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Cited by 374Attention Deficit Hyperactivity DisorderPharmaceutical studies and practicesPharmacovigilance and Adverse Drug Reactions

European guidelines on managing adverse effects of medication for ADHD

Open access
(for the European Guidelines Group), Graham, J., Banaschewski, T., Buitelaar, J., Coghill, D., Danckaerts, M., Dittmann, R. W., Döpfner, M. +15 more·2011·European Child & Adolescent Psychiatry
DOI 10.1007/s00787-010-0140-6PMC PMC3012210
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Abstract

The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.

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Written from the paper’s full text.

TL;DR

The EUNETHYDIS European Guidelines Group reviewed the literature and consulted specialists on adverse effects of ADHD medications licensed in Europe, focusing on methylphenidate, dexamfetamine/mixed amfetamine compounds, and atomoxetine. It concluded that many adverse effects are mild, temporary, or difficult to distinguish from risks associated with untreated ADHD, but rare serious outcomes such as sudden death, suicidality, and psychosis remain uncertain and require further study.

Key findings

  • Cardiac risks: general paediatric sudden death rates range from 0.8 to 8.5/100,000 patient-years, with a median of 1.2–1.3/100,000/year; reported sudden death on ADHD medication in children was 0.2–0.5/100,000 patient-years, and dexamfetamine and methylphenidate were each 0.6/100,000/year. Stimulants and atomoxetine raise average blood pressure by 1–4 mmHg systolic and 1–2 mmHg diastolic; atomoxetine produced above-95th-percentile systolic elevations in 6.8% and diastolic in 2.8%, versus 3% and 0.5% with placebo. Average heart rate increases were 1–2 beats/min, with rare increases up to 50 beats/min; average QTc was not significantly changed.
  • Suicide-related events and psychosis: atomoxetine trials showed suicidal ideation in 5/1,357 atomoxetine-treated children versus 0/851 placebo-treated, with NNH 227 versus NNT 5; there was one suicide attempt and no completed suicide. An FDA review of 49 RCTs found 11 psychosis/mania events during 743 person-years of ADHD drug exposure versus none with placebo, giving 1.48 per 100 person-years and NNH 526; post-marketing surveillance found 865 psychosis reports from 2000–2005, half in children under age 10.
  • Growth, sleep, tics, substance use, and seizures: stimulants reduced height by approximately 1 cm/year during the first 1–3 years and weight by about 3 kg less than predicted over 3 years; in preschoolers, methylphenidate was associated with annual growth rates 20.3% less than expected for height (1.38 cm/year) and 55.2% for weight (−1.32 kg/year). Methylphenidate increased sleep-onset latency more than atomoxetine, and in a 44-child actigraphy study total sleep duration was shorter with methylphenidate than placebo. First-onset tics with methylphenidate did not differ from placebo (0–20%), while about 5–10% of pre-existing tics may worsen reversibly. SUD hazard ratios ranged from 1.2 to 3, up to 7.9 for drug dependence; stimulant therapy was associated with reduced subsequent SUD risk in one meta-analysis (HR = 1.9; adolescence HR = 5.8; adulthood HR = 1.4), though later follow-up found no significant differences. Seizure relative risks were 0.8 for methylphenidate and 1.1 for atomoxetine.
  • Management recommendations include routine pulse and blood pressure monitoring, no routine ECG before ADHD medication, at least 6-monthly growth monitoring, caution with a history of suicidality or psychosis, and limited evidence for drug holidays.

Methods

  • A EUNETHYDIS European Guidelines Group reviewed published literature on immediate-release methylphenidate, modified-release methylphenidate, dexamfetamine and mixed amfetamine compounds, and atomoxetine; unlicensed drugs were excluded except where relevant, and the focus was children and adolescents with additional adult data.
  • The group requested unpublished safety information from licence holders, invited company presentations and questions, consulted paediatric, cardiology, and endocrinology specialists, and held consensus conferences; data submitted to the EMA were not provided to the group.
  • Meta-analysis was not feasible because of heterogeneity in reported information; where quantitative data were available, the group used the indices reported in the papers.

Limitations

  • The paper states that meta-analysis was not feasible due to heterogeneity, EMA-submitted data were not given to the group, rare severe effects remain uncertain, under-reporting is likely, some studies are contradictory or limited, long-term follow-up is insufficient, and some management guidance—such as for sleep problems and drug holidays—is not properly evidence based.
  • The text makes evident additional limitations: the guidelines group received pharmaceutical industry support, many authors reported extensive conflicts of interest, and several recommendations rely on expert consensus or post-marketing/spontaneous reports with unknown denominators rather than robust controlled evidence.

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

Integrity signals

Registry

Crossref · 10.1007/s00787-010-0140-6

Cites

170 of 170 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 146 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Some adverse effects of ADHD medications examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations.

    “Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The median of published sudden death rates in children is 1.2-1.3/100,000/year.

    “The median of these published sudden death rates in children is at 1.2–1.3/100,000/year.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [20] Berger S, Utech L, Fran Hazinski M (2004) Sudden death in children and adolescents. Pediatr Clin North Am 51:1653–1677 source

      Not checked in the free run.

    • cites [30] Corrado D, Basso C, Thiene G (2001) Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res 50:399–408 source

      Not checked in the free run.

    • cites [98] Neuspiel DR, Kuller LH (1985) Sudden and unexpected natural death in childhood and adolescence. JAMA 254:1321–1325 source

      Not checked in the free run.

    • cites [99] Nissen SE (2006) ADHD drugs and cardiovascular risk. N Engl J Med 354:1445–1448 source

      Not checked in the free run.

    • cites [159] Wren C (2002) Sudden death in children and adolescents. Heart 88:426–431 source

      Not checked in the free run.

  • Findingnone given

    The average QTc interval is not changed significantly by any of the drug groups (methylphenidate, mixed amfetamine salts and atomoxetine).

    “The average QTc interval is not changed significantly by any of the drug groups (methylphenidate, mixed amfetamine salts and atomoxetine).”
    Quote in the paperSubstantial claim
  • Findingcitation

    Two of the 25 sudden deaths on ADHD medication occurred with initiation of stimulant medication.

    “Caveats to the above include the observation that 2 of the 25 sudden deaths on ADHD medication occurred with initiation of stimulant medication.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites FDA

      Not checked in the free run.

