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WHO Essential Medicines List and methylphenidate for ADHD in children and adolescents – Authors' reply
2024; Elsevier BV; Volume: 11; Issue: 2 Linguagem: Inglês
10.1016/s2215-0366(23)00437-6
ISSN2215-0374
AutoresSamuele Cortese, David Coghill, Gregory W. Mattingly, Luís Augusto Rohde, Ian Chi Kei Wong, Stephen V. Faraone,
Tópico(s)Attention Deficit Hyperactivity Disorder
ResumoSébastien Ponnou and colleagues and Ole Jakob Storebø and colleagues expressed concerns around our plea for methylphenidate to be included in the WHO Model List of Essential Medicines (EML). Ponnou and colleagues claim that methylphenidate is an amphetamine analogue with addictive potential. Methylphenidate has—as does dexamfetamine—a very different pharmacology to stimulant drugs that are misused, such as methamphetamine and cocaine. These differences, primarily pharmacokinetic in nature, reduce drug-liking effects, misuse potential, and the development of addiction. Substantial evidence suggests that, when used therapeutically, stimulant treatments for ADHD do not increase, and might even protect against, the likelihood of later substance use problems.1Faraone SV Banaschewski T Coghill D et al.The World Federation of ADHD international consensus statement: 208 evidence-based conclusions about the disorder.Neurosci Biobehav Rev. 2021; 128: 789-818Crossref PubMed Scopus (418) Google Scholar Both Ponnou and colleagues and Storebø and colleagues claim that there is a low level of certainty about evidence on the efficacy of methylphenidate for reducing symptoms of ADHD. That claim is based on Storebø and colleagues' meta-analyses of methylphenidate, which used an idiosyncratic application of the Cochrane risk of bias tool.2Banaschewski T Buitelaar J Chui CS et al.Methylphenidate for ADHD in children and adolescents: throwing the baby out with the bathwater.Evid Based Ment Health. 2016; 19: 97-99Crossref PubMed Scopus (25) Google Scholar We believe that data from randomised clinical trials are clear: methylphenidate is not only efficacious, it is among the most efficacious drugs in all of medicine.1Faraone SV Banaschewski T Coghill D et al.The World Federation of ADHD international consensus statement: 208 evidence-based conclusions about the disorder.Neurosci Biobehav Rev. 2021; 128: 789-818Crossref PubMed Scopus (418) Google Scholar Both Ponnou and colleagues and Storebø and colleagues express concerns about the long-term effectiveness and safety of methylphenidate. Their claim that there is no strong evidence for the long-term effectiveness of methylphenidate ignores data from relapse prevention studies, which demonstrate the persistence of clinically meaningful benefits for people with ADHD with continued long-term methylphenidate treatment.3Matthijssen AM Dietrich A Bierens M et al.Continued benefits of methylphenidate in ADHD after 2 years in clinical practice: a randomised placebo-controlled discontinuation study.Am J Psychiatry. 2019; 176: 754-762Crossref PubMed Scopus (37) Google Scholar Findings from many naturalistic studies, from multiple medical registries around the world, also document longer-term effects of methylphenidate across key real-world outcomes, including decreased risk of suicide, car accidents, and unintentional injuries.1Faraone SV Banaschewski T Coghill D et al.The World Federation of ADHD international consensus statement: 208 evidence-based conclusions about the disorder.Neurosci Biobehav Rev. 2021; 128: 789-818Crossref PubMed Scopus (418) Google Scholar The ADDUCE study,4Man KKC Häge A Banaschewski T et al.Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study.Lancet Psychiatry. 2023; 10: 323-333Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar which confirmed the safety of methylphenidate over a 2-year period in children and adolescents, found that long-term methylphenidate use was associated with small increases in heart rate and blood pressure, but these increases were present only during the day and recovered overnight. A recent observational study found that longer cumulative use of methylphenidate, for up to 14 years, was associated with a statistically significant increased risk of hypertension and arterial disease, but no increased risk for other serious cardiovascular conditions (including heart failure).5Zhang L Li L Andell P et al.Attention-deficit/hyperactivity disorder medications and long-term risk of cardiovascular diseases..JAMA Psychiatry. 2023; (published online Nov 22. https://doi.org/10.1001/jamapsychiatry.2023.4294)Crossref Scopus (3) Google Scholar Although these findings reinforce the recommendations found in all evidence-based guidelines to monitor cardiovascular parameters when prescribing methylphenidate, they are not an argument to withhold such an effective treatment from those who would benefit. Safety and efficacy data have been reviewed in great depth by regulators (eg, the US Food and Drug Administration and the European Medicines Agency), the developers of evidence-based national guidelines (eg, the UK National Institute for Health and Care Excellence and the American Academy of Pediatrics), and government agencies who have endorsed these guidelines (eg, the Australian National Health and Medical Research Council). These groups all conclude that methylphenidate is safe and effective and should be considered as a first-line pharmacological treatment for ADHD. Although WHO has not yet agreed to include methylphenidate on the EML, they do support the use of methylphenidate as a treatment for ADHD, including in non-specialist settings within low-income and middle-income countries. The 2023 WHO Mental Health Gap Action Programme guideline for mental, neurological, and substance use disorders makes a clear recommendation that methylphenidate should be considered for children aged 6 years and older who have ADHD, noting specifically that, "methylphenidate treatment shows substantial effects on symptom reduction".6WHO Mental health gap action programme guideline for mental, neurological and substance use disorders.https://www.who.int/publications/i/item/9789240084278Date: Nov 20, 2023Date accessed: December 27, 2023Google Scholar A crucial perspective missing from the Correspondence of Ponnou and colleagues and Storebø and colleagues is the voice of people with lived experience of ADHD. Listening to what those with lived experience are saying is essential for evaluating evidence and determining policy. When preparing our original Correspondence for The Lancet Psychiatry, we consulted with seven large lived-experience associations from across the world.7Cortese S Coghill D Mattingly GW Rohde LA Wong ICK Faraone SV WHO Model Lists of Essential Medicines: methylphenidate for ADHD in children and adolescents.Lancet Psychiatry. 