Amphetamines and methylphenidate for paediatric ADHD: meta-analysis of n-of-1 trials

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Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders, with an estimated prevalence of about 5% in school-age children (Polanczyk et al, 2007; Polanczyk et al, 2014) and 2.5% in adults. (Simon V et al, 2009).

The recommended treatment of ADHD is multimodal, including pharmacological and non-pharmacological interventions. Medications for ADHD include psychostimulant (e.g., methylphenidate and amphetamine derivatives) and non-psychostimulant drugs (e.g., atomoxetine and guanfacine).

Psychostimulants are the most common drugs used for ADHD worldwide. A large body of evidence from randomised controlled trials (RCTs), summarised in several meta-analyses in children, adolescents and/or adults, shows that different classes of psychostimulants [e.g., methylphenidate (Castells X. et al. 2011b; Koesters M. et al. 2009; Schachter H.M. et al. 2001; Van der Oord S. et al. 2008) or mixed amphetamine salts (Faraone S.V. and Biederman J., 2002) and other amphetamine derivatives (Castells X. et al. 2011a)] are efficacious, at least in the short term, and generally well tolerated, for the treatment of ADHD core symptoms, with mean effect sizes around 0.8 to 0.9.

However, two recent Cochrane reviews (Storebo et al, 2015; Punja et al, 2016a) questioned the quality of the evidence from available RCTs (see also a previous Mental Elf blog by Chris Hollis on this review).

Whilst meta-analyses of interventions (such as the available ones on ADHD drugs) often include parallel RCTs, no meta-analysis so far had pooled n-of-1 trials, defined as multiple crossover trials performed in a single participant, often with randomisation and blinding. Meta-analysing data from n-of-1 trials would allow aggregating data on individual response to treatment.

Punja and colleagues (Punja et al, 2016b) performed the first meta-analysis of n-of-1 trials, focusing on psychostimulants (methylphenidate and amphetamine derivatives) for ADHD, for which numerous N-of-1 trials have been published.

This is the first published meta-analysis of n-of-1 trials, defined as multiple crossover trials performed in a single participant.

This is the first published meta-analysis of n-of-1 trials, defined as multiple crossover trials performed in a single participant.

Methods

As in standard meta-analyses, Punjja et al. (Punja et al, 2016b) searched major electronic databases (MEDLINE, EMBASE, and PsychINFO) (from 1950 to June 2013). They limited the search to studies in English. They also endeavoured to identify grey literature searching in Network Digital Library of Theses and Dissertations (NDLTD), ProQuest Dissertations and Theses and Google Scholar.

They retained n-of-1 trials including single patients or a series of children/adolescents with ADHD, diagnosed according to DSM-III or DSM-IV criteria or equivalent; in the latter case, studies were included in the meta-analysis if individual patient data (IPD) were available.

As in standard meta-analyses, two independent reviewers performed the data extraction. Risk of bias was assessed using the standard Cochrane risk of bias tool (2014).

The primary outcome was the improvement of ADHD core symptoms (i.e., inattention, hyperactivity and impulsivity) on standardised ADHD rating scales completed by parents or teachers (scores from teachers and parents were meta-analysed separately). As for tolerability, IPD were used; if these were not available, the authors relied on the reported summary data. Data were analytically aggregated using the Der Simonian-Laird method (DerSimonian et al, 1986).

Results

Amphetamine derivatives

  • With regards to amphetamines derivatives, nine studies met inclusion criteria for the systematic review. However, only three studies could be pooled in the meta-analysis, including a total of 40 patients. The length of treatment period ranged from 1 to 30 days.
  • The meta-analysis showed that amphetamine derivatives were statistically superior to placebo in all the assessed outcomes on hyperactivity/impulsivity and inattention rated with a range of different scales by teachers or parents, except for inattention, rated by parents on the Conners’ scale.
  • The total number of adverse events, including headache, nausea, loss of appetite and insomnia was slightly higher for amphetamine derivatives (n = 139) as compared with placebo (n = 111).
  • In terms of risk of bias, most of the studies were rated as unclear in the majority of the Cochrane risk of bias tool.

Methylphenidate

  • As for methylphenidate, whilst 10 studies met inclusion criteria for the systematic review, only three, including a total of 71 participants, could be used for the meta-analysis. The length of treatment period ranged from 1 to 14 days.
  • Except for parents reports on the Conners’ rating scales, hyperactivity and ADHD index, and total scores of ADHD symptoms (teacher or parent rated), for the other AHD-related outcomes, methylphenidate was superior to placebo.
  • Methylphenidate was associated with a slightly more adverse events, including headache, nausea, loss of appetite and insomnia, (n = 128) as compared with placebo (n = 117).
  • In terms of risk of bias, most studies were rated as unclear in most of the Cochrane Risk of bias tool, expect for the domain “selective reporting”, where most studies were deemed at low risk.
Both amphetamine derivatives and methylphenidate were superior to placebo in the majority of teacher and parent-rated outcomes related to ADHD core symptoms. The number of adverse events was only slightly higher for psychostimulants compared to placebo.

Both amphetamine derivatives and methylphenidate were superior to placebo in the majority of teacher and parent-rated outcomes related to ADHD core symptoms. The number of adverse events was only slightly higher for psychostimulants compared to placebo.

Conclusions

The authors concluded:

Meta-analysis of n-of-1 trials suggests that amphetamine and methylphenidate are effective treatments for pediatric ADHD.

Strengths

  • This is the first published meta-analysis of n-of-1 trials. It allowed pooling of individual responses to treatment, rather than relying on group means. This is in line with the relatively recent trend to move towards individual patient data meta-analyses, which allows for more powerful and precise assessment of treatment effects
  • The authors endeavoured to include not only published, but also grey literature.