    • cites Health Canada

      Not checked in the free run.

  • Findingcitation

    Averaging of data in clinical studies can hide a small proportion where the heart rate increment is larger, up to 50 beats/min in rare cases.

    “The averaging of data in clinical studies can hide a small proportion where the increment is larger; indeed up to 50 beats/min in rare cases [150].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Wernicke JF, Faries D, Girod D, Brown J, Gao H, Kelsey D, Quintana H, Lipetz R, Michelson D, Heiligenstein J (2003) Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf 26:729–740 source

      Not checked in the free run.

  • May combine two claims. 54
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingcitation

    The small average change in blood pressure includes patients where the rise is more significant, and there are data showing increases above the 95th centile in individuals taking ADHD medications.

    “While the average increases range from 1–4 mmHg systolic and 1–2 mmHg diastolic, this small average change includes patients where the rise in blood pressure is more significant, and there are also data showing increases above the 95th centile in individuals taking ADHD medications.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Wernicke JF, Faries D, Girod D, Brown J, Gao H, Kelsey D, Quintana H, Lipetz R, Michelson D, Heiligenstein J (2003) Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf 26:729–740 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Findingcitation

    The odds ratio for stimulant use with sudden death in that study was 7.4 (95% CI 1.4-74.9).

    “The odds ratio was reported to be 7.4 (95% CI 1.4–74.9); from which the authors conclude a possible association of stimulant use with sudden death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Gould MS, Walsh BT, Munfakh JL, Kleinmann M, Duan N, Olfson M, Greenhill L, Cooper T (2009) Sudden death and use of stimulant medications in youths. Am J Psychiatry 166:992–1001 source

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    Effects of stimulants on growth are usually minor, but there is substantial variability: some children are completely unaffected, whereas for others treatment results in significant growth suppression.

    “Effects are usually minor, but there is substantial variability: some children are completely unaffected, whereas for others treatment results in significant growth suppression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The pooled analysis of all data on sleep architecture gave contradictory results about any alterations in REM sleep and no alterations on percentage of slow wave sleep.

    “However, the pooled analysis of all data on sleep architecture gave contradictory results about any alterations in REM sleep and no alterations on percentage of slow wave sleep.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Cortese S, Faraone SV, Konofal E, Lecendreux M (2009) Sleep in children with attention-deficit/hyperactivity disorder: meta-analysis of subjective and objective studies. J Am Acad Child Adolesc Psychiatry 48:894–908

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    There was one suicide attempt in the atomoxetine-treated group and no completed suicide occurred during the trials.

    “There was one suicide attempt in the atomoxetine-treated group and no completed suicide occurred during the trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Bangs ME, Tauscher-Wisniewski S, Polzer J, Zhang S, Acharya N, Desaiah D, Trzepacz PT, Allen AJ (2008) Meta-analysis of suicide-related behavior events in patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry 47:209–218 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A meta-analysis of the data showed that suicidal ideation was more frequently observed in clinical trials among children and adolescents treated with atomoxetine (5/1,357) compared to those treated with placebo (0/851), with a number needed to harm (NNH) of 227 compared to the number needed to treat (NNT) of 5 to achieve remission of ADHD symptoms.

    “A meta-analysis of the data showed that suicidal ideation was more frequently observed in clinical trials among children and adolescents treated with atomoxetine (5/1,357) compared to those treated with placebo (0/851), with a number needed to harm (NNH) of 227 compared to the number needed to treat (NNT) of 5 to achieve remission of ADHD symptoms [15].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Bangs ME, Tauscher-Wisniewski S, Polzer J, Zhang S, Acharya N, Desaiah D, Trzepacz PT, Allen AJ (2008) Meta-analysis of suicide-related behavior events in patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry 47:209–218 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In a placebo-controlled cross-over actigraphic monitoring study of 44 children, sleep latency was similar in children with ADHD on methylphenidate versus placebo, but total sleep duration was shorter with methylphenidate than placebo.

    “In a placebo-controlled cross-over actigraphic monitoring study of 44 children, sleep latency was similar in children with ADHD on methylphenidate versus placebo, but total sleep duration was shorter with methylphenidate than placebo [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Schwartz G, Amor LB, Grizenko N, Lageix P, Baron C, Boivin DB, Joober R (2004) Actigraphic monitoring during sleep of children with ADHD on methylphenidate and placebo. J Am Acad Child Adolesc Psychiatry 43:1276–1282 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Methylphenidate, dexamfetamine and atomoxetine are effective drugs for ADHD, and meta-analyses have led guidelines to recommend their use as part of a comprehensive treatment programme.

    “They are effective drugs, and meta-analyses investigating their use have led to our guidelines recommending their use as part of a comprehensive treatment programme [13, 140].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Banaschewski T, Coghill D, Santosh P, Zuddas A, Asherson P, Buitelaar J, Danckaerts M, Dopfner M, Faraone SV, Rothenberger A, Sergeant J, Steinhausen HC, Sonuga-Barke EJ, Taylor E (2006) Long-acting medications for the hyperkinetic disorders: a systematic review and European treatment guideline. Eur Child Adolesc Psychiatry 15(8):476–495 source

      Not checked in the free run.

    • cites [140] Taylor E, Dopfner M, Sergeant J, Asherson P, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Rothenberger A, Sonuga-Barke E, Steinhausen HC, Zuddas A (2004) European clinical guidelines for hyperkinetic disorder—first upgrade. Eur Child Adolesc Psychiatry 13(Suppl 1):17–30

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hundreds of trials involving ADHD drugs indicate they are associated with a range of adverse effects that are generally acceptable because they are mild and/or temporary.

    “There are hundreds of trials involving the ADHD drugs, all of them indicating that they are associated with a range of adverse effects that are generally acceptable, because they are mild and/or temporary.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Graham J, Coghill D (2008) Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management. CNS Drugs 22:213–237 source

      Not checked in the free run.

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

    Premisecitation

    Among young persons with known congenital heart disease, the highest risks of sudden death (0.2% per year) occur with specific conditions such as aortic stenosis.

