Refining treatment choices for ADHD
Authors: Anne Arnett, Mark Stein
Journal: The Lancet Psychiatry (2018)

As diagnostic rates of attention-deficit hyperactivity disorder (ADHD) increase worldwide, the most common questions asked by patients are whether to start a medication, which one, and for how long. In The Lancet Psychiatry, Samuele Cortese and colleagues report findings of a comprehensive network meta-analysis1Cortese 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; (published online Aug 7.)http://dx.doi.org/10.1016/S2215-0366(18)30269-4PubMed Google Scholar in which they synthesised crucial information for development of guidelines that will inform clinical decision-making. By including studies published up to April, 2017, and previously unpublished information, Cortese and colleagues' results clarify inconsistencies in earlier reviews and meta-analyses, some of which have generated much controversy.2Storebø 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: h5203Crossref PubMed Scopus (107) Google Scholar, 3Romanos M Coghill D Gerlach M et al.Check and double check: the Cochrane review by Storebø et al (2015) is indeed flawed.Z Kinder Jugendpsychiatr Psychother. 2016; 44: 336-337Crossref PubMed Scopus (6) Google Scholar Furthermore, Cortese and colleagues assessed secondary safety and tolerability outcomes, reflecting growing recognition that acute symptom reduction is only half the battle in treatment of ADHD, which ultimately should target impairment or function.4Gordon M Antshel K Faraone S et al.Symptoms versus impairment: the case for respecting DSM-IV's criterion D.J Atten Disord. 2006; 9: 465-475Crossref PubMed Scopus (156) Google Scholar, 5Sasser T Schoenfelder EN Stein MA Targeting functional impairments in the treatment of children and adolescents with ADHD.CNS Drugs. 2017; 31: 97-107Crossref PubMed Scopus (13) Google Scholar For highly prevalent disorders such as ADHD, guidelines for clinical care should be informed by both public health and precision medicine perspectives.6Walkup JT Stossel L Rendleman R Beyond rising rates: personalized medicine and public health approaches to the diagnosis and treatment of attention-deficit/hyperactivity disorder.J Am Acad Child Adolesc Psychiatry. 2014; 53: 14-16Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar The network meta-analysis by Cortese and colleagues directly addresses the public health approach to pharmacological intervention and confirms the robust short-term efficacy of ADHD medications, although not all medications had the same effects. Moreover, their results present useful clinical indications for close monitoring of blood pressure and weight changes, not only with stimulants but also with atomoxetine. From a precision medicine angle, the findings of the network meta-analysis were limited by the paucity of existing longitudinal and active comparator studies. The results support a moderating effect of age on first-line medication choice, consistent with current use patterns in the USA,7Safer DJ Recent trends in stimulant usage.J Atten Disord. 2016; 20: 471-477Crossref PubMed Scopus (33) Google Scholar with greatest support for methylphenidate in children and adolescents and amphetamine formulations in adults. However, the analyses lacked power to further differentiate effects between children (aged 5–12 years) and adolescents (aged 13–18 years). Thus, the network meta-analysis was unable to address a major challenge in ADHD treatment, which is the high rate of discontinuation that occurs around puberty despite continuation and even increased severity of impairments at that age.8Brinkman WB Simon JO Epstein JN Reasons why children and adolescents with attention-deficit/hyperactivity disorder stop and restart taking medicine.Acad Pediatr. 2018; 18: 273-280Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar The network plots in the current network meta-analysis, in which placebo dominates the picture, underscore the need for a paradigm shift toward comparative treatment research. Despite evidence for preferential response to either methylphenidate or amphetamines at the individual level,9Stein MA Waldman ID Charney E et al.Dose effects and comparative effectiveness of extended release dexmethylphenidate and mixed amphetamine salts.J Child Adolesc Psychopharmacol. 2011; 21: 581-588Crossref PubMed Scopus (54) Google Scholar we still cannot predict a patient's response to first-line or second-line treatments, let alone indications for multiple interventions in cases of part response. In terms of treatment algorithm development for a frequently chronic problem for which monotherapy is seldom sufficient, we remain stuck at the very first branch. This network meta-analysis presents an advanced methodology to summarise and compare findings from treatment studies. Regarding the three common questions patients ask, the extant literature meant that the network meta-analysis could derive only part answers, including general support for short-term medication use, basic guidelines about first-line medications based on age, and little to no data for duration of treatment. These results—and particularly limitations of the data obtained—call for future research that translates directly to clinical practice. Ultimately, this need will require funding agencies to support longitudinal and active comparison designs, attention to sequencing and combining pharmacological and behavioral interventions,10Pelham Jr, WE Fabiano GA Waxmonsky JG et al.Treatment sequencing for childhood ADHD: a multiple-randomization study of adaptive medication and behavioral interventions.J Clin Child Adolesc Psychol. 2016; 45: 396-415Crossref PubMed Scopus (97) Google Scholar and development of big datasets that permit identification of patient predictors, which have thus far remained elusive. We declare no competing interests. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysisOur findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. Full-Text PDF Open Access