Abali 2007
Methods | A patient report of hallucinations during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 14 years oldIQ: 99Sex: femaleMethylphenidate naïve: not statedEthnicity: not statedCountry: TurkeyComorbidity: depression, behavioural disorderComedication: fluoxetine (20 mg/day) Sociodemographics: not stated |
Interventions | Methylphenidate dosage: 20 mg/dayAdministration schedule: 10 mg in the morning and 10 mg in the afternoonDuration of treatment: 15 days Treatment compliance: not stated |
Outcomes | Serious adverse events:Methylphenidate for 15 days: audio‐visual hallucinations. Occurrence 30 minutes after ingestion. Duration: 30 minutesCessation of methylphenidate: no hallucinations Further trials with methylphenidate caused hallucinations, which immediately disappeared after discontinuation |
Notes | Key conclusions of the study authors: here, we report a 14‐year old girl with a diagnosis of ADHD, major depression and conduct disorder. During her treatment with methylphenidate 20 mg/day and fluoxetine 20 mg/day, she developed visual and auditory hallucinations. It may be concluded that methylphenidate in some cases may cause hallucinations in patients Supplemental information regarding IQ received through personal email correspondence with the authors in November 2013 (Abali 2013 [pers comm]) |
Abbas 2006
Methods | A cohort study with 2 study samples (N = 60 and N = 30) where participants were part of a 6‐month audit regarding the use of methylphenidate and to determine if the NICE guidelines were followed |
Participants | Number of participants screened: 420Number of participants included: 90Number of participants followed up: not statedNumber of withdrawals: not statedSex: 85 males, 5 femalesDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 10 years oldIQ: none with intellectual disabilityMethylphenidate‐naïve: not statedEthnicity: not statedCountry: UKSetting: not statedComorbidity: 28.8% general learning difficulties, 21% sleeping problems, 28.8% mental health problemsComedication: not statedSociodemographics: not stated Inclusion criteria:
|
Interventions | Methylphenidate dosage: most were treated with RitalinAdministration schedule: not statedDuration of intervention: 6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:12% reported side effects on methylphenidate, most were transient In 3 cases, medication was stopped due to side effects |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: for 3 patients the side effects resulted in medication stop. 2 patients stopped because of headaches and 1 because of hair lossEthics approval: not statedFunding: noneVested interest/authors' affiliations: not stated Key conclusions of the study authors: the guidelines were followed, but not fully. However this was improved significantly in the second part due to increased professional awareness about ADHD because we held many seminars on this subject. The mental health team worked more closely than before with community paediatricians via joint ADHD clinics with child and adolescent psychiatrists. Families were getting better support via the ADHD family project which was jointly funded by health, education, and social services. The audits lead to a better provision of services for children with ADHD via specialist ADHD clinics Comments from the review authors: the reference was a poster, and no full text article has been published on the subject Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding study information received through personal email correspondence with the authors in December 2013 (DeSoysa 2013 [pers comm]) |
Abbasi 2011
Methods | A 6‐week, parallel group, RCT with 2 arms
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Participants | Number of participants screened: 68Number of participants included: 40Number of participants randomised: ALC + MPH: 20, P + MPH: 20Number of participants followed‐up: MPH + P: 19Number of withdrawals: MPH + P: 1 Methylphenidate + placebo Diagnosis of ADHD: DSM‐IV‐TR (combined type: 100%)Age: mean 8.36 (1.53), range: 7‐13 years oldSex: 25 males, 5 femalesMethylphenidate‐naïve: 100%Ethnicity: PersianCountry: IranComorbidity: not statedComedication: not statedIQ: > 70Sociodemographics: not statedInclusion criteria:
Exclusion criteria:
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Interventions | Participants were randomly assigned to MPH and ACL or MPH and placeboMethylphenidate type: not statedMethylphenidate dosage: 20‐30 mg/day depending on weight (20 mg/day for < 30 kg and 30 mg/day for > 30 kg)Administration schedule: morning and middayDuration of intervention: 6 weeksTitration period: 3 weeks after randomisation Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:
|
Notes | Sample calculation: yesAny withdrawals due to adverse events: noEthics approval: yesFunding: this study was supported by a grant from Tehran University of Medical Sciences Key conclusions of the study authors: the principal measure of outcome was the Teacher and Parent attention deficit/hyperactivity disorder Rating Scale‐ IV. No difference was observed between the 2 groups. Side effects consisting of headache and irritability were observed more frequently in the methylphenidate plus placebo group. The results of this study do not support the application of ALC as an adjunctive therapy to methylphenidate in children and adolescents with ADHD. Comments from the review authors: patients are randomised to receive MPH plus acetyl‐L‐carnitine (ALC) or MPH plus placebo: no outcome measures regarding effect are relevant, because the study does not include a placebo or no‐intervention group. The co‐intervention (ALC/placebo) is not the same in the 2 groups, and therefore we can only use AE data regarding group 2 (MPH+P group). Supplemental data has not been possible to receive from the authors through email correspondence in August and October 2013. No reply |
Adrian 2001
Methods | A patient report of a 10‐year‐old boy referred to a tertiary neurodevelopmental assessment clinic for a second opinion on the management of his ADHD, with particular concern being expressed about aggressive outbursts and poor tolerance of methylphenidate |
Participants | Diagnosis of ADHD: ICD‐10 (subtype: unknown)Age: 10 years oldIQ: average intelligenceSex: maleMethylphenidate naïve: not statedEthnicity: not statedCountry: UKComorbidity: not statedComedication: not stated Sociodemographics: Uneventful pregnancy |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: started 20 mg/day at 7 years and gradually increased to 40 mg/dayDuration of treatment: 2‐3 years Treatment compliance: treatment was administered until 9 to 10 years of age when parents discontinued treatment due to obsessive compulsive symptoms |
Outcomes | Non‐serious adverse events:
The other adverse events were not found at the assessment 10 months after he stopped methylphenidate treatment |
Notes | Key conclusions of the study authors: clinically explosive outbursts can be induced by the pharmacological treatment of ADHD and should not be mistaken for a symptom of the disorderComments from the study authors: explosive episodes were coincident with a period of treatment with methylphenidateFunding/vested interest: not statedAuthors' affiliations: Great Ormond Street Hospital London Supplemental information regarding diagnostic criteria and treatment duration obtained through personal email correspondence with the authors in October 2013 (Adrian 2013 [pers comm]) |
Agarwal 2008
Methods | A patient report of the combination of atomoxetine and methylphenidate in the treatment of ADHD |
Participants | Diagnosis of ADHD: DSM‐III‐R/DSM‐I (subtype: combined)Age: 8 years oldIQ: normal (attends school)Sex: maleMethylphenidate naïve: noEthnicity: not statedCountry: IndiaComorbidity: not statedComedication: not stated. No atomoxetine (in the period relevant for this review) Sociodemographics: not stated |
Interventions | Immediate release methylphenidate gradually increased to 50 mg/dayAdministration schedule: 3‐4 divided dosagesDuration of intervention: 6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Decreased appetite and delayed sleep onset |
Notes | Key conclusions of the study authors: the combination of atomoxetine and methylphenidate may be used more often in patients who are not able to tolerate high doses of methylphenidate or develop tolerance to it |
Aguilera‐Albesa 2010
Methods | 2 patient reports of the appearance of hallucinations few hours after methylphenidate ingestion |
Participants | Case 1Diagnosis of ADHD: DSM‐IV (subtype: inattentive)Age: 8 years oldIQ: > 85Sex: maleMethylphenidate naïve: not statedEthnicity: whiteCountry: SpainComorbidity: procedural learning disorderComedication: not statedSociodemographics: not stated Case 2 Diagnosis of ADHD: DSM‐IV (subtype: inattentive)Age: 6 years oldIQ: > 85Sex: femaleEthnicity: whiteCountry: SpainComorbidity: noneComedication: noneSociodemographics: not stated |
Interventions | Case 1Extended release methylphenidate 18 mg/day (0.51 mg/kg/day)Administration schedule: once dailyDuration of intervention: 2 daysTreatment compliance: not stated Case 2 50% extended release, and 50% immediate release methylphenidate 10 mg/day (0.45 mg/kg/day) for 3 days and 20 mg/day (0.9 mg/kg/day) for 1 dayAdministration schedule: once dailyDuration of intervention: 4 daysTreatment compliance: not stated |
Outcomes | Serious adverse events: Case 1After the first dose: irritability, emotional lability, motor restlessness and facial motor ticsAfter the second dose: added auditory hallucinations (noise and unintelligible verbal expressions), and visual hallucinations (shadows approaching and receding)24 hours after discontinuation: the symptoms remitted Case 2 After the first dose and the following days: intermittent visual hallucinations (insects, especially flies, flying around her). The symptoms improved at nightAfter increased dose (20 mg) on day 4: visual hallucinations were associated with dread of going outside and cries of panic1 day after discontinuation: the symptoms remitted |
Notes | Key conclusions of the study authors: these patient reports suggest an individual susceptibility to psychotic symptoms after taking methylphenidate. This side effect is considered idiosyncratic, extraordinary and unpredictable. Case 2 suggests the existence of a dose‐effect relationship Supplemental information regarding diagnostic criteria and IQ received through personal email correspondence with the authors in July 2013 (Aguilera‐Albesa 2013 [pers comm]) |
Akhondzadeh 2003
Methods | A 4‐week randomised, double‐blind, clinical trial, parallel‐design where children with ADHD are randomised to methylphenidate or selegiline |
Participants | Number of participants screened: not statedNumber of participants included: 28Number of participants randomised: selegiline: 14; methylphenidate: 14Number participants followed‐up in each arm: selegiline: 13; methylphenidate: 10Number of withdrawals in each arm: selegiline: 1; methylphenidate: 4 Methylphenidate group Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: mean 7.37 years old (SD 1.59)IQ: above 70Sex: 10 males, 4 femalesMethylphenidate‐naïve: 100%Ethnicity: PersianCountry: IranSetting: outpatient clinicComorbidity: not statedComedication: noneSociodemographics: not statedInclusion criteria
Exclusion criteria
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Interventions | Participants were randomly assigned to receive treatment using either selegiline 5 mg/day (under 5 years of age) and 10 mg/day (over 5 years of age) or methylphenidate 1 mg/kg/day for a 4‐week double‐blind clinical trialMethylphenidate type: not statedAdministration schedule: not statedTitration period: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:
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Notes | Sample calculation: not statedAny withdrawals due to adverse events: not statedEthics approval: not explicitly stated but inferred: informed consent (parent and children) was received before the administration of any study procedure or dispensing of study medication in accordance with the ethical standards of the investigative site's institutional review board and with the Helsinki Declaration of 1975, as revised in 2000Funding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: the results of the study must be considered preliminary, but they do suggest that selegiline may be beneficial in the treatment of ADHD. In addition, a tolerable side effect profile may be considered as one of the advantages of selegiline in the treatment of ADHD Supplemental information requested from the study authors twice in June 2013 with no answer |
Akhondzadeh 2004
Methods | A 6‐week double‐blind, placebo‐controlled, parallel group trial with 2 interventions:
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Participants | Number of participants screened: not statedNumber of participants included: 22Number of participants followed up: 20Number of withdrawals: 2Diagnosis of ADHD: DSM‐IV (subtype: combined (100%))Age: mean: 7.73 (1.63), range: 5‐11IQ: > 70Sex: 12 males, 10 femalesMethylphenidate‐naïve: 100%Ethnicity: PersianCountry: IranSetting: outpatient clinicComorbidity: not statedComedication: not statedSociodemographics: not stated Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 1 mg/kg/day (+ placebo: sucrose, 55 mg)Administration schedule: twice daily, 7 am and 3 pmDuration of each medication condition: 6 weeks Treatment compliance: not stated |
Outcomes | Systematically recorded throughout the study and were assessed using a checklist administered by a resident of psychiatry on days 7, 14, 21, 28 and 42 Non‐serious adverse events:
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Notes | Sample calculation: not statedAny withdrawals due to adverse events: noneEthics approval: not explicitly stated but inferred: informed consent (parent and children) was received before the administration of any study procedure or dispensing of study medication in accordance with the ethical standards of the investigative site's institutional review board and with the Helsinki Declaration of 1975, as revised in 2000Funding/vested interests/authors' affiliations: not stated Key conclusions from study authors: this double‐blind, placebo‐controlled study demonstrated that zinc as a supplementary medication might be beneficial in the treat‐ ment of children with ADHD. However, further investigations and different doses of zinc are required to replicate these findings in children with ADHD. Comments from the study authors: the limitations of the present study, including lack of a full placebo group, using only a moderate dose of methylphenidate, the small number of participants, short period of follow‐up and lack of plasma zinc concentration should be considered so further research in this area is needed Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Alpaslan 2015
Methods | A patient report of stuttering associated with the use of methylphenidate |
Participants | Diagnosis of ADHD: DSM‐5 (subtype: predominantly hyperactive‐impulsive)Age: 7 years oldIQ: 94Sex: maleMethylphenidate naïve: yesEthnicity: white/TurkishCountry: TurkeyComorbidity: noneComedication: none Sociodemographics: both parents had advanced no further than elementary school. The parents' history was unremarkable |
Interventions | Short‐acting methylphenidate 10 mg/dailyAdministration schedule: not statedDuration of treatment: 4 weeks Treatment compliance: good according to regular visits record |
Outcomes | Non‐serious adverse events: 10 days after beginning short‐acting methylphenidate treatment, the client began to stutter. Treatment was stopped. 1 week later, the patient's speech was back to normal. 4 weeks later atomoxetine treatment was started with no reoccurrence of stuttering |
Notes | Key conclusions of the study authors: evidence for stuttering associated with the use of short‐acting methylphenidate is presented. Clinicians should be aware that an additional adverse effect of methylphenidate may be a beginning of a stutterFunding/vested interest: the authors received no financial support for the research and/or authorship of this article. The authors report no conflicts of interest Supplemental information regarding IQ, ethnicity and treatment compliance received through personal email correspondence with the authors in April 2016 (Alpaslan 2016 [pers comm]) |
Altin 2013
Methods | A observational, prospective and non‐interventional study of methylphenidate, atomoxetine and nootropic medication use for 12 months |
Participants | Number of participants screened: not statedNumber of participants included: 546Number of participants randomised: methylphenidate: 221. Atomoxetine: 234. Nootropic medicine: 91Number followed‐up in each arm: methylphenidate: 133 (60.2%). Atomoxetine: 146 (62.4%). Nootropic med: 77 (84.6%)Number of withdrawals in each arm: methylphenidate: 52. Atomoxetine: 59. Nootropic med: 16Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean: 9.6 (2.8) + 9.9 (2.7) + 9.4 (2.5), range: 6‐17 years oldIQ: not statedSex: male: 206 (88.0%) 180 (81.4%) 70 (76.9%)Methylphenidate‐naïve: not statedEthnicity: white 129 (55.1%) + 93 (42.1%) + 91 (100.0%); Asian: 102 (43.6%) + 128 (57.9%) + 0 (0.0%); Black or African American: 2 (0.9%) + 0 (0.0%) + 0 (0.0%); other: 1 (0.4%) + 0 (0.0%) + 0 (0.0%).Country: Russian Federation, China, Taiwan, Egypt, United Arab Emirates, and LebanonSetting: outpatient clinicComorbidity: yesComedication: yesSociodemographics: not stated Inclusion criteria:
Exclusion criteria: Discontinuation of the original prescribed monotherapy |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: 12 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: 3 patients discontinued treatment in the methylphenidate group due to headache, anxiety and depressed mood |
Notes | Sample calculation: yesEthics approval: yesFunding/vested interest: sponsored by Eli LillyAuthors' affiliations: Eli Lilly Neuroscience, Eli Lilly & Company Turkey; Eli Lilly Egypt; Eli Lilly Canada; Lilly Research Laboratories, Indianapolis; Eli Lilly and Company, Hungary; Dept. of Neurology, Neurosurgery and Medical Genetics of Pediatric Faculty, Moscow, Russian Federation; Dept of Psychological Medicine, Children's Hospital of Fudan University, Shanghai, China Key conclusions of the study authors: after 12 months of treatment, clinical and functional outcomes were improved in children and adolescents from non‐Western countries who initiated and remained on their prescribed pharmacological monotherapy Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested from the study authors twice in June 2016 with no answer |
Amiri 2008
Methods | A 6‐week, parallel group, randomised controlled trial with 2 arms: |
Participants | Number of patients screened: not statedNumber included: 60Number randomised to methylphenidate: 30 and (modafinil): 30Number followed‐up: MPH: 27Number of withdrawals: MPH: 3Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (100%))Age: mean 8.96 years oldIQ: > 70Sex: 24 males, 6 femalesMethylphenidate‐naïve: not statedEthnicity: PersianCountry: IranComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Participants were randomly assigned to methylphenidate or modafinilMetylphenidate type: not statedMethylphenidate dosage: 20‐30 mg/day depending on weight (20 mg/day for < 30 kg and 30 mg/day for > 30 kg)Administration schedule: not statedDuration of intervention: 6 weeksTitration period: 3 weeks, initiated after randomisation Treatment compliance: not stated |
Outcomes | Side effect checklist (20 side effects) administered by a child psychiatrist on days 7, 21 and 42Haematology tests, baseline and weeks 2, 4 and 6 serum chemistry and urinalysis, baseline and week 6Body weight and vital signs, baseline and weeks 1, 2, 4, and 612‐lead ECG and physical examinations, baseline and week 6 Non‐serious adverse events: Abdominal pain, anxiety/nervousness, decreased appetite, sadness, difficulty falling asleep, weight loss, nausea, dry mouth, irritability, headaches |
Notes | Sample calculation: yesEthics approval: yesFunding/vested interest: this study was supported by a grant (grant number: 3317) from Tehran University of Medical SciencesAuthors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: no significant differences were observed between the 2 groups (modafinil vs methylphenidate) on the Parent and Teacher Rating Scale scores. Side effects of decreased appetite and difficulty falling asleep were observed more in the methylphenidate group. The results of this study indicate that modafinil significantly improved symptoms of ADHD and was well tolerated and it is beneficial in the treatment of children with ADHD Comments from the study authors: the limitations of the present study, including lack of a placebo group, using only ADHD Rating Scale for measuring outcome and the small number of participants should be considered so further research in this area is needed Comments from the review authors: checklist with 20 possible side effects administered, but only the 10 observed side effects are reported Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental adverse event data has not been possible to receive through personal email correspondence with the authors in June‐August 2013 |
Arabgol 2015
Methods | A 6‐week double‐blind clinical trial comparing methylphenidate and risperidone |
Participants | Number of participants screened: 38Number of participants included: 33Number of participants randomised: methylphenidate: 18; risperidone: 20Number of participants followed‐up in each arm: methylphenidate: 15; risperidone: 18Number of withdrawals in each arm: methylphenidate: 3; risperidone: 2
Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (57.57%), hyperactive‐impulsive (33.33%), inattentive (9.09%))Age: mean for the methylphenidate group: 4.73 (SD 0.77) years old (range 3‐6)IQ: > 70Sex (in the methylphenidate group): 12 males, 3 femalesMethylphenidate‐naïve: not stated, but all were with no drug history since 2 weeks agoEthnicity: not statedCountry: IranSetting: outpatient clinicComorbidity: not statedComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Metylphenidate was started at dose 2.5 mg/day and gradually (every week) increased based on the therapeutic response and the patient's toleranceMethylphenidate type: not statedMean methylphenidate dosage: 12.83 (SD 0.56) mg/dayAdministration schedule: optimal dose was 20 mg/day in 2 divided dosesDuration of intervention: 6 weeksWashout prior to study initiation: 2 weeks Treatment compliance: not stated |
Outcomes | Patients were assessed by a child and adolescent psychiatrist at baseline (T0); T1, 2 weeks; T2, 4 weeks and T3, 6 weeks after the intervention started. Side effects were measured using the Methylphenidate Side Effects Form Non‐serious adverse events: One 4.5‐year old girl discontinued due to severe anorexia in the second week. One 5‐year old boy discontinued because of crying and sadness in the second week. One 5‐year old boy discontinued due to increased symptoms and aggression More common side effects were anorexia (55.55%), nervousness (33.33%) and disturbed sleep (27.77%) |
Notes | Sample calculation: noAny withdrawals due to adverse events: 3
Ethics approval: yes, the Hospital's Institutial Review Board and Iranian Randomized Clinical Trial
Funding/vested interest: none. Funded by Behavioral Sciences Research Center affiliated with Shahid Beheshti Medical University
Authors' affiliations: not stated Key conclusions of the study authors: this double‐blind, randomised and controlled study suggests risperidone is effective in alleviating total symptoms of ADHD and related co‐morbid symptoms in preschoolers and that there is no statistically significant difference between the 2 groups in alleviating ADHD symptoms Comments from the study authors: our study assessed a relatively small sample of patients in a short‐term intervention. ADHD is a generally chronic neuropsychiatric condition that may last many years, we do not know whether therapeutic effects of risperidone last for a long term or not. Also further investigations are needed to assess long‐term safety when risperidone is prescribed for very young children, regarding the possibility of adverse effects on the developing brain. Also trials are needed to evaluate eventual metabolic and cardiovascular adverse effects of risperidone in very young children. We recommend further future studies to assess the therapeutic efficacy of risperidone in preschooler ADHD with different co‐morbidities Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Ardic 2014
Methods | A retrospective chart review of osmotic release oral system methylphenidate and immediate release methylphenidate use for 8 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 122 (68 in the OROS‐MPH group and 54 in the IR‐MPH group)Diagnosis of ADHD: DSM‐IV (subtype: combined (89.00%), hyperactive‐impulsive (0%), inattentive (11%))Age: mean 9.1 (1.7), range: 7‐15 years oldIQ: OROS‐MPH: 98.2 (SD 16.5). IR‐MPH: 99.4 (SD 12.8)Sex: 98 males, 24 females (OROS‐MPH: 58 males, 10 females; IR‐MPH: 40 males, 14 females)Methylphenidate naïve: not statedEthnicity: not statedCountry: TurkeyComorbidity: noneComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS) and immediate releaseMean methylphenidate dosage: OROS‐MPH 30.8 (SD 11.5) mg/day; IR‐MPH 27.5 (SD 6.1) mg/dayAdministration schedule: OROS‐MPH once daily, IR‐MPH twice dailyDuration of intervention: 8 weeks Treatment compliance: not stated |
Outcomes | Serious adverse events:No severe or life‐threatening adverse effects were reported in either group Non‐serious adverse events: ≥ 1 adverse effect in 76% of the OROS‐MPH group and in 79.6% of the IR‐MPH group. 88% adverse events disappeared/decreased over time. Emotional changes were more frequent in IR‐MPH than OROS‐MPH group (51.9% and 32.4%, respectively; P = 0.03) |
Notes | Sample calculation: not stated
Ethics approval: local approval was obtained from hospital administration for using the data on the Hospital Information System retrospectively