    “Among young persons with known congenital heart disease, the highest risks of sudden death (0.2% per year) occur with specific conditions such as aortic stenosis [128].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Silka MJ, Hardy BG, Menashe VD, Morris CD (1998) A population-based prospective evaluation of risk of sudden cardiac death after operation for common congenital heart defects. J Am Coll Cardiol 32:245–251 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Newer forms of ADHD drugs, introduced with enhanced monitoring standards, have resulted in signals of potential harm, raising the possibility that some adverse outcomes may also apply to methylphenidate.

    “Also the introduction and regulatory approval of newer forms of the drugs, which have been accompanied by enhanced standards of monitoring, have resulted in signals of potential harm, raising the possibility that some of these adverse outcomes may also apply to methylphenidate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ADHD drug adverse effects predominantly include neurological effects (headache, dizziness, insomnia, seizures), psychiatric effects (mood/anxiety, tics, psychotic symptoms), and gastroenterological effects including poor appetite and possible growth restriction.

    “These symptoms predominantly include neurological effects (headache, dizziness, insomnia, seizures); psychiatric effects (mood/anxiety, tics, psychotic symptoms); and gastroenterological effects including poor appetite and overlapping with possible growth restriction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Graham J, Coghill D (2008) Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management. CNS Drugs 22:213–237 source

      Not checked in the free run.

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

    Premisecitation

    In children with ADHD, the risk of death from all causes is estimated at 58.4/100,000 patient-years.

    “In children with ADHD, the risk of death from all causes is estimated at 58.4/100,000 patient-years [157]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A (2007) Cardiac safety of central nervous system stimulants in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 120:e1494–e1501 source

      Not checked in the free run.

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

    Premisecitation

    Sudden death rates in children range from 0.8 to 8.5/100,000 patient-years.

    “Sudden death rates range from 0.8 to 8.5/100,000 patient-years [20, 30, 98, 99, 159].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [20] Berger S, Utech L, Fran Hazinski M (2004) Sudden death in children and adolescents. Pediatr Clin North Am 51:1653–1677 source

      Not checked in the free run.

    • cites [30] Corrado D, Basso C, Thiene G (2001) Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res 50:399–408 source

      Not checked in the free run.

    • cites [98] Neuspiel DR, Kuller LH (1985) Sudden and unexpected natural death in childhood and adolescence. JAMA 254:1321–1325 source

      Not checked in the free run.

    • cites [99] Nissen SE (2006) ADHD drugs and cardiovascular risk. N Engl J Med 354:1445–1448 source

      Not checked in the free run.

    • cites [159] Wren C (2002) Sudden death in children and adolescents. Heart 88:426–431 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In the FDA post-marketing reports, many of the identified subjects were receiving polypharmacy, which may moderate risk of sudden death.

    “In the FDA post-marketing reports, many of the identified subjects were receiving polypharmacy, which therefore may moderate risk of sudden death.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites FDA

      Not checked in the free run.

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

    Interpretationreasoning

    If childhood deaths on ADHD medications are under-reported to a greater degree than assumed, then some incremental risk could potentially be present.

    “If childhood deaths on ADHD medications are under-reported to a greater degree than we have assumed, then some incremental risk could potentially be present.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: A 50% under-reporting rate can be assumed when estimating the sudden death risk of children on ADHD medications.

  • May combine two claims.

    Premisecitation

    In another study, the incidence of sudden death in children prescribed ADHD drugs was not found to be statistically different to that in the general population, but the study was limited by its sample size.

    “In another study the incidence of sudden death in children prescribed ADHD drugs was not found to be statistically different to that in the general population; but this study was limited by its sample size [91].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] McCarthy S, Cranswick N, Potts L, Taylor E, Wong IC (2009) Mortality associated with attention-deficit hyperactivity disorder (ADHD) drug treatment: a retrospective cohort study of children, adolescents and young adults using the general practice research database. Drug Saf 32:1089–1096 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    This risk might potentially be increased by treatment with drugs with pressor adverse effects, although evidence is lacking, and sudden death more commonly will be the first presentation of the underlying condition.

    “This risk might potentially be increased by treatment by drugs with pressor adverse effects, although evidence is lacking, and sudden death more commonly will be the first presentation of the underlying condition.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The patient information leaflet for methylphenidate products in Europe indicates that the drug may increase systolic and diastolic blood pressure by more than 10 mmHg.

    “The patient information leaflet for methylphenidate products in Europe indicates that the drug may increase systolic and diastolic blood pressure by more than 10 mmHg.1”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    QTc prolongation (and sudden death and increased heart rate) have been reported with methylphenidate and dexamfetamine and with atomoxetine.

    “QTc prolongation (and sudden death and increased heart rate) have been reported with methylphenidate and dexamfetamine [99] and atomoxetine [34].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [99] Nissen SE (2006) ADHD drugs and cardiovascular risk. N Engl J Med 354:1445–1448 source

      Not checked in the free run.

    • cites [34] Eli Lilly and Co. (2006) Strattera safety information

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Children with a BMI above the 95th percentile had a hypertension prevalence of 10.7% in one study, in contrast to children with a BMI below the 85th percentile, who had a hypertension prevalence of only 2.6%.

    “children with a BMI above the 95th percentile had a hypertension prevalence of 10.7% in one study; in contrast to children with a BMI below 85th percentile, who had a hypertension prevalence of only 2.6% [130].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Sorof JM, Lai D, Turner J, Poffenbarger T, Portman RJ (2004) Overweight, ethnicity, and the prevalence of hypertension in school-aged children. Pediatrics 113:475–482 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The assessment of sudden deaths with relation to patient-years of treatment described atomoxetine deaths at 0.5 per 100,000 patient-years, and methylphenidate at 0.2 per 100,000 patient-years.

    “The assessment of sudden deaths with relation to patient-years of treatment described atomoxetine deaths at 0.5 per 100,000 patient-years, and methylphenidate at 0.2 per 100,000 patient-years [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Aagaard L, Weber CB, Hansen EH (2010) Adverse drug reactions in the paediatric population in Denmark: a retrospective analysis of reports made to the Danish Medicines Agency from 1998 to 2007. Drug Saf 33:327–339 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Individuals with an undetected cardiac pathology, such as a cardiomyopathy or conduction problem, might as a result of ADHD medication have their illness at best 'revealed' or at worst aggravated with a potentially fatal outcome, and this remains to be excluded as an extremely rare possible outcome.

