Genetic profile may clarify ADHD drug response

The fact that some children with attention-deficit/hyperactivity disorder do not respond to the medications that are most commonly prescribed for the condition could be blamed on their genes, according to a study published in the July issue of Neuropsychopharmacology.

Researchers tested nearly 50 children for variations in the 3'-untranslated region of the dopamine transporter gene and changed medication dosages over a four-week period. Those who were homozygous for the less common 9-repeat DAT1 VNTR sequence were far less likely to respond to methylphenidate, a stimulant that is often the first line of treatment for ADHD. They were also less likely to improve as dosages were increased.

"This is an exciting finding, because ADHD is such a common disorder, and it's often difficult to know how patients will respond to ADHD medications," said Mark Stein, PhD, principal investigator and director of the Hyperactivity, Attention and Learning Problems Clinic at the University of Illinois, Chicago.

This finding could lead to genetic testing before prescribing to reduce the amount of time a patient spends taking a drug that is not likely to be effective, the authors said. This is particularly key for ADHD, since it may be weeks before it becomes apparent that the drugs are not working.

"There has always been an art to choosing and titrating medications for ADHD," Dr. Stein said. "It would be tremendous if we could scientifically predict medication response or nonresponse prior to treatment."

There is also hope that this strategy will lead to fewer patients dropping out of treatment by reducing the frustration that could result from trying and testing out various regimens of limited effectiveness.

"We could prevent a lot of aggravation and expense with more targeted treatments," Dr. Stein said.

Experts praised the paper for moving ADHD treatment further in the direction of pharmacogenomics, which most feel is the future of medicine.

"This is the way medicine is going," said Floyd Sallee, MD, PhD, vice chair of psychiatry at the University of Cincinnati. "First, genetic testing will reduce side effects and serious consequences from medications. Later, it will be more about deciding which therapy is best for which patient."

Physicians who treat ADHD children also appreciated the fact that this paper gives a clue to why some children do not respond to the meds. It could be something inherent in their make-up rather than an external factor, such as whether they're taking the drug correctly or at all.

"This is a very important paper," said Leonard Sax, MD, a Poolesville (Md.) family physician who also holds a PhD in psychology. "We all see kids who meet the criteria for ADHD, and we all have kids who don't seem to respond to medication. But we don't know which kids will respond and which won't. If this study is replicated, it could be very, very useful."

Experts cautioned, however, that testing for this genetic sequence is not quite ready for medical practice outside of a research setting. This study was small and the conclusions need to be duplicated by other larger studies.

"It doesn't explain enough," said Nancy Stevens, MD, MPH, professor in the Dept. of Family Medicine at the University of Washington. "And it's no substitute for knowing the parent and the child."

Also, it is too soon to answer questions about the test's potential to impact prescribing habits and be cost-effective. "Genetics are tremendously complicated," said James Perrin, MD, professor of pediatrics at Massachusetts General Hospital for Children and former co-chair of the American Academy of Pediatrics subcommittee on the disorder.

"But this gets us closer to being able to determine who's going to respond or not."