The first multisite study of methylphenidate (Ritalin) in preschoolers with ADHD is finally beginning after intense scrutiny and review. The Preschool Attention Deficit/Hyperactivity Disorder Treatment Study (PATS) has set a high standard for future psychotropic drug studies in preschoolers to follow.

"Although Ritalin has been approved by the FDA for use in children aged 6 and up for nearly 40 years, we approached our study as if it was a new drug, because we know so little about its impact on preschoolers," said Lawrence Greenhill, M.D., the study’s principal investigator. He described the project at a research forum sponsored by the American Academy of Child and Adolescent Psychiatry in October in New York.

The goal of the one-day forum was to recommend optimal strategies for developing and implementing psychopharmacological studies in preschoolers.

Funded by the National Institute of Mental Health (NIMH), the three-year pediatric study will answer many questions that researchers, clinicians, policymakers, and members of the public have about methylphenidate’s safety and efficacy in preschoolers.

The need for more information about the medication’s use in preschoolers has taken on a sense of urgency as reports have revealed that physicians are prescribing the drug to an increasing number of youngsters in this age group.

Julie Magno Zitto, Ph.D., and her colleagues reported in the February 23 Journal of the American Medical Association that from 1991 through 1995, there was a three-fold increase in the number of Ritalin prescriptions for children aged 2 to 5. The prescription records were from two Medicaid and one private HMO database.

This trend exists despite the drug maker’s label warning not to use Ritalin in children under age 6 because safety and efficacy information has not been established for this age group. Only a handful of drug studies has been conducted in preschoolers, with inconclusive results.

The Zitto report concerned some parents, educators, lawmakers, and clinicians, because the central nervous systems and brain neurotransmitters targeted by methylphenidate are still developing in preschoolers, said Greenhill.

The controversy surrounding the drug’s safety, especially in preschoolers, led to a study design that has extremely rigorous eligibility criteria.

About 4,000 children will be recruited and screened for ADHD at six university sites: Columbia, Duke, Johns Hopkins, New York University, and the University of California at Los Angeles and Irvine.

Clinicians experienced in treating ADHD and preschool-aged children will evaluate each child and prepare systematic clinical narratives for review by several experts to determine the child’s eligibility.

The preschoolers must also get an extremely high score on the ADHD symptom rating scale resulting in less than 4.28 percent of a preschool sample being identified. Their symptoms must be present for at least 9 months rather than the 6 months specified by DSM-IV.

"We wanted to ensure that we treat preschoolers with severe ADHD whom everyone agrees clearly needs help," said Greenhill.

Because of the rigorous eligibility criteria, Greenhill estimates that only 312 preschool (ages 3 through 5) and school-aged (ages 6 through 8) children will make it into the first phase of the study. Sixty-six school-aged children will serve as the control group.

Once the children are accepted into the study, their parents will be trained in behavioral management techniques that have been shown to be effective in moderating ADHD symptoms, said Greenhill.

He added this component to the protocol because some children may respond well to behavioral therapy. On the basis of a previous large study comparing methylphenidate with behavior therapy in school-aged children, Greenhill estimates that 58 children will respond to the behavioral therapy techniques.

He estimates that the remaining 198 preschoolers and 66 school-aged children will be enrolled in the randomized medication trial.

Determining the safest and most effective dose for each child is the goal of the first 12 weeks of the trial. Doses of methylphenidate are titrated from 1.25 mg three times daily to 10 mg three times daily during the first three weeks and then increased from 2.5 mg daily to 10 mg three times daily in the following nine weeks.

"The review boards wanted us to start with the lowest dose possible for safety reasons," explained Greenhill.

Once the best dose is established, subjects are maintained for 40 weeks on Ritalin or placebo and then taken off. The children will be followed for one year.

Another goal of the study is to compare the response times and dose responses in preschoolers with those of school-aged subjects. "We know significantly more about the safety and efficacy of Ritalin in school-aged children than we do in preschool children," said Greenhill.

Greenhill said that the controversy over prescribing methylphenidate led to numerous reviews of PATS. The process involved the NIMH Special Emphasis Panel, NIMH Council Workgroup on Ethics, NIMH Data Monitoring and Safety Board, the Food and Drug Administration Division of Neuropharmacological Drug Products, and each of the six sites’ institutional review boards, according to Greenhill.

These were among the recommendations made by the reviewers, which Greenhill and his colleagues incorporated into the final study design:

• Start with the lowest dose possible.

• Obtain informed consent from parents at every stage of the trial.

• Exclude children with bipolar, pervasive developmental, and psychotic disorders.

• Ensure that children can speak English in phrases so they can communicate any problems to adults.

• Have experienced pediatric educators serve as consultants at all sites.

• Have a community and parent representative on each site’s Institutional Review Board.

• Provide age-appropriate furniture and toys at the study sites.

The researchers also established parental advisory panels at each site.