    “That individuals with an undetected cardiac pathology, such as a cardiomyopathy or conduction problem, might as a result of ADHD medication, have their illness at best ‘revealed’ or at worst aggravated with a potentially fatal outcome, remains to be excluded as an extremely rare possible outcome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Adverse events are frequently under-reported in general, but sudden deaths in young individuals on relatively new medications may be better reported.

    “While it is recognised that adverse events are frequently under-reported in general, it is likely that sudden deaths in young individuals on relatively new medications may be better reported.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Prolongation of the QTc interval in individuals without congenital long QT syndrome or previously recognised long QT interval can be caused by a variety of medications and is a recognised risk factor for ventricular tachyarrhythmias and sudden death.

    “Prolongation of the QTc interval in individuals (without a congenital long QT syndrome or previously recognised long QT interval) can be caused by a variety of medications and is a recognised risk factor for ventricular tachyarrhythmias and sudden death [160].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Yap YG, Camm AJ (2003) Drug induced QT prolongation and torsades de pointes. Heart 89:1363–1372 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ECG screening is not currently considered cost-effective or appropriate for prevention of sudden death in the general paediatric population in Europe (or the US).

    “ECG screening is, however, not currently considered cost-effective or appropriate for prevention of sudden death in the general paediatric population in Europe (or the US), for example, as reported by Denchev et al. [32] in a recent economic evaluation of the issue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Denchev P, Kaltman JR, Schoenbaum M, Vitiello B (2010) Modeled economic evaluation of alternative strategies to reduce sudden cardiac death among children treated for attention deficit/hyperactivity disorder. Circulation 121:1329–1337 source

      Not checked in the free run.

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

    Premisecitation

    Measurement of the QTc interval is not without difficulties, and at least six alternative methods of rate correction are available.

    “Finally, it should be noted that measurement of the QTc interval is not without difficulties, and at least six alternative methods of rate correction are available [83, 149].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [83] Luo S, Michler K, Johnston P, Macfarlane PW (2004) A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol 37(Suppl):81–90 source

      Not checked in the free run.

    • cites [149] Wernicke JF, Faries D, Breitung R, Girod D (2005) QT correction methods in children and adolescents. J Cardiovasc Electrophysiol 16:76–81 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    More important than the average change in QTc in a study cohort is the proportion with an increment in QTc to above the safe threshold (usually accepted as above 470-500 ms).

    “More important than the average change in a study cohort is the proportion with an increment in QTc to above the safe threshold (usually accepted as being above 470–500 ms).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In adults, a 2 mmHg lowering of usual systolic blood pressure would result in about 10% lower stroke mortality and about 7% lower mortality from ischemic heart disease or other vascular causes in middle age.

    “In adults a 2 mmHg lowering of usual systolic blood pressure would result in about 10% lower stroke mortality and about 7% lower mortality from ischemic heart disease or other vascular causes in middle age [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Lewington S, Clarke R, Qizilbash N, Peto R, Collins R (2002) Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360:1903–1913 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Any persistent heart rate increases seen with ADHD treatment are usually very small and unlikely to be a risk factor for exacerbation of underlying cardiac pathology, but a less common larger persistent rise in heart rate may theoretically do so.

    “In terms of potential mechanisms whereby ADHD medications may cause cardiac risk, any persistent heart rate increases seen with ADHD treatment are usually very small and unlikely to be a risk factor for exacerbation of underlying cardiac pathology, but a less common larger persistent rise in heart rate may theoretically do so.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Categorical hypertension data for methylphenidate are not published so far but are likely to be of a similar order of magnitude on the basis of changes in mean pressures.

    “Categorical hypertension data for methylphenidate are not published so far but are likely to be of a similar order of magnitude on the basis of the changes in mean pressures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    It is not known whether children with ADHD have a coexisting increased incidence of hypertension, although there is evidence of a link.

    “It is not known whether children with ADHD have a coexisting increased incidence of hypertension, although there is evidence of a link [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Keltikangas-Jarvinen L, Pulkki-Raback L, Puttonen S, Viikari J, Raitakari OT (2006) Childhood hyperactivity as a predictor of carotid artery intima media thickness over a period of 21 years: the cardiovascular risk in young Finns study. Psychosom Med 68:509–516 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Physical and mental health comorbidities associated with the disorder that requires stimulant treatments may themselves increase the risk of sudden death from other causes.

    “In addition, the physical and mental health comorbidities associated with the disorder that requires stimulant treatments may themselves increase the risk of sudden death from other causes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These two parts of the same study are probably not yet sufficient evidence for ruling out growth problems as an adverse effect of atomoxetine, and there is one study describing the medication as an effective adjunct to weight loss in obese women.

    “These two parts of the same study are probably not yet sufficient evidence for ruling out growth problems as an adverse effect of atomoxetine, and indeed there is one study describing the medication as an effective adjunct to weight loss in obese women [45]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Gadde KM, Yonish GM, Wagner HR, Foust MS, Allison DB (2006) Atomoxetine for weight reduction in obese women: a preliminary randomised controlled trial. Int J Obes (Lond) 30(7):1138–1142 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preschool children may be particularly vulnerable to growth effects: the National Institute of Mental Health Preschool ADHD Treatment Study reported that children between 3 and 5 years of age treated with methylphenidate had annual growth rates 20.3% less than expected for height (1.38 cm/year) and 55.2% for weight (−1.32 kg/year).

    “Preschool children may be particularly vulnerable to growth effects: the National Institute of Mental Health Preschool ADHD Treatment Study reported that children between 3 and 5 years of age treated with methylphenidate had annual growth rates 20.3% less than expected for height (1.38 cm/year) and 55.2% for weight (−1.32 kg/year) [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Swanson J, Greenhill L, Wigal T, Kollins S, Stehli A, Davies M, Chuang S, Vitiello B, Skrobala A, Posner K, Abikoff H, Oatis M, McCracken J, McGough J, Riddle M, Ghuman J, Cunningham C, Wigal S (2006) Stimulant-related reductions of growth rates in the PATS. J Am Acad Child Adolesc Psychiatry 45:1304–1313 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Follow-up periods are not yet sufficiently long, nor sample sizes big enough, to allow firm conclusions about the effect of stimulants on final adult height.