2023; 10: 743-744Summary Full Text Full Text PDF Scopus (3) Google Scholar These associations were unanimous in recognising the crucial role methylphenidate has had in improving the lives of people with ADHD, and supporting inclusion of methylphenidate in the EML. As clinicians and researchers, we cannot ignore their message. We hope that members of the WHO EML committee evaluating methylphenidate will, in the future, take into account both the scientific evidence and the views of people with lived experience of ADHD. SC declares honoraria from the Association for Child and Adolescent Mental Health, British Association of Psychopharmacology, Canadian ADHD Resource Alliance, and Medice. DC declares grants from the National Health and Medical Research Council and Medical Research and Futures Fund; royalties from Oxford University Press and Cambridge University Press; honoraria from Takeda, Medice, Servier, and Novartis; and support for attending meetings, travel, or both, from the European College of Neuropsychopharmacology and South African Society of Psychiatry. DC is an unpaid director for the Australian ADHD Professionals Association and European Network for Hyperkinetic Disorders. GWD declares consulting fees, honoraria, and participation on data safety monitoring boards for Corium, Supernus, Ironshore, Tris, Akilly, Lumos Lab, and Revibe; and holds stock in Revibe. LAR declares grants from the National Council for Scientific and Technological Development and a United States National Institutes of Health (grant R01MH120482); royalties from ARTMED and Oxford Press; consulting fees from Adium, Apsen, Medice, Novartis, Sandoz, Shire, and Takeda; honoraria from Abdi Ibrahim, Abbott, Aché, Adium, Apsen, Bial, Medice, Novartis, Sandoz, Pfizer, Upjohn, Viatris, Shire, and Takeda; support for attending meetings from the Stavros Niarchos Foundation; and participation in data safety monitoring boards for Adium, Apsen, Medice, Novartis, Sandoz, Shire, and Takeda. LAR is president of the International Association of Child and Adolescent Psychiatry and Allied Disciplines, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund in Hong Kong. ICKW declares grants from Amgen, Janssen, GSK, Novartis, Pfizer, Bayer, Bristol-Myers Squibb, Takeda, Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia, and The European Union's Seventh Framework Programme for research and technological development; consulting fees from IQVIA and WHO; and payment for expert testimony for the Court of Appeal in Hong Kong. ICKW is a member of the Pharmacy and Poisons Board, the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization, and the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government; and is a non-executive director of Jacobson Medical in Hong Kong. SVF declares grants from Otsuka, Shire, Takeda, Supernus, and Arbor; royalties from Elsevier, Guilford Press, and Oxford University; consulting fees from Arbor, Aardvark, Aardwolf, the Association for Infant Mental Health, Atentiv, Aveksham Axsome, Genomind, Ironshore, Corium, Kanjo, Johnson & Johnson, Kenvue, KemPharm and Corium, Sky Theraperutics, Medice, Noven, Rhodes, Supernus, Tris Pharma, and Vallon; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Supernus, Sabndoz, Otsuka, and Tris Pharma; and support for attending meetings, travel, or both, from Ironshore and Supernus. SVF has US patent (US20130217707 A1) for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD planned, issued or pending; and holds stock or stock options in Aardvark, Aardwolf, Akili, Ironshore, Sky Therapeutics, and Genomind. WHO Essential Medicines List and methylphenidate for ADHD in children and adolescentsIn 2019, and again in 2021, the WHO Expert Committee on the selection and use of essential medicines declined to grant methylphenidate the status of an essential medicine. This decision was made after a thorough examination using a commonly accepted and consensus-based procedure, which concluded that "evidence for efficacy is inconclusive, with a high risk of bias or unclear data in a substantial proportion of studies; lack of data beyond 12 weeks; lack of data in children under 5 years old; concerning adverse effects; non-pharmacological interventions are the first-line therapy for ADHD."1 Full-Text PDF WHO Essential Medicines List and methylphenidate for ADHD in children and adolescentsIn a Comment from Samuele Cortese and colleagues1 on the Review by Papola and colleagues that describes the 2023 changes to the WHO Model List of Essential Medicines (EML),2 Cortese and colleagues focus on the EML committee's decisions not to support the inclusion of methylphenidate as an essential medicine for the treatment of ADHD in children and adolescents. Two applications were made to WHO, one in 2018 and one in 2020, to include methylphenidate in the EML. Both applications were rejected by the EML committee due to uncertainty about the quality of the evidence and the benefit to harm balance of methylphenidate over long-term use (ie, 52 weeks and beyond). Full-Text PDF
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