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Cited by 1,402Attention Deficit Hyperactivity DisorderPharmaceutical studies and practicesPharmacology and Obesity Treatment

Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis

Open access
Cortese, Samuele, Adamo, Nicoletta, Del Giovane, Cinzia, Mohr-Jensen, Christina, Hayes, Adrian J, Carucci, Sara, Atkinson, Lauren Z, Tessari, Luca +11 more·2018·The Lancet Psychiatry
DOI 10.1016/s2215-0366(18)30269-4PMC PMC6109107
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Abstract

BACKGROUND: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. METHODS: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. FINDINGS: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD -1·02, 95% CI -1·19 to -0·85 for amphetamines, -0·78, -0·93 to -0·62 for methylphenidate, -0·56, -0·66 to -0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD -0·82, 95% CI -1·16 to -0·48) and modafinil (-0·76, -1·15 to -0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD -0·79, 95% CI -0·99 to -0·58), methylphenidate (-0·49, -0·64 to -0·35), bupropion (-0·46, -0·85 to -0·07), and atomoxetine (-0·45, -0·58 to -0·32), but not modafinil (0·16, -0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36-3·89) and adults (3·26, 1·54-6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20-5·81); and atomoxetine (2·33, 1·28-4·25), methylphenidate (2·39, 1·40-4·08), and modafinil (4·01, 1·42-11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs -0·46 to -0·24) and adults (-0·94 to -0·29). We did not find sufficient data for the 26-week and 52-week timepoints. INTERPRETATION: Our 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. FUNDING: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and network meta-analysis of 133 double-blind randomised controlled trials found that most ADHD medications were more efficacious than placebo for short-term treatment, but efficacy and tolerability varied by age group and drug. The authors conclude that methylphenidate is supported as first-choice in children and adolescents, and amphetamines in adults, for short-term ADHD treatment.

Key findings

  • For clinician-rated ADHD core symptoms closest to 12 weeks in children and adolescents, all included drugs were superior to placebo, including amphetamines (SMD −1·02, 95% CI −1·19 to −0·85), methylphenidate (−0·78, −0·93 to −0·62), and atomoxetine (−0·56, −0·66 to −0·45). For teacher-rated outcomes, only methylphenidate (−0·82, −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were superior to placebo.
  • In adults, clinician-rated efficacy was superior to placebo for amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59).
  • Tolerability: amphetamines were inferior to placebo in children and adolescents (OR 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior in children and adolescents only (2·64, 1·20–5·81); atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only.
  • In head-to-head comparisons, only efficacy differences were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). No sufficient data were found for 26-week and 52-week timepoints.

Methods

  • Systematic review and network meta-analysis of published and unpublished double-blind randomised controlled trials of oral monotherapy with amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, or modafinil versus each other or placebo in children, adolescents, and adults with ADHD.
  • Searched multiple databases and trial registries from inception to April 7, 2017, with no language restrictions, and contacted authors and manufacturers for unpublished data; 133 trials were included (81 in children and adolescents, 51 in adults, one in both).
  • Primary outcomes were efficacy (change in ADHD core symptoms by clinicians’ ratings; teachers’ ratings also for children and adolescents) and tolerability (dropout due to side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks; random-effects pairwise and network meta-analyses estimated SMDs and ORs, with Cochrane risk-of-bias and GRADE assessments.

Limitations

  • The paper states that missing information cannot be ruled out, the latest study update was April 2017, some network nodes included few studies, most included studies compared active drug with placebo, and comparative efficacy was frequently based on indirect comparisons.
  • The paper states that few data were available for 26-week and 52-week outcomes, so analyses at these timepoints were not possible; findings can inform only short-term medication treatment.
  • The paper states that confidence in estimates was low or very low for many comparisons, especially indirect comparisons, and that paucity of data prevented all planned sensitivity analyses; evident from the text, risk of bias was unclear or high in most included studies, and the authors could not assess some prespecified effect modifiers such as gender, age within paediatric groups, low risk of bias, medication status, and industry sponsorship.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s2215-0366(18)30269-4

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

19 of 35 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Information from multiple raters increases the validity of ADHD diagnosis.

