Posted by Phillipa on November 17, 2011, at 20:54:43
For those in the know maybe you can help explain this article. Phillipa
From Medscape Medical News > Psychiatry
Gene Variants Predict Response to ADHD Treatment
Deborah BrauserAuthors and Disclosures
October 21, 2011 Gene variants in children can help predict their response to medication for attention-deficit/hyperactivity disorder (ADHD), according to new research.A randomized, crossover trial of almost 90 school-aged children with ADHD showed that those who carried a polymorphism of the dopamine receptor D4 (DRD4) gene had a better response to increasing doses of methylphenidate than did those without, especially for symptoms of hyperactivity-impulsivity.
However, those who carried specific variants of the dopamine transporter (DAT) gene had less improvements compared with those who did not carry it.
"These findings do make sense in terms of what we suspect about the function of these particular genetic variants," principal investigator Tanya Froehlich, MD, assistant professor of developmental and behavioral pediatrics at Cincinnati Children's Hospital Medical Center, Ohio, told Medscape Medical News.
Dr. Tanya FroehlichShe noted that personalized treatment for these children is the hope and the goal for the future.
"Because we know that treatment response is a very individual thing, and we don't yet know what predicts improvement, our hope is that we can use some of these genetic tools to increase our ability to tell us important information in advance."
The study is published in the October issue of Journal of the American Academy of Child and Adolescent Psychiatry.
Exploring Genomic Effects
Dr. Froehlich said that clinicians currently use "a trial-and-error approach" when it comes to treating ADHD symptoms.
"As a result, finding an effective treatment can take a long time. But with more information about genes that may be involved in ADHD medication response, we may be able to predict treatment course, tailor our approach to each child, and improve symptom response while decreasing healthcare costs."
The DRD4 gene encodes dopamine receptor protein and helps control the release of dopamine. The DAT gene removes dopamine from the brain synapses. Past research has suggested that ADHD is associated with a lack of synaptic dopamine.
The researchers enrolled 89 children aged 7 to 11 years with ADHD (73% male; mean age, 8.13 years). All participants were stimulant-naive at baseline and received 1 week each of placebo and 3 different doses of long-acting methylphenidate: 18, 27, or 36 mg for the children weighing 25 kg or less and 18, 36, or 54 mg for those weighing over 25 kg.
Both teachers and parents used the Vanderbilt ADHD rating scales to evaluate each child's response to all levels of medication.
Dr. Froehlich noted that because academic functioning is so important for children with ADHD, understanding the effect of medication while at school, as well as at home, is especially crucial.
Saliva samples were collected from all children and assessed for whether they carried any of 4 polymorphisms commonly found in those with ADHD: the 3' untranslated region of DAT, exon 3 on DRD4, codon 158 on catechol-O-methyltransferase, and the adrenergic α2A-receptor promoter.
Increased Response
"The most statistically significant gene-by-dose interactions were observed on hyperactive-impulsive symptoms for DRD4 and DAT polymorphisms," report the researchers.
The children who did not have the DAT 10-repeat variant had greater symptom improvements as methylphenidate dose increased compared with those who did carry the variant (P = .008).
"Thus, individuals with no 10-repeat alleles would have a mean decrease of 56% in their hyperactive-impulsive score compared with placebo, whereas 10-repeat carriers would have a less robust decrease of 37% to 44%," write the investigators.
"Because those with the 10-repeat have more 'sucking out' of dopamine from the synapses, it makes sense that these medications may not be as effective. You're basically working against a gradient that is trying to take more dopamine away," added Dr. Froehlich.
The participants who did not have the DRD4 4-repeat allele had less symptom improvement across doses of methylphenidate than did the 4-repeat carriers (P = .02).
"Those with the 4-repeat allele have a receptor that works really well and responds favorably to that extra dopamine that comes from medication. Those who lack the 4-repeat seem to have a pokier, more unresponsive receptor. So perhaps even adding in more dopamine can't overcome that receptor's sluggishness," Dr. Froehlich further explained.
Still, the study authors note that further research into this area is needed.
"As the field moves toward personalized ADHD treatment, pharmacogenetic studies with larger samples and a range of outcomesare needed to determine the clinical utility of genomic information."
Dr. Froehlich said that future studies will need to also examine what would happen if a child has both the DAT and DRD4 genes and to assess whether the effects found in this study are the same for all ADHD medications.
"We are currently planning on looking at whether these dopamine gene variations predict side effects, because that's extremely important in whether a child will continue taking medications, and we're enrolling more children into our study so that we'll have a large sample as we further examine these issues."
The study was supported by grants from the National Institute of Mental Health and by a Cincinnati Children's Hospital Center for Education and Research Therapeutics Award. The study authors report several disclosures, which are listed in the original article.
J Am Acad Child Adolesc Psychiatry. 2011;50:1129-1139.
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