da angelo maria inverso » 29 ago 2025, 18:09
A tutti i colleghi, salute e ben ritrovati dopo la pausa estiva.
Vi propongo la lettura breve ma interessante di due lettere di commento pubblicate da Lancet Psychiatry.
Una breve premessa alla lettura è indispensabile per la loro piena comprensione.
Il Comitato di esperti dell'OMS sulla selezione e l'uso dei farmaci essenziali ha rifiutato di concedere al metilfenidato lo status di farmaco essenziale. con due successive deliberazioni :2019 e 2021.
Samuele Cortese e colleghi hanno contestato questa decisione ( Cortese 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: 743–44) e la revisione Cochrane effettuata da Storebo e colleghi su cui la decisione si era in larga parte basata ( Storebø OJ, Krogh HB, Ramstad E, et al. Methylphenidate for attention-deficit/ hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ 2015; 351: h5203.)
Nel febbraio 2024 Lancet Psychiatry ha pubblicato due lettere di commento alla vicenda di interessantissima lettura. La seconda dello stesso Storebo che nel 2024 replica gli stessi risultati del 2019.( Storebø OJ, Storm MRO, Pereira Ribeiro J, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2023; 3: CD009885.)
Vi invito a leggerle, vi si apre un mondo davanti. Davvero!
Per correttezza di informazione vi dico che nello stesso numero è contenuta una replica di Cortese e colleghi che potete ugualmente leggere. Gli autori non propongono argomenti sostanziali che modifichino la revisione Cochrane. In ogni modo potete leggere anche quella e trarre le vostre personali conclusioni.
State bene
Angelo
Ps non riesco a caricare l'allegato. Lo ricopio qui sotto insieme alla referenza (per chi non si fida)
Sébastien Ponnou, Sami Timimi, Xavier Briffault, Laura Batstra, Peter C Gøtzsche, François Gonon
WHO Essential Medicines List and methylphenidate for ADHD in children and adolescents In 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 f irst-line therapy for ADHD.” A Comment by Samuele Cortese and colleagues pleads for this decision to be rethought, and argues that methylphenidate has a proven track record of efficacy and safety.2 Cortese and colleagues criticise a comprehensive Cochrane review,3 which concluded that all the trials included were of poor quality, that unmasking was probably common, and that there was little evidence on long-term outcomes, and therefore the review authors could not conclude that methylphenidate would improve the lives of children and adolescents with ADHD. A 2023 update of the review came to the same conclusions,4 as do other Cochrane reviews. The trials presented by Cortese and colleagues are short-term,2 but patients are usually treated for several years. Trials with long-term follow up, such as the Multimodal Treatment of ADHD trial, have not found any positive long-term effects of methylphenidate on ADHD behaviours, academic performance, or the risks of delinquency, addiction, depression, anxiety, or impairment.5,6 to misuse of methylphenidate have been rising in the USA.10 Other studies found that when there are differences in long-term outcome, children on stimulants (such as methylphenidate) often have worse outcomes than those not taking them, regardless of initial severity, with physical (eg, blood pressure), psychiatric (eg, mood disorders), and academic problems found to be more common in patients on long-term medication.7,8 Cortese and colleagues claim that, “individuals with ADHD have significantly fewer unintentional physical injuries, motor vehicle accidents, substance use disorders, and criminal acts, and have an improvement in academic functioning during periods when they are taking methylphenidate, compared with periods when they are not taking methylphenidate.”2 The studies Cortese and colleagues quote use individuals as their own controls; however such studies cannot account for withdrawal reactions, the reasons for disengagement from treatment (such as other psychiatric conditions or life stressors), or if participants were actually taking medication at the time of the event. Methylphenidate is an amphetamine analogue, and therefore a potentially addictive controlled substance. As a CNS stimulant, methylphenidate increases parameters such as blood pressure, body temperature, and heart rate. People using amphetamines and their analogues generally want less sleep, have less appetite, and, according to the US Food and Drug Administration package insert, are at increased risk of serious health consequences, such as sudden death, heart attack, or stroke. It is not known whether amphetamines and their analogues hamper brain development, but it is known that methylphenidate reduces growth in children.9 Increasing circulation of a potentially addictive substance in any society means that it has so-called street value, and can expose people with or without a diagnosis of ADHD to unnecessary harms—emergency room visits linked From our perspective, the decision on methylphenidate by the WHO expert committee aligns with the latest WHO guidelines and international scientific literature. WHO now rightly advocates for expanding the horizons of practice, research, and public policy beyond the biomedical model, in favour of psychosocial interventions and a more person centred rights-based approach that holistically considers all life contexts.
