Treatment with methylphenidate (multiple brands) may affect the development of the brain's signal-carrying white matter in boys with attention deficit/hyperactivity disorder (ADHD), new research suggests.

Results of a randomized placebo-controlled study conducted in treatment-naive boys and men with ADHD show that 4 months of treatment with methylphenidate affected specific tracts in brain white matter in boys but not in their adult counterparts. The researchers found no changes in the brains of boys who received placebo.

"The results show that ADHD medications can have different effects on the development of brain structure in children versus adults. In adult men with ADHD, and both boys and adult men receiving placebo, changes in FA [fractional anisotropy] measures were not present, suggesting that the effects of methylphenidate on brain white matter are modulated by age," principal investigator Liesbeth Reneman, MD, PhD, Department of Radiology and Nuclear Medicine, Academic Medical Center, University of Amsterdam, the Netherlands, said in a release.

Reneman told Medscape Medical News the findings point to the need for more research.

"We do not yet know whether these effects are reversible or not and whether they are related to functional or behavioral changes over a longer period of time. Our study highlights the importance for further research on this topic in children and adolescents treated with methylphenidate," she said.

She noted that the findings are relevant to an increasing group of children who are being treated with stimulants but who do not suffer from ADHD. Such stimulants may be used, for example, to increase school performance or because of misdiagnosis.

"What our data already underscore is that the use of ADHD medications in children must be carefully considered until more is known about the long-term consequences of prescribing methylphenidate at a young age. The drug should only be prescribed to children who actually have ADHD and are significantly affected by it," said Reneman.

The study was published online August 13 in Radiology.

"Small but Significant Increases"

Preclinical research suggests that medications such as antidepressants and stimulants may induce lasting or even permanent changes in young brains that are still developing. For instance, previous animal research by Reneman's group showed that methylphenidate increased FA in adolescent rats but not in adult animals.

FA reflects various aspects of white matter, including nerve fiber density, size, and myelination, the process that coats nerve fibers to protect the nerve and help it transmit brain signals more efficiently.

Reneman noted that many of the drugs frequently prescribed to children have only been tested in adults or in children "for a very short period of time."

Methylphenidate's effect on brain development, including white matter, which is important for learning, brain functions, and coordinating communication between different brain regions, is largely unknown.

A previous meta-analysis showed that use of methylphenidate was associated with compromised white matter integrity in both children and adult patients with ADHD. The current investigators point out, however, that only retrospective studies were included in that meta-analysis and that the potential confounding effects of ADHD medication were not taken into account.

"Previous studies all have tried to statistically control for the effects of ADHD medications, but we are the first to study medication-naive patients in this context, which, of course is crucial if you want to know how ADHD medications affect the developing brain," said Reneman.

To learn more about the potential impact of stimulants on young brains, the investigators conducted a prospective randomized control trial. The trial included 50 stimulant-naive boys aged 10–12 years and 49 adult men aged 23–40 years who had been diagnosed with ADHD (all types). Participants were randomly allocated to receive treatment with methylphenidate (n = 25 boys, n = 24 men) or placebo (n = 25 boys, n = 24 men) for 16 weeks.

One week before treatment initiation and 1 week after treatment cessation, all study participants underwent MRI, including diffusion tensor imaging.

The study's primary outcome measure was change in FA in three brain regions of interest (ROIs) — the whole brain, bilateral anterior thalamic radiation, and the corpus callosum. The investigators also conducted a voxel-based analysis of brain white matter.

Findings showed that in boys with ADHD, 4 months of treatment with methylphenidate was associated with increased white matter FA. However, this was not the case in men who received methylphenidate. There were no changes in FA measures in the brains of boys and adult men in the placebo group.

The study revealed no baseline differences between any of the study groups for any of the regions of interest (for all, P > .2). Similarly, no three-way interactions were found with respect to time, age, and medication in any of the ROIs.

In addition, there was no two-way interaction between time and medication in either the young or adult study participants, and there was no main effect of time on FA in any of the ROIs.

Owing to missing data, voxel-based analysis was performed on 47 children and 43 adults. This analysis revealed FA changes in children who received methylphenidate, which the researchers described as "small but significant increases."

"Higher Level of Evidence"

These changes were observed in several association fibers, including parts of the left superior longitudinal fasciculus, the inferior longitudinal fasciculus, and the inferior fronto-occipital fasciculus, as well as commissural fibers (lateral in the truncus of the corpus callosum).

"The take-home message is that the ADHD medication methylphenidate lastingly affects white matter development of boys with ADHD. This is probably because the brain is plastic, since we did not observe these changes in the men with ADHD," said Reneman.

The findings, she said, support results from previous studies but provide "a higher level of evidence.

"We have measures before and after treatment and, in addition, assigned children to methylphenidate or placebo, so we are pretty sure the effects are due to methylphenidate and not something else," Reneman told Medscape Medical News.

The researchers note that the fact that interaction effects occurred only in voxel-wise comparisons and not in the selected ROIs suggests that the effects of the drug are "particularly subtle," perhaps indicating that such local differences may be averaged out over the entire ROI. The findings might also indicate that certain brain regions are more susceptible to the stimulating effects of methylphenidate than others.

They note that the 16-week study period may have have had a bearing on the findings, because changes observed after such a short period will likely be small and restricted to tract subclusters rather than the entire tract.

Reneman cautioned that at this point, the findings are relevant only for boys of a certain age — 10 to 12 years — who have ADHD.

"As girls differ considerably in brain white matter development, we do not know if our findings are applicable to them as well. Also, we do not know if our findings are applicable to older or younger boys with ADHD or to boys without ADHD," she said.

Commenting on the findings for Medscape Medical News, Susan L. Andersen, PhD, of Harvard Medical School, Boston, Massachusetts, noted that the "combination of the prospective design and assessment at two different ages contributes more conclusive evidence that the childhood treatment of ADHD with methylphenidate influences brain development.

"Building on earlier findings by Castellanos, the current study found that methylphenidate treatment in children with ADHD, but not controls or adults with the disorder, increases fractional anisotropy," commented Andersen, who was not involved in the study. "The behavioral outcome from increased fractional anisotropy has yet to be determined."

Andersen noted that the findings "further underscore the importance of additional investigation into timing medication as a preventative intervention in the course of ADHD."

Drug Company Weighs In

Reached for comment, Novartis AG, which is the manufacturer of Ritalin, one of the commercially available formulations of methylphenidate, noted that the company is aware of studies intended to better understand the affected neural structures in gray and white matter of the brain in ADHD patients.

"Changes in these neural structures in ADHD patients treated with methylphenidate and other stimulant drugs were also reported by some researchers," the company said in a statement to Medscape Medical News. "We are continuously evaluating the new information concerning the benefits and risks of Ritalin (methylphenidate).

"Approximately 2,000 patients were studied in clinical trials with different formulations of Ritalin/Focalin," the Novartis statement continued. "Ritalin was first marketed in 1954 and continues to treat patients with ADHD and narcolepsy, with approximately 15.5 million patient treatment years."

The study was supported by faculty resources of the Academic Medical Center, the University of Amsterdam, and by a grant through the Sixth Framework Programme of European Research Area Network Priority Medicines for Children. The authors and Andersen have disclosed no relevant conflicts of interest.

Radiology. Published online August 13, 2019. Full text

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