Funding/vested interest/authors' affiliations: while making the study no support has been taken. Eyup Sabri Ercan is in charge in the advisory board of Lilly and Janssen‐Cilag, and the other authors declare no competing financial interests Key conclusions of the study authors: OROS‐MPH was effective and safe for Turkish children and adolescents, compared to MPH‐IR Comments from the study authors: an important limitation of our study is our inability to assess treatment adherence in both medication groups. 88% of the adverse effects in the OROS‐MPH group and 86% of those in the IR‐MPH group decreased or disappeared over time Comments from the review authors: adverse events rating scale was created by study authors, but it seems to be very similar to Barkley rating scale. According to the Methods section, heart rate, blood pressure, and weight were measured but are not reported in the paper Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not explicitly stated, but it seems that only methylphenidate‐responders were included Supplemental information regarding heart rate, blood pressure and weight has not been possible to receive from the authors. We have written twice in June 2016 without reply |
Arman 2013
Methods | A cohort study measuring heart rate and cardiac abnormalities at the second to fourth week of treatment with methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 15Number of participants followed‐up: 15Number of withdrawals: 0Diagnosis of ADHD: not stated (subtype: combined (53%), inattentive (47%))Age mean: 9.08 years (range: 7‐13 years)IQ: not statedSex: 11 males, 4 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: TurkeyComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria: None statedExclusion criteria:
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Interventions | Methylphenidate dosage: 0.25‐1 mg/kg/dayMean methylphenidate dosage: 0.6 mg/kg/dayAdministration schedule: not statedDuration of intervention: not stated, but the outcome measures were monitored from week 2 to 4 Treatment compliance: not stated |
Outcomes | Serious adverse events:Cardiac rhythm abnormalities monitored by 12‐lead‐surface electrocardiogram and 24‐hour‐ambulatory Holter monitorisation Non‐serious adverse events: Heart rate variability (HRV) monitored by 12‐lead‐surface electrocardiogram and 24‐hour‐ambulatory Holter monitorisation |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interest/authors' affiliations: not statedAny withdrawals due to adverse events: not stated Key conclusions of the study authors: our study showed a significantly increased heart rate and decreased heart rate variability due to methylphenidate treatment in children with ADHD, suggesting an increased sympathetic tonus especially at the daytime. Risk of sudden cardiac death and serious arrhythmia has not been demonstrated Comments from the review authors: no full text available, only an abstract. No information on ADHD diagnosis so we are only able to use data on serious adverse events Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through personal email correspondence with the authors in August 2014. They were not able to provide further information |
Arnold 2004
Methods | A 7‐centre US study consisting of a 6‐week, open‐label, dose‐titration phase (Part A) and a 2‐week, double‐blind, randomised, parallel, placebo‐controlled withdrawal study (Part B) with 2 arms:
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Participants | Part ANumber of participants screened: 116Number of participants included: 89Number of participants followed up: 76Number of withdrawals: 13Diagnosis of ADHD: DSM‐IV (subtype: combined (80%))Age: range 6‐16 years oldSex: 72 males, 17 femalesIQ: not statedMethylphenidate‐naïve: 71,9%Ethnicity: not statedCountry: USAComobidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Part AMethylphenidate type: dexmethylphenidateMethylphenidate dosage: 2.5 to 10 mg twice daily depending on individual participants' prior medication experienceChildren who had received dl‐MPH began with half their total daily dl‐MPH dose administered as d‐MPH, but not more than 20 mg/day; those who had not previously received dl‐MPH started d‐MPH at 2.5 mg twice dailyDuration of intervention: 6 week Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Part A and B: monitoring AEs and changes from baseline in vital signs (pulse and blood pressure), physical examination, and clinical laboratory parameters throughout the study |
Notes | Sample calculation: not statedEthics approval: not statedFunding: not statedVested interests/authors' affiliations: Key conclusions of the study authors: d‐MPH is safe, tolerable, and effective, with a 6‐hour duration of effect suggested by the significant difference from placebo at 6 hours on a double‐blind discontinuation Comments from the study authors: limitations: study design (withdrawal): treatment effects in such trials may be larger than those seen in unselected populations, because randomised, withdrawal phase preselected responders to the drug from the open‐label titration phase. Another possible limitation is the duration of the discontinuation (2 weeks) Supplemental information received through email correspondence with the authors in October 2013 (Arnold 2013b [pers comm]) However, authors advise us to contact the sponsoring drug company for additional information. We contacted them in November 2013 (Jones 2013 [pers comm]), but did not succeed in getting further information. |
Arnold 2010
Methods | A multisite cohort study of transdermal methylphenidate following abrupt withdrawal of extended release methylphenidate with follow‐up of 4 weeks |
Participants | Number of participants screened: 194Number of participants included: 171Number followed‐up: 150 but 164 in ITT analysisNumber of withdrawals: 21Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (77%), hyperactive‐impulsive (2%), inattentive (21%))Age: mean 9.4 yearsIQ: normalSex: 117 males, 47 femalesMethylphenidate‐naïve: noneEthnicity: white (79%), African American (12%), Asian (0.6%), others (9%)Country: USAComorbidity: noneComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Transdermal methylphenidate following abrupt withdrawal of extended release methylphenidateWeek 1: predefined dose‐transition schedule based on previous daily dose of oral extended release methylphenidateWeek 2 + 3: transdermal methylphenidate titrationWeek 4: stable dose transdermal methylphenidateMean final transdermal methylphenidate dosage: 26.63 mg/dayAdministration schedule: patches were applied to alternating hips once daily in the morning and were worn for up to 9 hours per dayDuration of intervention: 28 days Treatment compliance: compliance with the treatment regimen was measured by patch counts weekly. Data not stated |
Outcomes | Participant and/or parent reporting of adverse events, application site reactions (assessed on a scale ranging from 0 (no irritation) to 7 (strong reaction)), physical examinations, vital signs and ECGs. Adverse events were recorded throughout the study and for 30 days after the last dose of study drug Serious adverse events:No deaths were reportedNo reports of sudden death, stroke, or other serious cardiovascular events
Non‐serious adverse events:
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Notes | Sample calculation: yesEthics approval: yesFunding: Shire Development Inc, USAVested interest/authors' affiliations: multiple authors are employees or have received research support from pharmaceutical companies, including Shire, Novartis, Ortho‐McNeil Pharmaceuticals and Neuropharm Key conclusions of the study authors: abrupt conversion from a stable dose of oral ER‐MPH to transdermal MPH was accomplished using a predefined dose‐transition schedule without loss of symptom control; however, careful titration to optimal dose is recommended. Most AEs were mild to moderate and, with the exception of application site reactions, were similar to AEs typically observed with oral MPH This study demonstrates that MTS, when carefully titrated to optimal dose, may further improve child and family HRQL, as well as behavioural, medication worry, and economic impact item scores in participants switching to MTS from a stable dose of routinely prescribed oral ER‐MPH after a short treatment period. Furthermore, following the abrupt conversion from oral ER‐MPH to MTS, the majority of caregivers reported being highly satisfied with MTS as a treatment option for their children with ADHD. (Bukstein 2009)Comments from the study authors: study limitations: open‐label, with no control group, non‐randomised design. Relatively short duration. Spontaneous AE reporting. These results may not be generalisable to participants who are not on a stable dose of oral methylphenidate or who have a poor response Supplemental information regarding adverse outcome data received through personal email correspondence with the authors in September 2013 (Arnold 2013 [pers comm]) |
Artul 2014
Methods | A patient report of severe recurrent pancreatitis during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM (version and subtype: not stated)Age: 10 years oldIQ: > 70Sex: maleEthnicity: ArabicCountry: IsraelComorbidity: noneComedication: none Sociodemographics: good socioeconomic status |
Interventions | Methylphenidate dosage: 30 mg dailyAdministration schedule: not statedDuration of treatment: 3 weeks Treatment compliance: not stated |
Outcomes | Serious adverse events: After 3 weeks of treatment at 30 mg/daily: severe relapsing pancreatitis, 3 times in 2 months within 3 weeks after starting treatment with methylphenidate. Discontinuation: free of symptoms |
Notes | Key conclusions of the study authors: acute pancreatitis in paediatric age could be due to the use of methylphenidateFunding/vested interests: the authors have no conflicts of interest to disclose
Authors' affiliations: Department of Radiology, Nazareth Hospital, EMMS, Faculty of Medicine, Bar‐Ilan University, Israel. Faculty of Medicine in the Galilee, Bar‐Ilan University, Safed, IsraelDepartment of Nuclear Medicine, Meir Hospital, 44410 Betah Tekva, Israel. Department of Internal Medicine, EMMS Hospital, 16100 Nazareth, Israel. Pediatric Department, Nazareth Hospital, Israel Supplemental information regarding IQ, ethnicity, comorbidity and comedication received through personal email correspondence with the authors in August 2016. No information regarding exact IQ level was available, but authors state that it was above 70 (Artul 2016 [pers comm]) |
Arun 2014
Methods | 2 patient reports of suicidal ideation during methylphenidate treatment |
Participants | Case 1Diagnosis of ADHD: DSM‐IV TR (subtype: combined)Age: 8 years oldIQ: > 70Sex: maleEthnicity: HinduCountry: IndiaComorbidity: noneComedication: noneSociodemographics: living in joint family Case 2 Diagnosis of ADHD: DSM‐IV TR (subtype: combined)Age: 7 years oldIQ: averageSex: maleEthnicity: HinduCountry: IndiaComorbidity: noneComedication: noneSociodemographics: living in nuclear family |
Interventions | Case 1Immediate release methylphenidate dosage: 5 mg/dayAdministration schedule: once daily in the morningDuration of treatment: 2 daysTreatment compliance: not stated Case 2: Methylphenidate type: not statedMethylphenidate dosage: 10 mg/dayAdministration schedule: once dailyDuration of treatment: 12 daysTreatment compliance: not stated |
Outcomes | Serious adverse eventsSuicidal ideation Non‐serious adverse events Impairment in sleep onset for 1 night |
Notes | Key conclusions of the study authors: depressed mood or affective symptoms may occur as an adverse effect during Methylphenidate treatment, and impulsivity may result in attempted suicide even in ADHD children without depression. In view of the current findings and existing literature, clinicians need to be alert to the adverse effects of methylphenidate during examination of every case. Equally important is ensuring that the patients' parents and teachers of the patients are appropriately educated regarding potential adverse effects of methylphenidate Comments from the study authors: there was no depressive symptoms reported along with it, and the ideation could not be explained on the basis of impulsivity eitherFunding/vested interest: nil, none otherwise declared Authors' affiliations: Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India Supplemental information received through personal email correspondence with the authors in September 2014 (Arun 2014 [pers comm]) |
Ashkenasi 2011
Methods | A single‐centre, open‐label, randomised cross‐over study of transdermal methylphenidate effect on sleep disturbance, where participants were randomised to 1 of 4 groups with different sequences of patch wear time (9,10,11,12 hours a day)
Phases:
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Participants | Number of participants screened: not statedNumber of participants included: 26Number of participants followed up: 24Number of withdrawals: 2Diagnosis of ADHD: DSM‐IV (subtype: combined (77%))Age: mean 9.3 years, range 6‐12 years oldIQ: > 70Sex: 19 males, 7 femalesMethylphenidate‐naïve: not statedEthnicity: not statedComorbidity: sleep disturbancesComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Participants were randomly assigned to different drug condition ordersMethylphenidate type: methylphenidate transdermal systemMean methylphenidate dosage: 20 mgAdministration schedule: once daily in the morning, switching between 9, 10, 11 and 12 hour alternating wear time across 4 consecutive weeks. Patch wear times were maintained Monday through Thursday of each week. Patients followed the standard 9‐hour wear time schedule on weekends (i.e. Friday through Sunday)Duration of intervention: 4 weeksWashout before study initiation: 1 week before titration period to optimal dose. And a minimum of 12 hours between 2 consecutive days during the trialTitration period: before randomisation Treatment compliance: 1 participant discontinued because of non‐compliance. No information about the others |
Outcomes | Serious adverse events:Hallucinosis: 1 child "withdrew after completing the randomization phase because of a significant medication side effect that emerged later in the study (i.e., hallucinosis)". No hospitalisation, symptoms withdrew after medication was discontinued Non‐serious adverse events: Skin reactions were coded on a 3‐point scale, where 0 ¼ no change, 1 ¼ slight pink/pink, and 2 ¼ slight red/ red. Rated by caregiversSleep was assessed according to a daily sleep diary, with entries for time of patch application and removal, sleep timing (e.g. bedtime, time to fall asleep, number of awakenings, time awake at night, and final wake time), and ratings of sleep quality (on a 5‐point scale). Entries were recorded at baseline, after determination of the optimal patch dose, daily during wear time titration, and at endpoint. The sleep diary was documented by caregivers Monday through Sunday of every week throughout the wear time titration |
Notes | Funding: investigator‐sponsored grants from Shire Pharmaceuticals, Inc. and Noven Pharmaceuticals, Inc.
Vested interest/authors' affiliations: Shire Pharmaceuticals, Noven Pharmaceuticals. "..these companies were not involved in the conduct of the study or the preparation of the manuscript" Key conclusions of the study authors: patch wear time exerted no significant effect on sleep latency or total sleep time, although a trend toward improved sleep quality was evident (P ¼ 0.059) with longer patch wear times. Sleep parameters were not adversely affected by longer methylphenidate transdermal system patch wear times Comments from the study authors: limitations of the study: small sample size, for instance resulting in a weaker randomisation to patch wear time sequence that was not completely effective in balancing baseline covariates Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes. Children with previous intolerance or adverse events on methylphenidate were excluded Supplemental information received through personal email correspondence with the authors in September 2013. Not possible to get the necessary supplemental information on non‐serious adverse events (Ashkenasi 2013 [pers comm]) |
Atzori 2009
Methods | A cohort study of methylphenidate use for 36 months and factors influencing compliance and persistent use |
Participants | Number of participants screened:187Number of participants included: 134Number of participants followed up: 134Number of withdrawals: 72 (were followed up but had stopped treatment at 36 months follow‐up)Diagnosis of ADHD: DSM‐IV (subtype: combined (83.6%), hyperactive‐impulsive (4.5%), inattentive (11.9%))Age: mean 9 (SD 2), range 4‐16IQ: 83 (SD 16), range 51‐114; 88 (SD 19), range 54‐129; 84 (SD 18), range 41‐124Sex: 122 males, 12 femalesMethylphenidate‐naïve: noneEthnicity: not statedCountry: ItalyComorbidity: 80.6%Comedication: not statedSociodemographics: double parents: 74.6%. Urban residence: 56% Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: immediate release methylphenidateMethylpenidate dosage: mean 0.42 mg/kg/per dose, range 0.3‐0.5Administration schedule: 2‐3 daily doses of maximum 1 mg/kg per doseDuration of intervention: 36 months (15.5 months in those suspended for functional remission, 14.7 months in those suspended for other reasons) Treatment compliance: 14.9% non‐adherent (non‐adherence as taking less than 80% of medication for ≥ 8 months per year) |
Outcomes | Clinician‐designed questionnaire asking for the adverse events reported in the Switzerland SPC, self‐reported, unclear 53 children did not start chronic treatment due to side effects |
Notes | Sample calculation: noneEthics approval: not stated Funding/vested interests: supported in part by Sardinian Public Health Secretariat and by the Agenzia Italiana del Farmaco Authors' affiliations: Dr Zuddas has received research grants from Eli Lilly and Shire Laboratories and has been a speaker for Eli Lilly and Sanofi‐Synthelabo and has an advisory or consulting relationship with Eli Lilly, Shire Laboratories, UCB, and Astra ZenecaKey conclusions of the study authors: clinical outcome of ADHD treatment is heterogeneous. Specific clinical and social predictive parameters for long‐term methylphenidate use and compliance can be identified. An accurate tailoring of clinical intervention to the individual child appears crucial for good outcome Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
Ayaz 2014
Methods | A case‐control study of methylphenidate use for 12 months |
Participants | Number of participants screened: 2171Number of participants included: 1348Number of participants followed up: 877 (methylphenidate only: 788)Number of withdrawals: 195Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean continuing: 9.01 (SD 2.36); mean discontinuing: 9.52 (SD 2.37). Range: 6‐18 years oldIQ: > 70Sex: 687 males, 132 femaleMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: ODD, CD, learning disorders, mood disorders, anxiety disorders, tic, elimination disordersComedication: atomoxetineSociodemographics: low educational level of mother: children continuing: 67.9%; children discontinuing: 73.4%, low educational level of father: children continuing: 54.3%; children discontinuing: 56.9% Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: immediate and extended releaseMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: 12 months Treatment compliance: 265 continued treatment 12 months after the initiation of the prescription |
Outcomes | Since data includes atomoxetine no outcomes are usable |
Notes | Sample calculation: noAny withdrawals due to adverse events: yesEthics approval: yesFunding/vested interest/authors' affiliations: none stated Key conclusions of the study authors: medication persistence, in Turkish children, can be influenced by younger age, higher hyperactivity/impulsivity scores, use of long acting MPH, addition of another ADHD medication, and addition of other psychotropic medications, absence of adverse events, efficacy level perceived by the parents Comments from the study authors: limitations due to retrospective approach of the study, the determination of medication persistence, lack of sufficient data about the treatment efficacy and side effects after each medication was switched, and information obtained on the side effects spontaneously by parental reports. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, methylphenidate responders only Supplemental information requested from the study authors in April 2016. No answer |
Balázs 2011
Methods | A cohort study of dyskinesia in children routinely using methylphenidate after a single dose of methylphenidate compared to community controls |
Participants | Number of participants screened: 94Number of participants included in the ADHD group: 37Number of cases followed up: 34Number of withdrawals: 3Diagnosis of ADHD: DSM‐IV (subtype: combined (67.6%), hyperactive‐impulsive (10.8%), inattentive (21.6%))Age: mean 10.8 years, range 7‐17 years oldIQ: normalSex: 32 males, 5 femalesMethylphenidate‐naïve: 0%. Median prior exposure to methylphenidate: 1074 daysEthnicity: not statedCountry: HungaryComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMethylphenidate dose: not statedAdministration schedule: single dose, the same dose which they had been prescribed for their regular treatmentDuration of treatment: 1 day Treatment compliance: 3 children left the study after baseline measurements were taken |
Outcomes | Non‐serious adverse events: Dyskinesia measured before and 90‐120 minutes after administration of a single dose of methylphenidate by using the Abnormal Involuntary Movement Scale (AIMS) (0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe) |
Notes | Sample calculation: not statedEthics approval: yes, the study was approved by the Regional Ethics CommitteeFunding: none reportedVested interest/authors' affiliations: the authors report no conflict of interest Key conclusions of the study authors: methylphenidate‐treated children with ADHD had more dyskinesia than children in the control group. Dyskinesia did not worsen after a single dose of methylphenidate Higher dyskinesia scores in the methylphenidate‐treated younger age group warrant caution in the methylphenidate treatment of ADHD; however, further studies are needed to clarify the possible causal relationship between dyskinesia and methylphenidate treatment and/or age and/or the disease itselfComments from the study authors: we found no relationship between prior methylphenidate exposure of the children with ADHD and the total severity of dyskinesia. We believe that this lack of association is because most of our patients had been receiving long‐term methylphenidate treatment before enrolment in the study. Limitations: no inclusion of treatment‐naïve children with ADHD Comments from the review authors: none of the participants were methylphenidate‐naïve, and the results from the measurements before methylphenidate administration (baseline) are therefore in fact reflecting long‐term use (median prior exposure to methylphenidate: 1074 days). This needs to be taken into account when assessing the results from the measurements after methylphenidate administration in the study (short‐term challenge). |
Barbaresi 2006
Methods | A study of stimulant use for ADHD in a birth cohort born between 1976 and 1982 |
Participants | Number of participants screened: 5718Number of participants included: 379Number of participants followed up: 295 using stimulants which included 251 receiving methylphenidateNumber of withdrawals: 84Diagnosis of ADHD: DSM‐IV (subtype: combined (67.5% stimulants, 72.1% MPH), hyperactive‐impulsive (7.4%, 4.8%), inattentive (24.6%, 21.1%))Mean age at onset stimulant treatment: 10.4 (SD 3.6). Age at last follow‐up: 17.6 yearsIQ: not statedSex: 284 males, 95 females (stimulant treatment). 198 males, 53 females (MPH)Methylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: not statedComedication: yes, 2 stimulantsSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: the dose of each stimulant was initially converted to methylphenidate equivalent units (MEUs) and then each dose was weighted by the duration of use. 24.4 (11.1) mg/dayAdministration schedule: not statedDuration of intervention: 33.8 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:63 (22.3%) of the 283 children treated with stimulants had ≥ 1 side effectDextroamphetamine were significantly more likely to be associated with a side effect compared to methylphenidate (10.0% vs 6.1%, OR 1.8, 95% CI 1.1 to 3.0; P = 0.034) 6.1% of 717 MPH treatment episodes (i.e. period of time during which participant was treated with MPH at a specific dose) were associated with a side effect |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interest: the project was supported by research grants from the Public Health Service, National Institutes of Health and by an investigator‐initiated research grant from McNeil Consumer and Specialty PharmaceuticalsAuthors' affiliations: Department of Pediatric and Adolescent Medicine, Division of Developmental and Behavioral Pediatrics, Mayo Clinic College of Medicine. Department of Health Sciences Research, Division of Clinical Epidemiology, Mayo Clinic College of Medicine. Department of Psychiatry and Psychology, Mayo Clinic College of Medicine. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine Key conclusions of the study authors: clinicians made appropriate treatment decisions; there are disparities in the rates ADHD treatment for boys/girls; efficacy was comparable to clinical trials Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Barrickman 1995
Methods | Double‐blind, cross‐over study comparing methylphenidate and bupropion |
Participants | Number of participants screened: not statedNumber of participants included: 18 patientsNumber of participants followed up: 15Number of withdrawals: 3
Diagnosis of ADHD: DSM‐III‐R (subtype: not stated)
Age: 11.8 (SD 3.3), range 7‐16IQ: full scale WISC‐R score 106 (SD 10), range 84‐123Sex: 12 males, 3 femalesMethylphenidate‐naïve: 5 (33.33%)Ethnicity: whiteCountry: USAComorbidity: conduct disorder (n = 2), oppositional defiant disorder (n = 2), developmental learning disorder (n = 5)Comedication: none. Before washout methylphenidate (n = 9), methylphenidate + imipramine (n = 1)Sociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Participants were randomly assigned to 1 of 2 possible drug condition orders, methylphenidate or bupropion.Mean methylphenidate dosage: 31 (n = 11) mg/day (20‐60 mg/day) or 0.7 (n = 0.2) mg/kg/day (0.4‐1.3 mg/kg/day)Administration schedule: morning, noon, and 4 pm if neededDuration of intervention: 6 weeksWashout prior to study initiation: 14 daysMedication‐free period between intervention: 14 daysTitration period: methylphenidate was administered in a dose of 0.4 mg/kg per day during the first week and the to the maximum effective dose during the next 2 weeks. Dosage was fixed for the final 3 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:
Adverse effects checklist monitored by a physician by the end of each week.
