Methylphenidate Best First-Line Drug Choice for ADHD in Kids

Damian McNamara

August 10, 2018

Methylphenidate (multiple brands) appears to be the best first-line medication choice for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, new research shows.

In what researchers call the most comprehensive comparison to date of seven common oral medications for ADHD, methylphenidate emerged as the most effective and tolerable.

The systematic review and network meta-analysis also showed that amphetamines are the best choice for adults with the disorder.

"The present network meta-analysis will help guide clinicians in the selection of first-line treatment," study author Andrea Cipriani, MD, PhD, associate professor of psychiatry, Medical Sciences Division, University of Oxford, United Kingdom, told Medscape Medical News.

"For example, in children, while amphetamines were marginally more efficacious than methylphenidate, amphetamines were less well tolerated, giving rise to the preference for methylphenidate as first line in this age group when both parameters are considered," he said.

In contrast, in adults with ADHD, amphetamines were more efficacious than other agents and were equally well tolerated.

"An important new finding is the difference between children and young people on the one hand and adults on the other. The difference in tolerability of amphetamines across age groups had not been appreciated previously," Cipriani said. The reasons behind this difference are unclear, he added.

The study was published online August 7 in Lancet Psychiatry.

Significant Impact

Helping clinicians select the most appropriate front-line treatment could have a significant impact, the researchers note. ADHD affects an estimated 5% of school-aged children and 2.5% of adults worldwide. In addition, the estimated annual costs associated with ADHD run between $143 billion to $266 billion in the United States alone.

Over the past few decades, prescriptions for ADHD medications have increased in the United States and other countries. Treatment guidelines are inconsistent because there are few head-to-head drug comparisons, the researchers note.

To strengthen the available evidence, the investigators evaluated 133 double-blind randomized controlled trials — 81 in children and adolescents, 51 in adults, and one in both — comparing amphetamines (including lisdexamfetamine [Vyvanse, Shire]), atomoxetine (Strattera, Lilly), bupropion (multiple brands), clonidine (multiple brands), guanfacine (Intuniv, Shire) methylphenidate (multiple brands), and modafinil (Provigil, Cephalon) with each other or placebo. Published and unpublished studies were included in the analysis.

The primary outcomes were efficacy and tolerability at time points closest to 12 weeks, 26 weeks, and 52 weeks. Efficacy was defined as change in severity of ADHD core symptoms. Tolerability was determined on the basis of the proportion of patients who dropped out of studies because of side effects.

The investigators estimated summary odds ratios (ORs) and standardized mean differences (SMDs) using pairwise and network meta-analysis with random effects.

For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD, 1.02; 95% confidence interval [CI], -1.19 to -0.85 for amphetamines; SMD, -0.78; 95% CI, -0.93 to -0.62 for methylphenidate; SMD, -0.56; 95% CI, -0.66 to -0.45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD, -0.82; 95% CI, -1.16 to -0.48) and modafinil (SMD, -0.76; 95% CI, -1.15 to -0.37) were more effective than placebo.

Similarly, in adults, amphetamines, methylphenidate, bupropion, and atomoxetine were each superior to placebo (SMDs: -0.79, -0.49, -0.46, and -0.45, respectively). Modafinil, however, was not (SMD, 0.16). The studies did not include adult data for guanfacine or clonidine.

Overall, ADHD medications were more effective and better tolerated in children and adolescents compared to adults. The reason for this disparity is unknown.

A Starting Point

Amphetamines, methylphenidate, atomoxetine, and modafinil caused weight loss in children, adolescents, and adults. Amphetamines and atomoxetine increased blood pressure in children and adolescents; methylphenidate increased blood pressure in adults.

"Our findings will hopefully help people with ADHD in the US find the best treatment for them by clarifying which drugs should be first-, second- and third-line treatments," Cipriani said in a news release. "With an increasing number of people being diagnosed with ADHD and given a drug prescription...our study provides a starting point for medication and hopefully helps patients more quickly find a drug that works for them."

