Long-term ADHD Med Use: No Benefit, Negative Impact on Growth

Liam Davenport

March 20, 2017

Children who are treated with stimulant medication for attention-deficit/hyperactivity disorder (ADHD) and who continue that treatment into adulthood may experience a suppression of height as adults without experiencing any ongoing reductions in symptoms, results of a long-term follow-up study indicate.

The Multimodal Treatment Study (MTA) showed that although the number of children with ADHD who consistently received treatment into adulthood is relatively small, those who continued to receive these medications showed no differences in symptom severity in comparision those who took treatment holidays or who stopped treatment all together.

However, the average adult height of children who continued treatment was more than 2 cm shorter than those who stopped treatment. For patients who continue to receive treatment, the cumulative d,l-methylphenidate equivalent (ME) doses may run to more than 100,000 mg.

These findings suggest that "childhood-onset ADHD is a chronic disorder with persistence of symptoms into adulthood...and extended use of stimulant medication from childhood through adolescence is associated with suppression of adult height but is not associated with reduced symptom severity," the authors, led by James M. Swanson, PhD, director of the Child Development Center and professor of pediatrics at the University of California, Irvine, write.

The study was published online March 10 in the Journal of Child Psychology and Psychiatry.

Concern Is Not With Growth but Efficacy

The study is a continuation of the Multimodal Treatment Study of Children With ADHD, which was initially a 14-month randomized controlled trial that compared medication management, behavior modification, a combination of both, or treatment as usual for a community comparison in 579 children with ADHD aged 7.0 to 9.9 years.

The trial was then transitioned into a long-term observational study in which 515 original study participants took part, as well as 289 individuals from the same schools, who were recruited to act as a local normal comparison group. Of these control participants, 258 did not have ADHD.

The participants were assessed eight times 2 to 16 years after baseline. The number of days on which patients were treated with stimulant medication and the daily doses that were administered since the previous assessment were recorded.

Using preestablished cutoffs for medication use, participants were classified as consistent, inconsistent, or negligible users. After they had reached adulthood, the participants completed the Conners Adult ADHD Rating Scale to determine symptom persistence.

Follow-up data in adulthood were available for 92.4% of the ADHD group and for 93.4% of the non-ADHD comparison group who started the observational phase. The majority of adult assessments were from the 16-year follow-up.

During follow-up, there was a fourfold decrease in the overall percentage of ADHD patients who were classified as having greater than minimal use of medication use; 23.5% were classified as having a negligible pattern of medication use; 61.9% as having an inconsistent pattern; and 7.4% as having a consistent pattern.

The prospective average cumulative ME doses for the three groups were calculated to be 2153 mg, 60,567 mg, and 117,102 mg, respectively.

The researchers found that there was a significant difference in average scores for symptom severity between the overall ADHD group and the comparison group, at a mean difference of 0.514 (P < .0001).

There was also a significant difference between average parent-report and self-report symptom severity scores, at 0.21 (P < .0001), suggesting that there was a source discrepancy.

However, the team found no significant difference in average symptom scores between the negligible, inconsistent, and consistent medication use groups, at 0.063 (P = .2331) for consistent/inconsistent vs negligible groups, and -0.011 (P = .9003) for consistent vs inconsistent groups, indicating that ongoing medication use did not reduce symptom severity.

With respect to adult height, it was determined that participants in the overall ADHD group were shorter by a significant 1.29 ± 0.55 cm than those in the comparison group (P < .01).

Moreover, individuals in the consistent/inconsistent groups were significantly shorter than those in the negligible group, at an average height reduction of 2.55 ± 0.73 cm (P < .0005). Those in the consistent group were on average 2.36 ± 1.13 cm shorter than those in the inconsistent group, a difference that was again significant (P = .04).

Dr Swanson told Medscape Medical News that the evidence that fewer than 10% of ADHD participants in the study were consistently using stimulant medications into adulthood is "really remarkable," as they were being treated "in the modern era in the United States, when medication use was increasing tremendously."

The question, he said, is not about growth but about efficacy.