Physical examination
Children's Depression Inventory (CDI), rated each week by physician. Revised Children's Manifest Anxiety Scale (R‐CMAS), rated each week by physician |
Notes | Sample calculation: yes
Ethics approval: not stated
Funding: not stated
Vested interest/authors' affiliations: not stated Key conclusions of the study authors: bupropion and methylphenidate were both effective and did not differ in their overall efficacy as treatment for ADHD. Thus, results of nearly all of the rating scales trended in favour of methylphenidate. There is a possibility that this insignificant difference might be a function of the relatively small dose of bupropion used in this study Supplemental information requested through personal email correspondence with the authors in June 2014. No reply |
Berek 2011
Methods | A multicentre, prospective, open‐label, single‐arm, non‐interventional study of methylphenidate use for 3 months. 5 visits: baseline, 1, 3 and 6 weeks of treatment, as well as after 3 months or upon premature termination |
Participants | Number of participants screened: not statedNumber of participants included: 822Number of participants followed up: 74% completed the 12‐week trialNumber of withdrawals: total number of dropouts was not reported, 60 dropped out due to AEsDiagnosis of ADHD: ICD‐10 (subtype: F90.0: n = 519 (63.14%). F90.1: n = 316 (38.44%). F90.8: n = 14 (1.70%). F90.9: n = 21 (2.55%). Others: n = 65 (7.91%)Age: mean 11.1, range 6‐18 (6‐9 years old (n = 251, 30.54%), 10‐12 (n = 332, 40.39%), 13‐15 (n = 197, 23.97%), 16‐18 (n = 42, 5.11%))IQ: not statedSex: 698 (84.91%) males, 124 (15.09%) femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: Germany
Comorbidity: F91.X: n = 187 (22.75%). F91 incl. F91.3: n = 140 (17.03%). F41: n = 32 (3.89%). F42: n = 15 (1.82%). F1X: n = 6 (0.73%). None: n = 496 (60.34%). Other: n = 73 (8.88%)Comedication: not statedSociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type: OROS methylphenidateMethylphenidate dosage: starting dose 31.53 (SD 13.52) mg/day. Min: 18, med: 36, max: 108. Final dose: 35.47 (SD 14.04) mg/dayAdministration schedule: once dailyDuration of intervention: 84.10 (SD 29.49) days Treatment compliance: not stated |
Outcomes | Blood pressure and heart rate measured at baseline and all visits (week 1, 3, 6 and 12 or last visit), weight measured at first and last visitAdverse events were coded according to WHO Adverse Reaction Terminology (WHOART) Sleep quality and appetite were assessed at each visit, using a 5‐point scale with categories: very good, good, satisfactory, sufficient and insufficient |
Notes | Sample calculation: not statedEthics approval: independent ethics committee, Freiburg, Germany
Funding: the study was funded by Janssen‐Cilag GmbH, Neuss GermanyVested interest/authors' affiliations: KR is a consultant working for GEM, Meerbusch, Germany, who was hired by Janssen‐Cilag to carry out the statistical analyses. LS and BS are employees of Janssen‐Cilag; at the time the study was conducted, MG was also an employee of Janssen‐Cilag. MG is currently employed by Ipsen Pharma. AL has, in the past 3 years, been a speaker for Shire and Novartis. He is not an employee or a shareholder of any of these companies and has no other financial or material support, including expert testimony, patents or royalties Key conclusions of the study authors: our study suggest a clinically meaningful increase in efficacy upon transitioning onto OROS methylphenidate in the treatment of children/adolescents with ADHD who had insufficient response to and/or poor tolerability with extended release methylphenidate or atomoxetine Comments from the review authors: the data extraction is based on Berek (2011), rather than an independent synthesis of the many articles published on this study Supplemental information requested through personal email correspondence with the authors in August 2014. No reply |
Bereket 2005
Methods | A longitudinally study of 16 months of methylphenidate treatment in newly diagnosed and untreated children |
Participants | Number of participants screened: not statedNumber of participants included: 72Number of participants followed up: 14Number of withdrawals: 58Diagnosis of ADHD: DSM‐IV (subtypes: not stated)Age: mean 8.12 years, range 6.47‐10.32IQ: none with mental retardationSex: 10 males, 4 femalesMethylphenidate‐naïve: 100%Ethnicity: TurkishCountry: TurkeyComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 0.75 mg/kgAdministration schedule: not statedDuration of intervention: 16 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Height measured with a Harpenden stadiometer. Performed every 4 monthsWeight measured "with minimal clothing". Performed every 4 months Height and weight measurements were transformed to SDs before the statistical analyses using normative data for Turkish children. BMI values were transformed to SDs according to data from Cole 2007 |
Notes | Sample calculation: noEthics approval: approved by local ethics committeeFunding: supported by a TUBITAK grantVested interest/authors' affiliations: not stated Key conclusions of the study authors: prepubertal children with ADHD had normal height, weight, BMI, serum IGF‐I and IGFBP‐3 and thyroid functions. Methylphenidate treatment had no sustained effects on growth parameters, IGF‐I and IGFBP‐3 during the follow‐up period of this study. However, it caused a mild decrease in total and free T4, which may warrant further monitoring Supplemental information received through personal email correspondence with the authors in January 2014 (Bereket 2014 [pers comm]) |
Bernhard 2009
Methods | A patient report of a 4‐year‐old boy with T‐cell acute lymphoblastic leukemia and in maintenance therapy with purinethol and methotrexate experiencing a hepatotoxic reaction after onset of methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: hyperactive‐impulsive)Age: 4 years and 6 months oldIQ: unknownSex: maleEthnicity: not statedCountry: GermanySetting: outpatient clinicComorbidity: T‐ALL; severe damage to white matter induced by chemo‐ and radiotherapyComedication: purinethol and methotrexate Sociodemographics: unknown |
Interventions | Methylphenidate type: short acting RitalinMethylphenidate dosage: 10 mg, 0.6 mg/kgAdministration schedule: once daily in the morningDuration of treatment: 3 weeks titration. 6 weeks treatment in total. Treatment compliance: not stated |
Outcomes | Serious adverse events: A hepatotoxic reaction: liver enzymes were elevated prior to therapy. Vomiting starting 5 weeks after onset of methylphenidate therapy and increased within the next 3 days. Abdominal pain increased in intensity. Liver transaminases elevated over 30 times of the normal level, CK level also increased |
Notes | Key conclusions of the study authors: hepatotoxicity of methylphenidate can be considered minimal. However, methylphenidate therapy in children with prior or possible hepatic damage should be monitored clinically and by laboratory testing in short intervals Comments from the study authors: liver enzymes elevated prior to treatmentFunding/vested interests: none Authors' affiliations: Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany |
Blader 2010
Methods | A non‐randomised trial with no placebo group of methylphenidate use and the factors associated with aggression that is responsive versus refractory to individualised optimisation of stimulant monotherapy |
Participants | Number of participants screened: 304Number of participants included: 68Number of participants followed up: 65Number of withdrawals: 3Diagnosis of ADHD: not stated (subtype: not stated)Age: mean: 8.95, range: 6‐13 years oldIQ: > 70Sex: 50 males, 15 femalesMethylphenidate‐naïve: noneEthnicity: white: 72%, African American: 12%, Hispanic: 8%, others: 8%Country: USASetting: outpatient clinicComorbidity: ODD: 94%; CD: 6%; anxiety disorder: 29%; depressive disorder: 65%Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: triphasic‐release methylphenidateMethylphenidate dosage: 64 mg (refractory) and 52 mg (non‐refractory)Administration schedule: weekly dosage adjustments from 18 mg of normally 18 mg increments to reach best tolerated dosage associated with greatest overall improvement in ADHD symptoms and aggression to a maximum dosage of 90 mg/day; once daily after waking but no later than 8.30 amDuration of intervention: average 63.26 days (SD 23.98) Treatment compliance: 3 withdrawals due to low adherence |
Outcomes | Non‐serious adverse events:Weight, observer, weeklyHeight, observer, weeklyBlood pressure, observer, weeklyHeart rate, observer, weeklyBarkley Behaviour and Adverse Events Questionnaire Modified, parent, weekly A BBAEQ‐M item was considered present when the parent rated it at least moderate |
Notes | Sample calculation: noEthics approval: no, approved by institutional review boards of 2 clinical sitesFunding/vested interests: National Institutes of Health Grants K23MH064975 and M01RR10710, a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression and a grant for investigator‐initiated research from Abbot Laboratories Authors' affiliations:all authors have received research support in the past from pharmaceutical companies and/or consulting and/or speaking fees. Key conclusions of the study authors: among children whose aggressive behaviour develops in the context of ADHD and of oppositional defiant disorder or conduct disorder, and who had insufficient response to previous stimulant treatment in routine clinical care, systematic, well‐monitored titration of stimulant monotherapy often culminates in reduced aggression that averts the need for additional agents Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, according to exclusion criteria no. 2 |
Buchmann 2007
Methods | A cohort study of methylphenidate use for 10‐14 days |
Participants | Number of participants screened: not statedNumber of participants included: 18Number of participants followed up: 18Number of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean: 11 years, SD: 1.91 years oldIQ: > 85Sex: 15 males, 3 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: GermanyComorbidity: no psychiatric comorbidityComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: extended release methylphenidateMean methylphenidate dosage: 0.78 (SD 0.26) mg/kg/dayAdministration schedule: once a day in the morningDuration of intervention: 10‐14 days Treatment compliance: children were inpatients for the duration of the study and received supervision when taking their medication |
Outcomes | Data on adverse events were not systematically collected, so we could not use this data |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: not statedEthics approval: not statedFunding/vested interest: not statedAuthors' affiliations: Department of Child and Adolescence Psychiatry and Neurology University of Rostock, Rostock, Germany. Key conclusions of the study authors: the methylphenidate group had the short interval cortical inhibition, intracortical facilitation and long interval cortical inhibition changes restored by the medication ‐ this was a very similar finding, compared to control group Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: all participants were methylphenidate‐naïve Supplemental information regarding methods received through personal email correspondence with the authors in June 2014 (Buchmann 2014 [pers comm]) |
Cakin‐Memik 2010
Methods | A patient report of a 14‐year‐old male with ADHD who presented with priapism after administration of immediate‐release methylphenidate. When the usage of immediate‐release methylphenidate was terminated, priapism spontaneously disappeared |
Participants | Diagnosis of ADHD: not stated (subtype: not stated)Age: 14 years oldIQ: not statedSex: maleEthnicity: not statedCountry: TurkeyComorbidity: noComedication: no Sociodemographics: not stated |
Interventions | Immediate‐release methylphenidate started at 10 mg/day and after 2 months increased to 20 mg/dayAdministration schedule: not statedDuration of treatment: 2 months and 3 days Treatment compliance: not stated |
Outcomes | Serious adverse events: Priapism: up to 3‐4 episodes per day lasting 40 to 45 minutes beginning 3 days after the dose was increased to 20 mg/day |
Notes | Funding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: in the case of immediate‐release methylphenidate prescription to adolescent male patients, the probability of the development of priapism should not be ignoredThe lack of inquiry and reporting of this side effect can lead to potentially irreversible impotence. Thus, it is important that the clinician be aware of this side effect and counsel the children/adolescents and their families about its occurrence in order to improve the adaptation of methylphenidate treatment Comments from the study authors: it is important to note that, as in this case, adolescent males may be too embarrassed to report this side effect particularly when they do not know it may be linked to methylphenidate |
Chandler 1989
Methods | A patient report of 2 boys on methylphenidate treatment. 1 with preexisting tics that were aggravated by stimulants and 1 with stimulant induced tics |
Participants | Case 1Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: 12 years oldIQ: > 70Sex: maleEthnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Case 2 Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: 9 years oldIQ: > 70Sex: maleEthnicity: not statedCountry: USAComorbidity: noneComedication: not statedSociodemographics: not stated |
Interventions | Case 1Methylphenidate type: not statedMethylphenidate dosage: 0.2 mg/kgAdministration schedule: twice dailyDuration of treatment: 1 monthTreatment compliance: not stated Case 2 Methylphenidate type: not statedMethylphenidate dosage: 0.2 mg/kgAdministration schedule: twice dailyDuration of intervention: not statedTreatment compliance: not stated |
Outcomes | Non‐serious adverse events: Case 1: after a month, the child's mother reported motor and phonic tics again Case 2: he was treated first with methylphenidate, and then with nortriptyline, with both drugs he manifested severe facial grimacing and phonic tics. Apparently, the tics had only occurred in the past when the child was treated with methylphenidate |
Notes | Funding/vested interests/authors affiliations: not stated Key conclusions of the study authors: we report 2 cases of AD/HD children, 1 with pre‐existing tics that were aggravated by stimulants and 1 with stimulant induced tics. With combined stimulant/L‐tryptophan treatment there was sustained improvement in AD/HD symptoms and no motor or phonic tics.Side effects such as hypomania, hyperreflexia, and diaphoresis have been reported in patients on the combination of a monoamine oxidase inhibitor and tryptophan. By itself, L‐tryptophan may be mildly sedating. In light of such a favorable side effect profile, and no evidence for adverse interaction with stimulants, and at least some rationale from preclinical research, it should be investigated further as a means of alleviating some of the harsh consequences of psychostimulant treatment in AD/HD Supplemental information regarding diagnosis and IQ received through personal email correspondence with the authors in September 2013 (Gualtieri 2013 [pers comm]) |
Chazan 2011
Methods | An open clinical trial of methylphenidate use for 6 months |
Participants | Number of participants screened: 189Number of participants included: 130Number of participants followed up: 125Number of withdrawals: 5Diagnosis of ADHD: DSM‐IV (subtype: combined (63.1%), hyperactive‐impulsive (7.7%), inattentive (23.1%))Age: mean 9.8 (2.8) years (range 5‐17)IQ: mean 92.34 (12.61)Sex: 96 males, 34 femalesMethylphenidate‐naïve: 86.9%Ethnicity: white: 77.7%Country: BrazilComorbidity: ODD (46.9%); CD (13.1%); any mood disorder (13.1%); any anxiety disorder (40.8%)Comedication: yesSociodemographics: classes: A + B (55%); C + D (45%) Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: immediate release and extended releaseMean methylphenidate dosage: 0.48 mg/kg/day (SD 0.22)Administration schedule: not statedDuration of intervention: 6 months Treatment compliance: 76.4% adherence |
Outcomes | Barkley side effects rating scale |
Notes | Sample calculation: noEthics approval: yesFunding: this work was supported by research grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil; Edital MCT/CNPq 02/2006‐Universal, 478202/2006‐7) and Hospital de Clínicas de Porto AlegreVested interests/authors' affiliations: Prof Rohde has served as a speaker and/or consultant for Eli‐Lilly, Janssen‐Cilag, and Novartis for the last 3 years. Currently, his only industry‐related activity is taking part in the advisory board/speakers' bureau for Eli Lilly, Novartis, and Shire (USD 10,000 per year and reflecting 5% of his gross income per year). The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last 3 years: Abbott, Bristol‐Myers Squibb, Eli‐Lilly, Janssen‐Cilag, Novartis, and Shire. Prof Polanczyk has served as a speaker for Novartis. Drs Chazan, Borowski, Pianca, and Ludwig report no conflict of interest Key conclusions of the study authors: our results suggest that ADHD combined subtype, maternal ADHD symptoms, and social adversities are independent negative predictors of methylphenidate response in children and adolescents with ADHD. Our study provides evidence for the involvement of clinical characteristics, maternal psychopathology, and environmental stressors in the response to methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Cherland 1999
Methods | A retrospective cohort study conducted as a chart review |
Participants | Number of participants screened: 192Number of participants included: 98Number of participants followed up: 98Number of withdrawals: not statedDiagnosis of ADD and ADHD: DSM‐III‐R and DSM‐IV (subtype: not stated)Age: range 4‐17IQ: not statedSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: CanadaComorbidity: not statedComedication: 2%Sociodemographics: not stated Inclusion criteria:
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: range 5‐80 mg per dayAdministration schedule: not statedDuration of treatment: mean 1 year and 9 months Treatment compliance: not stated |
Outcomes | Serious adverse events:The reviewers rated whether the symptoms suggesting psychosis were side effects of the medication or part of the child's psychopathology. DSM‐IV criteria for definitions for psychotic and mood‐congruent psychotic symptoms were used98 children treated with stimulant medication
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Notes | Sample calculation: noAny withdrawals due to adverse events: methylphenidate was withdrawn from all children and adolescents experiencing psychotic symptomsEthics approval: not statedFunding/vested interests: not statedAuthors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: awareness of the potential for psychotic side effects from stimulant medications is important when prescribing for children. A large prospective study would be useful to predict the frequency and classification of the side effects in children Comments from the study authors: most of the children and adolescents improved upon withdrawal of the methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding IQ, sex distribution, comedication and safety data were requested through personal email correspondence with the authors in February 2014. No reply |
Cho 2012
Methods | A 12 week prospective, exploratory, open‐labeled cohort study to achieve symptomatic remission by OROS‐methylphenidate. The purpose of the study was to investigate a possible association between norepinephrine genes and cardiovascular side effects of OROS‐methylphenidate in Korean children with ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 101Number of participants followed up: 101Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (67.6%), hyperactive‐impulsive (5.8%), inattentive (26.4%))Age: 8.73 (SD 1.78) years, range 6‐12IQ: 102.3 (SD 11.9)Sex: 81 males, 20 femalesMethylphenidate‐naïve: 100%Ethnicity: AsianCountry: South KoreaComorbidity: anxiety disorders (8.8%), ODD (6.8%), transient tic disorder (6,8%), enuresis (5.9%)Comedication: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate: osmotic release oral systemMean methylphenidate dosage: 0.98 (SD 0.52) mg/kgAdministration schedule: not statedDuration of intervention: 12 weeks Titration: initial dosage was determined by child's body weight: if ≥ 30 kg, 27 mg was administered; if < 30 kg, 18 mg was administered. The dosages were increased every 2 weeks for 9 weeks until they were sufficient to achieve a therapeutic effect, on the basis of the investigators and parents' assessments of symptoms and side effects, and then these doses were maintained until the 12th week. Treatment compliance: not stated |
Outcomes | Electrocardiographic (ECG) parameters, including QT interval. Resting heart rate, seated pulse, blood pressure. All measures collected at 12 weeks after treatment. These measurements were obtained 60‐120 minutes after a dose was given. The cardiovascular parameters for all participants were measured manually |
Notes | Sample calculation: yesEthics approval: approved by the institutional review board (IRB) for human subjects at the Seoul National University Hospital and at 5 other hospitals in South Korea. Parents/guardians provided written informed consent, and the children or adolescents provided verbal assent regarding participation in this study.Funding: BN Kim was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) and by the Korean Janssen Pharmaceutical CompanyVested interest/authors' affiliations: Janssen Korea Key conclusions of the study authors: the overall cardiovascular effects of OROS‐methylphenidate were modest. However, our findings show a positive association between norepinephrine‐related gene polymorphisms and cardiovascular response induced by methylphenidate in Korean children with ADHD. Consideration must be given to such children or adults with specific norepinephrine‐related genotypes, especially if they show significant changes in heart rate or diastolic blood pressure after OROS‐methylphenidate administration Comments from the study authors: monitoring only occurred at baseline and after 12 weeks of methylphenidate treatment. 9% of the study participants with ADHD had co‐morbid anxiety disorders which may have affected cardiovascular measures. As this study was exploratory we did not apply multiple comparison corrections for the 3 cardiovascular outcomes; future studies may strengthen and perhaps extend the current findings by applying such corrections in larger samples. According to the inclusion and exclusion criteria, no children enrolled in this study had clinical histories of hypertension, hypotension or cardiovascular disease. Therefore, no conclusions can be made about the use of methylphenidate in children with significant cardiovascular dysfunction or risk factors Supplemental information regarding outcome measures and protocol requested twice in January 2014 with no answer |
Chou 2012a
Methods | A 10‐week non‐comparative observational study in 6 outpatient clinics identifying the optimal dose of OROS‐methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 521Number of participants followed up: 439Number of withdrawals: 82Diagnosis of ADHD: DSM‐IV (subtype: combined (65.6%), hyperactive‐impulsive (3.1%), inattentive (31.3%))Age: mean 10.4 years (range 7‐17)IQ: normalSex: 461 males, 60 femalesMethylphenidate‐naïve: noneEthnicity: AsianCountry: TaiwanComorbidity: ODD (4.4%), anxiety disorder (0.2%), other disorders (3.5%)Comedication: clonidine (0.6%), antipsychotics (0.4%)Sociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral systemMethylphenidate dosage: participants receiving an immediate release methylphenidate dosage < 15 mg, 15‐30 mg, and > 30 mg day were converted to 18, 36, and 54 mg once dailyAdministration schedule: morningDuration of intervention: 10 weeks Treatment compliance: not stated |
Outcomes | Parents or caregivers completed the Chinese version of the Barkley Side Effect Scale at each visit. An adverse event was any undesirable sign, symptom, or medical condition occurring after starting the therapy and was reported by investigators. Pre‐existing medical conditions/diseases were also considered adverse events if they worsened during treatment |
Notes | Sample calculation: noAny withdrawals due to adverse events: not statedEthics approval: approved by the Joint Institute Review Board, Taipei, TaiwanFunding: the study was supported by Janssen‐Cilag, Taipei, TaiwanVested interests/authors' affiliations: Janssen‐Cilag. 5 authors had conducted clinical trials on behalf of Eli & Lilly Co and 1 on behalf of Janssen‐Cilag. 9 were speakers and consultants for Janssen‐Cila Key conclusions of the study authors: the findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced‐titration scheme Comments from the review authors: data are not pertinent to our review. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information received through personal email correspondence with the authors in February 2014 (Chou 2014 [pers comm]) |
Chou 2012b
Methods | A prospective, single‐arm, open‐label, 8‐week, multicentre cohort study of methylphenidate use for 8 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 296Number of participants followed up: 230Number of withdrawals: 66Diagnosis of ADHD: DSM‐IV (subtype: combined (67.9%), hyperactive‐impulsive (1%), inattentive (30.4%))Age: mean 9.5 (SD 2.4), range 6.0‐17.0 years oldIQ: not statedSex: 247 males, 49 femalesMethylphenidate‐naïve: noneEthnicity: not statedCountry: TaiwanComorbidity: participants with serious or unstable medical illness, or who have clinically significant gastrointestinal problems, glaucoma, ongoing seizure disorders, or a psychotic disorder are excludedComedication: participants who are taking concomitant medication that is likely to interfere with safe administration of methylphenidate are excluded.Sociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: 18 mg, 36 mg or 54 mg. Dose was adjusted for each participant based on clinical responses and/or side effectsAdministration schedule: once dailyDuration of intervention: 8 weeks Treatment compliance: not stated |
Outcomes | Adverse events (AEs) data were reported for each visit as total data for AEs; not analysed. In addition to the AEs reported in the below table, a category of AEs titled 'Other' was reported, as no dictionary was used and events under this category were not further specified. Total no. affected by other AEs is minimum number of participants affected |
Notes | Sample calculation: not statedEthics approval: not statedFunding: sponsored by Johnson & Johnson Taiwan LtdVested interests/authors' affiliations: principal investigators are not employed by the organisation sponsoring the study. There is an agreement between principal investigators and the sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo Key conclusions of the study authors: comparing with the baseline, OROS‐methylphenidate had been demonstrated that it could significantly improve participants' ADHD behavioural symptoms and their social adjustment at school and at home Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: participants hypersensitive to methylphenidate were excluded Supplemental information regarding IQ requested through personal email correspondence with the authors in August 2014 with no reply |
Cockcroft 2009
Methods | A comparative cohort study of sleepiness in ADHD children treated with methylphenidate compared to methylphenidate‐naïve |
Participants | Number of patients screened: not statedNumber of participants included: 30Number included as cases: methylphenidate (n = 12), methylphenidate naïve (n = 11)Number followed up in each arm: methylphenidate: 12 and methylphenidate naïve: 11Number of withdrawals: 7 in the medication group were excluded because they were taking another medication, or matches with unmedicated children could be not be madeDiagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age range: 6.4‐12.7 years oldIQ: normalSex: 16 male, 7 femaleMethylphenidate‐naïve: 11Ethnicity: not statedCountry: South AfricaComorbidity: not statedComedication: noSociodemographics: not stated Inclusion criteria: Children in grades 1 through 6 from 3 South African Gauteng Department of Education (GDE) remedial primary schoolsADHD diagnosis according to DSM‐IV‐TRExclusion criteria: Children taking medications other than methylphenidate |
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: not knownAdministration schedule: twice daily, morning and lunchtimeDuration of intervention: 1 day Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Parental questionnaire: formulated by the authors and rated at 2 time points during the day, between 1:00 pm and 3:00 pm and between 5:00 pm and 7:00 pm. Included the child's sleep habits, sleep patterns, total sleep time, sleep latency, night time arousals, daytime naps and comments regarding daytime sleepiness in the children from appropriate adults, as well as symptoms and signs of the common sleep disorders as delineated in the DSM‐IV. It also included a visual analogue scale anchored at 'not at all sleepy' to 'very sleepy' on which the parents were requested to rate their children's general levels of sleepiness Wits Faces Sleepiness: a subjective, pictorial scale designed specifically for children which consists of 5 cartoon faces depicting increasing levels of sleepiness. Rated at 8:30 am and 1:00 pm |
Notes | Sample calculation: not statedEthics approval: approved by the Committee for Research on Human Subjects of the University of WitwatersrandVested interest/funding/authors' affiliations: not stated Key conclusions of the study authors: in a group of children with ADHD taking methylphenidate, there was a significant increase in sleepiness a few hours after taking the medication, which may then have a significant impact on their learning. The data also imply that part of the mechanism of action of methylphenidate effects in these children may be by reduction of daytime sleepiness Comments from the study authors: it is highly recommended that school‐aged children diagnosed with ADHD be routinely screened for daytime sleepiness. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding IQ, duration of study and methylphenidate dosage received through personal email correspondence with the authors in October 2013 and January 2014 (Cockcroft 2014 [pers comm]) |
Cohen 1992
Methods | 2 patient reports on fixed drug eruption of the scrotum due to methylphenidate treatment |
Participants | Number of participants: 2Diagnosis of ADD: DSMAge: 8 and 10 years oldIQ: > 80Sex: maleEthnicity: unknownCountry: IsraelComorbidity: unknownComedication: none Sociodemographics: unknown |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mgAdministration schedule: once dailyDuration of intervention: case 1: 5 days. Case 2: 7 days Treatment compliance: unknown |
Outcomes | Non‐serious adverse effects:Fixed drug eruption (FXD) (a term used to describe a sharply localised dermatitis that characteristically recurs at the same site each time the offending drug is administered) Case 1 5 days of methylphenidate treatment: hospitalisation due to 2 days of severe swelling and redness of the scrotum. The skin eruption resolved spontaneously 4 days after methylphenidate was discontinued. 2 weeks later, 18 hour after methylphenidate retrial, the same skin eruption of the scrotum was documented. Discontinued once again, and followed by a complete resolution of the rash after 4 daysCase 2 7 days of methylphenidate treatment: 6 hours of severe swelling and redness of the scrotum. Discontinuation of methylphenidate was followed by a complete resolution of rash after 3 days. Re‐challenge with methylphenidate 2 months later was followed by the same skin eruption of the scrotum within 2 days. Complete resolution was seen after drug withdrawal |
Notes | Key conclusions of the study authors: fixed drug rash induced by methylphenidate is a possible but rare phenomenon. Because this drug is prescribed so often, it is important for physicians to be familiar with this phenomenon Supplemental information regarding ADHD diagnosis and IQ received through personal email correspondence with first author in July 2013 (Cohen 2013 [pers comm]) |
Coignoux 2009