    “For children and adolescents, we also considered teachers' ratings as a primary efficacy outcome because they provide a complementary view to clinicians' ratings, and information from multiple raters increases the validity of ADHD diagnosis.34”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Martel, 2015, Integration of symptom ratings from multiple informants in ADHD diagnosis: a psychometric model with clinical utility, Psychol Assess source
  • Premisecitation

    Current guidelines are inconsistent in their treatment recommendations for ADHD.

    “Furthermore, current guidelines are inconsistent in their treatment recommendations.9, 10, 11, 12, 13, 14”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10] Bolea-Alamanac, 2014, Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology, J Psychopharmacol source
    • cites [11] Kooij, 2010, European consensus statement on diagnosis and treatment of adult ADHD: the European Network Adult ADHD, BMC Psychiatry source

      The Background section (Stigma in general and among professionals; page unavailable) says NICE recommends stimulants as usual first-line treatment for adults, while their use remains controversial and licensing differs across countries. The Conclusions also acknowledge that local regulatory rules may dictate differently. These passages support variation in treatment policy, but do not establish that guidelines themselves make inconsistent treatment recommendations. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [12] Pliszka, 2007, Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder, J Am Acad Child Adolesc Psychiatry source
    • cites [13] Wolraich, 2011, ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents, Pediatrics source

      The Introduction describes this guideline’s treatment recommendations and says its medication recommendations are similar to those of the previous AAP guideline. Our copy does not compare current ADHD guidelines or say their treatment recommendations are inconsistent (searched for inconsistency and differences in treatment recommendations). (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Interpretationreasoning

    Whereas previous pairwise or network meta-analyses of ADHD medications rated all comparisons as low or very low quality, we could rate some comparisons as high or moderate quality.

    “Whereas previous pairwise16, 51 or network meta-analyses19 of ADHD medications rated all comparisons as low or very low quality, attributable in part to unpublished information that we gathered and a more nuanced assessment, we could rate some comparisons as high or moderate quality.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [16] Punja, 2016, Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents, Cochrane Database Syst Rev source
    • cites [51] Storebo, 2015, Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD), Cochrane Database Syst Rev

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [19] Catala-Lopez, 2017, The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: a systematic review with network meta-analyses of randomised trials, PLoS One source
  • Findingown data

    We did a PubMed search in May, 2018, and found only three additional studies that met our inclusion criteria.

    “We did a PubMed search in May, 2018, and found only three additional studies that met our inclusion critieria.48, 49, 50”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [48] Weisler, 2017, Efficacy and safety of SHP465 mixed amphetamine salts in the treatment of attention-deficit/hyperactivity disorder in adults: results of a randomized, double-blind, placebo-controlled, forced-dose clinical study, CNS Drugs source
    • cites [49] Brams, 2018, SHP465 mixed amphetamine salts in the treatment of attention-deficit/hyperactivity disorder in children and adolescents: results of a randomized, double-blind placebo-controlled study, J Child Adolesc Psychopharmacol source
    • cites [50] Griffiths, 2018, Response inhibition and emotional cognition improved by atomoxetine in children and adolescents with ADHD: the ACTION randomized controlled trial, J Psychiatr Res source
  • Findingown data

    Methylphenidate had a standardised mean difference of −0·78 (95% CI −0·93 to −0·62) versus placebo for clinician-rated ADHD core symptoms in children and adolescents closest to 12 weeks.

    “For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The heterogeneity parameter τ is equal across all comparisons in the network meta-analysis.
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Premisecitation

    Lisdexamfetamine is metabolised differently from other amphetamines, which could affect its efficacy and tolerability.

    “Finally, to investigate possible differences between lisdexamfetamine and other amphetamines, we did a post-hoc analysis separating this compound, because lisdexamfetamine is metabolised differently from other amphetamines, which could affect its efficacy and tolerability.45”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] Ermer, 2016, Lisdexamfetamine dimesylate: prodrug delivery, amphetamine exposure and duration of efficacy, Clin Drug Investig source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    The efficacy and safety of ADHD medications remains controversial.