    “Nevertheless, follow-up periods are not yet sufficiently long enough, nor the sample sizes big enough, to allow firm conclusions to be drawn.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The rate of self-harm in UK 11-15 year olds with no mental disorder was 1.2, 9.4% in those with anxiety disorders, 18.8% in children with depression, 12.6% in those with conduct disorder and 8.5% among children with hyperkinetic disorder.

    “the rate of self-harm in UK 11–15 year olds with no mental disorder was 1.2, 9.4% in those with anxiety disorders, 18.8% in children with depression, 12.6% in those with conduct disorder and 8.5% among children with hyperkinetic disorder [92].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Meltzer H, Harrington R, Goodman R, Jenkins R (1999) Children and adolescents who try to harm, hurt or kill themselves. A report of further analysis from the national survey of the mental health of children and adolescents in Great Britain in 1999. HMSO, London, pp 15–49

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The effect of sleep impairment differs greatly from one individual to another, but can be distressing to both the child and the family and may give rise to behavioural and learning difficulties in the daytime.

    “The effect of sleep impairment differs greatly from one individual to another, but can be distressing to both the child and the family and may give rise to behavioural and learning difficulties in the daytime [103, 107].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [103] Paavonen EJ, Raikkonen K, Lahti J, Komsi N, Heinonen K, Pesonen AK, Jarvenpaa AL, Strandberg T, Kajantie E, Porkka-Heiskanen T (2009) Short sleep duration and behavioral symptoms of attention-deficit/hyperactivity disorder in healthy 7- to 8-year-old children. Pediatrics 123:e857–e864 source

      Not checked in the free run.

    • cites [107] Pesonen AK, Raikkonen K, Paavonen EJ, Heinonen K, Komsi N, Lahti J, Kajantie E, Jarvenpaa AL, Strandberg T (2009) Sleep duration and regularity are associated with behavioral problems in 8-year-old children. Int J Behav Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These children were also impaired in some actigraphic and polysomnographic measures indicating fragmented sleep and poor sleep efficiency, sleep disordered breathing, and excessive daytime sleepiness.

    “These children were also impaired in some actigraphic and polysomnographic measures indicating fragmented sleep and poor sleep efficiency, sleep disordered breathing, and excessive daytime sleepiness [122].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Sadeh A, Pergamin L, Bar-Haim Y (2006) Sleep in children with attention-deficit hyperactivity disorder: a meta-analysis of polysomnographic studies. Sleep Med Rev 10:381–398 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small effects on growth were seen for atomoxetine during the first 2 years of treatment; but in those who received prolonged treatment for up to 5 years no long-term effects on growth were apparent apart from an overweight subgroup.

    “Small effects were seen for atomoxetine during the first 2 years of treatment; but in those who received prolonged treatment for up to 5 years no long-term effects on growth were apparent apart from an overweight subgroup [133, 134].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [133] Spencer TJ, Kratochvil CJ, Sangal RB, Saylor KE, Bailey CE, Dunn DW, Geller DA, Casat CD, Lipetz RS, Jain R, Newcorn JH, Ruff DD, Feldman PD, Furr AJ, Allen AJ (2007) Effects of atomoxetine on growth in children with attention-deficit/hyperactivity disorder following up to five years of treatment. J Child Adolesc Psychopharmacol 17:689–700 source

      Not checked in the free run.

    • cites [134] Spencer TJ, Newcorn JH, Kratochvil CJ, Ruff D, Michelson D, Biederman J (2005) Effects of atomoxetine on growth after 2-year treatment among pediatric patients with attention-deficit/hyperactivity disorder. Pediatrics 116:e74–e80 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Effects of stimulants on growth may be greater for children than adolescents, but overall there are too few studies to allow firm conclusions in either of these areas.

    “Effects may be greater for children than adolescents, but overall there are too few studies to allow firm conclusions in either of these areas.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acute effects on growth hormone and prolactin have been observed, but do not yet explain persisting growth deficits.

    “Acute effects on growth hormone and prolactin have been observed, but do not yet explain persisting growth deficits [18, 37, 84].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Bereket A, Turan S, Karaman MG, Haklar G, Ozbay F, Yazgan MY (2005) Height, weight, IGF-I, IGFBP-3 and thyroid functions in prepubertal children with attention deficit hyperactivity disorder: effect of methylphenidate treatment. Horm Res 63:159–164

      Not checked in the free run.

    • cites [37] Faraone SV, Biederman J, Morley CP, Spencer TJ (2008) Effect of stimulants on height and weight: a review of the literature. J Am Acad Child Adolesc Psychiatry 47:994–1009

      Not checked in the free run.

    • cites [84] Lurie S, O’Quinn A (1991) Neuroendocrine responses to methylphenidate and d-amphetamine: applications to attention-deficit disorder. J Neuropsychiatry Clin Neurosci 3:41–50 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    These emotional and behavioural changes could in principle be markers to states of distress that can lead to suicidal acts, but no causal link between the emergence of such symptoms and the emergence of suicidal impulses has been established.

    “These could in principle be markers to the states of distress that can lead to suicidal acts; but no causal link between the emergence of such symptoms and the emergence of suicidal impulses has been established.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Comorbidities occurring with ADHD (such as depression and conduct disorder) may in themselves be associated with an increase in the risk of suicidal ideation and/or behaviour.

    “Comorbidities occurring with ADHD (such as depression and conduct disorder) may in themselves be associated with an increase in the risk of suicidal ideation and/or behaviour.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An observational report suggested that some patients with ADHD are able to get to sleep easily within just a few hours of taking a dose of stimulant medication, others need an interval of up to 6-8 h.

    “An observational report suggested that some patients with ADHD are able to get to sleep easily within just a few hours of taking a dose of stimulant medication, others need an interval of up to 6–8 h [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Brown TE, McMullen WJ Jr (2001) Attention deficit disorders and sleep/arousal disturbance. Ann NY Acad Sci 931:271–286 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Current data indicate that the initial effect of stimulants on growth appears to attenuate over time, and early studies of adult outcomes of children treated with stimulant medications have suggested that final adult height is not affected.

    “Current data indicate that the initial effect of stimulants on growth appears to attenuate over time [39, 114, 139] and early studies of the adult outcomes of children treated with stimulant medications have suggested that final adult height is not affected [55, 71].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [39] Faraone SV, Giefer EE (2007) Long-term effects of methylphenidate transdermal delivery system treatment of ADHD on growth. J Am Acad Child Adolesc Psychiatry 46:1138–1147 source

      Not checked in the free run.

