Children with certain dopamine system gene variants respond better to ADHD drug

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ScienceDaily (Oct. 21, 2011) — Children with certain dopamine system gene variants have an improved response to methylphenidate -- the most commonly prescribed medication for Attention Deficit Hyperactivity Disorder -- a finding that could help eliminate the guesswork from prescribing effective medications for children with ADHD.

Researchers reporting their results in the Oct. 21 Journal of the American Academy of Child and Adolescent Psychiatry tested 89 children with ADHD between ages 7 and 11. They found that children with specific variants of the dopamine transporter (DAT) and dopamine receptor D4 (DRD4) genes showed greater improvement in hyperactivity and impulsivity after taking methylphenidate compared to children with alternative DAT and DRD4 versions.

"Physicians don't have a good way of predicting who will experience great improvement in ADHD symptoms with a particular medication, so currently we use a trial-and-error approach. Unfortunately, as a result, finding an effective treatment can take a long time," explained Tanya Froehlich M.D., lead investigator on the study and a physician in the division of Developmental and Behavioral Pediatrics at Cincinnati Children's Hospital Medical Center.

"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 health care costs," she added.

The study is the first-ever placebo-controlled pharmacogenetic drug trial for ADHD in school age children to evaluate the effects of dopamine system genes variants using teacher as well as parent ratings of children's symptoms. Given the importance of academic functioning for children with ADHD, Dr. Froehlich said it is crucial to consider medication impact at school as well as at home. Children in the study were not already taking stimulant medications for their ADHD.

Participants were prescribed one week each of placebo and three different doses of methylphenidate for their ADHD. Parents and teachers assessed and scored the children's behavioral symptoms based on the Vanderbilt ADHD Parent and Teacher Rating Scales.

The researchers analyzed DNA from saliva samples to see which ADHD-related gene types the children carried. They looked initially at four genes frequently implicated in ADHD -- DRD4, DAT, COMT and ADRA2A. DRD4 and DAT, the most well studied genes for ADHD, showed the strongest effects on methylphenidate dose-response in study participants, according to the researchers.

The DRD4 gene encodes the dopamine receptor protein, which helps control the synthesis and release of dopamine and the firing rate of neurons. The DAT gene encodes the dopamine transporter protein, which removes dopamine from the brain synapses.

Children who lack what is known as the DAT 10-repeat variant showed greater improvement after taking methylphenidate compared to those carrying the 10-repeat. Children without the DRD4 gene 4-repeat variant showed less symptomatic improvement with methylphenidate compared to 4-repeat carriers. A "repeat" is a short nucleotide coding sequences in a gene that is repeated.

Dr. Froehlich and her colleagues indicate in their study that although findings are promising, additional research is needed in larger patient samples to confirm current study findings and their clinical relevance.

Also collaborating on the study were researchers from the University of Cincinnati College of Medicine, the University of Arkansas for Medical Sciences, the University of Illinois (Chicago) and Duquesne University. Funding support came from the National Institute of Mental Health (NIH) and a Cincinnati Children's Hospital Medical Center Education and Research Therapeutics Award.

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The above story is reprinted from materials provided by Cincinnati Children's Hospital Medical Center.

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Journal Reference:

Tanya E. Froehlich, Jeffery N. Epstein, Todd G. Nick, Maria S. Melguizo Castro, Mark A. Stein, William B. Brinkman, Amanda J. Graham, Joshua M. Langberg, Robert S. Kahn. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 2011; DOI: 10.1016/j.jaac.2011.08.002

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New insights into insulin resistance could lead to better drugs for diabetics

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ScienceDaily (Oct. 20, 2011) — Research published in the October Molecular and Cellular Biology moves us closer to developing drugs that could mitigate diabetes.

Diabetes afflicts an estimated 26 million Americans, while 79 million have prediabetes. In other words, one in three Americans confronts this disease. Diabetes raises the risk of heart disease and stroke by as much as fourfold, and it is the leading cause of blindness among adults 20-74. It is also the leading cause of kidney failure.

In earlier research, four years ago another team of researchers showed that they could boost insulin sensitivity in experimental rodents by giving the animals a drug called myriocin. People with diabetes have a condition called insulin resistance, which renders them poorly able to process sugar. That results in high blood sugar, which damages the blood vessels, leading to many of diabetes' ills. In their study, that team, led by Johannes M. Aerts of the University of Amsterdam, observed a decrease in a compound called ceramide, which sits on cell membranes in the circulatory system, which they postulated was responsible for the rise in insulin sensitivity.

In the new study, Xian-Cheng Jiang of Downstate Medical Center, Brooklyn, NY, and his collaborators set out to confirm this earlier work, using a genetic approach.

The new research provides strong evidence that ceramide was not causing insulin sensitivity, but that another membrane-bound compound, sphingomyelin, might be doing so.

Ceramide is the substrate for the last step in a five step cascade that produces sphingomyelin. In that step an enzyme called sphingomyline synthase 2 (SMS2) cleaves ceramide to produce sphingomyelin. The first enzyme in this pathway is called serine palmitoyltransferase (SPT).

To test the hypothesis that ceramide is involved in modulating insulin resistance the researchers used knockout mice for each of these enzymes. They postulated that (partially) knocking out the first enzyme in the cascade would decrease ceramide levels while knocking out the last enzyme in the sphingomyelin pathway would boost ceramide levels, since that enzyme uses ceramide to produce sphingomyelin. Thus, SPT knockout mice would have greater insulin sensitivity, while SMS knockout mice would have reduced insulin sensitivity.

Surprisingly, while ceramide levels changed as predicted, that change did not influence insulin sensitivity, which was higher in both groups.

The research has important implications for drug development for mitigating diabetes. Myriocin proved highly toxic and major efforts to modify the drug to reduce that toxicity have been fruitless. Myriocin's toxicity probably stems from the fact that it inhibits the first step of the sphingomyelin biosynthetic pathway, affecting all the downstream biology, says Jiang. The discovery that knocking out the last step in the biosynthetic pathway improves insulin sensitivity means that drug treatments could target that last enzyme, SMS, leaving the rest of that biosynthetic pathway to function normally.

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The above story is reprinted from materials provided by American Society for Microbiology.

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Journal Reference:

Z. Li, H. Zhang, J. Liu, C.-P. Liang, Y. Li, Y. Li, G. Teitelman, T. Beyer, H. H. Bui, D. A. Peake, Y. Zhang, P. E. Sanders, M.-S. Kuo, T.-S. Park, G. Cao, X.-C. Jiang. Reducing Plasma Membrane Sphingomyelin Increases Insulin Sensitivity. Molecular and Cellular Biology, 2011; 31 (20): 4205 DOI: 10.1128/MCB.05893-11

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