http://www.nytimes.com/2008/09/14/magazine/14bipolar-t.html?_r=1&scp=1&sq=bipolar%20kids&st=cse

After 3 months of continuous treatment with MPH- or amphetamine-based medications, no significant treatment-related increases were observed in any of 3 standard measures of cytogenetic damage among 47 children 6 to 12 years of age.

“Our results demonstrated that standard therapeutic levels of either methylphenidate or mixed amphetamine salt (MAS) products in our study did not increase measures of chromosome damage in white blood cells of children who had been treated continuously for 3 months,” study author Kristine L. Witt, MSc, from the National Institute of Environmental Health Sciences, toldMedscape Psychiatry.

With principal investigator Scott Kollins, PhD, from Duke University Medical Center, in Durham, North Carolina, the study is published online November 19 in the Journal of the American Academy of Child and Adolescent Psychiatry.

Cancer Scare

Investigators at the University of Texas MD Anderson Cancer Center in Houston, raised red flags when, in a 2005 study, they reported cytogenetic damage in the lymphocytes of 12 pediatric ADHD patients after 3 months of continuous MPH-based drug therapy (Cancer Lett. 2005;230:284-291).

These reported alterations consisted of increased frequencies of standard measures of cytogenetic damage, including sister chromatid exchanges (SCE), structural chromosomal aberrations (CA), and micronuclei.

“This raised concern among members of the medical community and families of children receiving MPH-based therapy because increased frequencies of CAs and micronuclei in peripheral blood lymphocytes are associated with an increased risk of cancer,” the authors of the current study write.

However, after publication of the 2005 study, the research community raised questions about the validity of findings based on, among other things, the small sample size and, most important, the fact that there was an absence of SCE data recorded for 6 of 11 children.

More recent research prompted by the 2005 study suggests that MPH does not cause genetic damage. However, despite the growing evidence that MPH-based stimulants are safe, said Ms. Witt, the investigators felt that the “enormous public-health significance of the issue” warranted further investigation.

Methylphenidate-based products have been prescribed for more than 50 years, but use of these drugs has increased sharply since 1990, as the number of children and adults diagnosed with ADHD has risen. In 1996, MAS, another stimulant medication, was also approved for the treatment of ADHD.

Larger, More Comprehensive Study

According to Ms. Witt, the primary goal of the current study was to determine whether the results of the study by the MD Anderson Cancer Center researchers could be independently replicated in a similarly designed trial with sufficient statistical power to detect an increase in genetic damage.

However, said Ms. Witt, given the fact that MAS products are also widely used to treat ADHD and there are currently no cytogenetic data on these drugs, they also decided to test MAS medications in addition to MPH.

The study examnined 63 children, aged 6 to 12 years, diagnosed with ADHD who had not been previously treated with stimulant medications. Baseline blood samples to determine cytogenetic measures were taken in each child, and a second sample was collected after 3 months of continuous treatment.

Of the total study group, 34 subjects were randomized to receive MPH and 29 to receive MAS. A total of 47 children completed the full 3-month treatment schedule.

There were no significant differences between the 2 treatment groups with respect to age, sex, race, body weight, height, or ADHD subtype. The groups had similar ADHD symptom levels at initial screening, and children in both groups responded equally well to the study medications.

Results “Completely Negative”

At the end of the study, the researchers found no cytogenetic changes in any of the study participants, including those children who left the trial early.

“These products do not induce genetic damage in white blood cells of children, and that is reassuring because those changes can be associated with an increased risk for cancer down the road, said Ms. Witt.

“This is a straightforward, simple study with a straightforward design meant to reproduce another study, and [our] results clearly did not reproduce the earlier findings and, in fact, are completely negative,” she continued.

Ms. Witt added that the 3-month study duration is sufficient to detect primary induction of cytogenetic change. She said there have been some studies looking at 6-month exposures to MPH, measuring the single micronuclei end point, and these have been similarly negative.

Typically, children on stimulant medications are long-term users and, therefore, said Ms. Witt, studies looking at the impact of long-term exposure with respect to other outcomes would help reassure parents and the medical community.

The study was supported by the National Institutes of Health. Dr. Kollins reports receiving research support and/or honoraria/consulting fees from Athenage, Eli Lilly, Psychogenics, Pfizer, New River Pharmaceuticals, Shire Pharmaceuticals, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and Environmental Protection Agency. Study author Allan Chrisman, MD, from the Duke University Medical Center, reports receiving honoraria and was on the speaker’s bureaus for Shire Pharmaceuticals and McNeil-PPC. The other authors have disclosed no relevant financial relationships.

J Am Acad Child Adolesc Psychiatry. Published online before print November 19, 2008.

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