We declare no competing interests.
*Sébastien Ponnou, Sami Timimi, Xavier Briffault, Laura Batstra, Peter C Gøtzsche, François Gonon
sebastien.ponnou-delaffon@univ rouen.fr Educational Sciences, University of Paris 8 (CIRCEFT-CLEF, EA 4384), 93200 Saint-Denis, France (SP);
Lincoln, UK (ST);
Centre for Research in Medicine, Sciences, Health, Mental Health, and Society (CERMES3), National Centre for Scientific Research,Université Paris Cité, Paris, France (XB);
Faculty of the Behavioural and Social Sciences, Department of Child and Family Welfare, University of Groningen, Netherlands (LB);
Institute for Scientific Freedom, Copenhagen, Denmark (PCG);
Institute of Neurodegenerative Diseases, National Centre for Scientific Research, University of Bordeaux, Bordeaux, France (FG)
1. WHO. A.21 Methylphenidate—attention deficit hyperactivity disorder—EML and EMLc. 2023.
https://www.who.int/groups/expert committee-on-selection-and-use-of essential-medicines/23rd-expert-committee/ a21-methylphenidate (accessed Nov 1, 2023).
2. Cortese 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: 743–44.
3. Storebø OJ, Krogh HB, Ramstad E, et al. Methylphenidate for attention-deficit/ hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ 2015; 351: h5203.
4. Storebø OJ, Storm MRO, Pereira Ribeiro J, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2023; 3: CD009885.
5. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007; 46: 989–1002.
6. Molina BSG, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009; 48: 484–500.
7. 7Currie J, Stabile M, Jones LE. NBER working paper series, 19105: do stimulant medications improve educational and behavioural outcomes for children with ADHD? June, 2013.
https://www.nber.org/system/files/working_ papers/w19105/w19105.pdf (accessed Nov 1, 2023).
8. Government of Western Australia, Department of Health. Raine ADHD study: long-term outcomes associated with stimulant medication in the treatment of ADHD in children. Feb 7, 2010.
https://www.health.wa. gov.au/Reports-and-publications/Raine ADHD-Study-Long-term-outcomes associated-with-stimulant-medication (accessed Nov 1, 2023).
9. Swanson JM, Arnold LE, Molina BSG, et al. Young adult outcomes in the follow-up of the multimodal treatment study of attention deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. J Child Psychol Psychiatry 2017; 58: 663–78.
10. Shearer RD, Jones A, Howell BA, Segel JE, Winkelman TNA. Associations between prescription and illicit stimulant and opioid use in the US, 2015–2020. J Subst Abuse Treat 2022; 143: 108894.
Ole Jakob Storebø, Johanne Pereira Ribeiro, Charlotte Lunde, Christian Gluud
In 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). Cortese and colleagues state that the first decision by WHO in 2018 to not add methylphenidate to the EML was largely based on our Cochrane review published in 2015.3 It is a bit disheartening to observe our work being referenced in a manner that does not accurately reflect the content of our review,3 the findings of which were supported by our Moreover, the risks of 2023 update.4 adverse events5 are discounted by Cortese and colleagues by reference only to recent observational evidence (rather than a more comprehensive assessment of harms in observational studies and randomised clinical trials).1 To accept a long-term pharma cological treatment for children when there is no strong evidence of effects is problematic.3,4,5,6 The latest EML for children was released by WHO on July 26, 2023.7 In the context of mental disorders, changes to the EML for children involved the eradication of the substances chlorpromazine, haloperidol, and fluoxetine. With these alternations, the current EML contains no medications of any kind to treat mental disorders in children younger than 12 years, which aligns with current evidence.8,9 WHO sends an important signal regarding the evidence required for medications to be accepted in the EML.7 WHO indicates that precautions are warranted regarding any pharmacological treatment of mental disorders for children younger than 12 years. From an evidence-based perspective, we believe the precautions to be an ethical and sound stance. WHO emphasises that decision makers in national health-care systems should seize the revision of the EML mental health section as an opportunity to take actions that improve the evidence base of both pharmacological and psychosocial interventions. Now, more than ever, mental health treatments should be f irmly placed on health-policy agendas worldwide, and these treaments should be based on solid evidence.