Methods | A patient report of ADHD and schizophrenia during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: hyperactive‐impulsive)Age: 14 years oldIQ: 135Sex: maleEthnicity: whiteCountry: FranceComorbidity: schizotypal personality disorder, infantile psychosis with schizophrenia, OD, CDDComedication: risperidone Sociodemographics: high cultural level |
Interventions | Methylphenidate type: extended releaseMethylphenidate dosage: 54 mg/dayAdministration schedule: once daily, morningDuration of treatment: 2 years Treatment compliance: not stated |
Outcomes | Serious adverse events: Development of gestural stereotypes and verbal aggressiveness towards his parents on methylphenidate treatment. After 6 months 4 mg risperidone is introduced. He improves, gets a less vindictive attitude but there remains some ritualised obsessive, defensive behaviour. His IQ has dropped 20 points |
Notes | Funding/vested interest: noneAuthors' affiliations: none Key conclusions of the study authors: this study revealed the limits of category‐based approach and international classifications as they do not express clinical singularities or possible neurobiological continuums. It also seems to confirm the possible risk of emergence of a psychosis for schizotypal participants, due to pharmaceutical induction by psychostimulants (methylphenidate). This emergence could be stopped by a combined antipsychotic treatment Comments from the study authors: in our case, the cognitive exploration was not precise enough to conclude, but emphasize that the negative development of IQ in the patient illustrates quite well the assumption of risk of change in adolescents with a significant and sharp decline in IQ to a psychotic disorder in adulthood Comments from the review authors: the authors state that methylphenidate might have induced the psychosis ‐ and therefore the patient report is included despite polypharmacy |
Confino‐Cohen 2005
Methods | A patient report of pruritic maculopapular skin rash developing during methylphenidate treatment. The rash improved with antihistamines, and re‐challenge at a lower dose caused the reappearance of the rash, though less severe. Desensitisation through graded exposure of methylphenidate in incremental doses prevented further rash development |
Participants | Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: 8 years oldIQ: normal IQSex: femaleEthnicity: IsraeliCountry: IsraelComorbidity: not statedComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: RitalinMethylphenidate dosage: 10 mgAdministration schedule: once dailyDuration of treatment: 1 week Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: After a week on 10 mg Ritalin the patient developed pruritic maculopapular skin rash over the back of her hands, which spread to face, chest, abdomen, and legs within the next 2 days. Ritalin was discontinued and antihistamine treatment was initiated, and the symptoms disappeared after a week. Re‐challenge with 5 mg Ritalin was attempted. 2 days later the same itchy rash appeared on her face and chest. Ritalin was once again discontinued and the symptoms disappeared after 2 days. A desensitisation protocol was follow over 10 days with 10 mg RItalin on the 10th day. No further adverse events were noticed |
Notes | Funding/vested interest: not statedAuthors' affiliations: not stated Key conclusions of the study authors: allergy to methylphenidate is rare. Whenever feasible, an alternate drug should be used if a reaction to the drug occurs. When an alternative is not available or the offending drug is still the best available choice, desensitisation should be considered (for mild rather than life‐threatening conditions/reactions) Comments from the study authors: from 4 months onwards, the patient had not taken medication at weekends (1‐2 days) or holidays with no adverse reaction on readministration of the drug Supplemental information regarding IQ and diagnostic criteria received through personal email correspondence with the authors in November 2013 (Confino‐Cohen 2013 [pers comm]) |
Congologlu 2009
Methods | A cohort study of voice recordings before and after methylphenidate use |
Participants | Number of patients screened: not statedNumber included: 22Number followed up: 22Number of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: combined 100%)Age: mean 9.05 (SD 1.43) years (range 7‐12)IQ: not statedSex: 22 malesMethylpenidate‐naïve: noneEthnicity: TurkishCountry: TurkeyComorbidity: noComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 0.5 mg/kg 1 hour before recording voice sampleMean MPH dosage: not statedDuration of intervention: single voice measurement after single dose of methylphenidate Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Speech samples using Multi Dimensional Voice Program (MDVP) Model 5105 Version 2.3 of the Computerized Speech, developed by Kay ElemetricsSpeech recordings for acoustic analysis were made from the participants in 2 sessions held before noon: no‐medication baseline session and the medication session after methylphenidate administration of 0.5 mg/kg (approximately 60 minutes later) We have not used these data |
Notes | Ethics approval: the study was approved by the Human Subject Review Committee at the Gülhane Military Medical AcademyFunding/vested interest/authors' affiliations: not statedAny withdrawals due to adverse events: no Key conclusions of the study authors: this clinical trial is the only study that examined the effects of stimulant medication on vocal acoustic parameters in children with ADHD and evaluated a small sample on and off their clinical doses of methylphenidate. We suggest that methylphenidate decreases fundamental frequency in children with ADHD, but our findings should be replicated under blind drug administration and by supporting other vocal analyses Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Corrigall 1996
Methods | A patient report of euphoria induced by methylphenidate in an 11‐year‐old boy diagnosed with hyperkinetic disorder |
Participants | Diagnosis of ADHD: ICD‐10 hyperkinetic disorderAge: 11 years oldIQ: no intellectual disabilitySex: maleEthnicity: not statedCountry: UKComorbidity: not statedComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate 10 mg/day for 4 weeks and then increased to 15 mg/day for 5 daysAdministration schedule: not statedDuration of treatment: 6 weeks Treatment compliance: abuse |
Outcomes | Non‐serious adverse events: Methylphenidate induced euphoria on 15 mg/day. Symptoms discontinued after methylphenidate was withdrawn |
Notes | Ethics approval: not statedFunding/vested interests: not statedAuthors' affiliations: Maudsley Hospital, London Key conclusions of the study authors: euphoria induced by methylphenidate can occur in young prepubertal children and this may lead to abuse of medication Supplemental information regarding the boys' intellectual functioning received through personal email correspondence with the authors in October 2013 (Corrigall 2013 [pers comm]) |
Cortese 2015
Methods | A cohort study using the Italian national ADHD registry of methylphenidate use from June 2007 to December 2012 |
Participants | Number of patients screened: 2411Number included in methylphenidate group: 1426Number followed up in methylphenidate group: 1414Number of withdrawals in methylphenidate group: 12Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (86.0%), hyperactive‐impulsive (2.5%), inattentive (11.6%))Age: mean: 10.55 (SD: 2.75) years old (range: 6‐18)IQ: not knownSex: 1247 (87.4%) males, 179 (12.6%) femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: ItalyComorbidity: oppositional defiant disorder (34.4%), conduct disorder (4.2%), depression (3.6%), anxiety (11.1%), learning disorder (35.9%)Comedication: not statedSociodemographics: not stated Inclusion criteria: Participants were children/adolescents (aged 6‐18 years) included in the Italian National ADHD Registry from June 2007 to December 2012.The diagnosis of ADHD was based on DSM‐IV‐TRExclusion criteria: Given the naturalistic design, no a priori exclusion criteria were applied |
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 0.3‐0.6 mg/kg/dose/dayMean methylphenidate dosage: 18.3 mg/dayAdministration schedule: 2‐3 times a dayDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Serious adverse events:Adverse events were classified as severe if their occurrence was followed by active notification by clinical centres to the Italian Medicines Agency; otherwise, they were labelled as mild. The Italian Medicines Agency requires active notification when an adverse event results in death, is life‐threatening, requires hospitalisation or prolongation of existing inpatients' hospitalisation, results in persistent or significant disability or incapacity, or leads to a congenital anomaly or birth defect Non‐serious adverse events: Data regarding adverse events are collected via a structured form, located in a restricted area of the website of the Italian ADHD registry (available upon request), which allows standardisation of the procedure across centres. Information about the following adverse events is collected via the aforementioned structured form: cardiovascular risk, hepatic toxicity, any neurological disorder, any psychiatric symptomatology, acute diseases of the skin, and any clinically relevant gastrointestinal events |
Notes | Sample calculation: noEthics approval: yesFunding/vested interest/authors' affiliations: Prof Curatolo has received honoraria from Shire for participation in Advisory Board Meetings. Drs. Cortese, Panei, Arcieri, Germinaro, Capuano, Margari, and Chiarotti declare no competing interests Key conclusions of the study authors: our naturalistic postmarketing phase IV pharmacovigilance observational study showed that while mild and severe adverse events were observed in children treated with methylphenidate and in those treated with atomoxetine, those who received atomoxetine were significantly more likely to experience adverse events Comments from the study authors; the results should be considered in light of the study limitations. This was not a randomised study, and data on adverse events were not available for all participants at follow‐up visits following the baseline assessment and treatment assignment. Our study could not be informative with regard to adverse events occurring with extended‐release formulations of methylphenidate or with other class of ADHD drugs. Average dose of methylphenidate were rather low for usual standards of treatment, the naturalistic design did not allow assessment of whether children were adequately titrated for either medications. Data on validity and reliability of measures across centres are not available, and the study did not include a control group of healthy participants Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding IQ received through personal email correspondence with the authors in June 2016 (Panei 2016 [pers comm]) |
Coşkun 2008
Methods | A patient report of tactile and visual hallucinations with the combination of OROS methylphenidate and fluoxetine |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 10 years oldIQ: intellectual capacity within normal rangeSex: maleEthnicity: TurkishCountry: TurkeyComorbidity: oppositional defiant disorder, generalised and separation anxiety disordersComedication: fluoxetine 10 mg/dayMPH‐naïve: yes Sociodemographics: not stated |
Interventions | OROS MPH 18 mg/day, comedication: fluoxetine, 10 mg/dayOROS MPH 18 mg/day monotherapy, 2 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Tactile and visual hallucinations. Worsening of previous sleep disturbance and decreased appetite |
Notes | Funding/vested interests: the authors have no conflict of interest with any commercial or other associations, and no financial ties to disclose in connection with the submitted article Key conclusions of the study authors: here we report a paediatric patient who developed tactile and visual hallucinations with the combination of OROS methylphenidate and fluoxetine Comments from the study authors: in conclusion, we think that the causative agent was the combination of both medications rather than either medication alone. However, in either situation, it is important to note that this distressing side effect may occur even in the absence of underlying psychotic or substance‐related disorders, and clinicians' awareness is important in this issue, particularly in cases where polypharmacy is considered Supplemental information regarding ADHD diagnostic criteria, subtype of ADHD and ethnicity received through personal email correspondence with the authors in August 2013 (Coşkun 2013 [pers comm]) |
Coşkun 2009a
Methods | A patient report of decreased appetite during immediate‐release methylphenidate treatment and maculopapular pruritic skin eruptions during OROS‐methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 8 years oldIQ: > 70Sex: maleEthnicity: not statedCountry: TurkeyComorbidity: EEG abnormalitiesComedication: valproate, gabapentin Sociodemographics: not stated |
Interventions | Immediate release methylphenidate 10‐20 mg/day for 2 monthsTreatment compliance: reported forgetting to take his medication sometimesOROS methylphenidate 18 mg/day for 1 week and 9 days Treament compliance: not stated |
Outcomes | Non‐serious adverse events:Immediate release methylphenidate 10‐20 mg/day and valproate 400 mg/day: decreased appetite, no weight decreaseOROS‐methylphenidate 18 mg/day and valproate 400 mg/day: maculopapular pruritic skin eruptions on the patient's neck, arms, and legs, 1 week after starting OROS methylphenidate treatmentOROS‐methylphenidate free period for 5 weeks: skin lesions were almost healedRe‐administering of OROS‐methylphenidate 18 mg/day and gabapentin 300 mg/day: same skin eruptions with same severity, 9 days after starting OROS‐methylphenidate treatment againDiscontinuation of medication: skin lesions abated within the next several weeks Restart of immediate release methylphenidate 10‐20 mg/day and gabapentin 300 mg/day, 4 months: no skin eruptions |
Notes | Funding/vested interests: the authors report no conflicts of interest or ties Key conclusions of study authors: the patient reported AEs with OROS MPH on 2 different occasions, but no AE with IR MPH at 2 different trials. Emergence of AE with OROS MPH and disappearance with discontinuation at both trials may suggest enough causality between AE and OROS MPH treatment Comments from the review authors: unclear whether the authors believe methylphenidate caused the adverse events |
Coşkun 2009b
Methods | 2 patient reports of sexual side effects during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: 50% combined, 50% unknown)Age: 15 and 8 years oldIQ: > 70Sex: 2 malesEthnicity: TurkishCountry: TurkeyComorbidity: borderline mental capacity: 50%Comedication: unknown Sociodemographics: unknown |
Interventions | Case 1Immediate release methylphenidate: 10‐30 mg/day in a divided dosage, 1 month. Treatment compliance: lowOsmotic release oral system methylphenidate: 18 mg/day, 1 month. Treatment compliance: unknownOsmotic release oral system methylphenidate: 36 mg/day, 3 weeks. Treatment compliance: unknown Case 2 Osmotic release oral system methylphenidate: 18 mg/day, 10 days. Treatment compliance: unknownImmediate release methylphenidate: 10‐20 mg/day, 3 weeks. Treatment compliance: unknownOsmotic release oral system methylphenidate: 18 mg/day. Treatment compliance: unknown |
Outcomes | Non‐serious adverse events: Case 1Immediate release methylphenidate, 10‐30 mg/day: initial headache and nauseaOsmotic release oral system methylphenidate, 18 mg/day: emotional side effects (sense of nervousness in the chest, occasional emotional numbing), multiple daily erections (unrelated to sexual stimuli, painless, without ejaculations, onset: a few hours after ingestion of methylphenidate, duration: 5‐10 minutes)Medication‐free period, 1 week: no erections unrelated to sexual stimuliRe‐administering of osmotic release oral system methylphenidate, 36 mg/day, 3 weeks: reemerging of erections, longer duration compared with osmotic release oral system‐methylphenidate 18 mg/day. Headache. Nausea. Same emotional side effects. Drug‐free days: no erectionsDiscontinuation of medication: no erections Case 2 Osmotic release oral system methylphenidate, 18 mg/day: loss of appetite, headache, abdominal pain, sleep problems, and conjunctival injection. Headache and abdominal pain almost disappeared after 1 week. Hypersexual behaviours. Morning erections before ingestion of methylphenidate, duration: 1 hour. Weight loss: 1.5 kg within 2 months. Drug‐free days: almost no hypersexual behaviour during the day and no erection the following morningImmediate release methylphenidate, 10‐20 mg/day: morning erections and hypersexual behaviours decreased dramatically. Sleep and appetite problems improved mildly. No conjunctival injection (after 3 weeks). Possible withdrawal symptoms (increased irritability and hyperactivity, getting tearful easily), several hours after each dosageOsmotic release oral system methylphenidate, 18 mg/day: next‐morning erections, hypersexual behaviour during the day. Drug‐free days: almost no hypersexual behaviourOsmotic release oral system methylphenidate, 18 mg/day, 6:00 am: no morning erections, but still hypersexual behaviour. Sleep and appetite problems. Conjunctival injections. Sense of pins and needles in his legs after 10 daysDiscontinuation of osmotic release oral system methylphenidate: no morning erections or hypersexual behaviours |
Notes | Funding: no financial ties or conflicts of interest Supplemental information was received through personal email correspondence with the authors in August 2013 (Coşkun 2013b [pers comm]) |
Coşkun 2010
Methods | Cohort study of methylphenidate treatment in participants with ADHD and comorbid anxiety‐ or depressive disorders |
Participants | Number of participants screened: not statedNumber of participants included: 7Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: combined (57%), inattentive (43%))Age: mean 11.85 (SD 2.91), range: 8‐16 years oldIQ: normalSex: 4 males, 3 femalesMethylphenidate‐naïve: noneEthnicity: TurkishCountry: TurkeyComorbidity: generalised anxiety (86%), social anxiety (86%), panic (29%), separation anxiety (29%), obsessive‐compulsive (29%) and major depressive disorder (14%), special phobia (29%) and agoraphobia (14%)Comedication: SSRIs (57%)Sociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type and dosage: immediate release (15‐20 mg/day), osmotic release oral system (18‐54 mg/day), IR/OROS (10‐18 mg)Administration schedule: not statedDuration of intervention: 4‐30 months, mean 14.28 (SD 9.41) Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:
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Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: the authors reported no conflict of interest related to this article Key conclusions of the study authors: young participants with diagnosis of ADHD and comorbid anxiety and depressive disorders may benefit from mirtazepine addition particularly in the presence of methylphenidate‐ or SSRI‐related sleep and/or appetite problems Comments from the review authors: the adverse events reported here are from before the start of the mirtazepine treatment which means the participants are under no treatment but methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information received through personal email correspondence with the authors in August 2013 (Coşkun 2013c [pers comm]) |
Coşkun 2011
Methods | A patient report of obsessive‐compulsive symptoms during methylphenidate treatment |
Participants | Diagnosis of ADHD: unknown (subtype: combined)Age: 10 years oldIQ: normalSex: femaleEthnicity: TurkishCountry: TurkeyComorbidity: subsyndromal social and generalised anxiety disordersComedication: unknown Sociodemographics: unknown |
Interventions | Osmotic release oral system methylphenidate, 18 mg/day, 1 yearTreatment compliance: unknownOsmotic release oral system methylphenidate, 27 mg/day, 3 + 3 weeks Treatment compliance: unknown |
Outcomes | Non‐serious adverse events:Osmotic release oral system methylphenidate, 18 mg/day: decreased appetite and initial headacheOsmotic release oral system methylphenidate, 27 mg/day: obsessive‐compulsive symptoms, decreased appetite, facial grimace, nail picking/bitingDiscontinuation of medication: gradually disappearance of symptoms, still subsyndromal obsessive‐compulsive symptoms Re‐administering of osmotic release oral system methylphenidate, 27 mg/day: mild facial grimace, similar obsessive‐compulsive symptoms. After 3 weeks: Children's Yale‐Brown Obsessive‐Compulsive Scale (CY‐BOCS), total score = 21 |
Notes | Key conclusions of the study authors: clinicians treating children should be familiar with the emergence and management of these unusual side effects Supplemental information was received through personal email correspondence with the authors in August 2013 (Coşkun 2013d [pers comm]) |
Davari‐Ashtiani 2010
Methods | A 6‐week randomised, parallel, double‐blind clinical trial with 2 arms: |
Participants | Number of participants screened: not statedNumber of participants included: 34Number of participants randomised to methylphenidate: 16Number of participants followed up: 16Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (100%))Age: mean 8.62, range 6‐12 years oldIQ: normalSex: not statedMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: IranComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: initiated at 0.5 mg/kg/day and adjusted to the optimal effect. Maximum dose: 60 mg/day. Range: 0.3‐1 mg/kg/dayAdministration schedule: not statedDuration of intervention: 6 weeksDuration of titration period: not stated Treatment compliance: not stated |
Outcomes | Serious adverse events:No serious adverse drug effects were observed during the trial Non‐serious adverse events Possible side effects were systematically recorded throughout the study and assessed using a checklist administered by a child psychiatrist on weeks 2, 4, 6Decreased appetite (n = 11), decreased sleep (n = 7) |
Notes | Sample calculation: statistical power calculated on the basis of the projected group size, a response rate of 30% and an alpha level of 0.05.Ethics approval: yes, approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences (Tehran, Iran).Funding/vested interests: this work was supported in part by the grant from the Behavioral Sciences Research Center of Shahid Beheshti University of Medical Sciences (Tehran, Iran) Key conclusions of the study authors: no significant differences were observed between the 2 protocols on the total scores of parent and teacher ADHD Rating Scale, but methylphenidate was superior to buspirone in decreasing the symptoms of inattention. The side effects of buspirone were mild and rare in comparison with methylphenidate Comments from the study authors:main limitations: small sample size, minimal dosage necessary for response and duration of treatment. The effect of buspirone on different DSM‐IV subtypes of the disorder was not explored Comments from the review authors: the article in Farsi presents the preliminary results, and the article in English presents the final results. Therefore, the data reported in the Farsi article are not used in our review Supplemental information received through personal email correspondence with the study authors in January 2014 (Davari‐Ashtiani 2014 [pers comm]) |
Delignieres 2011
Methods | A before‐after study comparing 21 children with epilepsy and ADHD with 21 ADHD‐only children using a short 'attentional capture test' after being given methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 21 epilepsy + ADHD and 21 ADHD onlyNumber of participants followed up: 21 in each groupNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: range: 6‐13 years oldIQ: not statedSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: FranceComorbidity: epilepsyComedication: anti‐epileptic drugsSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate given to children in a before‐after trial, comparing 2 groups and evaluated by an attentional capture paradigmMethylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Safety issue reported in abstract |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: not statedEthics approval: not statedFunding/vested interest: not statedAuthors' affiliations: not stated Key conclusions of the study authors: methylphenidate is safe and effective in children with epilepsy and ADHD Comments from the review authors: the authors state that methylphenidate is safe and effective in children with epilepsy and ADHD, but this seems to be a general statement rather than a conclusion from their findings. No data are presented in the abstract to support either conclusions on the safety or on the efficacy of methylphenidate in epilepsy and/ or ADHD Supplemental information and full text article requested through email correspondence with the authors in June and November 2013. No reply |
Dirksen 2002
Methods | A multicentre, open‐label, cohort study of the effectiveness and tolerability of an extended release methylphenidate in treated and untreated children and adolescents with ADHD over 3 weeks |
Participants | Number of participants screened: 332Number of participants included: 310Number of participants initiating treatment: 308Number of participants followed up: 287Number of withdrawals: 23Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 11.0, range 6‐17 years oldIQ: > 80Sex: 222 males (72.1%), 86 females (27.9%)Methylphenidate‐naïve: 41%Ethnicity: white (82.1%), African American (10.4%), others: (7.5%)Country: USAComorbidity: noneComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: extended release methylphenidate hydrochloride (Metadate CD)Methylphenidate dosage: 20‐60 mgAdministration schedule: once daily, in the morning before breakfastDuration of intervention: 3 weeksTreatment compliance: not stated Dosage was titrated on a weekly basis according to clinical judgement |
Outcomes | Safety and tolerability were assessed by laboratory tests, vital signs and adverse events collected through spontaneous reports by parents, general questioning of the child, and investigators' observations. Assessed at 3 study visits with 7 days apart Adverse event data were collected as pre‐study events (to assess the presence of pre‐existing symptoms and events) |
Notes | Sample calculation: not statedEthics approval: approved by the Institutional Review Boards at each study centreFunding: Celltech Americas Inc.Vested interest/authors' affiliations: 3 of the 4 authors were employed by Celltech Americas Inc. Key conclusions of the study authors: methylphenidate hydrochloride is effective and well‐tolerated for clinical use in ADHD Comments from the study authors: the absence of a placebo control group makes it difficult to determine whether there was bias in evaluating effectiveness or relatedness of adverse events Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental data requested through personal email correspondence with the study authors with in March 2014. No reply |
Dittmann 2014
Methods | An observational prospective cohort study of methylphenidate use for 12 months |
Participants | Number of participants screened: not statedNumber of participants included: 247 in stimulant group (short‐ or long‐acting methylphenidate)Number of participants followed up: 191Number of withdrawals: 56.
Diagnosis of ADHD: ICD‐10 (subtype: F90.0 (74.9%), F90.8 (0.8%), F98.8 (8.9%)). DSM‐IV (subtype: combined (8.1%), inattentive (4.9%), hyperactive/impulsive (2.0%), combined and ODD (0.4%))
Age: mean: 9.3 (SD 2.4) years (range 6‐16)
IQ: low IQ (70‐84) 19 (7.7%), normal IQ (85‐114) 197 (79.8%), high IQ (115‐129) 29 (11.7%), very high IQ (> 129) 2 (0.8%)Sex: 179 males, 68 femalesMethylphenidate‐naïve: 100%
Ethnicity: not statedCountry: Germany
Comorbidity: conduct disorder (14.6%), ODD (13%), anxiety disorder (5.7%), depression (4.9%), tic disorder/Tourette (4.1%), other (10.1%))Comedication: 239 (96.8%) received no concomitant medication
Sociodemographics: nuclear family (66.8%), 1 biological parent, 1 step‐parent (13.8%), single mother (13.8%), foster parents (0.4%), adoptive parents (1.2%), single father (0.8%), supervised living arrangement (0.8%), family members other than parents (1.2%), unknown (1.2%) Inclusion criteria
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Interventions | Methylphenidate type: anyMean methylphenidate dosage: 0.37 (SD 0.23) mg/kgAdministration schedule: not statedDuration of intervention: 12 months Treatment compliance: 178 (74.2%) had a PCSR (Pediatric Compliance Self‐Rating instrument) score ≥ 5 at every visit |
Outcomes | Adverse events were analysed for patients on initial monotherapy only Adverse effects were rated at baseline, end of week 1, 2, months 1, 3, 6, 9, and 12 |
Notes | Sample calculation: not statedEthics approval: the study was approved by the responsible Ethics Committee (ERBat Medical Faculty Mannheim, University of Heidelberg, Germany)Funding: research was funded by Lilly DeutschlandGmbH, Bad Homburg, Germany, and by Eli Lilly & Co., Indianapolis, USA
Vested interests/authors' affiliations: not stated Key conclusions of the study authors: all outcome parameters (effectiveness) considered in this open‐label, non‐interventional trial with respect to ADHD core symptoms, ADHD‐related difficulties, and emotional expression significantly improved over time in children and adolescents with ADHD who were treated with pharmacotherapy (i.e. atomoxetine or psychostimulants) in a naturalistic setting with regard to their degree and time course, which corresponds with the well‐established findings from double‐blind controlled clinical trials Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Dodangi 2011
Methods | A 6 ‐week parallel trial with 2 arms:
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Participants | Number of participants screened: 34Number of participants included: 34Number of participants randomised to methylphenidate: not statedNumber of participants followed up: 15 in the methylphenidate groupNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: range 11‐18 years oldIQ: not statedSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: IranComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria Not stated |
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Children Depressive Inventory (CDI) measured at the end of the trialRevised Children's Manifest Anxiety Scale (RCMAS) at the end of the trial Drug side effects evaluated each 2 weeks during the study |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: yes, 3 gastrointestinal symptoms and 1 maniaEthics approval: not statedFunding/vested interests: not stated Key conclusions of the study authors: our study showed that duloxetine may be as effective as methylphenidate in treatment of ADHD in adolescents. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information regarding side effects received from the author in November 2013 (Dodangi 2013 [pers comm]) |
Dubnov‐Raz 2011
Methods | A case‐control study of 17 months of methylphenidate treatment using a chart review of computerised medical records |
Participants | Number of participants screened: 529Number of participants included: 275Number included as cases: 135 (methylphenidate treated) and controls: 140 (untreated)Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean 10.4 years old, range 6‐16IQ: > 70Sex: 200 males, 75 femalesMethylphenidate‐naïve: cases (none), controls (100%)Ethnicity: multiethnicCountry: IsraelComorbidity: noneComedication: noneSociodemographics: a variety of different family patterns and socioeconomic status among the groups. Those who were already methylphenidate treated were 7 months older, on average, than the methylphenidate‐naïve patients, and they had a higher proportion of males. Weight, height, and body mass index z scores, which inherently correct for age and sex, did not differ significantly between these 2 subgroups. Rates of overweight and obesity were also comparable Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: regular (n = 52), slow‐release/long‐acting (n = 61), or osmotic release oral system (n = 22)Baseline methylphenidate mean dose: 0.43 mg/kg (SD 0.22), range: 0.1‐1.0 mg/kg (each 4.5 mg of osmotic release was regarded as 1 mg methylphenidate)Administration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Height and weight measured by a certified nurse at baseline and follow‐up visits Body mass index |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interests: the authors received no financial support for the research and/or authorship of this article Key conclusions of the study authors: physicians should be aware of the possibility of height and weight abnormalities in children with ADHD, with or without treatment Comments from the review authors: only the data on the methylphenidate‐treated and untreated participants with ADHD are used in this review Supplemental information requested from the authors in July 2013, but they did not have the time to find the relevant information |