    “However, even though recommended in clinical guidelines,9, 10, 11, 12, 13, 14 the efficacy and safety of ADHD medications remains controversial.15, 16, 17”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [15] Banaschewski, 2016, Methylphenidate for ADHD in children and adolescents: throwing the baby out with the bathwater, Evid Based Ment Health source

      The Abstract describes a dispute over methylphenidate’s efficacy, and the ‘Serious adverse effects (SAEs) of MPH’ section disputes how its safety evidence was interpreted. This supports the existence of controversy for methylphenidate in children and adolescents, but the paper does not establish the claim for ADHD medications generally. The indexed passages provide no page numbers. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [16] Punja, 2016, Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents, Cochrane Database Syst Rev source

      The review’s “Why it is important to do this review” section calls psychostimulant use a major controversy in ADHD treatment. Its authors’ conclusions report short-term benefit from amphetamines alongside adverse events and limited long-term evidence. The cited review concerns amphetamines in children and adolescents, so it does not establish the claim for all ADHD medications. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [17] Romanos, 2016, Methylphenidate for attention-deficit/hyperactivity disorder, JAMA source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The certainty of evidence was estimated with the GRADE approach for network meta-analyses.

    “We estimated the certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analyses (appendix pp 18, 19).33”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Salanti, 2014, Evaluating the quality of evidence from a network meta-analysis, PLoS One source

  • May combine two claims.

    Premisecitation

    Previous network meta-analyses in ADHD have focused on either children and adolescents or adults only, have typically compared only a few drugs, or have addressed exclusively the safety of treatments.

    “Previous network meta-analyses in ADHD have focused on either children and adolescents19, 20, 21, 22, 23, 24 or adults only,25, 26, 27, 28 have typically compared only a few drugs,24, 25, 27, 29 or have addressed exclusively the safety of treatments.26”
    Quote in the paperSubstantial claim5 of 10 sources checked
    • cites [19] Catala-Lopez, 2017, The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: a systematic review with network meta-analyses of randomised trials, PLoS One source
    • cites [20] Joseph, 2014, Systematic literature review and mixed treatment comparison of Gxr versus other treatments in children and adolescents with attention deficit hyperactivity disorder (ADHD), Value Health source
    • cites [21] Joseph, 2017, Comparative efficacy and safety of attention-deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison, Eur Child Adolesc Psychiatry source
    • cites [22] Li, 2017, An evaluation on the efficacy and safety of treatments for attention deficit hyperactivity disorder in children and adolescents: a comparison of multiple treatments, Mol Neurobiol source
    • cites [23] Luan, 2017, Efficacy and tolerability of different interventions in children and adolescents with attention deficit hyperactivity disorder, Front Psychiatry source
    • cites [24] Roskell, 2014, Systematic evidence synthesis of treatments for ADHD in children and adolescents: indirect treatment comparisons of lisdexamfetamine with methylphenidate and atomoxetine, Curr Med Res Opin source
    • cites [25] Bushe, 2016, A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients, J Psychopharmacol source
    • cites [26] de Chierrito, 2017, Safety of treatments for ADHD in adults: pairwise and network meta-analyses, J Atten Disord source
    • cites [27] Zimovetz, 2018, A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK, Eur J Health Econ source
    • cites [28] Peterson, 2008, Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis, Psychopharmacology (Berl) source

  • May combine two claims.

    Interpretationnone given

    We have addressed limitations of previous network meta-analyses, which focused selectively on children and adolescents or adults, or included only published material, non-blinded trials, or non-core ADHD outcomes.

    “We have addressed the limitations of previous network meta-analyses, which focused selectively on children and adolescents19, 20, 21, 22, 23, 24 or adults,25, 26, 27, 28 or included only published material,21, 22, 23, 24, 26 non-blinded trials,19, 21, 22, 23, 24 or non-core ADHD outcomes.19, 22, 25, 28”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [19] Catala-Lopez, 2017, The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: a systematic review with network meta-analyses of randomised trials, PLoS One source
    • cites [20] Joseph, 2014, Systematic literature review and mixed treatment comparison of Gxr versus other treatments in children and adolescents with attention deficit hyperactivity disorder (ADHD), Value Health source
    • cites [21] Joseph, 2017, Comparative efficacy and safety of attention-deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison, Eur Child Adolesc Psychiatry source

  • May combine two claims.