JPR, OJS, and CG have been co-authors of a Cochrane systematic review on methylphenidate for children with ADHD. All other authors declare no competing interests.
*Ole Jakob Storebø, Johanne Pereira Ribeiro, Charlotte Lunde, Christian Gluud
ojst@regionsjaelland.dk Center for Evidence-Based Psychiatry, Psychiatric Research Unit, Psychiatry Region Zealand, 4200 Slagelse, Denmark (OJS, JPR);
Department of Psychology (OJS, JPR) and Department of Regional Health Research (CG), The Faculty of Health Science, University of Southern Denmark, Odense, Denmark; Centre for Medical Ethics, University of Oslo, Oslo, Norway (CL);
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark (CG)
1. Cortese 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: 743–44.
2. Papola D, Ostuzzi G, Todesco B, et al. Updating the WHO Model Lists of Essential Medicines to promote global access to the most cost-effective and safe medicines for mental disorders. Lancet Psychiatry 2023; 10: 809–16.
3. Storebø OJ, Ramstad E, Krogh HB, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2015; 2015: CD009885.
4. Storebø OJ, Storm MRO, Pereira Ribeiro J, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2023; 3: CD009885.
5. Storebø OJ, Pedersen N, Ramstad E, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents—assessment of adverse events in non-randomised studies. Cochrane Database Syst Rev 2018; 5: CD012069.
6. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta analysis. Lancet Psychiatry 2018; 5: 727–38.
7. WHO. Web Annex B: World Health Organization Model List of Essential Medicines—9th List, 2023. In: The selection and use of essential medicines 2023: executive summary of the report of the 24th WHO Expert Committee on the selection and use of essential medicines, 24–28 April, 2023. Geneva: World Health Organization, 2023: 41.
8. 8 Zhou X, Teng T, Zhang Y, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7: 581–601.
9. Yee CS, Bahji A, Lolich M, Vázquez GH, Baldessarini RJ. Comparative efficacy and tolerability of antipsychotics for juvenile psychotic disorders: a systematic review and network meta-analysis. J Clin Psychopharmacol 2022; 42: 198–208
Authors’ reply Samuele Cortese,David Coghill,Gregory W Mattingly,Luis A Rohde,Ian C K Wong,Stephen V Faraone
Sébastien Ponnou and colleagues and Ole Jakob Storebø and colleagues expressed concerns around our plea for methylphenidate to be included in theWHO 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.1 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.2 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.1 Both Ponnou and colleagues and Storebø and colleagues express concerns about the longterm 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 l o n g - t e r m m e t h y l p h e n i d a t e treatment.3 Findings from many naturalistic studies, from multiple medical registries around the world, also document longer-term effects of methylphenidate across key realworld outcomes, including decreased risk of suicide, car accidents, and unintentional injuries.1 The ADDUCE study, 4 which c o n f i r m e d t h e s a f e t y o f 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).5 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 firstline 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”.6 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.7 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
RIFERIMENTO: The Lancet Psychiatry Feb 2024 Volume 11Number 2.
WHO Essential Medicines List and methylphenidate for ADHD in children and adolescents
Sébastien Ponnou,Sami Timimi,Xavier Briffault,Laura Batstra,Peter C Gøtzsche,François Gonon
WHO Essential Medicines List and methylphenidate for ADHD in children and adolescents
Ole Jakob Storebø,Johanne Pereira Ribeiro,Charlotte Lunde,Christian Gluud
A tutti i colleghi, salute e ben ritrovati dopo la pausa estiva.
