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Evaluation of Methylphenidate Safety and Maximum-Dose Titration Rationale in Attention-Deficit/Hyperactivity DisorderA Meta-analysis

Educational Objective
To determine the evidence on dose titration and adverse events associated with dose titration of stimulants for attention-deficit/hyperactivity disorder (ADHD).
1 Credit CME
Key Points

Question  What evidence is available on maximum dose, dose titration, and adverse events associated with dose titration of stimulants for attention-deficit/hyperactivity disorder?

Findings  This meta-analysis of 11 randomized clinical trials and 38 cohort studies found a wide variation of dose ranges for stimulant medications for attention-deficit/hyperactivity disorder, although whether the doses were arbitrarily selected or evidence based is unclear. Common adverse effects of methylphenidate treatment included insomnia, anorexia, abdominal pain, and headache.

Meaning  The literature recommends a range of maximum doses for methylphenidate but offers no discernable scientific justification for any particular dose; future studies into the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds without reference to any set maximum dose are needed.

Abstract

Importance  Evidence on the titration of stimulant medications for attention-deficit/hyperactivity disorder (ADHD) is lacking. However, this lack of evidence has not prevented medication guidelines from specifying apparently arbitrary dose limitations, which could discourage clinicians from titrating methylphenidate to higher and, perhaps for some patients, more efficacious doses.

Objective  To determine the evidence on dose titration and adverse events associated with dose titration of stimulants for ADHD.

Data Sources  MEDLINE from 1946, Embase from 1974, and PsycINFO from 1806 through April 1, 2019, were searched to identify relevant articles.

Study Selection  The inclusion criteria were that (1) the study was conducted on children up to 18 years of age; (2) children had a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, or hyperkinetic disorder according to the International Classification of Diseases codes; and (3) the dose of methylphenidate was determined by titration.

Data Extraction and Synthesis  The PRISMA guidelines for abstracting data and assessing data quality and validity were followed. Quality assessment was undertaken using the Jadad scoring system. Statistical analysis was undertaken using a random-effects model.

Main Outcomes and Measures  The outcomes of interest were (1) the doses used in published clinical trials, (2) the clinical justification given by researchers for their selected dose range, and (3) the adverse effects associated with methylphenidate when the dose is established by titration.

Results  A total of 11 randomized clinical trials and 38 cohort studies were analyzed. The randomized clinical trials involved 1304 participants treated with methylphenidate and 887 controls; the 38 cohort studies included 5524 participants. Maximum doses of methylphenidate ranged from 0.8 to 1.8 mg/kg/d. Some studies detailed their method of titration, including starting dose, titration interval, increment dose, and maximum dose. Not all of these studies reported justification for the chosen dose range. Common adverse effects of methylphenidate included insomnia (odds ratio, 4.66; 95% CI, 1.99-10.92; P < .001), anorexia (5.11 higher than for those who took placebo; 95% CI, 1.99-13.14; P < .001), abdominal pain (1.9 times more likely; 95% CI, 0.77-4.77; P = .16), and headache (14% of participants; 95% CI, 10%-20%; P < .001).

Conclusions and Relevance  A range of maximum doses for methylphenidate was recommended in clinical studies; no discernable scientific justification for any particular dose was given. Reports of life-threatening adverse events were absent; further studies of the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds, without reference to any set maximum dose, are needed.

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Article Information

Accepted for Publication: February 5, 2019.

Corresponding Author: Alison S. Poulton, MD, MB, BChir, Charles Perkins Centre Nepean, The University of Sydney, Department of Paediatrics, Nepean Hospital, PO Box 63, Penrith, New South Wales 2751, Australia (alison.poulton@sydney.edu.au).

Published Online: May 28, 2019. doi:10.1001/jamapediatrics.2019.0905

Author Contributions: Dr Eslick had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Eslick, Poulton.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ching.

Critical revision of the manuscript for important intellectual content: Eslick, Poulton.

Statistical analysis: Eslick.

Administrative, technical, or material support: Ching, Eslick.

Supervision: Eslick, Poulton.

Conflict of Interest Disclosures: Dr Poulton reported personal fees and nonfinancial support from Shire outside of the submitted work. No other disclosures were reported.

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