Study Evaluates Two Medications For ADHD

University of Illinois at Chicago researchers are comparing two drugs commonly used to treat attention deficit hyperactivity disorder to determine if genetic factors predict which children will respond to either or both drugs.

Many different medications are used to treat ADHD, including stimulants and non-stimulants, says Dr. Mark Stein, principal investigator of the National Institute of Mental Health-funded study and director of the Hyperactivity, Attention, and Learning Problems Clinic at UIC.

“Unfortunately, clinicians are unable to predict in advance who will respond or not respond to a particular medication,” Stein said.

The study will be conducted in Chicago and New York. Stein and colleagues will enroll 160 children and adolescents between ages 7 and 17 in Chicago. Dr. Jeffrey Newcorn of Mt. Sinai School of Medicine heads the New York site.

Participants will undergo psychiatric evaluations, IQ and achievement tests, a blood test, an electrocardiogram and a physical exam. They will then receive several doses of atomoxetine (a non-stimulant medication), melthylphenidate (a stimulant medication), and a placebo, during a carefully monitored blinded dosing sequence to determine their optimal response to each medication.

During the 12 to 15-week study, researchers will assess the children’s ADHD symptoms, social functioning, problem-solving skills and sleep patterns to determine the efficacy and tolerability of each medication.

Previous research conducted by Stein and colleagues found that children with a variant form of a dopamine transporter gene — a variant known to be associated with ADHD — responded poorly to stimulant medication and had more side effects at lower doses. The new study will test whether patients with this genetic marker respond better to non-stimulant medication.

“At the end of the study we hope to be able to look at a child’s biological characteristics to statistically predict who is more likely to respond to a certain medication and to determine who is more likely not to respond or to have a particular side effect,” Stein said.

“The study provides an idealized standard of care in that the children will be carefully evaluated during their treatment with two different medications, with frequent monitoring that typically does not occur during the normal course of ADHD treatment,” said Stein.

At the end of the trial, participants will be referred back to their primary care provider or given a referral for ongoing treatment with information learned from the study.

Popular ADHD Drug Safe And Effective For Pre-schoolers?

A new study by researchers from the Johns Hopkins Children’s Center and five other medical centers concludes that carefully measured, low doses of methylphenidate (Ritalin) are safe and effective for attention-deficit and hyperactivity disorder (ADHD) in preschoolers. Investigators warn, however, that 3- to 5-year-olds appear more sensitive to the drug’s side effects, which include irritability, insomnia and weight loss, than are older children with ADHD and require closer monitoring.

Children who took the drug also experienced somewhat slower growth rates. On average, children on the drug grew half an inch per year less than expected and gained 2.9 pounds less than expected. Researchers recommend that pediatricians weigh the risks of slowed growth rates against the benefits of treatment. Children on long-term treatment with methylphenidate should be monitored carefully several times a year to assess growth changes over time.

Methylphenidate is the most widely prescribed drug for the treatment of ADHD in children but is not approved by the Food and Drug Administration (FDA) for use in children younger than 6.

Results of the federally funded research, the first large-scale, long-term study of the safety and value of the drug in younger children, appear in a special section of the November issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

“These results give us the missing links in the decision to prescribe a drug that’s been widely used off-label in preschool-age children,” says Mark Riddle, M.D., director of Child and Adolescent Psychiatry at the Children’s Center and a co-author on the study, which followed 303 children between 3 and 5 over 70 weeks. “We were able to confirm what many already suspected-that even lower doses in preschoolers can safely achieve the desired therapeutic effect and indeed that low doses are often optimal.”

Children in the study were started on a low-dose regimen of medication ranging from 3.75 mg total daily to 22.5 mg total daily. By comparison, the cumulative daily dose for older children ranges from 15 mg per day to 50 mg per day. The optimal dose needed to reduce symptoms ranged widely in preschool-age children, but on average, 14 mg daily was effective in reining in symptoms.

“One of the surprises was that in some cases, doses as low as even 3 to 4 mg a day were helpful to some preschoolers, which goes to show that lower doses need to be given a chance before higher doses are tried,” Riddle explains.