Vi propongo la lettura breve ma interessante di due lettere di commento pubblicate da Lancet Psychiatry.
Una breve premessa alla lettura è indispensabile per la loro piena comprensione.
Il Comitato di esperti dell'OMS sulla selezione e l'uso dei farmaci essenziali ha rifiutato di concedere al metilfenidato lo status di farmaco essenziale. con due successive deliberazioni :2019 e 2021.
Samuele Cortese e colleghi hanno contestato questa decisione ( Cortese 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: 743–44) e la revisione Cochrane effettuata da Storebo e colleghi su cui la decisione si era in larga parte basata ( Storebø OJ, Krogh HB, Ramstad E, et al. Methylphenidate for attention-deficit/ hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ 2015; 351: h5203.)
Nel febbraio 2024 Lancet Psychiatry ha pubblicato due lettere di commento alla vicenda di interessantissima lettura. La seconda dello stesso Storebo che nel 2024 replica gli stessi risultati del 2019.( Storebø OJ, Storm MRO, Pereira Ribeiro J, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2023; 3: CD009885.)
Vi invito a leggerle, vi si apre un mondo davanti. Davvero!
Per correttezza di informazione vi dico che nello stesso numero è contenuta una replica di Cortese e colleghi che potete ugualmente leggere. Gli autori non propongono argomenti sostanziali che modifichino la revisione Cochrane. In ogni modo potete leggere anche quella e trarre le vostre personali conclusioni.
State bene
Angelo
Ps non riesco a caricare l'allegato. Lo ricopio qui sotto insieme alla referenza (per chi non si fida)
[b]Sébastien Ponnou, Sami Timimi, Xavier Briffault, Laura Batstra, Peter C Gøtzsche, François Gonon[/b]
WHO Essential Medicines List and methylphenidate for ADHD in children and adolescents In 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 f irst-line therapy for ADHD.” A Comment by Samuele Cortese and colleagues pleads for this decision to be rethought, and argues that methylphenidate has a proven track record of efficacy and safety.2 Cortese and colleagues criticise a comprehensive Cochrane review,3 which concluded that all the trials included were of poor quality, that unmasking was probably common, and that there was little evidence on long-term outcomes, and therefore the review authors could not conclude that methylphenidate would improve the lives of children and adolescents with ADHD. A 2023 update of the review came to the same conclusions,4 as do other Cochrane reviews. The trials presented by Cortese and colleagues are short-term,2 but patients are usually treated for several years. Trials with long-term follow up, such as the Multimodal Treatment of ADHD trial, have not found any positive long-term effects of methylphenidate on ADHD behaviours, academic performance, or the risks of delinquency, addiction, depression, anxiety, or impairment.5,6 to misuse of methylphenidate have been rising in the USA.10 Other studies found that when there are differences in long-term outcome, children on stimulants (such as methylphenidate) often have worse outcomes than those not taking them, regardless of initial severity, with physical (eg, blood pressure), psychiatric (eg, mood disorders), and academic problems found to be more common in patients on long-term medication.7,8 Cortese and colleagues claim that, “individuals with ADHD have significantly fewer unintentional physical injuries, motor vehicle accidents, substance use disorders, and criminal acts, and have an improvement in academic functioning during periods when they are taking methylphenidate, compared with periods when they are not taking methylphenidate.”2 The studies Cortese and colleagues quote use individuals as their own controls; however such studies cannot account for withdrawal reactions, the reasons for disengagement from treatment (such as other psychiatric conditions or life stressors), or if participants were actually taking medication at the time of the event. Methylphenidate is an amphetamine analogue, and therefore a potentially addictive controlled substance. As a CNS stimulant, methylphenidate increases parameters such as blood pressure, body temperature, and heart rate. People using amphetamines and their analogues generally want less sleep, have less appetite, and, according to the US Food and Drug Administration package insert, are at increased risk of serious health consequences, such as sudden death, heart attack, or stroke. It is not known whether amphetamines and their analogues hamper brain development, but it is known that methylphenidate reduces growth in children.9 Increasing circulation of a potentially addictive substance in any society means that it has so-called street value, and can expose people with or without a diagnosis of ADHD to unnecessary harms—emergency room visits linked From our perspective, the decision on methylphenidate by the WHO expert committee aligns with the latest WHO guidelines and international scientific literature. WHO now rightly advocates for expanding the horizons of practice, research, and public policy beyond the biomedical model, in favour of psychosocial interventions and a more person centred rights-based approach that holistically considers all life contexts.