Dupuy 2008
Methods | A controlled before‐after study investigating the effects of stimulants on EEG coherence in girls with ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 9Number of participants followed up: 9Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: combined or Inattentive)Age: range 7‐12 years oldIQ: > 85Sex: femaleMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: AustraliaComorbidity: noneComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: 6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: If participants experienced any problems with their medication, parent(s) were asked to contact their doctor, their medication was changed, and they were removed from the study; this did not occur with these participants |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: noneEthics approval: Illawarra area health/University of Wollongong Human Research Ethics CommitteeFunding/vested interest: not statedAuthors' affiliations: Brain & Behaviour Research Institute and School of Psychology, University of Wollongong, Australia Sydney Developmental Clinic, Australia Key conclusions of the study authors: intrahemispheric and interhemispheric coherences in ADHD stimulant medicated girls. Girls had elevated frontal coherence across all frequency bands Comments from the review authors: only children who had a positive response on stimulants were included in the study. We can only use this study qualitatively and not in the analyses. Exclusion of MPH non‐responders/children who have previously experienced adverse events on MPH: no |
Durá‐Travé 2012
Methods | A 4‐year cohort study examining OROS‐methylphenidate effects on growth conducted as a review of random medical records |
Participants | Number of participants screened: not statedNumber of participants included: 187Number of participants followed up: 160Number of withdrawals: 27Diagnosis of ADHD: DSM‐IV‐R (subtype: combined (84.5%), inattentive (15.5%))Age: mean at time of diagnosis: 8.14, range: 6‐10 years oldIQ: not statedSex: 129 males, 58 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: SpainComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: sustained release, osmotic release oral systemMethylphenidate dose: at baseline 0.89 mg/kg/day, gradually increased to 1.31 mg/kg/day at 48 monthsAdministration schedule: once dailyDuration of intervention: 48 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Height, weight, and BMI measured at baseline (time of ADHD diagnosis and start of methylphenidate treatment), 6, 12, 18, 24, 30, 36, 42, and 48 months. Weight and height measurements were taken with patients wearing only underwear and no shoes, precision of 100 g and 0.1 cm. The growth charts and data tables of the Centro Andrea Prader (Zaragoza, Spain, 2002) were used as standard references |
Notes | Sample calculation: noAny withdrawals due to adverse events: not statedEthics approval: the study was approved by the Ethics Committee of the Navarra Hospital Complex, Pamplona, SpainFunding: the authors received no financial support for the research, authorship, and/or publication of this articleVested interests/authors' affiliations: the authors declared no potential conflicts of interest Key conclusions of the study authors: at the time the participants were diagnosed with ADHD, 1 out of every 3 patients was in a deficient nutritional situation (subnutrition or malnutrition). Continued treatment with OROS‐methylphenidate for 30 months had a negative influence on height and weight. However, we observed a recovery of anthropometric variables from the 30th to the 48th month of OROS‐methylphenidate treatment (growth‐rebound); this means that the effects of stimulant drugs, and specifically methylphenidate, on the growth curve would be a transitory condition that attenuates as time passes. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding IQ requested through personal email correspondence with the study authors with no reply |
Döpfner 2011a, OBSEER
Methods | The OBSEER study (Observation of Safety and Effectiveness of Equsym XL in Routine Care). A non‐interventional, non‐controlled, multicentre, prospective, observational, postmarketing surveillance study |
Participants | Number of participants screened: 852Number of participants included: 822Number of participants followed up: 777 (completed all 3 planned visits)Number of withdrawals: 45Diagnosis of ADHD: ICD‐10; F90.0 430 (55.41%), F90.1 282 (36.34%), F90.8 64 (8.25%)Age: mean 10.04 (SD 2.47) years (range 6‐17)IQ: above 70Sex: 663 males (81.25%), 153 females (18.75%)Methylphenidate‐naïve: 30.17%Ethnicity: not statedCountry: GermanyComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: once‐daily modified‐release methylphenidate, Equasym XL (30% immediate‐release‐ and 70% modified‐release methylphenidate)Methylphenidate dosage: 10 mg ‐ 120 mg, maximum recommended daily dose (60 mg/day) exceeded in 6 patientsAdministration schedule: once dailyDuration of intervention: 5 days to 12 months (mean 2.26 months) Treatment compliance: not stated |
Outcomes | Adverse events (AEs) were evaluated by the treating physician at each study visit, and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 11.1 and classified into AEs and serious AEs (death, life‐threatening conditions, hospitalisation or prolongation of hospitalisation, persistent injury/disability, incapacity for work, medically significant conditions and congenital abnormalities/birth defects) DAYAS (The Daily Profile of ADHD Symptoms) completed by teacher and parents at each visit |
Notes | Sample calculation: yesEthics approval: no approval was needed for this studyFunding/vested interests/authors' affiliations: the study was funded by UCB and the article (Döpfner 2011) is part of a supplement sponsored Shire Development Inc. Key conclusions from study authors: this open‐label, observational, post‐marketing surveillance study investigates the effectiveness and safety of Equasym XL which is a combination of 30% immediate‐release MPH and 70% modified‐release MPH, in the treatment of ADHD in daily clinical practice. The effectiveness of Equasym XL was rated better than prior or no therapy and generally well tolerated Comments from study authors: limitations on the study: open‐label, no control group: therefore, physicians and parents were not blinded to the study treatment or doseSome of the participants were previously treated with stimulants, therefore the results from this group can only be generalised to a population in which a switch to Equasym XL is planned due to suboptimal effects of the prior medication. This was an open‐label study with no control group, only data on adverse events are therefore extracted Supplemental information regarding data were attempted to retrieve from the authors by email. Sent twice, no answer |
Döpfner 2011b
Methods | A randomised, controlled, double‐blind, multicentre clinical cross‐over trial with 2 modified release methylphenidate interventions: |
Participants | Number of participants screened: 122Number of participants included: 113Number of participants followed up: 91Number of withdrawals: 22Diagnosis of ADHD: ICD‐10 diagnosis of hyperkinetic disorder. 61% had a subtype corresponding to DSM‐IV ADHD combined subtypeAge: regarding the 113 included: mean: 10.2, range 6.0‐17.11 yearsIQ: 99.2 (SD 9.7)Sex: 86 males, 27 femalesMethylphenidate‐naïve: 0%Ethnicity: not statedCountry: GermanyComorbidity: oppositional defiant disorder or conduct disorder (36%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: Medikinet (equal proportions of immediate‐ and slow‐release methylphenidate) and Concerta (immediate‐release and OROS‐methylphenidate)Methylphenidate dosage: participants were randomly assigned to 1 of 6 possible sequence combinationsEach patient received the following treatments in a sequence:Lower doses: Medikinet Retard 20 mg (10 mg immediate release) or 10 mg (5 mg immediate release)Lower doses: Concerta: 18 mg (4 mg immediate release)High dose: Medikinet Retard: 30 mg (15 mg immediate release) or 20 mg (10 mg immediate release)High dose: Concerta 36 mg (8 mg immediate release)Administration schedule: once dailyDuration of each medication condition: 1 week per treatment, 3 weeks in total Treatment compliance: the compliance was more than 99% |
Outcomes | Non‐serious adverse events:Both doctors, teacher and parents documented side effects weeklyThe DAY profile of ADHD Symptoms (DAYAS): potential adverse effects of ADHD medication were assessed by parents with 11 items for the whole week. Additionally, potential adverse effects of ADHD medication are assessed by teachers with 9 items for the whole week. Here the ratings from teachers and parents were obtained at the end of the week (Thursdays or Fridays) to provide a comprehensive assessment of the week and to avoid the possible impact of carry‐over treatment effectsFurthermore, from the final report from Medice: all AE were coded according to MedDRA. The onset of the event was significant for assignment of the AE to 1 of the treatment groups (dose group/pharmaceutical form). If an event lasted over several treatment groups it was only evaluated for the treatment group in which it first appearedBlood pressure, rated weekly by investigator Heart rate, rated weekly by investigator |
Notes | Sample calculation: yesEthics approval: yesFunding/vested interests/authors' affiliations: Manfred Döpfner is currently a consultant for Medice, Shire Pharmaceutical, and Eli Lilly; has in the last 3 years received grant funding from UCB‐Pharma, Medice, and Eli Lilly; has recently served on the advisory boards of Medice, Shire Pharmaceutical, and Eli Lilly; and has spoken at events sponsored by Medice, Shire Pharmaceutical, Eli Lilly, and Janssen Cilag. Claudia Ose is CEO at Center for Clinical Studies at University Hospital Essen Germany. R. Fischer is a full‐time employee of Medice. R. Ammer is Chief Executive Officer of Medice. Andre Scherag currently serves as trial statistician on a data safety and monitoring board for Boehringer Ingelheim KG. The study is funded by Medice Company.Any withdrawals due to adverse events: 4 Key conclusions from study authors: in summary, based on the efficacy and safety data from this trial it can be claimed that Medikinet retard with a higher IR component than Concerta and an equivalent daily dose is superior to Concerta in the morning and that children and adolescents may also be treated with a lower daily dose of Medikinet retard without resulting in a clinically relevant worse effect during school time as assessed by SKAMP‐D. "Since there is no placebo group or no 'no‐intervention' group in the trial, we can only use the data on adverse events. We extract data from this study as if it was an observational study Comments from the study authors: in this study, carry‐over effects are expected to be negligible because of the short half‐life of methylphenidate. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, only participants who responded well to the medication were included Supplemental information regarding final report and protocol received through personal email correspondence with the medical director from Medice in December 2013 (Roland 2013 [pers comm]) |
Döpfner 2011c
Methods | A cohort study of methylphenidate use for 4‐6 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 467Number of participants followed up: 447Number of withdrawals: 20 (excluded in intention‐to‐treat analysis, but included in the tolerability evaluation)Diagnosis of ADHD: 48% ICD‐10 diagnosis of ADHD (subtype: not stated), 42% "hyperkinetic disorders which affected their social behavior" (subtype: not stated)Age: mean: 10.7 (2.5) years (range: 6‐17)IQ: not stated, but half of the children were in primary schoolSex: 361 males, 106 femalesMethylphenidate‐naïve: 14%Ethnicity: not statedCountry: GermanyComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: Medikinet retard (extended release)Mean methylphenidate dosage: 22.6 mg (range: not stated)Administration schedule: once dailyDuration of intervention: 4‐6 weeks Treatment compliance: was assessed by prescribing physician. In 57% of cases there was improved compliance after the medication switch; no change was observed in 39%, and compliance deteriorated in 4% |
Outcomes | Non‐serious adverse events:11 items in the paediatric diagnosis system KIDS assesses potential adverse events of the medication In 79 patients, adverse events were recorded by the physician, and these events were described as severe in 13 cases. The most frequent adverse events were appetite disorders, head‐ and stomachache and sleep disorders |
Notes | Sample calculation: noEthics approval: non‐interventional study pursuant to Section 4 sentence 3 and Section 67 AMG (German Medicines Act)Funding/vested interest/authors' affiliations: Prof Döpfner is employed as a consultant to the following companies and receives research funding from these companies: Janssen‐Cilag, Lilly, Medice, Novartis, Shire, UCB. Dr Fischer is an employee of Medice. Ms Ose is participating in studies which are supported by Medice and UCBAny withdrawals due to adverse events: 10 Key conclusions of the study authors: the overall evidence showed that Medikinet retard was well tolerated in routine clinical practice, can be used effectively to treat symptoms of ADHD, can improve compliance to medication and can contribute to a further improvement in symptoms in previously suboptimally treated patients Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: by implication, since treatment would not be indicated for non‐responders Supplemental information regarding data requested from the authors by email in June 2014. No answer received |
Efron 1997
Methods | A 4‐week double‐blind, cross‐over study with 2 arms:
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Participants | Number of participants screened: not statedNumber of participants included: 125 participants were randomly assigned to 1 of 2 possible drug condition orders (methylphenidate or dexamphetamine)Number of participants followed up: not statedNumber of withdrawals: 4 due to severe adverse events (2 on methylphenidate, 2 on dexamphetamine)Diagnosis of ADHD: DSM‐IV (subtype: combined (81.8%), hyperactive‐impulsive (1.6%), inattentive (17.6%))Age: mean 104.8 (SD 27.6) months (range 60‐179 months)IQ: mean 98.9 (SD 13.8)Sex: 114 males, 11 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: AustraliaComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate dosage: 0.3 mg/kg/dose, rounded off to the nearest capsule sizeAdministration schedule: twice a day, after breakfast and after lunchDuration of intervention: 2 weeks. 24‐hour washout period between interventions Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Barkley Side Effects Rating Scale (SERS): adverse events rated on a scale from 0 (absent) to 9 (severe). The list of side effects were compiled from those commonly reported anecdotally in the literature Parent rated at baseline and the end of each 14 day period |
Notes | Ethics approval: yes. The study protocol was approved by the Ethics in Human Research Committee of the Royal Children's Hospital, Melbourne, Australia, and written informed consent was obtained from parentsFunding: clinical research scholarship from the Royal Children's Hospital Research FoundationVested interests/authors' affiliations: not stated Key conclusions of the study authors: nightmares, stomachaches and anxiousness decreased in frequency on methylphenidate, whereas poor appetite increased on methylphenidate. Most children with ADHD improve significantly on both methylphenidate and dexamphetamine. There was a slight advantage to methylphenidate on most measures. Many symptoms commonly attributed to stimulant medication are actually preexisting characteristics of children with ADHD and improve with stimulant treatment Comments from the study authors: a significantly greater number of side effects were reported as present by parents at baseline than during the methylphenidate condition. Parents motivated to have their child diagnosed with ADHD may have over‐reported symptoms at baseline, including adverse events Supplemental information regarding adverse events received through personal email correspondence with the authors in October and December 2013 (Barker 2013 [pers comm]) |
El‐Fiky 2014
Methods | A cohort study of methylphenidate use for 6 weeks |
Participants | Number of participants screened: 31Number of participants included: 31Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐5 (subtype: combined (70.9%), hyperactive‐impulsive (6.5%), inattentive (22.6%))Age: females: mean 8.2 (SD 3), range 5‐14 years old. Males: mean 8.4 (SD 2.2), range 6‐14 yearsIQ: mean: females: 100.8, males: 106.5Sex: 21 males, 10 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: EgyptComorbidity: oppositional defiant and conduct disorders: 11 (35.4%); specific phobic disorders: 3 (9.6%); childhood depression: 2 (6.5%), multiple comorbid problems (of conduct, agoraphobia, social and specific phobias): 2 (6.5%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMean methylphenidate dosage: male: 0.75 mg/kg (SD 0.12); female: 0.76 mg/kg (SD 0.16)Administration schedule: not statedTime points: not statedDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Measure method: Stimulant Drug Side Effects Rating Scale of Barkley |
Notes | Sample calculation: not clear, but authors stated: "A pilot study involving 10 subjects (8 males, 2 females) was conducted to determine size and selection methods, interrater reliability and applicability of tools, and dose ranges of methylphenidate (0.4‐1 mg/kg)."Ethics approval: not statedFunding/vested interests/authors' affiliations: not statedAny withdrawals due to adverse events: not clearly stated, but no mention of dropouts Key conclusions of the study authors: no statistically significant gender differences; females recorded less improvement and showed more 'talk less' and 'less interest' as side effects. Conclusive evidence for the role of gender in ADHD require bypassing methodological limitations as well as confounding factors. Comments from the study authors: since the above mentioned gender differences were less apparent than expected in the absence of gender‐by‐ADHD interaction, they can be attributed to many confounding factors than modification of ADHD effect by gender Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information attempted to retrieve, but no contact information for the authors found |
El‐Zein 2005
Methods | A 3 months cohort study following 12 children taking methylphenidate |
Participants | Number of patients screened: 35Number included: 18Number followed up: 12Number of withdrawals: 6Diagnosis of ADHD: DSM‐IV (subtypes: not stated)Age: 8.5 (SD 3.5) years old, range: not statedIQ: not statedSex: 10 males, 2 femalesMethylphenidate‐naïve: 100%Ethnicity: white: 50%, African American: 33%, Hispanic: 16%Country: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type: not stated (clinician's given choice as to what they prescribed)Methylphenidate dosage: 20 to 54 mg/dayAdministration schedule: not statedDuration of intervention: 3 months Treatment compliance: not stated |
Outcomes | Serious adverse events:A 10 ml blood sample was taken before starting methylphenidate, and a second blood sample was collected after 3 months of treatment with this drug. Type of effect: 3 cytogenetic endpoints (chromosome aberrations, sister chromatid exchanges and micronuclei frequencies) measure method (peripheral blood lymphocytes obtained pre and post treatment) |
Notes | Sample calculation: not statedEthics approval: after being informed of the study, a parent or guardian signed an informed consent that was approved by the Institutional Review Board of UTMB, the child also assented, and the study participant was then enrolledFunding/vested interest/authors' affiliations: not stated Key conclusions of the study authors: in all participants, treatment induced a significant 3, 4.3 and 2.4‐fold increase in chromosome aberrations, sister chromatid exchanges and micronuclei frequencies, respectively (PZ0.000 in all cases). These findings warrant further investigations of the possible health effects of methylphenidate in humans, especially in view of the well‐documented relationship between elevated frequencies of chromosome aberrations and increased cancer risk Comments from the review authors: the critique of the study by Preston, Kollins et al needs to be read alongside this study as it highlights considerable methodological concerns in this small cohort/patient series |
Famularo 1987
Methods | A naturalistic observational study, where the effectiveness of drug treatment (methylphenidate) were tested by a drug treatment during a grading period and no drug treatment for the next grading period |
Participants | Number of patients screened: not statedNumber of participants included: 13Number of participants followed up: 10Number of withdrawals: 3Diagnosis of ADHD: DSM‐III diagnosis of ADD (subtype: inattentive)Age: mean: 9.4, range 7‐12 years oldIQ: above 90Sex: 4 males, 6 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: not stated, but see exclusion criteriaComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 0.4 to 1.2 mg/kg/dayAdministration schedule: twice dailyDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:1 child reported decreased appetite without weight lossAnother child's sleep onset was 15‐20 minutes later than usual after initiation of pharmacological treatment There were minimal and clinically insignificant increases in pulse |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: noEthics approval: not statedFunding/vested interest/authors' affiliations: not stated Key conclusions of the study authors: the results of this study provide tentative support for 2 conclusions: ADD without hyperactivity appears to be a potentially stimulant‐treatable condition, even though hyperactivity is specifically excluded from its symptomatology; and school grades in children with ADD without hyperactivity may be influenced by the use of stimulants Comments from the study authors: the fact that significant results were obtained with such a small sample reflects the consistency with which the effects of the medication were exhibited across participants. However, it cannot be argued that these 10 participants adequately represent all ADD without hyperactivity children. In addition, the results may have been affected by factors such as teacher bias, student motivation, and parental encouragement Supplemental information requested through personal email correspondence with the authors in August 2013 and January 2014. No reply |
Faraone 2007a
Methods | A long term, open‐label, longitudinal study of methylphenidate use for up to 37 months |
Participants | Number of participants screened: 268Number of participants included: 191Number of participants followed up: 127Number of withdrawals: 64Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: range 6‐12 years oldIQ: not statedSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type: transdermal system Methylphenidate dosage: 6.25 cm2 (0.5 mg/hour) to 50 cm2 (3.6 mg/hour)Administration schedule: 12 hour wear timeDuration of intervention: 37 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Weight, height and BMI, values were converted to age‐corrected standard scores (z scores) and percentiles using the normative growth charts and transformations provided by the Centers for Disease Control and Prevention |
Notes | Sample calculation: not stated
Ethics approval: the study was approved by each site's local institutional review board or by a central IRB
Funding/vested interests: this study was supported in part by a grant from Shire Pharmaceutical Development to SF
Authors' affiliations: Dr Faraone receives research support from McNeil Consumer & Specialty Pharmaceuticals, Shire US, and Eli Lilly; is on the speakers' bureaus of Eli Lilly, McNeil Consumer & Specialty Pharmaceuticals, Shire US, and Cephalon; and has had an advisory or consulting relationship with the McNeil Consumer & Specialty Pharmaceuticals, Noven Pharmaceuticals, Shire US, Cephalon, and Eli Lilly. Mr Giefer has no financial relationships to disclose Key conclusions of the study authors: methylphenidate transdermal system treatment is associated with growth deficits in both weight, height, and BMI, but growth deficits attenuate over time. Baseline growth influences the effect of MTS treatment on both height, weight, and BMI, whereas prior stimulant therapy, dose, and total time treated influences only weight and BMI Comments from the study authors: prior stimulant therapy predicted smaller weight and BMI (but not height) deficits during the course of treatment with MTS. Growth velocity analyses showed that the rates of weight and BMI increases were negative in the first year of the study but positive at later time points. These findings suggest that any adverse effects of MTS on weight or BMI occur near the commencement of treatment and show some attenuation over time Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Feeney 1997
Methods | A patient report of af 13‐year old boy developing a tonic‐clonic ictal event on sertraline and methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: 13 years oldIQ: > 70Sex: maleEthnicity: unknownCountry: USAComorbidity: depressionComedication: sertraline Sociodemographics: unknown |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 80 mg/day (1.8 mg/kg/day)Administration schedule: not statedDuration of treatment: 10 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: No significant side effects for approximately 10 months |
Notes | Funding/vested interests: not statedAuthors' affiliations: Wright State University, School of Medicine, Dayton, Ohio Key conclusions of the study authors: first reported seizure in a patient with combined methylphenidate and sertraline treatment Comments from the study authors: more research is needed Supplemental information regarding ADHD diagnosis and IQ received through personal email correspondence with the authors in September 2013 (Klykylo 2013 [pers comm]) |
Fernández‐Fernández 2010
Methods | A patient series of cardiac adverse effects of methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV‐R (subtype: combined)Age: 7, 8, and 10 years oldIQ: > 85Sex: 3 malesEthnicity: not statedCountry: SpainComorbidity: no cardiovascular diseasesComedication: not stated Sociodemographics: not stated |
Interventions | Case 1Extended release osmotic release oral system methylphenidate, 36 mg/day for 18 months. Treatment compliance: not statedExtended release osmotic release oral system methylphenidate, 18 mg/day. Treatment compliance: not stated Case 2 Extended release osmotic release oral system methylphenidate, 18 mg/day, > 9 months. Treatment compliance: not statedCase 3 Extended release osmotic release oral system methylphenidate, 18 mg/day. Treatment period: not stated. Treatment compliance: not statedDiscontinuationRe‐administration of extended release osmotic release oral system methylphenidate, 18 mg/day. Treatment period: not stated. Treatment compliance: not stated |
Outcomes | Serious adverse events: Case 3Re‐administration of extended release osmotic release oral system methylphenidate, 18 mg/day: recurrence of episodes of tachycardia. Emergency department: supraventricular tachycardia treated with adenosine Non‐serious adverse events: Case 1Extended release osmotic release oral system methylphenidate, 36 mg/day, 12‐18 months: elevated arterial blood pressure with 2 SDs. No other intercurrent factors or symptomsExtended release osmotic release oral system methylphenidate, 18 mg/day: normalisation of blood pressure Case 2 Extended release osmotic release oral system methylphenidate, 18 mg/day, 6 months: repetitive episodes of self‐limiting tachycardia. Duration: a few minutes. ECG: self‐limiting sinus tachycardia, 150 beats/minute. Maintaining methylphenidate treatment for > 3 months: some episodes of tachycardiaCase 3 Extended release osmotic release oral system methylphenidate, 18 mg/day: several episodes of tachycardia |
Notes | Funding/vested interests: not statedAuthors' affiliations: Unidad de Neurologiá Pediátrica. Hospital Universitario Infantil Virgen del Rocío. Sevilla, España Key conclusions of the study authors: these cases should make us be cautious and investigate the possible existence of family or personal cardiovascular pathology Comments from the study authors: to date, our patient is the youngest one diagnosed with supraventricular tachycardia secondary to methylphenidate treatment Supplemental information regarding ADHD diagnostic criteria and IQ received through personal email correspondence with the authors in August 2013 (Fernández‐Fernández 2013 [pers comm]) |
Fernández‐Fernández 2011
Methods | A patient report of infantile psychosis during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV‐R (subtype: combined)Age: 10 years oldIQ: > 70Sex: maleEthnicity: not statedCountry: SpainComorbidity: not statedComedication: not stated Sociodemographics: adopted |
Interventions | 2 years of extended release methylphenidate, dosage: 0.7/kg/day1 week of extended release methylphenidate, dosage: 1.2 mg/kg/dayAdministration schedule: once daily Treatment compliance: not stated |
Outcomes | Serious adverse events:Infantile psychosis. Significant behavioural changes with emotional lability, mood changes, disruptive behaviour and aggressive behaviour towards his mother and relatives. Presence of inner voices Discontinuation of methylphenidate treatment: no disruptive behaviour, aggressive attitude, nor inner voices |
Notes | Funding/vested interests: not statedAuthors' affiliations: Unidad de Neurologiá Pediátrica. Hospital Universitario Infantil Virgen del Rocío. Sevilla, España Key conclusions of the study authors: caregivers of children treated with psychostimulants should be informed of possible side effects in order to ensure proper treatment in case of appearance. Professionals must be familiar with the adverse reactions that may occur with methylphenidate treatment. Paediatric neurologists and child psychiatrists must be agile in handling these reactions when it comes to withdrawal of the medication, treatment of the adverse reactions and prevention of misdiagnosis or the establishment of a chronic antipsychotic or stimulant treatment Supplemental information regarding ADHD diagnostic criteria and IQ received through personal email correspondence with the authors in April 2013 (Fernández‐Fernámdez 2013b [pers comm]) |
Findling 1996
Methods | A patient report of an 11‐year old girl who experienced transient side effects after receiving MPH |
Participants | Diagnosis of ADHD: DSM‐III‐R (subtype: combined)Age: 11 years oldIQ: > 70Sex: femaleEthnicity: not statedCountry: USAComorbidity: major depression (single episode, marked severity)Comedication: sertraline 25 mg, twice daily Sociodemographics: not stated |
Interventions | Methylphenidate dosage: 5 mg twice dailyDuration of intervention: the patient was still taking methylphenidate at the follow‐up at 3 months. Adverse effects occurred in the initiation of the treatment Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Mild and transient anorexia, transient weight loss 2 kg observed at the initiation of methylphenidate therapy |
Notes | Ethics approval: not statedFunding/vested interests/authors' affiliations: not stated Key conclusions of study authors: these cases support previous suggestions that adjunctive treatment with psychostimulants might be a safe and effective intervention for children treated with fluoxetine or sertraline who have persistent ADHD symptoms and suggest that such combined treatment might be suitable for adults as well Supplemental information: email sent twice to author in order to get data on BP and HR. No reply |