About 11 percent of those enrolled in the study experienced side effects severe enough to drop out. These included weight loss, anxiety, skin picking, mood disturbances and insomnia.

“We want parents to know that trained professionals can make an accurate diagnosis and prescribe helpful and safe treatment in preschoolers with ADHD,” Riddle says. “But do expect your prescribing physician to monitor side effects closely and regularly and to tweak the dose if necessary.”

ADHD is characterized by a wide range of symptoms, including inability to concentrate, being easily distracted, fidgeting and restlessness, among others. Left untreated, ADHD can interfere with academic progress and social and emotional development. More than 4.4 million children in the United States have ADHD, according to estimates by the Centers for Disease Control and Prevention. About 2 percent of preschool-age children are believed to have ADHD.

Brain Imaging Designs ADHD Treatment With Lower Risk Of Abuse

An article by Thomas J. Spencer, M.D, on a new study in the March 2006 issue of The American Journal of Psychiatry (AJP), the official journal of the American Psychiatric Association (APA), shows how brain imaging is used to identify a form of methylphenidate, a stimulant drug used to treat patients with attention deficit/hyperactivity disorder (ADHD), that is less likely to be abused during treatment.

The study, “PET Study Examining Pharmacokinetics, Detection and Likeability, and Dopamine Transporter Receptor Occupancy of Short- and Long-Acting Oral Methylphenidate,” conducted by Dr. Spencer, Assistant Director of Massachusetts General Hospital Pediatric Psychopharmacology Unit, investigates a new once-a-day capsule developed to release methylphenidate more slowly. Instead of dissolving in the gastrointestinal tract, it absorbs body fluids and uses osmotic pressure to slowly push the medication out of the capsule.

Methylphenidate increases attentiveness for patients with ADHD and lowers their hyperactivity. However, methylphenidate, like other stimulants, can also be abused by patients. Methylphenidate acts by blocking a protein called the dopamine transporter, which transports the neurochemical dopamine out of brain synapses. Blockade of the dopamine transporter by methylphenidate augments dopamine activity in the frontal cortex and improves the children’s ability to pay attention. Rapid increase of dopamine activity in other brain areas is perceived as pleasurable and can lead to patient abuse of methylphenidate.

Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Using positron emission tomography (PET), Spencer conducted a clinical comparison of conventional tablets and the new osmotic capsules. The new capsules succeeded in producing an adequate effect on neurotransmission, with fewer reports of pleasurable effects associated with abusable behavior.

PET scanning, the most sophisticated brain imaging technique for measuring dopamine transporter blockade, showed that the 90-mg capsule with sustained osmotic release produced the same blockade in the brains of healthy adults as 40 mg of immediate-release methylphenidate, but these effects occurred more slowly with the osmotic-release capsule.

“The study represents the first use of PET imaging to detect directly what is happening in the brain during the treatment of ADHD and to use that information to improve treatment,” said Robert Freedman, M.D., AJP editor-in-chief.

Study participants were asked about their subjective reactions to the two different capsules; those taking controlled-release methylphenidate reported significantly less detection of an effect and less liking of the effect. Detecting and liking a drug’s effects signal future abuse potential. Therefore, the controlled-release preparation offers the benefit of once-a-day dosing for patients with ADHD with less likelihood of future abuse.

The main features of ADHD include hyperactivity, impulsiveness, and an inability to sustain attention or concentration. These symptoms occur at levels that cause significant distress and impairment and are far more severe than typically found in children of similar ages and developmental levels. ADHD is a neurobiological disorder that can persist from childhood through adolescence and continue into adulthood.

The “PET Study Examining Pharmacokinetics, Detection and Likeability, and Dopamine Transporter Receptor Occupancy of Short- and Long-Acting Oral Methylphenidate,” study is supported by the National Institute of Mental Health and McNeil Consumer & Specialty Pharmaceuticals.

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Reference:
(Am J Psychiatry. 2006; 163: 387-395).