We declare no competing interests.
*Sébastien Ponnou, Sami Timimi, Xavier Briffault, Laura Batstra, Peter C Gøtzsche, François Gonon
sebastien.ponnou-delaffon@univ rouen.fr Educational Sciences, University of Paris 8 (CIRCEFT-CLEF, EA 4384), 93200 Saint-Denis, France (SP);
Lincoln, UK (ST);
Centre for Research in Medicine, Sciences, Health, Mental Health, and Society (CERMES3), National Centre for Scientific Research,Université Paris Cité, Paris, France (XB);
Faculty of the Behavioural and Social Sciences, Department of Child and Family Welfare, University of Groningen, Netherlands (LB);
Institute for Scientific Freedom, Copenhagen, Denmark (PCG);
Institute of Neurodegenerative Diseases, National Centre for Scientific Research, University of Bordeaux, Bordeaux, France (FG)
1. WHO. A.21 Methylphenidate—attention deficit hyperactivity disorder—EML and EMLc. 2023. https://www.who.int/groups/expert committee-on-selection-and-use-of essential-medicines/23rd-expert-committee/ a21-methylphenidate (accessed Nov 1, 2023).
2. Cortese 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: 743–44.
3. Storebø OJ, Krogh HB, Ramstad E, et al. Methylphenidate for attention-deficit/ hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ 2015; 351: h5203.
4. Storebø OJ, Storm MRO, Pereira Ribeiro J, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2023; 3: CD009885.
5. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007; 46: 989–1002.
6. Molina BSG, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009; 48: 484–500.
7. 7Currie J, Stabile M, Jones LE. NBER working paper series, 19105: do stimulant medications improve educational and behavioural outcomes for children with ADHD? June, 2013. https://www.nber.org/system/files/working_ papers/w19105/w19105.pdf (accessed Nov 1, 2023).
8. Government of Western Australia, Department of Health. Raine ADHD study: long-term outcomes associated with stimulant medication in the treatment of ADHD in children. Feb 7, 2010. https://www.health.wa. gov.au/Reports-and-publications/Raine ADHD-Study-Long-term-outcomes associated-with-stimulant-medication (accessed Nov 1, 2023).
9. Swanson JM, Arnold LE, Molina BSG, et al. Young adult outcomes in the follow-up of the multimodal treatment study of attention deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. J Child Psychol Psychiatry 2017; 58: 663–78.
10. Shearer RD, Jones A, Howell BA, Segel JE, Winkelman TNA. Associations between prescription and illicit stimulant and opioid use in the US, 2015–2020. J Subst Abuse Treat 2022; 143: 108894.
[b]
Ole Jakob Storebø, Johanne Pereira Ribeiro, Charlotte Lunde, Christian Gluud[/b]
In 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). Cortese and colleagues state that the first decision by WHO in 2018 to not add methylphenidate to the EML was largely based on our Cochrane review published in 2015.3 It is a bit disheartening to observe our work being referenced in a manner that does not accurately reflect the content of our review,3 the findings of which were supported by our Moreover, the risks of 2023 update.4 adverse events5 are discounted by Cortese and colleagues by reference only to recent observational evidence (rather than a more comprehensive assessment of harms in observational studies and randomised clinical trials).1 To accept a long-term pharma cological treatment for children when there is no strong evidence of effects is problematic.3,4,5,6 The latest EML for children was released by WHO on July 26, 2023.7 In the context of mental disorders, changes to the EML for children involved the eradication of the substances chlorpromazine, haloperidol, and fluoxetine. With these alternations, the current EML contains no medications of any kind to treat mental disorders in children younger than 12 years, which aligns with current evidence.8,9 WHO sends an important signal regarding the evidence required for medications to be accepted in the EML.7 WHO indicates that precautions are warranted regarding any pharmacological treatment of mental disorders for children younger than 12 years. From an evidence-based perspective, we believe the precautions to be an ethical and sound stance. WHO emphasises that decision makers in national health-care systems should seize the revision of the EML mental health section as an opportunity to take actions that improve the evidence base of both pharmacological and psychosocial interventions. Now, more than ever, mental health treatments should be f irmly placed on health-policy agendas worldwide, and these treaments should be based on solid evidence.
