'Medium' Dose of Common ADHD Drug Most Effective for Kids

Liam Davenport

September 12, 2019

COPENHAGEN, Denmark — Increasing the dose of the attention deficit hyperactivity disorder (ADHD) drug methylphenidate (multiple brands) beyond a certain point will not increase the benefit to the child, new research suggests.

Investigators conducted a meta-analysis of 18 studies that included more than 600 children with ADHD. Pooled results showed that, compared with placebo, low and high doses of methylphenidate had an almost identical impact on neurocognitive tasks related to inhibitory control.

However, the strongest effect on test results was found with the medium dose.

The study's main message is that "if you start titrating up and you give higher and higher doses and it doesn't do anything, then keep in mind that it's not always a higher dose that gives a better effect," Karen Vertessen, MD, and a PhD student at the Vrije Universiteit Amsterdam, the Netherlands, told Medscape Medical News.

Vertessen presented the findings here at the 32nd European College of Neuropsychopharmacology (ECNP) Congress.

Common Disorder

ADHD is the most common childhood-onset psychiatric disorder, the researchers note. It is characterized by neurocognitive impairments, with inhibitory control as one of the primary underlying mechanisms.

Methylphenidate is the most commonly prescribed psychopharmacologic therapy for ADHD. Vertessen reported that, while there are other options available in the United States, it is the first-line medication in the Netherlands — where it is taken by 5% of children.

Evidence suggests there is a linear dose effect of methylphenidate on behavioral symptoms, and dose titration takes into account behavioral symptoms and adverse effects.

However, inhibitory control is a central neurocognitive function in ADHD and is predictive of school performance.

While methylphenidate has been slow to have a generally positive effect on neurocognitive functioning, the impact of dosing is unclear and it is not taken into account when titrating the dose.

The investigators conducted a meta-analysis of studies examining the effect of methylphenidate on inhibitory control, working memory, and cognitive flexibility, among other aspects of neurocognitive functioning.

They searched the Cochrane, PubMed, and PsycInfo databases for studies comparing placebo with low (0.10–0.40 mg/kg), medium (0.40–0.70 mg/kg), and high doses (0.70–1.00 mg/kg) of methylphenidate.

From 1875 studies initially screened, 176 were identified as suitable for inclusion. Of those 176, 18 of them (comprising 606 patients with ADHD) studied the impact of methylphenidate on inhibitory control and were selected for the current analysis.

Tasks used in the studies included the Anti-saccade, Go-NoGo, Stop-signal, Stroop, and CPT (continuous performance) tasks.

Improved Inhibitory Control

Results showed that all doses of methylphenidate were associated with significant improvement in inhibitory control vs placebo.

However, the highest standardized mean difference over placebo was shown with the medium dose of methylphenidate, at 0.432 (P = .009) vs 0.364 for the low dose (P = .000) and 0.346 for the high dose (P = .001).

Vertessen noted that when treating ADHD, the current focus is on behavioral symptoms. While not all children with the condition have issues around inhibitory control, "a lot of them do have problems with it and this is highly related to school outcomes," she said.

"That's a reason why a lot of parents seek help. And if that's our treatment outcome, maybe we should look at inhibitory control, because the studies that look at school outcomes have very different results," she added.

Vertessen cautioned that, while methylphenidate may have some positive effects in the longer term on school performance, "I don't think it's a good idea to put a kid on medication for a year to wait to see what the result might be."

"Elegant and Relevant"

In a press release, Kerstin von Plessen, MD, PhD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, described the study as "elegant and highly relevant."

It also "sheds light on an interesting phenomenon which has not received sufficient attention up to now," added von Plessen, who was not involved with the research.

However, the study "does not address the question of why some children receive this higher dosage," which she suggests may be due to the lower dose having a lower effect.

Consequently, "the findings agree with the clinical reality telling us that children who do not respond sufficiently to the regular dosages of methylphenidate require a second, more comprehensive diagnostic examination before increasing the medication," von Plessen said.

She noted that other treatment options should be explored. In addition, the study's conclusion that neurocognitive tests should be added to an evaluation "may be a highly useful option to further identify academic capacity and behavior but should not be a substitute for the clinical evaluation of impulsivity during any change of medication."

Vertessen and colleagues are now conducting a double-blind titration study comparing methylphenidate with usual care — not in the university environment but in the "natural setting" of the psychiatrist's office. They will recruit patients as they are prescribed methylphenidate.

The study was funded by the Innovation Fund Health Insurance (Innovatiefonds Zorgverzekeraars) as part of the MOVA project: Medication Optimization for ADHD. The investigators and von Plessen have disclosed no relevant financial relationships.

32nd European College of Neuropsychopharmacology (ECNP) Congress: Abstract P.831, presented September 10, 2019.

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