    Findingown data

    The risk of bias was overall low in 27·5% of studies in adults, unclear in 56·8%, and high in 15·7%.

    “The risk of bias was overall low in 27·5% of studies in adults, unclear in 56·8%, and high in 15·7% (appendix pp 382–458).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    133 double-blind randomised controlled trials were included: 81 in children and adolescents, 51 in adults, and one in both.

    “133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included.”
    • Also stated in: § Results · plain
      “133 studies were retained for the network meta-analysis, 81 in children and adolescents, 51 in adults, and one including children, adolescents, and adults.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The risk of bias was rated overall low in 23·5% of studies in children and adolescents, unclear in 65·4%, and high in 11·1%.

    “The risk of bias was rated overall low in 23·5% of studies in children and adolescents, unclear in 65·4%, and high in 11·1%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Medications for ADHD were less efficacious and less well tolerated in adults than in children and adolescents.

    “Medications for ADHD were less efficacious and less well tolerated in adults than in children and adolescents.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The heterogeneity parameter τ is equal across all comparisons in the network meta-analysis.

  • May combine two claims.

    Findingown data

    Included drugs were not equivalent, and their profile in terms of efficacy, tolerability, and acceptability varied across age groups.

    “However, included drugs were not equivalent, and their profile in terms of efficacy, tolerability, and acceptability varied across age groups.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The heterogeneity parameter τ is equal across all comparisons in the network meta-analysis.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    No teacher ratings were available for clonidine.

    “No teacher ratings were available for clonidine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    For 83% of studies, additional data and information not reported in the full-text paper were used.

    “For 83% of studies, additional data and information not reported in the full-text paper were used.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of 59 indirect comparisons, confidence in estimate was very low in 37, low in 20, and moderate in two.

    “Of 59 indirect comparisons, the confidence in estimate was very low in 37 comparisons, low in 20, and moderate in two (appendix pp 589–623, 633–43).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The network meta-analysis assumes transitivity across comparisons.

  • May combine two claims.

    Findingown data

    In general, we found no substantial differences in either efficacy or tolerability across the various medications when the maximum dose allowed was the dose defined by the FDA or by guidelines.

    “In general, we found no substantial differences in either efficacy or tolerability across the various medications when the maximum dose allowed was the dose defined by the FDA or by guidelines (suggesting in general higher maximum doses than the FDA).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The network meta-analysis assumes transitivity across comparisons.

  • May combine two claims.

    Findingown data

    In general, results for the primary outcomes were robust in our sensitivity analyses, suggesting that trials of short duration (<3 weeks), presence of psychiatric comorbidities, low IQ as an inclusion criterion, dose comparisons that we judged unfair, crossover design, and missing data imputation did not significantly affect the results.

    “In general, results for the primary outcomes were robust in our sensitivity analyses, suggesting that trials of short duration (<3 weeks), presence of psychiatric comorbidities, low IQ as an inclusion criterion, dose comparisons that we judged unfair, crossover design, and missing data imputation did not significantly affect the results.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The network meta-analysis assumes transitivity across comparisons.

  • May combine two claims.

    Findingown data

    Most included studies compared an active drug with placebo and the number of actual head-to-head trials was quite small, so comparative efficacy between interventions was frequently based on indirect comparisons.

    “Most included studies compared an active drug with placebo and the number of actual head-to-head trials was quite small, so comparative efficacy between interventions was frequently based on indirect comparisons.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The network meta-analysis assumes transitivity across comparisons.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    These comparisons included the most commonly used drugs for ADHD (ie, methylphenidate and amphetamines).

    “Of note, these comparisons included the most commonly used drugs for ADHD (ie, methylphenidate and amphetamines).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of 42 mixed comparisons, confidence in estimate for primary outcome comparisons was rated as very low in 13, low in 18, moderate in ten, and high in one.