    • cites [114] Poulton A, Cowell CT (2003) Slowing of growth in height and weight on stimulants: a characteristic pattern. J Paediatr Child Health 39:180–185 source

      Not checked in the free run.

    • cites [139] Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, Hechtman L, Epstein JN, Pelham WE, Abikoff HB, Newcorn JH, Molina BS, Hinshaw SP, Wells KC, Hoza B, Jensen PS, Gibbons RD, Hur K, Stehli A, Davies M, March JS, Conners CK, Caron M, Volkow ND (2007) Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry 46:1015–1027 source

      Not checked in the free run.

    • cites [55] Hechtman L, Weiss G, Perlman T (1984) Young adult outcome of hyperactive children who received long-term stimulant treatment. J Am Acad Child Psychiatry 23:261–269 source

      Not checked in the free run.

    • cites [71] Klein RG, Landa B, Mattes JA, Klein DF (1988) Methylphenidate and growth in hyperactive children. A controlled withdrawal study. Arch Gen Psychiatry 45:1127–1130 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The psychosocial functioning of ADHD + TD children is usually not worsened significantly when tic exacerbation by drugs takes place, since ADHD is commonly the more impairing disorder.

    “In terms of the impact of TD, the psychosocial functioning of ADHD + TD children is usually not worsened significantly when tic exacerbation by drugs takes place, since ADHD is commonly the more impairing disorder [117, 118].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Roessner V, Becker A, Banaschewski T, Freeman RD, Rothenberger A (2007) Developmental psychopathology of children and adolescents with Tourette syndrome—impact of ADHD. Eur Child Adolesc Psychiatry 16(Suppl 1):24–35 source

      Not checked in the free run.

    • cites [118] Roessner V, Becker A, Banaschewski T, Rothenberger A (2007) Executive functions in children with chronic tic disorders with/without ADHD: new insights. Eur Child Adolesc Psychiatry 16(Suppl 1):36–44 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several epidemiological studies find hazard ratios for SUD in ADHD subjects compared with unaffected groups varying from 1.2 to 3, and up to 7.9 for drug dependence.

    “Several epidemiological studies compare ADHD subjects with unaffected groups, and find hazard ratios for SUD varying from 1.2 to 3 [22, 35, 95] and up to 7.9 for drug dependence [68].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Biederman J, Petty CR, Dolan C, Hughes S, Mick E, Monuteaux MC, Faraone SV (2008) The long-term longitudinal course of oppositional defiant disorder and conduct disorder in ADHD boys: findings from a controlled 10-year prospective longitudinal follow-up study. Psychol Med 38:1027–1036 source

      Not checked in the free run.

    • cites [35] Elkins IJ, McGue M, Iacono WG (2007) Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry 64:1145–1152 source

      Not checked in the free run.

    • cites [95] Molina BS, Pelham WE (2001) Substance use, substance abuse, and LD among adolescents with a childhood history of ADHD. J Learn Disabil 34:333–342, 351 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several recent reviews indicate that stimulants are adequately safe in patients with both ADHD and tic disorders and should not be disregarded when planning treatment for ADHD in these individuals.

    “Several recent reviews [24, 119, 124] indicate that stimulants are adequately safe in patients with both ADHD and TD and should not be disregarded when planning treatment for ADHD in these individuals.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF (2009) Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry 48:884–893 source

      Not checked in the free run.

    • cites [119] Roessner V, Robatzek M, Knapp G, Banaschewski T, Rothenberger A (2006) First-onset tics in patients with attention-deficit-hyperactivity disorder: impact of stimulants. Dev Med Child Neurol 48:616–621 source

      Not checked in the free run.

    • cites [124] Scahill L, Erenberg G, Berlin CM Jr, Budman C, Coffey BJ, Jankovic J, Kiessling L, King RA, Kurlan R, Lang A, Mink J, Murphy T, Zinner S, Walkup J (2006) Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx 3:192–206 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a review of subjective reports on medicated versus unmedicated children with ADHD there were high rates of parental report of sleep problems, but few of these were confirmed by objective sleep data.

    “In a review of subjective reports on medicated versus unmedicated children with ADHD there were high rates of parental report of sleep problems, but few of these were confirmed by objective sleep data [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Cohen-Zion M, Ancoli-Israel S (2004) Sleep in children with attention-deficit hyperactivity disorder (ADHD): a review of naturalistic and stimulant intervention studies. Sleep Med Rev 8:379–402 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Findings from preclinical research have suggested that animals exposed to stimulants become sensitized: subsequent administration results in more robust behavioural responses, and/or they become more likely to self-administer drugs of abuse later in development.

    “Findings from preclinical research have suggested that animals exposed to stimulants become “sensitized”: subsequent administration results in more robust behavioural responses, and/or they become more likely to self-administer drugs of abuse later in development [72, 73].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Kollins SH (2008) ADHD, substance use disorders, and psychostimulant treatment: current literature and treatment guidelines. J Atten Disord 12:115–125 source

      Not checked in the free run.

    • cites [73] Kollins SH, English J, Robinson R, Hallyburton M, Chrisman AK (2008) Reinforcing and subjective effects of methylphenidate in adults with and without attention deficit hyperactivity disorder (ADHD). Psychopharmacology (Berl) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    For clonidine, there exists some evidence that it may reduce tics in frequency and severity, as well as improve ADHD symptoms; but worsening of tics may be seen in about a quarter of cases.

    “For clonidine, which is only occasionally used in Europe to treat TD and/or ADHD, but recommended by some authors (especially where TD is the predominant disorder) [116], there exists some evidence that it may reduce tics in frequency and severity, as well as improve ADHD symptoms; but on the other hand, worsening of tics may be seen in about a quarter of cases [3].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [116] Robertson MM (2006) Attention deficit hyperactivity disorder, tics and Tourette’s syndrome: the relationship and treatment implications. A commentary. Eur Child Adolesc Psychiatry 15:1–11 source

      Not checked in the free run.

    • cites [3] (2002) Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 58:527–536 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Even a single symptom of ADHD or conduct disorder may be associated with an increased risk for SUD; hyperactivity symptoms uniquely contributed to subsequent initiation of all types of substance use, to nicotine dependence, and cannabis abuse/dependence, even after controlling for CD, whereas impulsivity predicted alcohol misuse.