Limitations

  • A very limited number of studies (3 for amphetamine derivatives and 3 for methylphenidate) were included in the meta-analyses
  • The authors used the standard Cochrane risk of bias tool, which is not adapted to n-of-1 trials
  • The issue of possible carry-over effects, that characterise cross-over trials, could have been addressed more explicitly
  • In the inclusion criteria, there is no mention of the issue of including patients with ADHD and comorbid (neuro)psychiatric disorders, which are very frequent in individuals with ADHD
  • The authors limited their search to studies in English; therefore, it cannot be claimed that they performed a comprehensive systematic literature review.
A very limited number of studies were included in this review.

A very limited number of studies were included in this review.

Summary

Overall, this study provides empirical support, using a novel meta-analytical approach, to what many clinicians experience in their daily clinical practice, i.e., that psychostimulants are effective, for a sizeable portion of patients, at least in the short term, to reduce the severity of ADHD core symptoms (i.e., inattention, hyperactivity, and impulsivity). However, it should be noted that the quality of the included studies was rated as unclear in many domains.

Additionally, whilst at the aggregate level psychostimulants were superior to placebo, this meta-analysis confirmed that the response to psychostimulants varies from patient to patient, showing that some participants were improving on stimulants, for some placebo was superior, and for others there was no difference between stimulant and placebo. Interestingly, the total number of adverse events was only slightly superior for psychostimulants as compared to placebo, suggesting that, in their clinical practice, clinicians should be careful when attributing a particular adverse event to psychostimulants.

Most of the studies included in the meta-analysis were limited to a few days in duration. This is unfortunate since the bulk of current debate around psychostimulants is mostly around their effectiveness in the long term (Taylor E. 2014), which remains a matter of discussion and is clearly pivotal for decision making in clinical practice and for guidelines development.

From a methodological standpoint, this first meta-analysis paves the way for further refinement of the methodology that allows aggregating n-of-1 trials.

While this meta-analysis is in line with what clinicians (and patients) experience on the short-term beneficial effects of psychostimulants for ADHD core symptoms, it could not provide any information on their long term effectiveness.

While this meta-analysis is in line with what clinicians (and patients) experience on the short-term beneficial effects of psychostimulants for ADHD core symptoms, it could not provide any information on their long term effectiveness.

Links

Primary paper

Punja S, Xu D, Schmid CH, Hartling L, Urichuk L, Nikles CJ, Vohra S (2016b) Amphetamines and methylphenidate for pediatric ADHD: a systematic review and meta-analysis of n-of-1 evidence. J Clin Epidemiol, in press. doi: 10.1016/j.jclinepi.2016.03.026 Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/27107878

Other references

Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M (2011a) Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults. Cochrane Database Syst Rev CD007813.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/21678370

Castells X, Ramos-Quiroga JA, Rigau D, Bosch R, Nogueira M, Vidal X, Casas M (2011b) Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. CNS Drugs 25, 157-169. Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/21254791

DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7, 177-188. Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/3802833

Faraone SV, Biederman J (2002) Efficacy of Adderall for Attention-Deficit/Hyperactivity Disorder: a meta-analysis. J Atten Disord.6, 69-75. Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/12142863

Higgins JPT, Green S (editors).Cochrane Handbook for Systematic Reviews of InterventionsVersion 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Koesters M, Becker T, Kilian R, Fegert JM, Weinmann S (2009) Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder. J Psychopharmacol 23, 733-744.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=18562416

Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164, 942-948.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=17541055

Polanczyk GV, Willcutt EG, Salum GA, Kieling C, Rohde LA (2014) ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol. 43,434-42. Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=24464188

Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, Vohra S (2016a) Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev 2, CD009996.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/26844979

Schachter HM, Pham B, King J, Langford S, Moher D (2001) How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis. CMAJ. 165, 1475-1488. Pumed abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=11762571

Simon V, Czobor P, Balint S, Meszaros A, Bitter I (2009) Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry 194, 204-211.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=19252145

Storebo OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, Rosendal S, Groth C, Magnusson FL, Moreira-Maia CR, Gillies D, Buch RK, Gauci D, Zwi M, Kirubakaran R, Forsbol B, Simonsen E, Gluud C (2015) Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev 11, CD009885.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/26599576

Taylor E (2014) Uses and misuses of treatments for ADHD. The second Birgit Olsson lecture. Nord J Psychiatry 68, 236-242.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=24588649

Van der Oord S, Prins PJ, Oosterlaan J, Emmelkamp PM (2008) Efficacy of methylphenidate, psychosocial treatments and their combination in school-aged children with ADHD: a meta-analysis. Clin Psychol Rev 28, 783-800.Pubmed abstract: https://www.ncbi.nlm.nih.gov/pubmed/?term=18068284

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Samuele Cortese

I am currently Clinical Associate Professor at the University of Southampton and Honorary Consultant Child Psychiatrist at Solent NHS Trust. I am also Adjunct Associate Professor at the New York University, NY, USA. My research and clinical interests focus on the epidemiology neurobiology and treatment of neurodevelopmental disorders, in particular ADHD. I have published, as first author or co-author, more than 100 peer-reviewed papers in high impact journals, including first author papers in the American Journal of Psychiatry and the British Journal of Psychiatry. I sit on the editorial board of the Journal of the American Academy of Child and Adolescent Psychiatry, The Journal of Child Psychology and Psychiatry, CNS Drugs, the Journal of Child and Adolescent Psychopharmacology, and Attention Deficit Hyperactivity Disorders. I conduct part of my research activity as a member of the European ADHD Guidelines Group. I am the Branch Liaison officer for the Association of Child and Adolescent Mental Health (ACAMH) and member of the ACAMH Southern board.

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