    “Of 42 mixed comparisons (ie, combining direct and indirect evidence), the confidence in estimate for primary outcome comparisons was rated as very low in 13 comparisons, low in 18, moderate in ten, and high in one.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The network meta-analysis assumes transitivity across comparisons.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

    “The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The methods used for sequencing guideline recommendations are not always specified and most commonly incorporate national drug licencing regulatory approval and cost-effectiveness with expert opinion in conjunction with the few available head-to-head comparisons.

    “The methods used for sequencing these recommendations are not always specified and most commonly—including the 2018 UK National Institute for Health and Care Excellence (NICE) guidelines9—incorporate national drug licencing regulatory approval and cost-effectiveness with expert opinion in conjunction with the few head-to-head comparisons that are available.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The review included double-blind randomised controlled trials of at least 1 week's duration in children, adolescents, or adults with a primary diagnosis of ADHD.

    “We included double-blind randomised controlled trials (parallel group, crossover, or cluster), of at least 1 week's duration, that enrolled children (aged ≥5 years and <12 years), adolescents (aged ≥12 years and <18 years), or adults (≥18 years) with a primary diagnosis of ADHD according to DSM-III, DSM III-R, DSM-IV(TR), DSM-5, ICD-9, or ICD-10.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Data were extracted by at least two independent investigators.

    “Data were extracted by at least two independent investigators.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study followed the PRISMA extension for network meta-analyses.

    “We followed the PRISMA extension for network meta-analyses.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Hutton, 2015, The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations, Ann Intern Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Study authors and drug manufacturers were contacted to gather unpublished information and data.

    “We also contacted study authors and drug manufacturers to gather unpublished information and data (appendix p 15).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study protocol was registered with PROSPERO (number CRD42014008976).

    “Our study protocol was registered with PROSPERO (number CRD42014008976) and published.30”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    SCo, NA, CDG, and AC had full access to all data in the study, and AC was responsible for the final decision to submit for publication.

    “SCo, NA, CDG, and AC had full access to all data in the study, and AC was responsible for the final decision to submit for publication.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Network meta-analyses facilitate estimation of comparative efficacy and tolerability even when interventions have not been investigated head-to-head, and increase precision compared with standard pairwise meta-analyses.

    “Network meta-analyses facilitate estimation of the comparative efficacy and tolerability of two or more interventions, even when they have not been investigated head-to-head in randomised controlled trials.18 Thus, compared with standard pairwise meta-analyses, network meta-analyses have been found to increase the precision of the estimates.18”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Cipriani, 2013, Conceptual and technical challenges in network meta-analysis, Ann Intern Med source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Studies with enrichment designs were excluded.

    “We excluded studies with enrichment designs (eg, trials selecting drug responders only after a run-in phase), because these types of trial can potentially inflate efficacy and tolerability estimates.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Enrichment designs can potentially inflate efficacy and tolerability estimates.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Risk of bias was assessed with the Cochrane risk of bias tool.

    “We assessed risk of bias with the Cochrane risk of bias tool.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Because of a paucity of data, we were unable to properly undertake all the planned sensitivity analyses.

    “Moreover, because of a paucity of data, we were unable to properly undertake all the planned sensitivity analyses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    This scarcity of data reflects ethical issues associated with doing long-term, placebo-controlled, randomised controlled trials of effective treatments.

    “This scarcity of data reflects ethical issues associated with doing long-term, placebo-controlled, randomised controlled trials of effective treatments.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Long-term, placebo-controlled, randomised controlled trials of effective treatments raise ethical issues.

  • May combine two claims.

    Interpretationown data

    Even if these characteristics contributed to statistical heterogeneity, it is unlikely that they have implications in terms of clinical heterogeneity and affected the validity of our results.

    “These characteristics were quite evenly distributed across the included studies and across the different nodes in the network, therefore, even if they contributed to statistical heterogeneity, it is unlikely that they have implications in terms of clinical heterogeneity and affected the validity of our results.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    These characteristics were quite evenly distributed across the included studies and across the different nodes in the network.

    “These characteristics were quite evenly distributed across the included studies and across the different nodes in the network, therefore, even if they contributed to statistical heterogeneity, it is unlikely that they have implications in terms of clinical heterogeneity and affected the validity of our results.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The network meta-analysis assumes transitivity across comparisons.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    We planned to do analyses for outcomes closest to 12 weeks, 26 weeks, and 52 weeks, but few data were available for 26 weeks and 52 weeks and analyses at these timepoints were not possible.