Findling 2009
Methods | A multicentre, prospective, 12‐month, open‐label, flexible‐dose, phase III extension of 4 previous trials. This trial consisted of 3 phases: a dose‐optimisation period (4 weekly visits), a dose‐maintenance period (11 monthly visits), and a 30‐day follow‐up period |
Participants | Number of participants screened: not statedNumber of participants included: 327Number of participants followed up at 12 months: 157Number of withdrawals: 170.Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (82%), hyperactive‐impulsive (2.1%), inattentive (15.9%))Age: mean 9.2 (SD 1.9), range 6‐12 years oldIQ: normalSex: 212 males, 115 femalesMethylphenidate‐naïve: 47.4%, before participation in the antecedent studyEthnicity: white (73.7%), African American (14.7%), Asian (1.5%), others (10.1%)Country: USAComorbidity: not statedComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | The patients either continued their current optimised methylphenidate transdermal system dose (from the previous study) for 12 months or entered a 4‐week stepwise dose titration phase to an optimal methylphenidate transdermal system dose, followed by an 11‐month dose maintenance phaseMethylphenidate transdermal system dose: 10 mg, 15 mg, 20 mg, or 30 mgAdministration schedule: 7 am, patch removed after 9 hoursDuration of intervention: 12 months, the median duration of exposure to methylphenidate transdermal system during the extension study was 335 (range 7‐392) days Treatment compliance: not stated |
Outcomes | Serious adverse events:There were no serious cardiovascular events (e.g. sudden death, myocardial infarction or stroke) over the 12 months of the study. 3 serious AEs were reported in 3 participants. None of these considered related to treatment Non‐serious adverse events: Physical examinations were performed at baseline, 6 months, and the final visitHeight was measured at baseline, week 4, and months 2, 4, 6, 8, 10, and 12Weight was measured at baseline, weeks 1 through 4, and months 6, 8, 10, and 12Participants removed their clothing and shoes and wore a gown to ensure consistency between measurements. Height was measured using a calibrated stadiometer with the participant standing on a flat surface, shoes off, and the chin parallel to the floor. Weight was measured using the same calibrated scale at each visit:Vital signs (resting systolic and diastolic blood pressure (SBP and DBP), heart rate) were measured at baseline and all subsequent visitsBlood pressure and heart rate were measured in the same arm using the same cuff type in each participant after 5 minutes' rest in a seated position‐ Clinical laboratory tests and a 12‐lead electrocardiogram (ECG) were performed at baseline, week 4, months 3 and 6, and the end of the study, and analysed by unblinded paediatric cardiologistsAEs were monitored at each study visit, and coded and defined using the Medical Dictionary for Regulatory Activities version 7.0. The severity and relationship of AEs to study treatment were assessed by the study investigators. Severity was rated as mild (easily tolerated, does not interfere with usual activities), moderate (interferes with daily activities, but participant is able to function), or severe (incapacitating, participant is unable to work or complete usual activities)Current and previous patch application sites were examined and rated for skin reactions and discomfort by trained, unblinded investigators at baseline; weeks 1 through 4; months 2 through 6, 8, and 10; and the end of the study. Dermal response scale 0‐7 (no reaction ‐ strong reaction beyond site). Dermal discomfort scale: 0‐3 (no discomfort ‐ severe, intolerable discomfort)Sleep behaviour investigated by using Children's Sleep Habits Questionnaire (CSHQ, 33 items), completed by parents/caregivers at baseline; weeks 1 through 4; months 2 through 6, 8, and 10; and at the end of the study. Item scores range from 1 (rarely occurring, 0‐1 times/wk) to 3 (usually occurring, 5‐7 times/wk), with total scores ranging from 33‐991 month after the last dose of study drug, participants' parents or legally authorised caregivers were contacted by telephone regarding ongoing or new AEs.2 participants who had received MTS in the earlier studies had 1 AE each (tachycardia (154 beats/min) and worsening weight loss (6.6 kg)) that began before receipt of MTS in the present study. These AEs persisted and led to the participants' withdrawal after ˜1 and 4 months of treatment, respectively: blood pressure and pulseThe highest mean increase from baseline in SBP (5.8 mm Hg) across dose levels was recorded with the 30‐mg dose at month 10. The highest mean increase in DBP (5.5 mm Hg) was observed with the 20‐mg dose at week 2Across dose levels, the proportion of participants with an SBP above the upper limit of normal (> 123 mmHg) ranged from 1% to 10%, whereas 1.5% had an above normal SBP at baseline. No participants had an above normal DBP (> 90 mmHg) at baseline; however, 1 participant in each MTS dose group had an above normal DBP at some time in the studyThe highest mean increase in heart rate (5.6 beats/min) occurred with MTS 15 mg at month 3ECG. There were no apparent trends toward changes in ECG indices at any MTS dose. ECG abnormalities were considered clinically significant in 4 participants and were recorded as 4 AEs. 3 of these AEs were tachycardia (123, 136, and 122 beats/min) and 1 was prolongation of the corrected QT (QTc) interval. QTc. Another participant had a QTcB interval of 544 ms at 3 months (QTcF, 476 msec; heart rate, 133 beats/min). A repeat ECG performed ˜2 weeks later recorded a QTcB of 419 ms (QTcF, 380 ms; heart rate, 107 beats/min). Although the results of the ECG at 3 months were deemed abnormal because of the prolonged QTc interval, they were not considered clinically significant. Laboratory analyses. No clinically significant changes from baseline or in the pattern of abnormal values on haematology, clinical chemistry, or urinalysis tests Dermal AEs. 33 dermal AEs were reported by 28 participants. AEs occurring more than once were rash (n = 6), urticaria (n = 6), allergic dermatitis (n = 2), contact dermatitis (n = 2), eczema (n = 2), generalised pruritus (n = 2), and skin hyperpigmentation (n = 2). 1 participant receiving MTS 10 mg had a pruritic rash possibly related to study treatment. Another participant receiving MTS 10 mg discontinued due to allergic dermatitis on the waist and knees, also possibly related to MTS treatmentMean (SD) dermal response scores at current and previous patch application sites were 1.2 (1.1) and 0.8 (1.0), respectively, across study visits, indicating minimal erythema15 participants had 30 instances of a dermal response score of 5 at the current patch site, 4 participants had 6 instances of a dermal response score of 6, and 2 had 2 instances of a dermal response score of 7 Sleep behaviour. No apparent overall effect on sleep behaviour. Regarding insomnia, see below Weight. 32.9 kg SD 9.9, range: (16.3‐90.6 kg), height: 1.37 (SD 0.13), range: 1.08‐1.72 m.Weight loss in 33 participants (also in table 2), poor weight gain in 1, and increased weight in 2. Mean (SD) changes in the z scores for weight, height, and BMI at the end of the study were –0.2 (0.43), –0.0 (0.44), and –0.3 (0.72), respectively. The 95% CIs for weight change from baseline to end point were 0.70 to 2.99 for participants aged 6 to 9 years and 6.40 to 10.27 for participants aged ≥10 years At visit 16, mean (SD) weight changes from baseline in participants receiving MTS 10 mg, 15 mg, 20 mg, and 30 mg were 2.73 (2.53), 1.62 (3.44), 2.49 (3.44), and 1.61 (3.41) kg, respectively. At visit 16, mean (SD) weight changes from baseline in participants receiving MTS 10, 15, 20, and 30 mg were 2.73 (2.53), 1.62 (3.44), 2.49 (3.44), and 1.61 (3.41) kg, respectively |
Notes | Sample calculation: estimated enrollment 450Ethics approval: the study protocol was approved by the appropriate institutional review board or independent ethics committee for each siteFunding/vested interests: Shire Development Inc. provided study medication and support for study‐related care, and the company was involved in the study design, conduct, and data analysisAuthors' affiliations: all but 1 of the authors receives or have received research support from, acted as a consultant for, and/or served on a speaker's bureau for several pharmaceutical companies Key conclusions of the study authors: long‐term efficacy in paediatric patients was demonstrated by improvements in the ADHD‐RS‐IV, CGI‐I, and PGA assessments. Most adverse events (98.3%) were mild to moderate. With the exception of application‐site reactions associated with transdermal delivery of methylphenidate, adverse events were generally typical of those associated with methylphenidate Comments from the review authors: if < 7 days had passed between the completion of the previous study and entry into the present one, baseline assessments were used from the previous study Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information and adverse event data have not been possible to receive through personal email correspondence with the authors in October‐November 2013 |
Findling 2010
Methods | This was a Phase IIIB, randomised, double‐blind, parallel‐group, placebo‐controlled, multicentre, dose‐optimisation study evaluating the efficacy and safety of
The follow‐up was an open‐label extension study for evaluating the safety and efficacy of methylphenidate transdermal system (10‐, 15‐, 20‐ or 30 mg/9‐hour patches) for participants who completed all required study visits and consisted of 3 experimental periods |
Participants | For the open‐label extension:Number of participants screened: not statedNumber of participants included: 163 (110 previously on MPH and 53 on PL)Number of participants followed up: 162Number of withdrawals 1Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 14.5 (SD 1.24) years (range 13‐17)IQ: ≥80Sex: 121 males, 41 femalesMethylphenidate‐naïve: 56% (122)Ethnicity: white (78%), African American (17%), Asian (0.6%), others (4.4%)Country: USAComorbidity: noneComedication: not statedSociodemographics; not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: transdermal systemMean methylphenidate dosage at month 6: 10 mg (5.6.%), 15 mg (7.9%), 20 mg (32.6%), and 30 mg (53.9%); median exposure time: 168.0 days (range, 3‐200 days)Administration schedule: single patch in the morning, once daily for 9 hoursDuration of intervention: 6 monthsTitration period: 5 weeks of the 6 months Treatment compliance: 88 fulfilled the protocol |
Outcomes | Regarding the 6‐month open‐label study:Dose optimisation (5 weekly visits) versus dose maintenance (5 monthly visits):Adverse events were monitored at each study visit and assessed by an open‐ended inquiry along with specific dermatological questions asked by an investigator or qualified evaluator. AEs were considered treatment emergent if they began or worsened on or after application of the first patch and occurred before or at the same time as application of the patch. AEs coded and defined using the MedDRA, version 7.03) a 7‐day post‐treatment follow‐up. Height: measured at month 6 visit by the investigatorWeight: recorded at all 5 visits by the investigatorVital signs (systolic blood pressure, diastolic blood pressure pulse), measured at all study visits, by the investigator. 12‐lead ECG performed at entry, week 4, month 3, month 6, by the investigatorBlood and urine samples collected at entry, week 4, month 4, and month 6Dermal skin reaction: measured by DRS at each study visitSleep: measured by the non‐validated Post‐Sleep Questionnaire. Measured at the 6 month visit Any changes noted between evaluation data at study entry and data obtained at schedule visits deemed to be clinically significant by the investigator were considered an adverse event |
Notes | Sample calculation: yesEthics approval: yesFunding: this study was funded by Shire Development Inc., which was involved in the study design, conduct, and data analysisVested interests/authors' affiliations: Dr Findling has received research support, acted as a consultant, and/or served on speakers' bureaus for Abbott, Addrenex, As‐ traZeneca, Biovail, Bristol‐Myers Squibb, Forest, GlaxoSmith Kline, KemPharm, Johnson & Johnson, Eli Lilly, Lundbeck, Neuropharm, Novartis, Organon, Otsuka, Pfizer, Sanofi‐Aventis, Sepracor, Schering‐Plough, Shire, Solvay, Supernus Pharmaceuticals, Validus, and Wyeth. Dr Katic has received research support, acted as a consultant, and/or served on speakers' bureaus for Forest, GlaxoSmithKline, Lundbeck, Merck, Novartis, Sanofi‐Aventis, Sepracor, Shire, Somerset, and Wyeth. Dr Rubin has received research support, acted as a consultant, and/or served on speakers' bureaus for Abbott, Addrenex, Cephalon, Eli Lilly, Johnson, Johnson, McNeal, Novartis, Shire, and UCB Celltech. Dr Moon received research support, acted as a consultant, and/or served on speakers' bureaus for Abbott, AstraZeneca, CNS Response, Eli Lilly, Johnson & Johnson, McNeil, Novartis, Pfizer, Sanofi‐ Aventis, Shire, Synosia Therapeutics, Takeda, and UCB Inc. Drs Civil and Li are employees of Shire Development Inc. Dr Civil is an employee of Shire Development, Inc. At the time of this study, Dr Li was an employee of Shire Development, Inc. Key conclusions of the study authors: regarding the 6 months open‐label study: methylphenidate transdermal system was generally well tolerated, and AEs were generally typical of those associated with oral methylphenidate, with the exception of application‐site reactions associated with transdermal delivery of methylphenidate Comments from the study authors: it is important to note that participants who failed to respond to psychostimulants in the past and those with conduct disorder and other psychiatric comorbidities were excluded from the study. Regarding the 6‐month study: no clinically significant findings between laboratory evaluation parameters obtained postentry relative to screening values obtained at the antecedent study Comments from the review authors: as already stated, people who earlier had failed to respond to psychostimulants were not included in the study. Therefore results can only be generalised to responders. Regarding the 6‐month open‐label study: participants who had not reached an acceptable response by the end of week 5 were withdrawn from the study Supplemental information requested from the study authors and Noven Pharmaceuticals with no reply |
Gadow 1995
Methods | A randomised, placebo‐controlled, double‐blind, cross‐over trial with 2 interventions:
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Participants | Number of participants screened: not statedNumber of participants included: 34. Participants were randomly assigned to different orders of the 3 dosagesNumber of participants followed up: 12‐months follow‐up: 30; 18 months follow‐up: 26; 24 months follow‐up: 26Number of withdrawals: 8Diagnosis of ADHD: DSM‐III‐R (subtype: not stated)Age: mean: 8 years and 10 months, range: 6.1‐11.9 years oldIQ: mean: 105.9 (SD 13.7)Sex: 31 males, 3 femalesMethylphenidate‐naïve: 71%Ethnicity: white: 85%, African American: 3%, Asian: 3%, Hispanic: 9%Country: USAComorbidity (only data from 21 children from Gadow 1995): tics: 100%, anxiety and/or depressive disorder: 8/21 (38%), obsessive‐compulsive disorder: 3/21 (14%), most of the children furthermore had either oppositional defiant disorder or conduct disorder and academic problemsComedication: not during the RCT. During the follow‐up 4 children were treated with an anti‐tic medication in combination with methylphenidate (neuroleptic n = 3, clonidine, n = 1)Sociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate dosage: participants were randomly assigned to 1 of 4 possible drug condition orders of doses: 0.1 mg/kg (mean: 4.4 mg), 0.3 mg/kg (mean: 9.0 mg) and 0.5 mg/kg (mean: 14.0 mg) methylphenidate and placebo. Upper dosages limit was 20 mg. When the 0.5 mg/kg dose was not preceded by a low dose condition, the child was gradually build up to the moderate dose. The build‐up days occasionally fall on scheduled school observation days.The observer were unaware of these days, and observations were conducted as usual, but these data were excluded from the analysesAdministration schedule: 2‐3 times daily at morning and noon, approximately 3.5 hours apart, 7 days a weekDuration of each medication condition: 2 weeksWashout prior to study initiation: methylphenidate: 1 week, antipsychotic: 3 weeks, clonidine: 2 weeksMedication‐free period between intervention: noneTitration period: noneTreatment compliance: parents and nurses were asked to return unused medication envelopes, which allowed the researchers to assess compliance. However, no further description in the paper 24 month follow‐up: total daily dose of methylphenidate, MED (minimal effective dose ‐ after RCT): (mean 16.5 mg, range 5‐40 mg); second visit (mean 28.5 mg, range 15‐60 mg); third visit (mean 29.2 mg, range 10‐90 mg); and fourth visit (mean 34.5 mg, range 15‐92 mg) |
Outcomes | Non‐serious adverse events During the 8‐week RCTSide Effect Checklist (SSEC), 13 items, rated by parents on Saturday and Sunday and rated by teacher twice a weekGlobal Tic Rating Scale (GTRS), rated by parents on Saturday and Sunday and rated by teacher twice a weekMotor and vocal tic category was, were observers coded presence or absence of tics in the classroom, lunchroom or playground, 4 times for each medication condition Physician evaluations Yale Global Tic Severity Scale (YGTSS), rated every second weekTourette Syndrome Unidentified Rating Scale, rated every second weekGlobal Tic Rating Scale (GTRS) (only assessed in 22 patients), rated every second weekShapiro Tourette Syndrome Severity Scale (OBS! Only assessed in 22 patients), rated every second weekMotor tic frequency tics; rated in 180 5‐second intervals in a simulated classroom, and tics were coded as either present or not present in each interval, rated every second weekWeight, assessed every second weekHeart rate, assessed every second weekBlood pressure, assessed every second weekDuring the 24‐months follow‐up Physician evaluationsAll rated at MED (right after RCT) 6 months, 12 months, 18 months, and 24 monthsYale Global Tic Severity Scale (YGTSS)Shapiro Tourette Syndrome Severity Scale3 subscales from the Tourette Syndrome Unified Rating scaleTotal number of ticsNumber of tics observed in 2 minutes of quiet conversation with the physicianThe LeWitt Disability Scale which assesses tics and the symptoms of comorbiditiesThe Global Tic Rating Scale (GTRS)Blood pressureHeart ratePulseWeight Parents' ratings Based on the last 2 weeks and rated at MED (right after RCT) 6 months, 12 months, 18 months, and 24 monthsStimulant Side Effect Checklist (SSEC)GTRS |
Notes | Sample calculation: yesAny withdrawals due to adverse events: noEthics approval: no informationFunding: supported in part by a research grant from the Tourette Syndrome Association Inc and a Public Health Service Grant from the National Institute of Mental HealthVested interests/authors' affiliations: not stated Key conclusions from study authors: during the course of this short‐term drug evaluation, physician, teacher, and parent ratings were in uniform agreement that methylphenidate did not lead to a worsening in the severity of the children's tic disorder. Furthermore methylphenidate is an effective drug for the treatment of ADHD and oppositional and aggressive behaviour. Furthermore the follow‐up study showed that long‐term treatment with methylphenidate seems to be safe and effective for the management of ADHD behaviours in many (but not necessarily all) children with mild to moderate tic disorder. Nevertheless, careful clinical monitoring is mandatory to rule out the possibility of drug‐induced tic exacerbation in individual patients Comments from the study authors: the magnitude of clinical improvement associated with the 0.3 mg/kg dosage compared with 0.5 mg/kg dosage was generally trivial for many children. The 0.5 mg/kg dosage was associated with more side effects, but fortunately they were generally of limited clinical significance.The generalisability of the findings from this study are subject to several qualifications. First, our data pertain to observed treatment effects over an 8‐week period and therefore cannot address the issue of tic exacerbation as a function of long‐term drug exposure. Furthermore the findings pertain only to children with ADHD and with tics that are of mild to moderate severity and that occur frequently enough to be observed during 15‐minute intervals Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no, children were not excluded from participation in the study if they had prior experience with stimulant drug therapy or if such a therapy purportedly had exacerbated their tics. Comments from the review authors: 26 of the children received stimulant medication throughout the follow‐up interval, and of these children, 1 was switched to dextroamphetamine. However, we have chosen still to use the results for the 26 in our analyses. All of the included articles are a mix of different protocols, so the total number of included participants differ from article to article Supplemental information regarding cross‐over data requested through personal email correspondence with the authors in April 2013 (Gadow 2013 [pers comm]). No data regarding the interventions were available |
Galland 2010
Methods | A cross‐over trial with 2 interventions:
Part of a case‐control study: ADHD group randomly assigned to 2 nights on and 2 nights off of methylphenidate versus non‐medicated non‐ADHD control group |
Participants | Number of patients screened: not statedNumber included: 30. Participants were randomly assigned to methylphenidate or no treatmentNumber followed up: 27 for cross‐over RCT, 28 for observational dataNumber of withdrawals: 3 for RCT, 2 for observational data RCT Diagnosis of ADHD: DSM‐IV (subtype: combined (78%/21), inattentive (22%/6))Age: mean: 10 years 6 months, range: 6 years 7 months to 12 years 4 monthsIQ: above 70Sex: 21 males, 6 femalesMethylphenidate‐naïve: 0%Ethnicity: white: 23, Maori: 1, other: 3Country: New ZealandComorbidity: oppositional defiant disorder: 9 (33%), specific phobia: 1 (4%)Comedication: noSociodemographics: mean deprivation index: 5.5Inclusion criteria
Exclusion criteria
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Interventions | Participants were randomly assigned to methylphenidate or no medication.Methylphenidate type: RitalinMean methylphenidate dosage: not statedAdministration schedule: 7 children had standard methylphenidate formulation once daily, 9 twice daily and 2‐3 times daily; 4 children had slow release alone, 4 in combination with once daily standard and 1 in combination with twice daily standard formulationDuration of intervention: 2 nightsWashout prior to study initiation: noneMedication‐free period between interventions: not clear, there was 5 to 7 days between medication and non‐medication phasesTitration period: none, participants had been treated with methylphenidate for a median of 3 years 9 months (range 3 months to 6 years 8 months). ADHD children were randomised to either the first night as a medication‐ and caffeine‐free night for 48 hours prior to each study night, or a medication night where they maintained their methylphenidate dosage regimen 48 hours prior to each study night, but remained caffeine‐free Treatment compliance: urinary methylphenidate was reported as detected/or not detected. No control children returned a positive test on either night |
Outcomes | Non‐serious adverse events:Standard polysomnographic (PSG) recordings on the second night of 48 hours on or off MPHSleep questionnaire (28‐item), completed by the parent (predominantly mother) over that week General adverse events, parent rated, observational data |
Notes | Sample calculation: not reportedEthics approval: yes, Otago Ethics Committee approved the studyFunding/vested interests/authors affiliations: the project was supported by a grant from the Health Research Council of New Zealand Key conclusions from study authors: findings suggest that methylphenidate reduces sleep quantity but does not alter sleep architecture in children diagnosed with ADHD Comments from the study authors:1. It is possible that the longer sleep duration and shorter sleep latency on the off‐ compared to on‐medication night could be interpreted as purely rebound, or that the on‐medication night reflects a truer baseline and the off‐medication night reflects a medication withdrawal effect2. The dosages and formulations of methylphenidate were not standardised3. Only 1 PSG recording was conducted for each condition, which means the information collected could be subject to a first‐night effect Comments from the review authors: we considered this a RCT study even though the authors describe it as a case‐control study, because the ADHD children were randomly assigned to on‐ or off‐methylphenidate. Only observational data on adverse events is used here Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information received through personal email correspondence with the authors in August 2014 (Galland 2014 [pers comm]) |
Garg 2014
Methods | An open‐label randomised parallel group clinical trial of methylphenidate and atomoxetine use for 8 weeks |
Participants | Methylphenidate groupNumber of participants screened: not statedNumber of participants included: 33Number of participants followed up: 26Number of withdrawals: 7Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (66.7%), hyperactive‐impulsive (6.1%), inattentive (27.3%))Age: mean: 8.47 (SD 2.22), range: 6‐14 years oldIQ: > 70Sex: 27 males (81.1%), 6 females (18.2%)Methylphenidate‐naïve: 100%Ethnicity: not statedCountry: IndiaComorbidity: oppositional defiant disorder (15/45.5%), conduct disorder (1/3%)Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: immediate releaseMean methylphenidate dosage: 11.59 (2.83) mg/day, at conclusion of the study: 17.35 (7.52) mg/day (or 0.62 mg/kg/day)Administration schedule: once or twice dailyDuration of intervention: 8 weeks Treatment compliance: not stated |
Outcomes | The various side effects were noted on each assessment on the Adverse Events Checklist prepared for the study. It was a semi‐structured check list enlisting all the common side effects of methylphenidate and atomoxetine. The parents were asked to rate the severity of each side effects produced in their children as mild, moderate and severe. Those who reported mild side effects were continued on the same dose. For those who developed moderate severity of side effects, dose was reduced. Those who rated any adverse effect to be severe were taken out of the study after stopping the medication Non‐serious adverse events:18 (55%) patients developed side effects during the course of the study The commonest reported adverse effect was reduced appetite |
Notes | Sample calculation: not statedEthics approval: clearance was obtained from the ethics committee of the Government Medical College and Hospital, ChandigarhFunding/vested interest: none Key conclusions of the study authors: methylphenidate and atomoxetine are efficacious in Indian children with ADHD at lesser doses than previously used. Their efficacy and tolerability are comparable Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, exclusion of non‐responders Supplemental information received through personal email correspondence with author in July 2016 (Arneja 2016 [pers comm]) |
Gau 2006
Methods | An open, randomised, parallel, active‐controlled equivalent 28 day trial with
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Participants | Number of participants screened: not statedNumber of participants included: 64Number randomised to immediate release methylphenidate: 32, and to OROS methylphenidate: 32Number followed up in each arm: immediate release methylphenidate: 32, OROS methylphenidate: 32Number of withdrawals in each arm: 0Diagnosis of ADHD: DSM‐IV/ICD‐10 (combined 50 (78.1%), hyperactive‐impulsive 2 (3.1%), inattentive 12 (18.9%))Age: mean: 10.5, range: 6‐15 years oldIQ: > 80Sex: 58 males, 6 femalesMethylphenidate‐naïve: 0Ethnicity: Asian 100%Country: TaiwanComorbidity: noComedication: noSociodemographics: parents education: college: 55%, high school: 30%, junior high school: 10%, other: 5% Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: immediate release and osmotic release oral system methylphenidateMean methylphenidate dosage: OROS: 27.7 mg/day (SD 13.5); immediate release: 26.7 mg/day (SD 7.6)Administration schedule: OROS: once daily; immediate release: 3 times dailyDuration of intervention: 28 days Treatment compliance: parents were required to record the time of drug administration on an adherence sheet. Pill counting was performed for each participant. Days forgetting to take medication: immediate release group 8.6 (SD 5.7); OROS group 2.0 (SD 3.9) |
Outcomes | Non‐serious adverse events:Barkley's Side Effects Questionnaire at baseline, on day 14 and day 28 Vital signs. At baseline, on day 14 and day 28 |
Notes | Sample calculation: noEthics approval: IRB of National Taiwan University HospitalFunding/vested interest/authors' affiliations: the study was supported by Janssen‐Cilag, Taiwan. Drs. Susan S.F. Gau and Wei‐Tsuen Soong have conducted clinical trials on behalf of Janssen‐Cilag, Taiwan and Eli Lilly and Company, Taiwan. They have also been speakers for Janssen‐Cilag, Taiwan and Eli Lilly and Company, TaiwanAny withdrawals due to adverse events: no Key conclusions of the study authors: OROS methylphenidate has similar efficacy to immediate release methylphenidate, with less severity of decreased appetite. OROS methylphenidate is superior over immediate release methylphenidate in treating ADHD children and adolescents in the context of Chinese culture Comments from the study authors: the short study period limits our understanding regarding long‐term efficacy of methylphenidate and the possible side effects on appetite, cardiovascular functioning, and so on in the Chinese population Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information regarding IQ and diagnostic criteria received through personal email correspondence with the authors in October 2013 (Gau 2013 [pers comm]) |
Gau 2008
Methods | An observational national survey where all the children with bad adherence were switched to other medications among those OROS methylphenidate |
Participants | Cross‐sectional study, phase 1:Number of participants screened: not statedNumber of participants included: 607Diagnosis of ADHD: DSM‐IV (subtype: combined (59.6%), hyperactive‐impulsive (11.2%), inattentive (29.2%))Age: mean 9.5 (SD 2.4), range 5‐16 years oldIQ: 89.5% had an IQ > 70Sex: 504 males, 103 femalesEthnicity: not statedCountry: TaiwanComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
Cohort study, phase 2:(Patients from phase 1 with bad adherence)Number of participants screened: 604Number of participants included: 137Number followed up: 124Number of withdrawals: 13 The following data areon all patients from phase 2, n = 240. Diagnosis of ADHD: DSM‐IV (combined (60.8%), hyperactive‐impulsive (8.3%), inattentive (30.8%)).Age: mean: 10.9 (SD 2.8), range: 5‐16 years oldIQ: 95% > 70%Sex: 198 males, 42 femalesMethylphenidate‐naïve: none |
Interventions | Phase 1:Methylphenidate type: immediate releaseMethylphenidate dosage: 18 mgAdministration schedule: 3 times daily (n = 83), twice daily (n = 308), once daily (n = 162)Duration of intervention: st least 3 of the preceding 6 monthsTreatment compliance: poor adherence was defined as missing ≥ 1 doses on a school day on ≥ 2 days per week for 4 weeks. 240 patients defined as poor adherents Phase 2 Methylphenidate type: osmotic release oral systemMethylphenidate dosage: 24.9 mgAdministration schedule: once dailyDuration of intervention: 3 weeks or moreTreatment compliance: not statedPatients who took IR‐MPH 5 mg once, twice or thrice daily and IR‐MPH 10 mg once, twice or thrice daily were switched to OROS‐MPH 18 mg and 36 mg per day, respectively |
Outcomes | Safety measures assessed by the investigators were decreased appetite, dizziness/headache, gastrointestinal disturbance, poor sleep quality, and other side effects Non‐serious adverse events: 18.8% had poor adherence due to side effects |