    “Even a single symptom of ADHD or conduct disorder (CD) may be associated with an increased risk for SUD [35]: hyperactivity symptoms uniquely contributed to subsequent initiation of all types of substance use, to nicotine dependence, and cannabis abuse/dependence, even after controlling for CD, whereas impulsivity predicted alcohol misuse [36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Elkins IJ, McGue M, Iacono WG (2007) Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Arch Gen Psychiatry 64:1145–1152 source

      Not checked in the free run.

    • cites [36] Ernst M, Luckenbaugh DA, Moolchan ET, Leff MK, Allen R, Eshel N, London ED, Kimes A (2006) Behavioral predictors of substance-use initiation in adolescents with and without attention-deficit/hyperactivity disorder. Pediatrics 117:2030–2039 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The prevalence of childhood and adult ADHD in the substance-abusing population has been estimated to be about 3 times that in the general population; for instance, adults with a lifetime diagnosis of cocaine and/or opioid dependency show an ADHD lifetime prevalence of 5.2%, compared to 0.85% in individuals without SUD.

    “Correspondingly, the prevalence of childhood and adult ADHD in the substance-abusing population has been estimated to be about 3 times that in the general population: for instance, adults with a lifetime diagnosis of cocaine and/or opioid dependency show an ADHD lifetime prevalence of 5.2%, compared to 0.85% in individuals without SUD [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Arias AJ, Gelernter J, Chan G, Weiss RD, Brady KT, Farrer L, Kranzler HR (2008) Correlates of co-occurring ADHD in drug-dependent subjects: prevalence and features of substance dependence and psychiatric disorders. Addict Behav 33:1199–1207 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Probands with ADHD who did not differ from those without ADHD in absolute rates of SUD still had an earlier onset, a longer duration, and higher rates of severely impairing SUD as well as higher rates of alcohol and drug dependence than non-ADHD children.

    “Probands with ADHD who did not differ from those without ADHD in absolute rates of SUD, still had an earlier onset, a longer duration, and higher rates of severely impairing SUD as well as higher rates of alcohol and drug dependence than non-ADHD children [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Biederman J, Petty CR, Wilens TE, Fraire MG, Purcell CA, Mick E, Monuteaux MC, Faraone SV (2008) Familial risk analyses of attention deficit hyperactivity disorder and substance use disorders. Am J Psychiatry 165:107–115 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    It follows from the additive model that symptoms may be treated with a separate but parallel approach, i.e., in addition to stimulants or atomoxetine for ADHD, treatment with antipsychotic medication may help to reduce tics.

    “It follows, that the symptoms may be treated with a separate but parallel approach, i.e. in addition to stimulants or atomoxetine for ADHD, treatment with antipsychotic medication may help to reduce tics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A smaller, non-actigraphic study suggested that methylphenidate does not appear to affect sleep patterns adversely and possibly normalizes them in patients with ADHD.

    “However, a smaller, non-actigraphic study suggested that methylphenidate does not appear to affect sleep patterns adversely and possibly normalizes them in patients with ADHD [142].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Tirosh E, Sadeh A, Munvez R, Lavie P (1993) Effects of methylphenidate on sleep in children with attention-deficient hyperactivity disorder. An activity monitor study. Am J Dis Child 147:1313–1315 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The suggestion that antipsychotic medication may help to reduce tics is not evidence based, being derived from the experiences of clinical experts only; but it has been included in clinical guidelines.

    “The latter suggestion is not evidence based, being derived from the experiences of clinical experts only; but meanwhile it has been included in clinical guidelines [120].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Rothenberger A, Banaschewski T, Roessner V (2007) Tic-Störungen. Dritte Auflage, pp 319–325

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same study, both medications decreased night-time awakenings, but the decrease was greater for methylphenidate.

    “Both medications decreased night-time awakenings, but the decrease was greater for methylphenidate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Sangal RB, Owens J, Allen AJ, Sutton V, Schuh K, Kelsey D (2006) Effects of atomoxetine and methylphenidate on sleep in children with ADHD. Sleep 29:1573–1585 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In tic disorders, co-existence with ADHD can be found in about 50% of patients, while in ADHD patients a tic disorder is seen in about 20%; both figures are above the chance rate of combination.

    “In tic disorders (TD), co-existence with ADHD can be found in about 50% of patients, while in ADHD patients a TD is seen in about 20%: Both figures are above the chance rate of combination [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Rothenberger A, Roessner V, Banaschewski T, Leckman JF (2007) Co-existence of tic disorders and attention-deficit/hyperactivity disorder-recent advances in understanding and treatment. Eur Child Adolesc Psychiatry 16(Suppl 1):1–4 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In controlled studies of atomoxetine, its impact on tics was either not different from placebo or even showed some positive effect on tic frequency.

    “In the controlled studies of atomoxetine, its impact on tics was either not different from placebo or even showed some positive effect on tic frequency [8, 110, 135].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Allen AJ, Kurlan RM, Gilbert DL, Coffey BJ, Linder SL, Lewis DW, Winner PK, Dunn DW, Dure LS, Sallee FR, Milton DR, Mintz MI, Ricardi RK, Erenberg G, Layton LL, Feldman PD, Kelsey DK, Spencer TJ (2005) Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. Neurology 65:1941–1949 source

      Not checked in the free run.

    • cites [110] Poncin Y, Sukhodolsky DG, McGuire J, Scahill L (2007) Drug and non-drug treatments of children with ADHD and tic disorders. Eur Child Adolesc Psychiatry 16(Suppl 1):78–88 source

      Not checked in the free run.

    • cites [135] Spencer TJ, Sallee FR, Gilbert DL, Dunn DW, McCracken JT, Coffey BJ, Budman CL, Ricardi RK, Leonard HL, Allen AJ, Milton DR, Feldman PD, Kelsey DK, Geller DA, Linder SL, Lewis DW, Winner PK, Kurlan RM, Mintz M (2008) Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome. J Atten Disord 11:470–481 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several physician's desk references and drug administration mandates still note a contraindication for the use of stimulants in patients with tic disorders, and even in those with only a family history of tics.