    “We planned to do analyses for outcomes closest to 12 weeks, 26 weeks, and 52 weeks, but few data were available for 26 weeks and 52 weeks and analyses at these timepoints were, therefore, not possible.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Our findings represent the best currently available evidence base (not constrained by local costs and licencing) to inform future guidelines internationally and shared decision-making between patients, carers, and clinicians, when a balance has to be made between efficacy and tolerability of ADHD medications.

    “Notwithstanding these caveats, our findings represent the best currently available evidence base (not constrained by local costs and licencing) to inform future guidelines internationally and shared decision-making between patients, carers, and clinicians, when a balance has to be made between efficacy and tolerability of ADHD medications.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Although we included studies that used different rating scales to assess the core symptoms of ADHD, we selected carefully only validated scales that measure exclusively the same triad of symptoms-ie, inattention, hyperactivity, and impulsivity.

    “Although we included studies that used different rating scales to assess the core symptoms of ADHD, we selected carefully only validated scales that measure exclusively the same triad of symptoms—ie, inattention, hyperactivity, and impulsivity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Amphetamines significantly increased diastolic blood pressure in children and adolescents, but not in adults.

    “Additionally, amphetamines significantly increased diastolic blood pressure in children and adolescents, but not in adults.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    We cannot rule out the possibility of missing information.

    “Although we did our best to include all available trials and retrieve unpublished data, we cannot rule out the possibility of missing information.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Accounting for all included outcomes, our results support methylphenidate in children and adolescents, and amphetamines in adults, as the first pharmacological choice for ADHD.

    “Accounting for all included outcomes, our results support methylphenidate in children and adolescents, and amphetamines in adults, as the first pharmacological choice for ADHD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    We did not include studies of antipsychotic or tricyclic antidepressant compounds because they are not used routinely to treat ADHD core symptoms, and their inclusion would violate the assumption of transitivity in the networks.

    “Finally, we did not include studies of antipsychotic or tricyclic antidepressant compounds because, although commonly prescribed for patients with ADHD, they are not used routinely to treat ADHD core symptoms, and their inclusion would, therefore, violate the assumption of transitivity in the networks.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The network meta-analysis assumes transitivity across comparisons.
    • Rests on an assumption: Antipsychotic or tricyclic antidepressant compounds are not used routinely to treat ADHD core symptoms.

  • May combine two claims.

    Interpretationown data

    Included medications were not equivalent in relation to their mean effect size, which ranged from moderate to high and varied according to the type of rater.

    “However, the included medications were not equivalent in relation to their mean effect size, which ranged from moderate to high and varied according to the type of rater.”
    Quote in the paperSubstantial claim
41 of 41

  • The authors state this as an assumption.

    The heterogeneity parameter τ is equal across all comparisons in the network meta-analysis.

    “We did network meta-analyses within a frequentist framework assuming equal heterogeneity parameter τ across all comparisons and accounting for correlations induced by multiarm studies.37, 38”

  • The paper relies on this without support.

    Enrichment designs can potentially inflate efficacy and tolerability estimates.

    “We excluded studies with enrichment designs (eg, trials selecting drug responders only after a run-in phase), because these types of trial can potentially inflate efficacy and tolerability estimates.”

  • The authors state this as an assumption.

    The network meta-analysis assumes transitivity across comparisons.

    “To adhere to the assumption of transitivity and reduce the risk of biased estimates (for instance, those that included enrichment designs), we had to discard many studies that were initially selected as potentially relevant (appendix pp 26–235).”

  • The paper relies on this without support.

    There is considerable interindividual variation in terms of the most effective dose.

    “There is considerable interindividual variation in terms of most effective dose.”

  • The paper relies on this without support.

    Antipsychotic or tricyclic antidepressant compounds are not used routinely to treat ADHD core symptoms.