Notes | Sample calculation: noEthics approval: approved by the Joint Institute Review Board, Taiwan, and the institutional review boards of each study siteFunding/vested interest/authors' affiliations: the national health research institute.The work was supported by Janssen‐Cilag, Taipai, Taiwan Key conclusions of the study authors: poor adherence to medication may be an important reason for suboptimal outcome in ADHD treatment, physicians should ensure adherence with therapy before adjusting dosage or switching medication Comments from the study authors: the investigator's judgement with respect to adherence was based on patient and parent reports of missed doses without pill count, therefore, overestimate of adherence is very likely. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, excluded children with previous experience of adverse events |
Germinario 2013
Methods | A cohort study of 6‐ to 17‐year‐olds registered on the Italian ADHD National Registry from 2007 to June 2010 before beginning treatment with methylphenidate or atomoxetine (ATX) with follow‐up to 24 months |
Participants | Patients with outcomes on cardiovascular measuresNumber of participants screened: 840Number of participants included: 351Number of participants followed up: 214 at 6 months, 190 at 12 months, 77 at 24 monthsNnumber of withdrawals: 137 at 6 months, 161 at 12 months, 274 at 24 monthsDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 10.41, range 6‐17 years oldIQ: not statedSex: 305 males, 346 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: ItalyComorbidity: not stated for methylphenidate subgroupComedication: not statedSociodemographics: not stated Patients with outcomes on weight Number of participants screened: 840Number of participants included: 840Number of participants followed up: 296 at 6 months, 184 at 12 months, 55 at 24 monthsNnumber of withdrawals: 137 at 6 months, 161 at 12 months, 274 at 24 monthsDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 10.41, range 6‐17 years oldIQ: not statedSex: 305 males, 346 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: ItalyComorbidity: not stated for methylphenidate subgroupComedication: not statedSociodemographics: not statedNumber of patients screened: 840, number included: 840 followed up: 296 at 6 months, 184 at 12 months, 55 at 24 months number of withdrawals: 544 at 6 months, 656 at 12 months, 785 at 24 monthsThe rest of the demographic data regarding the sample were described together with the atomoxetine group, and therefore this data are not extractedPatients with outcomes on height Number of participants screened: 840Number included: 840, number followed up: 288 at 6 months, 167 at 12 months, 55 at 24 months, number of withdrawals: 552 at 6 months, 673 at 12 months, 785 at 24 monthsThe rest of the demographic data regarding the sample were described together with the atomoxetine group, and therefore this data are not extracted. All met DSM‐IV diagnostic criteria for ADHDPatients from the Campania Region Number of patients screened: 8, number included: 8, number followed up: 5, number of withdrawals:3The rest of the demographic data regarding the sample were described together with the atomoxetine group, and therefore this data are not extractedPatients from the Lombardy Region The national ADHD Registry contained data on 1733 patients treated with MPH or atomoxetine between June 2007 and May 2010. Number included: 229 were enrolled from 15 regional centres, 130 of these were drug‐naïve. Regarding the 130 drug naïve, 34 of these received MPHNumber included: 34 number followed up: 34, number of withdrawals: 10DSM‐4 diagnosis of ADHD: combined (79.4%), hyperactive‐impulsive (8.8%), inattentive (11.8%). Age (mean, 10.7 years). IQ: 2 participants had mental retardation. Sex (m: 28, f: 6), MPH‐naïve (100%). Ethnicity: not stated. Country: Italy. Comorbidity (type: % learning disorders 14, ODD 14, language disorder 5, mental retardation 2), comedication: 7 patients, sociodemographics: 2 were adopted, 11 only childArticle on adverse events Number of patients screened: not stated, number included: 1098 followed up: 931 number of withdrawals: 167Subtype: (combined, n = 941, inattentive = 124, hyperactivity, n = 32)Inclusion criteria: Patients aged 6 to 17 years with ADHD treated with atomoxetine or MPH who were registered with the Italian ADHD National Registry from 2007 onwardsTo be diagnosed with ADHD, participants had to present with significant functional impairment and symptoms had to be present before 7 years of age, persist for ≥ 6 months, be present in more than one settingExclusion criteria: Other mental or spectrum disorder; altered baseline ECG or no ECG assessment; or no information on drug therapy, only 1 follow‐up, or follow‐up of < 6 months |
Interventions | 902/1758 were treated with oral MPH chlorohydrate (Ritalin) 10 mg tablet at a dose of 0.3‐0.6 mg/kg/dose/day. The total daily dose (mean 18.4 mg) could be administered in 2‐3 doses per day at the discretion of the child's neuropsychiatrist. Duration of intervention: see under 'Description of participants'. A methylphenidate test dose of 0.3 mg/kg was administered first and the dosage increased up to 0.6 mg/kg/dose depending on clinical response and tolerabilityTreatment compliance: adherence to treatment was not evaluated. But participants with compliance problems were excludedRegarding the sample from the Lombardy Region MPH dosage: mean MPH dosage: 39.9 mg. Administration schedule: both stated. Duration of intervention: treatment compliance: daily dose of MPH ranged from 10 mg to 75 mg. All participants were drug‐naïve |
Outcomes | Serious adverse events:11 experienced serious adverse reactionsArrhythmia Non‐serious adverse events: BP and HR were assessed monthlyECG assessed at baseline and every 6 months. Prolongation of QTc interval was defined as any prolongation with respect to detected value at the screening before the first administration of the drug. ECG with alterations or pathological aspects were read by paediatric cardiologistLiver status assessed every sixth month at the follow‐upSuicidal thoughts assessed every sixth month at the follow‐upConvulsion assessed every sixth month at the follow‐upBMI assessed every sixth month at the follow‐upHeight and weight and BMI: monitoring was recommended monthly. The mean number of height measures per participant was 6.11, ranging from 1 to 33, whereas the mean number of weight measures per participant was 6.14 ranging from 1 to 33Any events occurring for the first time as well as a worsening of the disorder while on the study drug were defined as adverse events. Parents were requested in advance to report any adverse events during follow‐up visitsSample from the Campania region Participants were monitored for adverse events periodically by clinicians at the reference prescription centre at 1 week, 1 month, and every 3 months for the first year, and every 6 months thereafter, monitored by trained monitors. The median follow‐up period was 289 days |
Notes | Sample calculation: yes Ethics approval: approved by the Ethical Committee of the ISSFunding/vested interest: this study was supported by an independent grant n. FARM5AJL82_001 Italian Medicine Agency (AIFA)Any withdrawals due to adverse events: 30 patients dropped out due to adverse eventsAuthors' affiliations: authors declare no financial interestsKey conclusions of the study authors: regular monitoring of cardiovascular parameters (anamnestic history and BP and HR measurements) is recommended for all patients, but should be considered mandatory, perhaps at more frequent intervals, for participants at high risk. Furthermore; ADHD drugs show a negative effect on linear growth in children in middle term. Such effect appears more evident for ATX than for MPH. The study also suggests that ATX is more likely to be reported as causing harm than methylphenidate Comments from the study authors: Limitations: it is not clear whether the observed slowdown in growth is a transient effect or a permanent potential reduction for individual growth with respect to the final height. As our observation time was only 24 months of follow‐up, we were not able to evaluate if the negative effect on growth persisted after 24 months treatment. Second we could not assess if the negative effect observed on height would persist after permanent discontinuation of drugs. Third approximately 60% of participants could not be included in the analysesComments from Ruggiero 2012:Among all the ATX‐ or MPH‐base, most occurred in patients from Campania, probably because of our intensive monitoring program. During our study period, we introduced monitors who periodically and systematically interviewed clinicians at reference prescription centres. This was an active method to enhance the identification of adverse drug reactions (ADRs) by clinicians and to solicit them to report ADRsComments from the review authors: In the description of participants, we have chosen to divide them up according to outcome. Many of the participants will be found in several of the descriptions according to outcomesExclusion of MPH non‐responders/or children who have previously experienced adverse events on MPH: noSupplemental information regarding additional data and additional publications received through personal email correspondence with the authors in December 2013 and January 2014. Asked authors how they distinguished between serious adverse events and serious adverse reactions. Answer from authors: "We have catalogued the events reported compulsorily Italian Drug Agency as Serious adverse events. The serious adverse reactions are severe events for which reporting was not mandatory. I acknowledge that is a classification unorthodox [sic]" (Panei 2014 [pers comm]) |
Gerwe 2009
Methods | An 8‐week, multicentre, prospective, open‐label, single‐arm, non‐interventional trial with 2 groups:
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Participants | Number of participants screened: 313Number of participants included: 306Number of participants followed up: 263Number of withdrawals: 43 (14.1%) discontinued prematurely due to adverse events (n = 37, 12.1%), and/or lack of efficacy (n = 23, 7.5%), lost to follow‐up (n = 2), non‐compliant (n = 2), gave other reasons (n = 8)Diagnosis of ADHD: ICD‐10 (F90.0 (72.5%), F90.1 (34.3%), F90.8 (1.6%), F90.9 (3.3%), others (9.2%)).Age: 10.2 (SD 2.3), range 6‐14 years oldIQ: not statedSex: 246 males (80.4%), 60 females (19.6%)Methylphenidate‐naïve: 24.5%Ethnicity: not statedCountry: GermanySetting: outclinicComorbidity: 38.6%. Conduct disorder 25.5%, conduct disorder with ODD 24.2%, anxiety disorder 5.6%, OCD 1.3%Comedication: not statedSociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type: osmotic release oral systemMethylphenidate dosage, whole sample: 36 mg/day (median), 29.5 (SD 12.7) mg/day starting dose, 32.8 (SD 13.2) mg/day final dose, range: 18‐72 mg/day.Methylphenidate dosage, switch treatment subgroup: 31.6 (SD 12.7) mg/day starting dose, 34.4 (SD 13.5) mg/day final doseMethylphenidate dosage, initial treatment subgroup: 22.8 (SD 10.0) mg/day starting dose, 27.8 (SD 10.8) mg/day final doseAdministration schedule: once dailyDuration of intervention: 55 (SD 17.1) days, range 6‐113 days Treatment compliance: 2 patients discontinued due to lack of compliance |
Outcomes | Documentation of adverse events at week 1, 2 and 8 or premature termination. Measurement of blood pressure and pulse frequency and ratings of quality of sleep and appetite on Likert scales from 1 (very good) to 5 (very bad) at baseline, week 1, 2 and 8 or premature termination. Measurement of height, weight and documentation of tics at baseline and week 8 or premature termination. All ratings were performed by the treating physician. Measuring instruments for the documentation of adverse effects and tics are not stated Non‐serious adverse events:A total of 319 adverse events were reported by 160 (52.3%) of 306 patients. For 161 of 319 adverse events (50.5%) in 95 patients (31%) a causal relationship between the administration of OROS methylphenidate and the event was assessed as at least possible by the investigator Serious adverse events: 4 serious adverse events were reported in 2 patients |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: 37Ethics approval: the International Ethics Committee of the University of Freiburg, GermanyFunding: this study was supported by Janssen‐Cilag GmbH, GermanyAuthors' affiliations: authors are employees of Janssen‐Cilag or have received consulting fees Key conclusions of the study authors: transitioning from immediate release methylphenidate or no methylphenidate‐treatment to OROS‐methylphenidate in patients aged 6‐14 years with a diagnosis of ADHD was associated with significant improvements in daily functioning in several areas of life, severity of disease and quality of life Comments from the study authors: no further information about dosage or dosing regimen of a prior MPH treatment. Neither standardised diagnostic procedures nor a pre‐defined titration scheme were performed. No specification for transition period from MPH‐IR to OROS‐MPH was made. Methylphenidate‐naïve patients experienced somewhat more adverse effects, especially insomnia and anorexia, which probably also led to the slightly larger mean decreases in weight and tendencies to impaired quality of appetite and sleep, compared to the switch treatment group Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Ghanizadeh 2008a
Methods | A patient report of decrease in appetite during treatment with methylphenidate |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 8.5 years oldIQ: about 100 to 110Sex: maleEthnicity: not statedCountry: IranComorbidity: oppositional defiant disorderComedication: not stated Sociodemographics: not stated |
Interventions | MPH dosage: 20 mg dailyAdministration schedule: not statedDuration of intervention: 1 month Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Significant decrease in appetite |
Notes | Ethics approval: informed consent was obtainedFunding/vested interests: not stated Key conclusions of study authors: this report is about a child with ADHD who experienced insomnia, night terrors, and depression associated with the long‐term use of clonidine. He revealed resolution of insomnia and night terror when clonidine was removed Comments from the review authors: the adverse effects (decrease in appetite) occurred while the patient was only getting methylphenidate Supplemental information regarding IQ was retrieved through personal email communication with the author in July 2013 (Ghanizadeh 2013 [pers comm]) |
Ghanizadeh 2008b
Methods | A patient report of nocturnal enuresis during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 11 years oldIQ > 80Sex: maleEthnicity: PersianCountry: IranComorbidity: noComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate dose: 20 mg/day, 2 months. Discontinuation of methylphenidate for 1,5 months. Re‐administering of methylphenidate, 20 mg/day, 3 months Discontinuation of methylphenidate, some months. Re‐administering of methylphenidate, 20 mg/day, 2 months. Discontinuation of methylphenidate
Type of methylphenidate: not knownAdministration schedule: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Methylphenidate titrated to 20 mg/day: nocturnal enuresisDiscontinuation of methylphenidate: enuresis stopped immediatelyMethylphenidate, when titrated to 20 mg/day: immediate re‐occurence of nocturnal enuresisDiscontinuation of MPH: enuresis stopped immediatelyMethylphenidate, when titrated to 20 mg/day: immediate re‐occurence of nocturnal enuresis Discontinuation of MPH: enuresis stopped immediately |
Notes | Ethics approval: not statedFunding/vested interests: not stated Key conclusions of study authors: clinicians should be aware of this potential side effect of methylphenidate Comments from the study author: although both the boy and his mother were interviewed to obtain precise information, it should be noted that the boy may be suffering from a non‐standard type of enuresis or the parents may be biased to see a connection between drug and enuresis that does not exist. Future researches are necessary to study if there is any possible association Supplemental information was received through personal email correspondence with the author in July 2013 (Ghanizadeh 2013 [pers comm]) |
Ghanizadeh 2008c
Methods | A patient report of bilateral photophobia during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (K‐SADS‐PL) (subtype: combined)Age: 7 years oldIQ > 80Sex: maleEthnicity: PersianCountry: IranComorbidity: no (no history of general medical condition such as albinos or migraine headache, neither in the child nor in the parents. No positive history of head trauma, and the patient never wore contact lenses. No pathological findings on physical examination by an ophthalmologist)Comedication: no Sociodemographics: not stated |
Interventions | Methylphenidate type: not knownMethylphenidate dosage: 35 mg/dayAdministration schedule: not statedDuration of intervention: 1 year with discontinuation ≥ 3 times of 3 months each Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Photophobia, occurring a few days after initiation of methylphenidate treatmentDiscontinuation of methylphenidate ≥ 3 times with no symptoms of photophobia Re‐administration of methylphenidate: immediate reoccurrence of photophobia |
Notes | Ethics approval: not statedFunding/vested interests: not stated Key conclusions of study authors: to the authors' knowledge, no report of methylphenidate‐related photophobia has been found. This is the first report of methylphenidate‐associated photophobia. Although the underlying pathophysiology cannot be defined in a patient report, this possible side effect should be considered in patients on methylphenidate Supplemental information was received through personal email correspondence with the author in July 2013 (Ghanizadeh 2013 [pers comm]) |
Ghanizadeh 2009
Methods | A patient report of excessive talking during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 5 years oldIQ: > 70Sex: maleEthnicity: not statedCountry: IranComorbidity: noComedication: no Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mg/dayAdministration schedule: not statedDuration of treatment: about 7 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Mother and nursery teacher complained about increased hypertalkativity starting about 45 minutes after taking medication. The increased hyper‐talkativity continued for about 3‐4 hours. They scored hypertalkativity as 7‐9 on a 1‐10 visual analogue scale (10 is maximum) Re‐challenge was conducted more than 20 times and hyper‐talking reoccurred every time he took the medication |
Notes | Ethics approval: not statedFunding/vested interests: not stated Key conclusions of study authors: this is a report of excessive talking after taking methylphenidate in a child with ADHD. Further research is necessary to study if there is any possible association |
Ghanizadeh 2012
Methods | Double‐blind, placebo controlled parallel trial
No control/no‐intervention group |
Participants | Number of patients screened: 45Number included in trial: 43Number included in placebo group: 16First follow‐up in placebo group: 13Number of withdrawals in placebo group: 3Second follow‐up in placebo group: 13Lost to final evaluation in placebo group: 1Final evaluation in placebo group: 12
Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean: 8.9, range: 5‐14 years oldIQ: above 70Sex: 34 males, 9 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: IranComorbidity: primary enuresis (100%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 20 mg/day (< 30 kg), 30 mg/day (> 30 kg)Administration schedule: not statedDuration of intervention: 45 days Treatment compliance: not stated |
Outcomes | Spontaneously reported adverse eventsSystematically reported using a checklist, at baseline and 2 weeks and 4 weeks after onset of interventions, and 2 weeks after stopping the interventions Bedwetting, parent rated, daily |
Notes | Sample calculation: not statedEthics approval: yes, Shiraz University of Medical SciencesFunding: the author received a grantVested interest/authors' affiliations: not stated Key conclusions from study authors: nortriptyline decreases the frequency of enuresis in the children with ADHD and its effect disappears after the discontinuation of treatment Comments from the study authors: the sample size was relatively small and may result in type II errors. In addition, all children were diagnosed with ADHD and formed a clinical sample. Therefore, the results of this study cannot be generalised to other settings, such as a community sample. There was a predominantly higher number of boys than girls, and also it is not clear whether these results can be generalised to other age groups. In the literature there are contradictory reports about the relationship between enuresis and sociodemographic factors. Therefore, it is questionable whether the findings of this study can be applied to other cultures. This current trial was short‐term, and the children had not received an enuresis alarm or desmopressin. Therefore, they were not therapy‐resistant children. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information received through personal email correspondence with the authors in June 2014 (Ghanizadeh 2014 [pers comm]) |
Ghanizadeh 2013
Methods | An 8‐week parallel trial with 2 arms:
|
Participants | Number of patients screened: not statedNumber included: 49Number randomised to methylphenidate + placebo: 26Number randomised to methylphenidate + folic acid: 23Number followed up in methylphenidate + placebo: 13Number of withdrawals in methylphenidate + placebo: 13 Methylphenidate + placebo group Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 9.9, range 5‐16 years oldIQ: no estimated mental retardationSex: 23 males, 3 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: IranComorbidity: not statedComedication: not statedSociodemographics: not statedInclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMean MPH dosage: 10 mg/day (< 25 kg) and 20 mg/day (> 24 kg)Administration schedule: twice dailyDuration of intervention: 2 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Self‐reported measures upon dropout from study |
Notes | Sample calculation: yesEthics approval: approved by the Shiraz University of Medical Sciences Ethics Committee
Funding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: considering the marked limitations of this trial, this report suggests that methylphenidate may improve ADHD symptoms and the quality of life of children with ADHD. Current evidence does not support that folic acid as an adjuvant is effective for treating ADHD symptoms or aggression, or improving quality of life of children with ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Goetz 2011
Methods | A patient report of nocturnal visual hallucinations during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 7 years oldIQ: no mental retardationSex: femaleEthnicity: not statedCountry: Czech RepublicComorbidity: oppositional defiant disorderComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: 18 mg/dayAdministration schedule: once dailyDuration of treatment: 2.5 months Treatment compliance: not stated |
Outcomes | Serious adverse events:Complex nocturnal visual hallucinations that persisted for 3 hours. No recurrence of hallucinations occurred after methylphenidate was withdrawn Non‐serious adverse events: Mild abdominal pain and decreased appetite |
Notes | Ethics approval: not statedFunding/vested interest: supported by Charles University Grant GAUK 383/2010Authors' affiliations: Dr Goetz received research support, travel support and was speaker for Janssen and Lilly (stated in a 2012 paper) Key conclusions of study authors: careful sleep history should be taken before treatment, and reevaluated in the course of therapy, especially when the dose is increased, or switched to long acting formulas |
Goez 2012
Methods | A randomised, double‐blind, cross‐over study design where participants were randomly assigned to receive a single dose of either
Follow‐up 90 minutes |
Participants | Number of participants screened: not statedNumber of participants included: 28Number of participants followed up: 28Number of withdrawals: noneDiagnosis of ADHD: DSM‐IV (subtype; combined (100%))Age: mean 10.1 years, range 6‐15 years oldIQ: > 70Sex: 26 males, 2 femalesCountry: Canada and IsraelMethylphenidate‐naïve: not statedEthnicity: not statedComorbidity: no major psychiatric conditionsComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mgAdministration schedule: single doseDuration of treatment: single doseWash‐out: 2 weeks for those who received modafinil first Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Patients and their families were subsequently contacted and requested to report any adverse effects that might have occurred7 participants (25%) reported adverse events, including abdominal pain, diarrhoea, hyposomnia, and headaches. All adverse events were minimal and resolved spontaneously All appear to have been rated up to 90 minutes following administration of methylphenidate |
Notes | Sample calculation: not statedEthics approval: yesFunding: the authors received no financial support for the research, authorship, and/or publication of this articleVested interests/authors' affiliations: the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Key conclusions of the study authors: Modifinil may serve as an effective alternative treatment for ADHD in paediatric patients who do not respond well to methylphenidate or other stimulants Comments from the study authors: adverse events for both agents were mild and self‐limited. The study do not provide any information on long‐term drug effects and long‐term adverse effects. Furthermore, small number of participants and even smaller number of participants for whom numerical scores could be obtained. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: participants who have had an hypersensitivity reaction to either drug were excluded Supplemental information regarding the protocol and side effects requested from the study authors in October 2013 with no reply |
Golubchik 2011
Methods | A cohort study assessing methylphenidate use for 12 weeks on symptoms of ADHD and comorbid trichotillomania |
Participants | Number of patients screened: not statedNumber included: 9Number followed up: 9Number of withdrawals: none mentionedDiagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean 11.6, range 6‐18 years oldIQ: no mental retardationSex: 3 males, 6 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: IsraelComorbidity: trichotillomania (100%), tic disorder (n = 1)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 0.5‐0.7 mg/kgAdministration schedule: not statedDuration of intervention: 12 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Self‐reported by patient. Not clear if it was throughout 12‐week period or at specific time points Loss of appetite, headache, excessive preoccupation with one's hair, abdominal pain, motor tic exacerbation |
Notes | Sample calculation: noAny withdrawals due to adverse events: noEthics approval: yes, approved by Mental Health Center institutional review boardFunding/vested interest/authors' affiliations: not stated Key conclusions of the study authors: some efficacy of methylphenidate treatment was shown in trichotillomania patients with low rate of stressful life events. A large scale study is mandatory to evaluate the efficacy of methylphenidate for trichotillomania in ADHD/trichotillomania patients Comments from the study authors: the main limitations of this study are the open‐label design, the small sample size (N = 9), and the relatively short treatment duration (12 weeks) Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, exclusion of those with history of moderate or severe adverse events to methylphenidate |
Gracious 1999
Methods | A patient report of atrioventricular nodal re‐entrant tachycardia during stimulant treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 13 years oldIQ: > 70Sex: femaleEthnicity: African AmericanCountry: USAComorbidity: obsessive compulsive disorder and dysthymiaComedication: 50 mg/day sertraline Sociodemographics: not stated |
Interventions | First prescriptionMethylphenidate type: not statedMethylphenidate dosage: 30 mgAdministration schedule: twice daily: morning and noonDuration of treatment: 3 monthsTreatment compliance: noncompliant with the afternoon dose Second prescription Methylphenidate type: sustained release methylphenidateMethylphenidate dosage: 20 mgAdministration schedule: once daily: morningDuration of treatment: 11 monthsTreatment compliance: intermittently compliant |
Outcomes | First prescriptionNo serious or non‐serious adverse events reported Second prescription Serious adverse events:After 5 months of treatment; 2 15‐minute episodes of chest pain, associated with tingling in her fingers and shortness of breath. Heart rate: 96. Blood pressure: 155/79. 1 month later chest pain, shortness of breath, sweating, and palpitations beginning during urination. Heart rate: 100 No cardiac complaints in the following 5 months |
Notes | Funding/vested interests: noneAuthors' affiliations: Division of Child Psychiatry, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio Key conclusions of the study authors: stimulant medication may evoke onset of atrioventricular nodal tachyarrhythmias in patients who have the potential to develop them, possibly in combination with a selective serotonergic reuptake inhibitor Comments from the study authors: the cardiologist consulted believed this patient had a structural vulnerability of genetic etiology for the arrhythmia which was then precipitated by the stimulant Supplemental information regarding ADHD diagnostic criteria and IQ received through personal email correspondence with the authors in October 2013 (Gracious 2013 [pers comm]) |
Grcevich 2001
Methods | This retrospective review of medical charts compares the efficacy, safety, dosing frequency, and medication switch rates of Adderall with methylphenidate in children and adolescents with ADHD treated in a private, outpatient psychiatric clinic over 1992 to 1998. Of the evaluable patients, 54 received Adderall, and 75 received methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: not statedNumber of participants followed up: 75Diagnosis of ADHD: DSM‐IIIR or DSM‐IV (without hyperactivity: 12, with hyperactivity: 62)Age: mean 10.2 years oldIQ: not statedSex: 58 males, 16 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: disruptive behaviour: 9, depressive disorder: 7, anxiety disorder: 1, communication disorder: 4, impulse control disorder: 1, Asperger's: 1, other disorders: 7Comedication: no additional ADHD medicationsSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMean methylphenidate dosage: 27 mg/dayAdministration schedule: not statedDuration of treatment: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Different types of non‐serious adverse events |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: funded by Shire Redwood Inc. Key conclusions of the study authors: Adderall and methylphenidate provided comparable efficacy and safety in children and adolescents with ADHD Comments from the study authors: the population examined may be poorer responders to ADHD treatment than the general population. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information regarding IQ received October 2013 (Grcevich 2013 [pers comm]) |
Green 2011
Methods | A 6‐month follow‐up study of participants continuing methylphenidate treatment following a 1‐day, randomised parallel trial with 2 arms:
|
Participants | Number of participants screened: 34Number of participants included: 16Number of participants followed up: 15Number of withdrawals: 1 Patients participating in the 1‐day RCT Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (33.3%), inattentive (50%), not otherwise specified (17.7%))Age: mean 11.1 (SD 3.7) years old, range: 5‐20 years oldIQ: mean 81.4Sex: 20 males, 14 femalesMethylphenidate‐naïve: 61.8%Ethnicity: not statedCountry: IsraelComorbidity: 8 (53.3%) had a psychiatric co‐morbidity, including specific phobia (n = 4), ODD (n = 4), generalised anxiety disorder (n = 3), and eating disorder not otherwise specified (n = 1).Comedication: none of the participants was on any other psychotropic medication during the study period.Sociodemographics: not statedInclusion criteria: not stated |