"Why do people stop? Is the treatment no longer effective? That's one hypothesis. Or is it that people just don't want to take an effective medication? That's a critical question that is also generated by this prospective, long-term follow-up," he said.

Dr Swanson noted that even when medication was continued, there was "no clear benefit" in comparison with children who never took it or who stopped taking it.

"Certainly it's going to work the next day and the next week and the next year, and maybe some of the next 2 years, but my position is that it probably shouldn't be considered a medication that has a long-term benefit, and you shouldn't give it to get a long-term benefit if there's no longer a benefit," he said.

He also pointed out another question: was there "something special about the group that continued in treatment? Is it, in other words, not an effect of medication but an effect of those who were treated with medication?"

Dr Swanson said that the interesting thing about the group that continued to be treated was that they "had a lot of advantages," in that their family income was higher, and their IQ was slightly higher than those who did not continue treatment.

The question, therefore, is: "Why aren't they better? Just because of who they are?" He added: "So it isn't like a treatment selection bias, where the most difficult children or the poorest children or the most disadvantaged children were treated and it makes the treatment look bad, because these were actually children with many advantages relative to the other children with ADHD in the set.

"I think the uniqueness of this study is that it does provide information from very long-term follow-up, with a very well-diagnosed sample and in good retention of the sample.

"I think it just confirms what some have wondered about, and nobody had conducted a study that was long enough to answer the critical question of whether effects on growth would go away or whether they would stay when people stayed on medication," said Dr Swanson.

While acknowledging that there are a number of limitations to the study, the authors suggest future guidelines "could address strategies for reducing cumulative ME dose" by combining behavioral and psychosocial interventions in conjunction with reductions in average daily doses. Previous studies have shown that treatment efficacy is maintained through such an approach.

"The findings of the MTA suggest that these strategies — which appear to achieve full short-term symptom-related benefits in childhood — may reduce long-term growth-related costs in adulthood," they say.

Need to Investigate Metabolic Effects

Commenting on the findings for Medscape Medical News, Nicole Pratt, PhD, senior research fellow, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, said the results are "robust and suggest a potential dose response association between ADHD pharmacological treatment and height."

She told Medscape Medical News that one of the limitations of the study is that the number of consistently treated children is small. "On the other hand, it is fortunate that this group does represent a small proportion of children with ADHD, meaning that the impact in the real world is likely minimized," she said.

Anna Moffat, PhD, evaluation leader, Veterans' MATES Program, Quality Use of Medicines and Pharmacy Research Center, University of South Australia, added that the study "is particularly interesting in that it demonstrates a difference between those consistently treated and those with 'drug holidays,' which we know can be beneficial for a number of reasons.

"We are only just now beginning to understand the long-term effects of psychotropic medicine use in children, and all robust findings about the long-term impacts need to be carefully weighed against short-term gains at the point of administration," she said.

Dr Pratt pointed out that although the effects on height that were revealed in the study may not affect quality of life, the study suggests that other potential metabolic effects of ADHD medications should be investigated.

"We have researched the cardiovascular safety of ADHD medicines on children, finding small but significant increased risk of arrhythmia. Given the limited (or any) benefit of these medicines, this study only reinforces that the benefits of these medicines are outweighed by their risk," she said.

Dr Moffat concluded that more research is needed "to untangle the mechanism behind reduced height in children who take stimulant medications for ADHD," adding: "Previous work has shown that reductions in food intake as a result of medications is unlikely to explain this; however, nutrition and familial habits around food still needs further exploration.

"The size of the growth reduction may not be clinically significant, but identifying the mechanism underlying this is important and may be able to be targeted through intervention."

The study was funded by the National Institute of Mental Health, the National Institute on Drug Abuse, the University of California–Berkeley, Duke University, the University of California–Irvine, the Research Foundation for Mental Hygiene (New York State Psychiatric Institute, Columbia University), Long Island–Jewish Medical Center, New York University, the University of Pittsburgh, and McGill University. The authors have a number of relationships with pharmaceutical companies, as presented in the original article.

J Child Psychol Psychiatry. Published online March 10, 2017. Abstract

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