    “Finally, we did not include studies of antipsychotic or tricyclic antidepressant compounds because, although commonly prescribed for patients with ADHD, they are not used routinely to treat ADHD core symptoms, and their inclusion would, therefore, violate the assumption of transitivity in the networks.”

  • The paper relies on this without support.

    Long-term, placebo-controlled, randomised controlled trials of effective treatments raise ethical issues.

    “This scarcity of data reflects ethical issues associated with doing long-term, placebo-controlled, randomised controlled trials of effective treatments.”

  • The paper relies on this without support.

    Doses higher than those recommended in available guidelines poorly reflect common clinical practice.

    “We excluded some studies9, 46, 47 because they included doses higher than those recommended in available guidelines, thus poorly reflecting common clinical practice.”

  • The paper relies on this without support.

    Patients seen in real-world clinical practice tend to have similar variations.

    “On the contrary, heterogeneity can be seen as increasing the external validity of our findings, because the patients seen in real-world clinical practice tend to have similar variations.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Guanfacine has the most drop-outs due to side effects of all tested medications according to a network meta-analysis.

    “However, the tolerability of guanfacine in children with ADHD is poor. It has the most drop-outs due to side effects of all tested medications according to a network meta-analysis, closely followed by amphetamine-based medication such as lisdexamfetamine (25).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [25]

    The Methods define tolerability as dropping out because of side effects, and the Results report that guanfacine and amphetamines were less well tolerated than placebo in children and adolescents. But Table 2 gives clonidine a higher estimated dropout odds ratio versus placebo than guanfacine (4.52 versus 2.64), and the Results state that no tolerability differences were found between active drugs. The claim that guanfacine had the most dropouts of all tested medications is therefore not supported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Lisdexamfetamine reduces ADHD symptoms with large effect sizes in children and adults.

    “Meta-analyses have shown efficacy of lisdexamfetamine in improving ADHD symptoms with large effect sizes (32, 33).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [32]

    The Abstract Findings and Results report that amphetamines, a group including lisdexamfetamine, improved clinician-rated ADHD symptoms in children and adolescents (SMD −1.02) and adults (SMD −0.79). They do not give a large efficacy effect size specifically for lisdexamfetamine in both groups; the Discussion cautions that too few studies were available to draw firm conclusions from the analysis separating it from other amphetamines. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Guanfacine reduces ADHD symptoms with medium effect sizes in children with ADHD.

    “The newer licensed non-stimulant guanfacine which is an α2-adrenergic receptor agonist reduces ADHD symptoms with medium effect-sizes (0.5) in children with ADHD (25).”

    From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [25]

    The Results (Table 1) report that guanfacine reduced clinician-rated ADHD symptoms versus placebo in children and adolescents, with a moderate effect size. The reported SMD is −0.67, not the cited 0.5; the Results also note that guanfacine was not superior to placebo on parents’ ratings. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Although ADHD is distinct from new-onset post-RRSO executive functioning problems, the management of ADHD can be informative as LDX is a preferred treatment.

    “Although ADHD is distinct from new-onset post-RRSO executive functioning problems, the management of ADHD can be informative as LDX is a preferred treatment [25,26].”

    From Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine (2024) · cites this paper as [25]

    The Discussion (page not available in our copy) supports amphetamines as a first pharmacological choice for adults with ADHD and reports that NICE lists lisdexamfetamine (LDX) as a first choice. But the authors explicitly say they cannot recommend LDX over other amphetamines for adults, so the paper does not establish a specific preference for LDX. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Stimulants are generally used as first-line pharmacologic treatment owing to higher efficacy in symptomatology reduction compared to nonstimulant medications in all age groups.

    “Stimulants have generally been used as first-line pharmacologic treatment owing to a higher efficacy in symptomatology reduction compared to nonstimulant medications in all groups of age (children, adolescents and adults) [17, 33, 34].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [34]

    The Discussion supports stimulant medications as first pharmacological choices: methylphenidate for children and adolescents, and amphetamines for adults. But it bases those choices on efficacy, tolerability, and acceptability, not efficacy alone. It also says atomoxetine, a nonstimulant, had efficacy comparable with methylphenidate in adults, so the claimed efficacy advantage over nonstimulants across all age groups is too broad. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting adult diastolic blood-pressure result for amphetamines

    Minor

    The results state that amphetamines significantly increased diastolic blood pressure in children and adults, but the discussion says the increase was not significant in adults.

