1.25 mg three times daily to ease FDA concerns about adverse reactions.
There was also a 40-week open-label maintenance phase, with children receiving a mean total daily dose of 14 mg. During this phase, the child was given the dose that the clinician thought was appropriate. “What's interesting is that we see a noticeable increase of 23% in absolute dose,” Dr. Abikoff said.
At the end of this maintenance period, the optimal dose had increased to 20 mg/day. This suggests “the doses used here were a bit low in terms of clinical optimization,” he said.