ADHD Med Linked to Brain Changes in Kids After Stopping

Nancy A. Melville

August 09, 2016

Children treated with methylphenidate for attention-deficit/hyperactivity disorder (ADHD) show brain changes after discontinuing the drug, suggesting "neurochemical imprinting" on the developing brain, with uncertain long-term consequences, new research shows.

"In line with extensive preclinical data, we provide the first evidence, to our knowledge, that methylphenidate treatment during a specific period of maturation alters the cerebral blood flow response, likely reflecting increased dopamine neurotransmission due to neurochemical imprinting by methylphenidate," the authors, led by Liesbeth Reneman, MD, PhD, Brain Imaging Center at the University of Amsterdam, the Netherlands, report.

"In the short term, these alterations do not induce major benefits or harm regarding clinical improvement, but the long-term consequences remain to be established," they add.

The study was published online August 3 in JAMA Psychiatry.

Most Widely Prescribed ADHD Med

Methylphenidate (multiple brands) is the most widely prescribed medication for ADHD, and its use continues to increase for children as well as adults. However, the investigators note there is an "alarming paucity" of findings on the long-term effects of the drug on the developing brain.

To explore this issue, the investigators evaluated 99 male patients at ADHD referral centers in the Netherlands who had been diagnosed with ADHD in accordance with DSM-IV criteria. The patients had not been previously treated with stimulants.

Patients were randomly assigned to receive treatment with either methylphenidate (n = 50) or a matched placebo (n = 49) for 16 weeks.

Using pharmacologic MRI, the authors evaluated changes in cerebral blood flow between baseline and 1 week after the 4-month treatment period. A sustained increase in blood flow in response to an acute challenge with methylphenidate was indicative of a longer-lasting effect of the drugs' dopamine stimulation. The acute challenge consisted of a noninvasive probe for dopamine function.

One week after the end of treatment, results showed that there was a significant increase in cerebral blood flow in the thalamus among children aged 10 to 12 years in response to the challenge compared to baseline (mean difference, 6.5; 95% confidence interval [CI], 0.4 - 12.6; P = .04). They found no similar significant differences in adults or in patients of any age in the group receiving placebo.

Differences were also observed in the striatum among children treated with methylphenidate compared with those receiving placebo, but not in adults (mean difference, 7.7; 95% CI, 0.7 - 14.8; P = .03). Children in the methylphenidate group were treated with a mean dose of 31.3 mg; for adults, the mean dose was 51.6 mg.

The clinical improvement that would be expected to coincide with the increase in cerebral blood flow, which is indicative of a lasting increase in dopamine neurotransmission, was not observed in children 1 week after washout.

In contrast, adults, despite no increases in cerebral blood flow in response to the challenge, did show clinical improvement following washout.

According to Dr Reneman, the improvements in adults were "possibly due to continued coaching effects, combined with the pharmacological treatment."

Clinical Implications Unclear

Dr Reneman said these findings are consistent with the effects of neurochemical imprinting seen in studies on animals, in which administration of a drug when the animal's brain is still developing induces long-lasting and potentially permanent effects after the drug is withdrawn, whereas in adult animals, the effects are only "accommodated."

"However, the neurochemical imprinting theory also states that the effects are only fully expressed once the system is fully matured, typically during early adulthood," Dr Reneman told Medscape Medical News.

"So for now, we can't really say what the long-term effects are either on cerebral blood flow or clinical improvement. It is possible that the neurobiological effects precede the behavioral effects.

"We do not know if these lasting alterations persist for weeks, months or even years; thus, the clinical implications of methylphenidate altering the developing DAergic system are still unclear," she added.

The few other studies on the long-term effects of ADHD medication show conflicting results, the authors note. The Multimodal Treatment Study of Children With ADHD, for instance, found that 6 years after enrollment in the trial, medical management was associated with a transient increase in the prevalence of anxiety and depression.

And although one cohort study showed adult ADHD to be associated with a high rate of substance abuse, another showed that treatment with ADHD simulant medication in childhood may decrease this risk in later life.

The fact that ADHD diagnoses have sharply increased in recent years raises the added concern that some patients who are being treated with methylphenidate may not even be correctly diagnosed, said Dr Reneman.

"Our results call for a tighter regulation of ADHD diagnoses and more careful patient selection, as an increasing number of children are being treated with methylphenidate."

Unanswered Questions

Mark A. Stein, PhD, professor of psychiatry and behavioral medicine at the University of Washington and director of the PEARL Clinic and ADHD/Related Disorders Program at Seattle Children's Hospital, in Washington, agreed that the findings leave unanswered questions in terms of clinical implications.

"It is unclear if slight changes in cerebral blood flow in certain brain regions are clinically significant, since improvement does not persist after medications are discontinued," he told Medscape Medical News.

He speculated that the differences in clinical improvement may relate to adults' ability to express their improvement.

"Perhaps after several months of stimulant treatment and improvement, adults may differ in their ability to develop compensatory skills and perceive lasting improvement when things are going well and that affects their self-report of improvement, unlike children."

Dr Stein noted similar challenges with regard to previous studies of the differing effects of ADHD drugs on children and adults.

"It has been demonstrated in meta-analyses that that are larger effects of stimulants on ADHD symptoms in children than in adults, although this is confounded by measurement issues ― that is, parent and teacher ratings are used for children, and self-ratings are frequently used in adults."

The study received funding from the Academic Medical Center, University of Amsterdam, and by a grant from the European Research Area Network Priority Medicines for Children (Sixth Framework Programme). Study coauthor Wiro J. Niessen, PhD, is cofounder, shareholder, and part-time scientific officer of Quantib BV. No other authors have disclosed any relevant financial relationships. Dr Stein is a consultant to Shire and Alcobra Pharmaceuticals and has received research support from Ironshore, Pfizer, and Shire.

JAMA Psychiatry. Published online August 3, 2016. Abstract

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