Results from the Preschool ADHD Treatment Study (PATS) indicate that
children aged 3 to 5.5 years with attention-deficit/hyperactivity disorder
(ADHD) appear to benefit from low doses of methylphenidate. Tolerability was
lower than expected, however, as 11 percent of patients discontinued use,
following parental reports of adverse effects.
Food and Drug Administration labeling states that methylphenidate should
not be used in children under the age of 6, but the psychostimulant has become
the most commonly used drug for children that age with ADHD, even though the
safety and efficacy of the drug in preschoolers had not been tested until
recently, wrote the researchers in the November Journal of Child and
"This study demonstrates that medication can be a safe and effective
component of treatment for preschool children with ADHD," commented
David Fassler, M.D., a clinical professor of psychiatry at the University of
Vermont College of Medicine and an APA trustee-at-large, in an interview."
However, the results also indicate that very young children may be more
likely to experience side effects, at least on a short-term basis."
The PATS trial consisted of eight phases over 70 weeks and included
children aged 3 to 5.5 who had a diagnosis of ADHD and had not taken stimulant
medications. The trial was funded by the National Institute of Mental Health.
Parents at six academic sites were asked to sign consent forms at the start of
each phase of the study. Of the 303 patients initially enrolled in the trial
at six sites, 165 entered the crossover titration phase, and 95 completed the
study's final, open maintenance phase.
The preschoolers responded to doses of methylphenidate of 7.5 to 30 mg/day,
with a mean optimal dose of 14.22 +/-8.1 mg/day. By comparison, average dose
in the Multimodal Treatment Study of Children With ADHD (MTA) of 7- to
9.9-year-old children was 30.2-41.3 mg/day. Average adult daily dosage is in
the range of 20 mg to 30 mg.
"More children taking the active drug showed a decrease of ADHD
symptoms than did those on placebo," wrote Lawrence Greenhill, M.D., of
the Division of Child and Adolescent Psychiatry at the New York State
Psychiatric Institute, and colleagues. However, they did note a lower effect
size among the younger children than those in the MTA study of school-age
children. This may have been due not to differential response, but to the
complexities and increased attrition of the PATS trial.
"As a group, [the PATS subjects] were more severely impaired than the
school-age children recruited for the MTA study," they wrote.
"This study further reminds us that very young children may differ
significantly from older children and adolescents," said Fassler, who
was not involved in the PATS study. "Dosages, response rates, and side
effects all vary considerably."
The results suggest that early treatment is valuable, but several caveats
stand in the way of moving the trial's results directly into the clinic. For
one thing, the study drug was the immediate-release version, given two or
three times a day. The once-daily, controlled duration form of the drug is the
most commonly used today and has a further advantage for preschoolers because
it can be sprinkled on food.
PATS also had a fairly high attrition rate, which the researchers stated
may have to do with the protocol's requirement for parental reconsent at the
start of each new study phase and the options for parents to move their
children into the open maintenance phase of the trial.
Greenhill and his team suggested that preschoolers be started at low doses
of methylphenidate but noted that further studies are needed to test higher
doses, especially since conventional wisdom states that smaller children
actually need doses higher than their weights might indicate.
A second part of the study found that overall 30 percent of parents
reported adverse events in their children during the trial—from 16
percent to 30 percent of subjects taking the study drug and 15 percent to 20
percent of subjects on placebo. The most frequently reported events included
emotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts,
irritability, and decreased appetite. Emotional lability and some ADHD
behaviors (such as restlessness and impulsivity) were significantly associated
with withdrawal from the study. These may have been due as much to lack of
medication efficacy as to the action of the drug, said the researchers.
Reports from the manufacturer of the deaths worldwide of 14 children over
four years taking mixed amphetamine salts raised concerns about the cardiac
safety of psychostimulants and caused Health Canada to temporarily withdraw
that formulation from the market for six months in 2005. That event also
prompted the PATS researchers to monitor cardiovascular outcomes in the study.
Five subjects experienced a transient rise above average in blood pressure,
but researchers did not discontinue medication for any cardiovascular
Clinically, said the researchers, "those preschoolers with ADHD on
methylphenidate treatment still need to be carefully monitored. Other [adverse
events] that are stable (for example, appetite reduction, trouble sleeping)
may be managed with dose reductions, giving medication after breakfast, and
providing healthy snacks before bedtime."
"I would certainly concur with the authors' recommendation that
physicians and parents of preschool children with ADHD should carefully
evaluate the risks and benefits of medication before initiating
treatment," said Fassler. "I would also agree that very young
children should be followed closely and seen often to ensure that treatment is
effective and to monitor for possible side effects."
"Efficacy and Safety of Immediate-Release Methylphenidate
Treatment for Preschoolers With ADHD" can be accessed at<www.jaacap.com>
by clicking on "Archive" and then "November."▪