JPR, OJS, and CG have been co-authors of a Cochrane systematic review on methylphenidate for children with ADHD. All other authors declare no competing interests.
*Ole Jakob Storebø, Johanne Pereira Ribeiro, Charlotte Lunde, Christian Gluud
ojst@regionsjaelland.dk Center for Evidence-Based Psychiatry, Psychiatric Research Unit, Psychiatry Region Zealand, 4200 Slagelse, Denmark (OJS, JPR);
Department of Psychology (OJS, JPR) and Department of Regional Health Research (CG), The Faculty of Health Science, University of Southern Denmark, Odense, Denmark; Centre for Medical Ethics, University of Oslo, Oslo, Norway (CL);
The Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark (CG)
1. Cortese 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: 743–44.
2. Papola D, Ostuzzi G, Todesco B, et al. Updating the WHO Model Lists of Essential Medicines to promote global access to the most cost-effective and safe medicines for mental disorders. Lancet Psychiatry 2023; 10: 809–16.
3. Storebø OJ, Ramstad E, Krogh HB, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2015; 2015: CD009885.
4. Storebø OJ, Storm MRO, Pereira Ribeiro J, et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 2023; 3: CD009885.
5. Storebø OJ, Pedersen N, Ramstad E, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents—assessment of adverse events in non-randomised studies. Cochrane Database Syst Rev 2018; 5: CD012069.
6. Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta analysis. Lancet Psychiatry 2018; 5: 727–38.
7. WHO. Web Annex B: World Health Organization Model List of Essential Medicines—9th List, 2023. In: The selection and use of essential medicines 2023: executive summary of the report of the 24th WHO Expert Committee on the selection and use of essential medicines, 24–28 April, 2023. Geneva: World Health Organization, 2023: 41.
8. 8 Zhou X, Teng T, Zhang Y, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7: 581–601.
9. Yee CS, Bahji A, Lolich M, Vázquez GH, Baldessarini RJ. Comparative efficacy and tolerability of antipsychotics for juvenile psychotic disorders: a systematic review and network meta-analysis. J Clin Psychopharmacol 2022; 42: 198–208
[b]
Authors’ reply Samuele Cortese,David Coghill,Gregory W Mattingly,Luis A Rohde,Ian C K Wong,Stephen V Faraone[/b]
Sébastien Ponnou and colleagues and Ole Jakob Storebø and colleagues expressed concerns around our plea for methylphenidate to be included in theWHO 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.1 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.2 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.1 Both Ponnou and colleagues and Storebø and colleagues express concerns about the longterm 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 l o n g - t e r m m e t h y l p h e n i d a t e treatment.3 Findings from many naturalistic studies, from multiple medical registries around the world, also document longer-term effects of methylphenidate across key realworld outcomes, including decreased risk of suicide, car accidents, and unintentional injuries.1 The ADDUCE study, 4 which c o n f i r m e d t h e s a f e t y o f 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).5 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 firstline 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”.6 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.7 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
RIFERIMENTO: The Lancet Psychiatry Feb 2024 Volume 11Number 2.
WHO Essential Medicines List and methylphenidate for ADHD in children and adolescents
Sébastien Ponnou,Sami Timimi,Xavier Briffault,Laura Batstra,Peter C Gøtzsche,François Gonon
WHO Essential Medicines List and methylphenidate for ADHD in children and adolescents
Ole Jakob Storebø,Johanne Pereira Ribeiro,Charlotte Lunde,Christian Gluud