The investigators advise that clinicians consider environmental modifications and nonpharmacologic approaches to managing ADHD before considering medication. However, they add that medication can play an important role.

"There are now a number of different drugs available for the treatment of ADHD symptoms, and when clinicians are seeing patients, they want to know which ones are most likely to be effective, based on both their efficacy and tolerability," said Cipriani.

"Although methylphenidate and amphetamine were selected as the best first-line treatment of children and adults, respectively, it is important to note that alternatives, including atomoxetine and bupropion, and guanfacine in children, showed good efficacy, providing a choice of treatments," he said.

Currently, the UK National Institute for Health and Care Excellence (NICE) recommends methylphenidate as first-line drug treatment in children and adolescents, with lisdexamfetamine as the second option. Atomoxetine or guanfacine are recommended as third-line drugs. NICE also recommends methylphenidate and lisdexamfetamine as first choices in adults.

Increased Confidence

In the current study, there was not enough available evidence to determine whether lisdexamfetamine is more effective and tolerable for adults with ADHD than other amphetamines.

"Interestingly, these findings for first-line treatment are consistent with the recently updated guidance from NICE, but the present findings are based on a much more rigorous scientific comparison of the different drugs," Cipriani said.

"It is reassuring that the recommendations coming from different methodologies, one purely based on scientific grounds and directly comparing drugs, and the other not undertaking this direct comparison but also considering other issues, such as expert opinion and cost, have converged. This will further promote confidence of both clinicians and their patients and families," he added.

The researchers note that despite efforts to include all available trials and unpublished data, they could not rule out the possibility that studies were missed. Another potential limitation was a lack of data at 26 weeks and 52 weeks, which the investigators initially planned to include for assessing long-term safety and efficacy.

"The lack of randomized controlled trials with outcomes beyond 12 weeks highlights the need for research funding to assess the long-term effects of these drugs. However, the evidence we have about methylphenidate and amphetamines from our study is robust and should help inform clinical decisions," said Cipriani.

The researchers plan to investigate specific adverse events to inform clinical practice in the future. Another goal is to go beyond existing observational studies and determine the optimal duration of pharmacologic treatment for ADHD. One strategy to do this is to evaluate "discontinuation trials," in which patients are randomly assigned to either continue or stop medication after a specific time in a blinded fashion.

More Research Needed

In an accompanying editorial, Anne Arnett, PhD, of the Psychiatry and Behavioral Sciences Center on Human Development and Disability, University of Washington, in Seattle, and Mark Stein, PhD, director of the ADHD and Related Disorders Program at Seattle Children's Hospital, note that by including studies published up to April 2017 as well as previously unpublished information, the researchers "clarify inconsistencies in earlier reviews and meta-analyses, some of which generated much controversy."

The editorialists also note that the researchers' assessment of secondary and safety tolerability outcomes reflects the "growing recognition that acute symptom reduction is only half the battle in treatment of ADHD, which ultimately should target impairment or function."

They also write that the analyses lacked power to further differentiate effects between children (aged 5 - 12 years) and adolescents (aged 13 - 18 years).

"Thus, the network meta-analysis was unable to address a major challenge in ADHD treatment, which is the high rate of discontinuation that occurs around puberty despite continuation and even increased severity of impairments at that age," they write.

These limitations, they note, warrant "future research that translates directly into clinical practice."

The National Institute for Health Research (NIHR), the Oxford Health Biomedical Research Center, and Stichting Eunethydis (European Network for Hyperkinetic Disorders) supported the study. The NIHR MindTech MedTech, In vitro Diagnostic Co-operative, and the NIHR Nottingham Biomedical Research Center provided additional support. Dr Cipriani received support from the Oxford Cognitive Health Clinical Research Facility. Dr Arnett and Dr Stein have disclosed no relevant financial relationships.

Lancet Psychiatry. Published online August 7, 2018. Full text, Editorial

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