1 of 1

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Authors
Cortese, S., Adamo, N., Del Giovane, C., Mohr-Jensen, C., Hayes, A. J., Carucci, S., Atkinson, L. Z., Tessari, L., Banaschewski, T., Coghill, D., Hollis, C., Simonoff, E., Zuddas, A., Barbui, C., Purgato, M., Steinhausen, H.-C., Shokraneh, F., Xia, J., & Cipriani, A.
Affiliations
  • University of Nottingham (GB)
  • King's College London (GB)
  • Oxford Health NHS Foundation Trust (GB)
  • University of Cagliari (IT)
  • Heidelberg University (DE)
  • The University of Melbourne (AU)
  • University of Verona (IT)
  • University of Southern Denmark (DK)
  • University of Nottingham Ningbo China (CN)
Corresponding author
Cipriani, Andrea
ORCID
Venue
The Lancet Psychiatry
Publisher
Elsevier BV
Published
2018-09
Volume
5
Issue
9
Pages
727-738
ISSN
2215-0366 (ISSN-L)
DOI
10.1016/s2215-0366(18)30269-4
PMC
PMC6109107
OpenAlex
W2886298463
Semantic Scholar
db08057f3bcd37f42f541c90fdcbb0ba5deb7538
Cited by
1,402
References
50
Citations by year
2026: 204 · 2025: 200 · 2024: 223 · 2023: 189 · 2022: 182 · 2021: 172 · 2020: 130 · 2019: 74 · 2018: 17 · 2017: 1 · 2016: 1
FWCI
17.83
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Psychiatry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • VBN Forskningsportal (Aalborg Universitet) (publishedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Research Information System of Ardabil University of Medical Sciences (Ardabil University of Medical Sciences) (acceptedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion, other-oa)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Europe PMC (PubMed Central) (submittedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by)
  • BORIS (University Library Bern) (submittedVersion, cc-by)
  • Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
  • Nottingham ePrints (University of Nottingham) (submittedVersion, cc-by)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • Bristol Research (University of Bristol) (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Eli Lilly and Company
  • University of Pennsylvania
  • Ohio State University
  • Emory University
  • Cincinnati Children's Hospital Medical Center
  • Harvard University
  • State University of New York
  • University of Washington
  • Brandeis University
  • Lehigh University
  • Pennsylvania State University
  • Universität Basel
  • McGill University
  • University of South Carolina
  • University of Texas Health Science Center at Houston
  • Università degli Studi di Cagliari
  • University of Connecticut Health Center
  • York University
  • National Institute for Health and Care Research (BRC‐1215‐20005, NF-SI-0514-10073, NF-SI-0514-10119)
  • University of Southampton
  • King's College London
  • University of Sydney
  • Universiteit van Amsterdam
  • Radboud Universiteit
  • Vrije Universiteit Amsterdam
  • Albert-Ludwigs-Universität Freiburg
  • Bar-Ilan University
  • Dalhousie University
  • Universitat de València
  • University of Toronto
  • Karolinska Institutet
  • Ben-Gurion University of the Negev
  • Yancheng Teachers University
  • Universität zu Köln
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • Region Sjælland
  • Sykehuset Østfold
  • Stony Brook University
  • University of California, Irvine
  • State University of New York Upstate Medical University
  • Penn State College of Medicine
  • School of Pharmacy, University College London
  • NIHR Nottingham Biomedical Research Centre
  • National Institute of Mental Health
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
attention deficit hyperactivity disorder, ADHD medication, drug efficacy comparison, tolerability, amphetamine, lisdexamfetamine, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, modafinil, children and adolescents, adults, adverse effects, age differences in treatment response
MeSH terms
Network Meta-Analysis, Adolescent, Adult, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Child, Clonidine, Dose-Response Relationship, Drug, Humans, Methylphenidate, Randomized Controlled Trials as Topic, Bupropion, Adrenergic alpha-2 Receptor Agonists

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-16.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-16.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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