Gene may alter Ritalin's effects in ADHD.

Many children diagnosed with attention-deficit hyperactivity disorder (ADHD) calm down and otherwise improve when given the stimulant methylphenidate, or Ritalin. Others derive no benefit from the same medication.

Reasons for this variation in methylphenidate's impact on ADHD remain unclear. A new study, however, suggests that the drug fails to help youngsters who have inherited a specific form of a gene involved in dopamine transmission in the brain.

This finding stems from an analysis of 30 African-American boys, ages 7 to 11, who exhibited moderate-to-severe ADHD symptoms. The work sets the stage for larger genetic studies of methylphenidate response, say Bertrand G. Winsberg of Brookdale University Hospital and Medical Center in New York and David E. Comings of City of Hope National Medical Center in Duarte, Calif.

If the psychiatrists' linkage of this particular gene variant to poor methylphenidate response holds up, it may provide guidance to mental health clinicians faced with difficult decisions about prescribing drugs to children with ADHD (SN: 11/28/98, p. 343).

Of 14 boys with ADHD who showed little or no improvement after taking methylphenidate pills for 3 months, 12 had inherited a long form of the dopamine transporter gene (DAT1) from both parents, the researchers report in the December JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY. This version of DAT1 contains 10 copies of a particular amino acid sequence; other forms have five, eight, or nine copies.

In contrast, only 5 of 16 boys with ADHD who benefited from medication had inherited copies of the long DAT1 version from both parents.

Several teams have previously linked the gene DAT1 to ADHD, but not to children's responses to stimulants used to treat the condition.

Researchers know little about the functions of DAT1 and its various forms. Mice engineered to lack this gene become hyperactive. Stimulants, which act directly on dopamine-transporter molecules, nonetheless calm these genetically engineered mice. They are ineffective, however, if the mice also receive a drug that enhances the availability of another neurotransmitter, serotonin.

The new link between methylphenidate and DAT1 underscores the complexity of genetic influences on individual development, remarks psychiatrist Edwin H. Cook Jr. of the University of Chicago in a commentary published in the same journal. Further exploration of the properties of different forms of the DAT1 gene may open new treatment options for ADHD, Cook contends.

Variants of two genes for brain receptors for dopamine, known as DRD2 and DRD4, didn't appear to affect youngsters' responses to methylphenidate in Winsberg and Comings' study. Other investigations have implicated versions of these genes in ADHD, the researchers say.

Genetic research with larger, ethnically diverse groups of children diagnosed with ADHD may find that certain forms of DRD2 and DRD4 help or hinder methylphenidate's effectiveness, Cook says.

Winsberg and Comings have essentially launched the study of the relationship of genetic variation to the medication responses of children with psychiatric disorders, he adds.

"The reality is that whether any individual child with ADHD will respond to stimulants is largely an issue of luck because we have not measured all of the reasons for variability in response," Cook concludes.