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ADHD Gene Doesn't Predict Response to Drugs

But variant is linked to disease severity, researchers report

WEDNESDAY, June 25 (HealthDay News) -- Canadian researchers report that their discovery of a gene variant that seems to affect the severity of attention-deficit hyperactivity disorder did not help them predict which patients are likely to respond to a class of drugs widely used to treat the disorder.

The lack of a connection between the variant and response to methylphenidates was a blow for researchers, who have hoped to use genetic data to better predict who might be the best candidates for this treatment. Ritalin is one example of a methylphenidate.

"It is a negative study," said Dr. Andrew Adesman, chief of developmental and behavioral pediatrics at Schneider Children's Hospital in New Hyde Park, N.Y. "The goal is to try and better identify patients who are best going to respond to which medicine, and they didn't get the findings they were hoping to find. Their theory wasn't supported by the data."

The research was published Wednesday online in Neuropsychopharmacology.

Attention deficit-hyperactivity disorder (ADHD) is a complex syndrome affecting between 8 percent and 12 percent of school-aged children worldwide. Likely the result of a combination of genes and environmental factors, the biology of the disease has proven difficult to nail down.

Ridha Joober and his team from the Douglas Mental Health University Institute in Montreal focused on the gene encoding catechol-O-methyltransferase (COMT). COMT regulates levels of the brain chemical dopamine in the prefrontal cortex, and dopamine appears to regulate precisely the behaviors that tend to be disrupted in children with ADHD.

The COMT gene is marked by a particular genetic variant that changes an amino acid in the gene from a valine (Val) to methionine (Met).

"We know that the Met isoform is less active than the Val isoenzyme," he said. "Therefore, the hypothesis is that children who are carrying Met isoform would have more dopamine in their prefrontal cortex, because the enzyme is less active. And if they have more dopamine available in the prefrontal cortex, then they will be able to better orient their behavior towards their goals."

To address this hypothesis, Joober and his team studied 188 white children, average age 9, with ADHD. Each child was evaluated for a series of five attention measures four times over two weeks, once each week before receiving a methylphenidate or a placebo, and once an hour after treatment. Basically, the children were placed in a mock classroom, given an age-appropriate math assignment, and observed through a one-way mirror for "off-task" behaviors. Additionally, the researchers determined the status of the COMT gene variant in each child.

The team detected a correlation between the type of COMT variant and behavior, Joober said, with the Met isoform associated with less severe behavior.

"What we found is that the children who have two copies of the Val isoform had an even harder time orienting their goals than children who are homozygous for Met [that is, have two copies of the Met isoform] or even Val/Met," he said. Each person two copies of the COMT gene, one from each parent.

Yet the researchers observed no correlation between the type of variant and response to methylphenidates; the drug reduced ADHD behavior in all individuals regardless of genotype.

"We expected this polymorphism would also modulate response to medication, but it didn't," said Joober. "In other words, that means that whether you have the Val or Met allele, it will not change your level of response to medication with respect to task- or goal-oriented behavior."

Joober suggested these data have implications for treatment of children with ADHD, in that those with two copies of the Val variant may need additional intervention and assistance at school to complement their medications. First, however, the findings will need to be validated in other populations, he noted.

Dr. Mauricio Arcos-Burgos, of the University of Miami Miller School of Medicine, praised the study's sample size, method and interpretation.

"I think this is a very encouraging paper, very well-designed," he said. "They are following a rational logic, and the sample size is impressive."

More to the point, he said, the study design paves the way for other researchers to untangle the complexity of ADHD.

More information

For more on ADHD, visit the National Institute of Mental Health.

SOURCES: Ridha Joober, M.D., Ph.D., associate professor, psychiatry & human genetics, McGill University, and principal investigator, Douglas Mental Health University Institute, Montreal; Andrew Adesman, M.D., chief, Developmental & Behavioral Pediatrics, Schneider Children's Hospital, New Hyde Park, N.Y.; Mauricio Arcos-Burgos, M.D., Ph.D., research associate professor and director, research, Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine; June 25, 2008, Neuropsychopharmacology, online

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