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Cited by 70Attention Deficit Hyperactivity DisorderPharmaceutical studies and practicesBehavioral and Psychological Studies

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

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Ching, Cellina, Eslick, Guy D., Poulton, Alison S.·2019·JAMA Pediatrics
DOI 10.1001/jamapediatrics.2019.0905PMC PMC6547117
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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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  • Methylphenidate was associated with a 55% increase in adverse events versus placebo in youths, none life-threatening.

    “A meta-analysis of methylphenidate treatment studies reported a 55% increase in adverse events relative to placebo, none life-threatening (11 studies, over 2,100 youths), but a fivefold increase in anorexia (3 studies, 613 youths), and more than fourfold increase in insomnia (4 studies, 749 youths) (Ching et al., 2019).”

    From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Ching et al., 2019

    The Adverse Effects section reports that methylphenidate-treated participants were 1.55 times more likely than placebo recipients to experience adverse events; it also reports 5.11 times the risk of anorexia and 4.66 times the odds of insomnia. The Study section says no deaths were reported, but it does not establish that none of the adverse events were life-threatening; it notes that less common events were not examined. (LLM, conf=0.87)

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  • Methylphenidate was associated with a fivefold increase in anorexia in youths.

    “A meta-analysis of methylphenidate treatment studies reported a 55% increase in adverse events relative to placebo, none life-threatening (11 studies, over 2,100 youths), but a fivefold increase in anorexia (3 studies, 613 youths), and more than fourfold increase in insomnia (4 studies, 749 youths) (Ching et al., 2019).”

    From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Ching et al., 2019

  • Methylphenidate was associated with more than a fourfold increase in insomnia in youths.

    “A meta-analysis of methylphenidate treatment studies reported a 55% increase in adverse events relative to placebo, none life-threatening (11 studies, over 2,100 youths), but a fivefold increase in anorexia (3 studies, 613 youths), and more than fourfold increase in insomnia (4 studies, 749 youths) (Ching et al., 2019).”

    From The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder (2021) · cites this paper as Ching et al., 2019

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Authors
Ching, C., Eslick, G. D., & Poulton, A. S.
Affiliations
  • Western Sydney University (AU)
  • The University of Sydney (AU)
Corresponding author
Poulton, Alison S.
ORCID
Venue
JAMA Pediatrics
Publisher
American Medical Association (AMA)
Published
2019-07-01
Volume
173
Issue
7
Pages
630
ISSN
  • 1072-4710 (ISSN-L)
  • 2168-6203
DOI
10.1001/jamapediatrics.2019.0905
PMC
PMC6547117
OpenAlex
W2947628883
Semantic Scholar
8f07d2391408b4a9bd5945f6dfb3a2b07b515de2
Cited by
70
References
80
Citations by year
2026: 5 · 2025: 15 · 2024: 7 · 2023: 12 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 4
FWCI
1.31
Type
journal article
Language
en
Open access
Locations
  • Archives of Pediatrics and Adolescent Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Social Sciences › Psychology › Developmental and Educational Psychology › Behavioral and Psychological Studies
Keywords
methylphenidate, attention deficit hyperactivity disorder, dose titration, maximum dose, stimulant medication, adverse drug reactions, insomnia, anorexia, abdominal pain, hyperactivity, children and adolescents, dose-response relationship, treatment efficacy, dose reduction
MeSH terms
Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Child, Dose-Response Relationship, Drug, Humans, Methylphenidate, Randomized Controlled Trials as Topic

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