    “Several physician’s desk references and drug administration mandates still note a contraindication for the use of stimulants in patients with TD [110, 121]; and even in those with only a family history of tics.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Poncin Y, Sukhodolsky DG, McGuire J, Scahill L (2007) Drug and non-drug treatments of children with ADHD and tic disorders. Eur Child Adolesc Psychiatry 16(Suppl 1):78–88 source

      Not checked in the free run.

    • cites [121] Rothenberger A, Roessner V, Banaschewski T, Leckman JF (2007) Co-existence of tic disorders and attention-deficit/hyperactivity disorder-recent advances in understanding and treatment. Eur Child Adolesc Psychiatry 16(Suppl 1):1–4 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Whether stimulant medication adds to the risk for substance abuse is not clear; several studies suggest it does not.

    “Whether stimulant medication adds to the risk for substance abuse is not clear; several studies suggest it does not.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A meta-analytic review of six studies suggested that stimulant therapy in childhood may be associated with a reduction in risk, compared to unmedicated ADHD subjects, for subsequent drug and alcohol use disorders (HR = 1.9), with a stronger effect during adolescence (HR = 5.8) than adulthood follow-up (HR = 1.4); however, when this group was re-examined a further 5 years later no significant差异s

    “A meta-analytic review of six studies suggested that stimulant therapy in childhood may be associated with a reduction in risk, compared to unmedicated ADHD subjects, for subsequent drug and alcohol use disorders (HR = 1.9), with a stronger effect during adolescence (HR = 5.8) than adulthood follow-up (HR = 1.4) [155]; however, when this group was re-examined a further 5 years later no significant”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [155] Wilens TE, Faraone SV, Biederman J, Gunawardene S (2003) Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 111:179–185 source

      Not checked in the free run.

    • cites [21] Biederman J, Monuteaux MC, Spencer T, Wilens TE, Macpherson HA, Faraone SV (2008) Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study. Am J Psychiatry 165:597–603 source

      Not checked in the free run.

64 of 64

  • The authors state this as an assumption.

    A 50% under-reporting rate can be assumed when estimating the sudden death risk of children on ADHD medications.

    “assuming a 50% under-reporting rate”

  • The authors state this as an assumption.

    The effect on tic exacerbation is similar for both methylphenidate and dexamfetamine.

    “It can be assumed that the effect on tic exacerbation is similar for both methylphenidate and dexamfetamine.”

  • The authors state this as an assumption.

    A prescribing frequency of 3 per 100 school age children in the United States for ADHD drugs.

    “if we assume a prescribing frequency of 3 per 100 school age children in the United States”
3 of 3

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?

  • Short/medium term cardiovascular side-effects of stimulants are usually of no clinical significance, but long-term potential side-effects are less certain.

    “The general consensus on cardiovascular side-effects at this point is that the short/medium term side-effects are usually of no clinical significance, but the long-term potential side-effects are less certain [63].”

    From Advances in understanding and treating ADHD (2011) · cites this paper as [63]

Self-check

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

  • Number needed to harm does not match the stated suicidal-ideation counts

    Minor

    Five cases among 1,357 atomoxetine-treated patients and none among 851 placebo-treated patients give an absolute risk increase of 5/1,357, or a number needed to harm of 271.4-not 227. The reported value is approximately what six cases, rather than five, would yield.

    Reported 227 · recomputed 271.4

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Kinsbourne M (1973) Stimulants for insomnia. N Engl J Med 288:1129
  2. Meltzer H, Harrington R, Goodman R, Jenkins R (1999) Children and adolescents who try to harm, hurt or kill themselves. A report of further analysis from the national survey of the mental health of children and adolescents in Great Britain in 1999. HMSO, London, pp 15–49

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Authors
(for the European Guidelines Group), Graham, J., Banaschewski, T., Buitelaar, J., Coghill, D., Danckaerts, M., Dittmann, R. W., Döpfner, M., Hamilton, R., Hollis, C., Holtmann, M., Hulpke-Wette, M., Lecendreux, M., Rosenthal, E., Rothenberger, A., Santosh, P., Sergeant, J., Simonoff, E., Sonuga-Barke, E., Wong, I. C. K., Zuddas, A., Steinhausen, H.-C., & Taylor, E.
Affiliations
  • University of Dundee (GB)
  • University of Göttingen (DE)
  • Central Institute of Mental Health (DE)
  • Universitair Ziekenhuis Leuven (BE)
  • Universität Hamburg (DE)
  • University of Cologne (DE)
  • University of Nottingham (GB)
  • St Thomas' Hospital (GB)
  • Great Ormond Street Hospital (GB)
  • Vrije Universiteit Amsterdam (NL)
  • Ghent University (BE)
  • University of London (GB)
  • University of Cagliari (IT)
  • University of Zurich (CH)
Corresponding author
Graham, J.
ORCID
Venue
European Child & Adolescent Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2010-11-03
Volume
20
Issue
1
Pages
17-37
ISSN
  • 1018-8827 (ISSN-L)
  • 1435-165X
DOI
10.1007/s00787-010-0140-6
PMC
PMC3012210
OpenAlex
W2107612326
Semantic Scholar
d2e43215f1c896078185a61c7fe58cf6ac129903
Cited by
374
References
170
Citations by year
2026: 9 · 2025: 13 · 2024: 16 · 2023: 18 · 2022: 11 · 2021: 14 · 2020: 22 · 2019: 21 · 2018: 16 · 2017: 28 · 2016: 40 · 2015: 31 · 2014: 48 · 2013: 34 · 2012: 38
FWCI
18.97
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • European Child & Adolescent Psychiatry (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • HAL (submittedVersion, public-domain)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, public-domain)
  • ePrints Soton (University of Southampton) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
  • Research Portal (King's College London) (submittedVersion)
  • GRO (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Eli Lilly and Company
  • Sanofi
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
Keywords
ADHD medication, adverse drug reactions, drug safety, sudden cardiac death, suicidality, stimulants, hyperkinetic disorder, risk-benefit assessment
MeSH terms
Atomoxetine Hydrochloride, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Cardiovascular Diseases, Child, Clinical Trials as Topic, Drug Administration Schedule, Drug Tolerance, Europe, Humans, Monitoring, Physiologic, Propylamines, Suicide, Attempted, Drug Utilization Review, Risk Assessment, Adrenergic Uptake Inhibitors, Substance-Related Disorders, Drug Dosage Calculations

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