Interventions | RCT: participants were randomly assigned to MPH or placebo. Mean MPH dosage: 15.7 (SD 5.6) mg (0.5 mg/kg). Administration schedule: once. Duration of intervention: 1 day. Titration period: no mention. Washout prior to study initiation: 3 days. Treatment compliance: not statedFollow‐up: not statedMethylphenidate type: not statedMean methylphenidate dosage: not statedAdministration schedule: not statedDuration of treatment: 6 months Treatment compliance: 1 withdrew due to poor compliance. |
Outcomes | Non‐serious adverse events:Barkley Side Effects Rating Scale (modified Hebrew version) parent rated at 24 hours after methylphenidate administration and at 6‐month follow‐upThe most common side effects after 6 months of treatment included poor appetite (93.7%), headache (66.6%), and stomachache (56.2%) None of the patients exhibited psychotic symptoms or manic, hypomanic exacerbation during the 6‐month study period |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: noEthics approval: the study protocol was approved by the Institutional Review Board of Rabin Medical CenterFunding/vested interests: no institutional or corporate/commercial relationships for the past 36 months that might pose a conflict of interest Key conclusions of the study authors: the use of methylphenidate in children with velocardiofacial syndrome (VCFS) appears to be effective and relatively safe. A comprehensive cardiovascular evaluation for children with VCFS before and during stimulant treatment is recommended Comments from the study authors: "we found that all participants (100%) with VCFS treated with methylphenidate exhibited ≥ 1 side effect". "The rate of all side effects immediately observed following initiation of treatment remained similarly high after 6 months of treatment". "Thus, according to our findings, it seems that in children with VCFS, tolerance did not develop to methylphenidate side effects". However, none of the children withdrew due to side effectsExclusion of MPH non‐responders/or children who have previously experienced adverse events on MPH: no Supplemental information regarding ADHD diagnostic criteria and safety data (from the study sample excluding participants over 18 years of age or with an IQ below 70, or both), were received through personal email correspondence with the authors in November 2013 (Green 2013 [pers comm]) |
Greenberg 1987
Methods | A 6 week non‐randomised controlled before‐after study |
Participants | Number of participants screened: not statedNumber of participants included: 50Number of participants followed up: 49Number of withdrawals: 1Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: mean 9.6, range 6‐15 years oldIQ: > 70Sex: 32 males, 18 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: the children were predominantly from intact, middle class suburban families Inclusion criteria
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Interventions | Methylphenidate type: not statedMean methylphenidate dosage: regarding 41 responders: 0.33 mg/kg/dose to 0.5 mg/kg/dose (mean 0.4 mg/kg)Administration schedule: twice dailyDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Of the 50 participants, 8 experienced minor, transient side effects (appetite or sleep problems) and medication was terminated for 1 participant who experienced headaches associated with increased blood pressure and tachycardia |
Notes | Sample calculation: noEthics approval: not statedFunding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: not relevant Supplemental information has not been possible to retrieve due to lack of contact information |
Greenhill 1983
Methods | A 2‐night polysomnographic study of children with ADHD before and after 6 months of methylphenidate treatment |
Participants | Number of participants screened: not statedNumber of participants included: 9Number of participants followed up: 7Number of withdrawals: 2Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: mean 8.6 years (range 6.7‐10.7)IQ: > 70Sex: 9 malesMethylphenidate‐naïve: noneEthnicity: white: 3, Black: 4, Hispanic: 0Country: USAComorbidity: not statedComedication: not statedSociodemographics: all children were living at home with one or more parents Inclusion criteria
Exclusion criteria
|
Interventions | Mean methylphenidate dosage: 1.37 mg/kg/day by the end of 6 monthsAdministration schedule: 3 times dailyDuration of intervention: 6 months 2 weeks washout period off methylphenidate before entering study. Ongoing titration until satisfied dose was obtained |
Outcomes | Non‐serious adverse events:Side effect questionnaire ‐ rated monthly by a physicianPolysomnographic tests: total sleep time, sleep period time, sleep latency, sleep REM time, awake time, mean REM period length, mean REM period cycle, sleep effects All sleep parameters were recorded during a 48‐hour stay in a sleep unit. The sleep parameters were recorded pre‐drug (run 1) and on drug (run 2) |
Notes | Sample calculation: noEthics approval: not statedFunding: National Institute of Mental Health Key conclusions of the study authors: across and within (pre‐post) group comparisons showed that methylphenidate therapy was associated with delayed sleep onset, lengthened sleep, and changes in certain REM sleep variables Comment from the study authors: certain methodological problems limit the interpretation of these data, e.g. the ADHD sample was small and completely male. Most of the children did not have to be awakened since they were up before the catheter placement, but if some of the children were awakened, the total sleep for these participants is not correct. Furthermore, methylphenidate‐nonresponders and partially responders are excluded Supplemental information requested twice through personal email correspondence with the authors in September 2013. No reply |
Gross‐Tsur 2004
Methods | A patient series of 3 children with ADHD who manifested hallucinations during methylphenidate treatment at low therapeutic doses |
Participants | Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (33.3%), not stated (66.6%))Age: 7, 12, 7½ years oldIQ: > 70Sex: maleEthnicity: not statedCountry: IsraelComorbidity: ODD (33%), cerebral palsy (33%), mild learning disabilities (33%)Comedication: not stated Sociodemographics: adopted (33%) |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 0.25‐0.3 mg/kg, 7.5‐10 mgAdministration schedule: once dailyDuration of treatment: 1 for a short period, 2 for several months/1 year Treatment compliance: not stated |
Outcomes | Serious adverse events:Complex visual and haptic hallucinations Case 1 Methylphenidate, 1 year: visual and haptic hallucinations starting around 1 hour after drug ingestionPlacebo substitution of methylphenidate: immediate cessation of hallucinations> 2 years follow‐up: no psychiatric symptoms reappearedCase 2 Methylphenidate, short period: visual and haptic hallucinations starting 2 hours after drug ingestion, continuing for almost 2 hoursDiscontinuation of methylphenidate: no recurrenceRe‐challenge with methylphenidate: immediate recurrence of hallucinations3‐year follow‐up: uneventfulCase 3 Methylphenidate, several months: visual and haptic hallucinationsDiscontinuation of methylphenidate: hallucinations ceased2‐year follow‐up: no recurrence |
Notes | Funding/vested interests: the authors received a 1‐year research grant in excess of USD 10,000 from Novartis in 1997Authors' affiliations: no other affiliations to pharmaceutical companies stated Key conclusions of the study authors: we describe 3 children with ADHD who were treated with low doses of methylphenidate and developed complex visual and haptic hallucinations Comments from the study authors: the causal role of methylphenidate in the development of hallucinations was based on their appearance after ingestion of the drug, resolving after its withdrawal, and the absence of psychiatric comorbidity that could explain such phenomena. In 1 patient, the hallucinations reappeared after an inadvertent re‐challenge. Because methylphenidate is a widely used, well‐studied, and safe pharmacologic agent, physicians who prescribe methylphenidate should be aware of even rare adverse manifestations occurring at therapeutic doses Supplemental information regarding IQ and ADHD diagnostic criteria received through personal email correspondence with the authors in October 2013 (Shalev 2013 [pers comm]) |
Grossman 1985
Methods | A patient report on methylphenidate and idiopathic thrombocytopenic purpura (ITP) |
Participants | ICD‐9 diagnosis of ADHD (subtype: not known)Age: 7 years oldIQ: > 70Sex: femaleEthnicity: white Country: USAComorbidity: noneComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mgAdministration schedule: twice dailyDuration of intervention: 7 months Treatment compliance: not stated |
Outcomes | Serious adverse events: Idiopathic thrombocytopenic purpura: physical examination at the Pediatric Outpatient Department found countless petechiae over the entire dermal surface, most concentrated over her buttocks. Numerous areas of purpura were noted, especially over her buttocks and extremities. Multiple areas of buccal mucosal and gingival bleeding with a large haematoma presented on the left lateral surface of her tongue. Clotted blood was seen in her nostrils and ear canals bilaterally. Bone marrow aspiration showed normal to increased megakaryocytes with normal red and white cell precursors. Methylphenidate was stopped and the patient was admitted. After 1 week of treatment for the condition her petechia had begun to fade. She did not start on methylphenidate again. There has been no recurrence of petechiae or bruising 1 year later |
Notes | Ethics approval: not statedFunding/vested interests: not stated Key conclusions of study authors: it is hoped that the report of this case will stimulate others to report their experience, or lack thereof, regarding the association of methylphenidate and idiopathic thrombocytopenic purpura. Because of the importance of this drug to the management of certain children with attention deficit disorder and its widespread use in thousands of children, it seems important to justify with data the current precaution that "periodic CBC, differential and platelet counts are advised during prolonged therapy" or eliminate the precaution as a recommendation to clinicians Comments from the study authors: the authors describe, that the patient had a mild upper respiratory tract infection 2 weeks prior to the symptoms of ITP. They describe, it is highly possible that in the case just presented the aetiology of the patient's idiopathic thrombocytopenic purpura may well have been her preceding upper respiratory tract infection rather than the methylphenidate, which she had taken without difficulty for 7 months prior to the onset of her haematologic disorder Supplemental information regarding ADHD diagnosis received through personal correspondence with the authors in July 2013 (Grossman 2013 [pers comm]) |
Gucuyener 2003
Methods | A cohort study assessing methylphenidate use amongst patients with ADHD and concomitant active seizures or EEG abnormalities |
Participants | Number of participants screened: not statedNumber of participants included: 119 (57 with epilepsy, 62 with abnormal EEG but no seizure activity)Number of participants followed up: 119Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 9.3, range 6‐16 years oldIQ: mean 92.3, range 79‐112Sex: 98 males, 21 femalesMethylpenidate‐naïve: not statedEthnicity: not statedCountry: TurkeyComorbidity: epilepsy (47.9%)Comedication: antiepilepsy medication for those with epilepsySociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate dosage: 0.3‐1 mg/kgAdministration schedule: initially once daily in the morning before school and titrated to twice a day (drug free on holidays)Duration of intervention: 12 months Treatment compliance: not stated |
Outcomes | Serious adverse events:Seizure frequency, observer rated at 3 months intervalsEEG findings, observer rated at 3 months intervalsNo seizures were observed in any of the patients with ADHD and EEG abnormalitiesIn the ADHD with seizures group, 1 patient's seizure type, generalised tonic clonic, changed to a complex partial seizure, but the number of seizures did not increaseOnly 5 patients had an increased seizure frequency in the ADHD with seizures group and none of the patients in the ADHD with EEG abnormalities groupThe number of abnormal EEGs with nonepileptic activity was decreased significantly at the end of the study in both groups (P = 0.05) Adverse events: Drug‐related side effects |
Notes | Sample calculation: noEthics approval: not statedFunding/vested interests: not stated Key conclusions of the study authors: methylphenidate had a beneficial effect on EEG. Seizure frequency did not change from baseline. The side effects of methylphenidate were mild and transient. Methylphenidate is safe and effective in children with ADHD and concomitant active seizures or EEG abnormalities.The present data indicate that methylphenidate is a safe and effective agent in children with ADHD and active seizures of EEG abnormalities. Coadministration of methylphenidate and antiepilepsy drugs improves attention without any adverse effects on seizure threshold or EEG findings. We suggest that physicians give the combined medication to patients with ADHD and active seizures or abnormal EEG findings with close monitoring Comments from the study authors: EEG findings did not deteriorate when patients were on methylphenidate. There was a beneficial effect of methylphenidate of both EEG and seizure frequency. We observed these patients for only 1 year, and 57 epileptic patients were having active seizures. Therefore, the improvement in EEG and seizure frequency might not be completely attributable to maturation Comments from the review authors: all participants were on concomitant antiepilepsy medication Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Guerreiro 1996
Methods | A cohort study of methylphenidate treatment |
Participants | Number of participants screened: not statedNumber of participants included: 24Number of participants followed up: 22Number of withdrawals: 2Diagnosis of ADHD: DSM‐III diagnosis of ADHD (subtype: combined (around 80%), inattentive (around 20%))Age: mean 9.1 years (range: 6.5‐13)IQ: normal, learning appropriately in regular schoolsSex: 20 males, 4 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: BrazilComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Initiation of immediate‐release methylphenidate treatment: 5 mg once daily. Titrated if needed to a total maximum of 10 mg dailyAdministration schedule: once or twice daily. Treatment pause during weekends and holidaysDuration of intervention: mean 12.6 months, range: 1 month ‐ 3 years Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: The occurrence of adverse events were assessed by the family and teachers |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: not statedAuthors' affiliations: the study was conducted at the Discipline of Child Neurology, Department of Neurology, Faculty of Medical Sciences (FCM), State University of Campinas (UNICAMP) Key conclusions of the study authors: the satisfactory and partial responses of methylphenidate treatment of ADHD observed in this study (79.1%) are in accordance with the literature, revealing therapeutic success in approximately 75% of the cases. We observed nausea and headache in 1 child, and only headache in another. Nausea can be controlled by lowering the dose; on the contrary, headache can be severe enough to result in cessation of treatment. Growth retardation is one of the possible side effects, which is of greater concern. Fortunately we did not observe this undesirable effect in our patients. Comments from the study authors: we might not have observed growth retardation in our study due to the use of low doses of methylphenidate and the recommendation of drug holidays Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding ADHD subtype, IQ, and type of MPH received through personal email correspondence with the authors in December 2013 (Guerreiro 2013 [pers comm]) |
Gökce 2015
Methods | Case study |
Participants | Number of participants screened: no dataNumber of participants included: no dataNumber of participants followed up: no dataNumber of withdrawals: no dataDiagnosis of ADHD: combined type ADHDAge: 12IQ: no dataSex: maleMethylphenidate‐naïve: no dataEthnicity: no dataCountry: no dataComorbidity: no dataComedication: no dataSociodemographics: no data Inclusion criteria: no data Exclusion criteria: no data |
Interventions | Methylphenidate type: extended release MPHMethylphenidate dosage: 27 mg from 10 years of age. Suicide attempt: 10 tablets of 36 mg ER‐MPHAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Physical examination: tachycardia and mildly increased blood pressure, respiration and heart rate had been determinedPsychiatric examination: his mood was depressed, and tendency to sleepLaboratory tests, blood glucose level, blood urea nitrogen, creatinine, potassium (K), sodium (Na) and chloride (CL) were revealed normalThe electrocardiography (ECG) parameters such as QRS duration, QT interval, R wave and PR interval were normal; however, the heart rate was elevated There was no central nervous system finding except irritability and agitation |
Notes | No data |
Haertling 2015
Methods | A prospective, multicentre, observational cohort study of long‐acting methylphenidate use for 12 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 262Number of participants followed up: not statedNumber of withdrawals: 23Diagnosis of ADHD: ICD‐10 (subtype: combined (58%), hyperactive‐impulsive (34%), inattentive (8%))Age: mean 10.9 (SD 2.5) years old (range: 11‐18)IQ: not statedSex: 197 males, 63 females, 2 unknownMethylphenidate‐naïve: 19.1%Ethnicity: not statedCountry: GermanyComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: long‐acting methylphenidateMethylphenidate dosage: start with 20 mg once daily and to adjust in weekly 10 mg increments to a maximum of 60 mg/dayAdministration schedule: once in the morningDuration of intervention: 12 weeks Treatment compliance: not stated |
Outcomes | Measure method/instrument: AEs according to the Medical Dictionary for Regulatory Activities (MedDRA), version 13
A total of 63 AEs were reported in 36 (13.7%) patients. Severity was mild in 30.2%, moderate in 39.7%, and severe in 22.2% of AEs; 7.9% of data were missing. 28 patients had AEs believed to be treatment related (10.7%). By the end of the study, more than half of the AEs had resolved completelyThe most frequent AEs were loss of appetite, abdominal pain, and nausea. The most frequently affected System Organ Classes were metabolism and nutritional as well as psychiatric and nervous system disordersThe number of AE per patient sums up to 4 adverse reactions in 1 patient throughout the whole treatment course(50.79% of all AEs) the outcome was 'resolved'. In 20 AE‐cases (31.75%) the outcome was 'not yet resolved'. In 1 patient the outcome of the AE was not known Serious adverse events 3 (hospitalisation) (0.4% of patients)Non‐serious adverse events: 60 |
Notes | Sample calculation: not statedEthics approval: ethics committee approvalFunding/vested interest: this study was initiated and sponsored by Novartis Pharma Germany. B Mueller is a full‐time employee of Novartis Pharma GmbH, the market authorisation holder of Ritalin LA. F Haertling received honorariums during the participation of this study. O Bilke‐Hentsch received honorariums as principle investigator of this study
Authors' affiliations: Novartis Pharma Key conclusions of the study authors: Ritalin LA improved CGI and quality of life in children with ADHD under routine practice conditions Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated; however, children with poor response to previous treatment plans are included Supplemental information regarding IQ, comedication, comorbidity and additional AE tables requested through personal email correspondence with the authors in June 2016 (Mueller 2016 [pers comm]). The authors were not able to supply the information |
Halevy 2009
Methods | A patient report of complex visual hallucinations during methylphenidate treatment |
Participants | DSM‐IV‐R diagnosis of ADHD, combined typeAge: 15 years oldIQ: normal intelligenceSex: maleEthnicity: not statedCountry: IsraelComorbidity: no (no past experience with drugs, smoking habit, or alcohol consumption. Normal physical and neurological examinations. Normal visual acuity. Electroencephalography (EEG) during a symptomatic state revealed no abnormalities and no evidence of epileptic activity)Comedication: not stated Sociodemographics: not stated |
Interventions | At 8 years of age:Methylphenidate type: RitalinMethylphenidate dose: 10 mg daily (0.3 mg/kg)Administration schedule: not statedTreatment compliance: not statedDiscontinuation Reintroduction of methylphenidate 7years later Methylphenidate type: not statedMethylphenidate dose: 0.15 mg/kg dailyAdministration schedule: not statedTreatment compliance: not stated |
Outcomes | Serious adverse events:Hallucinations Several days after initiation of treatment: visual hallucinations of rats, accompanied by some tactile hallucinations. Only present during the time the patient was under the influence of methylphenidate and disappeared thereafter. Discontinuation: immediate complete resolution Reintroduction of methylphenidate treatment. After 2 days: same complex visual hallucinations. Discontinuation: immediate complete resolution |
Notes | Funding/vested interest: the authors have no conflicts of interest to disclose with regard to this article Key conclusions of the study authors: the occurrence of hallucinations after a very low dose of methylphenidate on 2 occasions may suggest an idiosyncratic reaction. The phenomenon might also be explained by a drug‐induced dysfunction of the monoamine transmitters Comments from the study authors: given the wide use of methylphenidate, clinicians should be aware of this possible side effect Supplemental information regarding IQ and diagnostic criteria received through personal email correspondence with the authors in August 2013 (Halevy 2013 [pers comm]) |
Hammerness 2009
Methods | An open‐label, prospective, long‐term study of osmotic release oral system methylphenidate for smoking prevention in adolescents with ADHD for 24 months |
Participants | Number of participants screened: 203Number of participants included: 154Number of participants followed up: 30Number of withdrawals: 124Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 15.3 years (range 12‐18)IQ: > 75Sex: 114 males, 40 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: noneComedication: not statedSociodemographics: not statedSupplementary data from a 6 months period during the main studyNumber of participants screened: 152Number of participants included: 114Number of participants followed up: 57Number of withdrawals: 57Age: mean 14.1 years (range 12‐18)Sex: 83 males, 31 females Inclusion criteria
Exclusion criteria
Participants were dropped from the study if in the investigator's opinion there was lack of efficacy, intolerable adverse events, and/or clinically significant laboratory values, pregnancy, clinical worsening, or noncompliance with the study protocol |
Interventions | Methylphenidate type: osmotic release oral systemMean methylphenidate dosage: 63.1 mg at week 6 and 67.2 mg after 6 monthsAdministration schedule: morningDuration of intervention: 24 months Treatment compliance: not stated |
Outcomes | Serious adverse events:Adverse events were systematically recorded at each visit. Adverse events were assessed according to a general query by the treating physician, monitoring emergent and/or ongoing subjective complaints. Adverse effects were followed to resolutionThere were no serious adverse events or serious cardiovascular adverse events (AEs) in the first 6 months10 of 114 participants reported ≥ 1 cardiovascular complaintVital signs were collected as a single, first reading, typically 7 to 10 h after morning administration of medication, during after school office visitsParticipants with systolic blood pressure (SBP) or diastolic BP (DBP) readings (or both) at or above the 95th percentile for sex, age and height on ≥ 3 consecutive appointments were defined as hypertensiveParticipants with SBP and/or DBP readings above the 90th percentile for sex, age, and height on ≥ 3 consecutive appointments were defines as prehypertensiveDuring OROS methylphenidate treatment 8% (n = 9/114) of the sample met our defined criteria for prehypertension and 6% (n = 7/114) of the sample met criteria for hypertensionIt seems the denominator being used for calculation of adverse event proportions below 154 came from the 2‐year study on smoking. Incorporates 50 more participants than those studied in the present work Non‐serious adverse events Different types of adverse outcomes |
Notes | Sample calculation: noEthics approval: approved by the Massachusetts General Hospital Institutional Review board.Funding: not statedVested interests/authors' affiliations: the authors have several affiliations to the medical industry both as researchers, speakers, consultants, etc. Key conclusions of the study authors: treatment with relatively high doses of OROS methylphenidate was associated with small but statistically significant mean increases in BP and HR, primarily during the first 6 weeks of treatment, without clinically meaningful changes in ECG. These observations are consistent with previous reports using lower doses Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
Hammerness 2012
Methods | A longitudinal treatment study, receiving daily doses of osmotic release oral system for 6 weeks |
Participants | Number of participants screened: 27Number of participants included: 20Number of participants followed up: 10Number of withdrawals: 10Diagnosis of ADHD: DSM‐IV‐TRAge: mean 14.2, range 12‐17 years oldIQ: > 75Sex: not stated (majority males)Methylphenidate‐naïve: 10%Ethnicity: not statedCountry: USAComorbidity: medically healthyComedication: noSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: osmotic release oral systemMean methylphenidate dosage: 54 mg/day (0.90 mg/kg/day). Doses were clinically adjusted up to a maximal dose of 1.5 mg/kg/day, according to tolerability and symptoms, until the participant achieved an ADHD‐specific Clinical Global Impression Scale‐Improvement score of 1‐2Administration schedule: dailyDuration of intervention: 6 weeksTreatment compliance: not stated Wash out period prior to study: prior medication for ADHD participants was discontinued 1‐4 weeks prior to the initial study scan |
Outcomes | Non‐serious adverse events: Adverse events were systematically collected |
Notes | Sample calculation: noEthics approval: yes, approved by the Massachusetts General Hospital and McLean Hospital Institutional Review boardsFunding: this work was supported in part by the Pediatric Psychopharmacology Council Fund and by McNeil PharmaceuticalsVested interest/authors' affiliations: the authors have several affiliations to the medical industry both as researchers, speakers, consultants, etc. Key conclusions of the study authors: these preliminary findings suggest the presence of glutamatergic abnormalities in adolescents with ADHD, which may normalise with methylphenidate treatment. Documented clinical improvement and endpoint symptomatology by and ADHD‐specific rating scale Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
Haubold 2010
Methods | A retrospective cohort study of medical treatment of ADHD in a child and adolescent psychiatric practice, Germany, 1997‐2007 |
Participants | NB: the following characteristics include patients treated with methylphenidate, atomoxetine and amphetamineNumber of participants screened: 152Number of participants included: 103Number of participants followed up: 103Number of withdrawals: 0Diagnosis of ADHD: ICD‐10 (aubtype: predominantly inattentive (31.1%), predominantly hyperactive (68.9%))Age: mean: 9.5 years (range: 4‐18)IQ: not stated, however only 4 patients had comorbid mental retardationSex: 92 males (89.3%), 11 females (10.7%)Methylphenidate‐naïve: not statedEthnicity: not statedCountry: GermanyComorbidity: disruptive behaviour disorder: 68%, learning disorders: 29.1%, motor developmental disorder: 4.9%, autism spectrum disorders: 20.4%, adjustment disorder: 18.3%, emotional disorder: 6.8%, tics: 6.8%, anxiety disorder: 2.9%, Tourette syndrome: 2.9%, OCD: 1%, enuresis (plus partial encopresis): 6.8%, mental retardation: 3.9%, sleeping disorder: 1.9%, epilepsy: 1.9%, attachment disorder with disinhibition: 1.0%, adiposity: 1.0%, stutter: 1.0%, nail biting: 1.0%, harmful alcohol use: 1.0%, articulation disorder: 1%, no comorbidities: 9.7%Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: immediate‐release methylphenidate (Ritalin, Medikinet, Equasym), extended‐release methylphenidate (Ritalin SR and Ritalin LA) and IR‐MPH + ER‐MPH. A change of type of medication took place when adverse events occurred or the effect on the core symptoms of ADHD was not satisfactoryMean of medication changes: 4 (SD 2.9) times (range: 0‐13)Methylphenidate dosage per day: 0.6 mg/kg (IR‐MPH), ER‐MPH (0.8 mg/kg), IR‐MPH + ER‐MPH (0.2 mg/kg + 0.7 mg/kg)Administration schedule: not statedMean duration of intervention: 3.4 SD 2.10 years (range 2‐9.9)Drug holidays were permitted, and the cumulative dose of drug over the entire treatment duration of the children was calculated Treatment compliance: not stated |
Outcomes | Serious adverse events:Not stated Non‐serious adverse events: It was assumed that during an office visit, the doctor paid attention to all of the adverse events listed below and, if present, these have been logged. Timing, severity or duration of the occurrence of adverse events have not been described in the medical records with sufficient consistency and could therefore not be included in the evaluationNo/any adverse event: trouble falling asleep or sleeping problems, loss of appetite, tic disorder, headache, abdominal pain, anxiety disorder, OCD, nauseaBMI: BMI values of children in this study were compared with age and gender reference values (Appendix, Table 2 and Table 3) based on a sample of over 34,000 German children and adolescents of all ages and sexes |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: not statedEthics approval: not statedFunding/vested interests: not statedAuthors' affiliations: Faculty of Medicine, Eberhard Karls University, Tübingen, Germany. Other affiliations not stated Key conclusions of the study authors: the study shows that immediate‐release methylphenidate and the combination of immediate‐ with extended‐release methylphenidate should be first choice for ADHD drug treatment. For extended‐release methylphenidate as single treatment regimen and for atomoxetine and immediate‐release methylphenidate as combination treatment regimens, the benefit/risk ratio should be thoroughly weighed for each individual patient Exclusion of MPH non‐responders/children who have previously experienced adverse events on MPH: no |
Hazell 2003
Methods | A 6‐week, double‐blind, randomised, parallel study comparing clonidine vs placebo in methylphenidate‐treated children diagnosed with ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 29Number of participants followed up: 25Number of withdrawals: 4Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 125.4 months (range: 6‐14 years old)IQ: > 70Sex: 25 males, 4 femalesMethylphenidate‐naïve: noneEthnicity: whiteCountry: AustraliaComorbidity: borderline intellectual functioning: 12%, anxiety: 6%, pervasive developmental disorder: 1.5%Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Mean methylphenidate dosage: 0.67 mg/kg/dayAdministration schedule: not statedDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Parent and self‐report side effects checklists (Barkley)Pulse rate, and lying and standing blood pressure. Obtained at baseline and at weekly intervals for 6 weeks Height and weight assessed at baseline and at week 6 |
Notes | Sample calculation: yesAny withdrawals due to adverse events: noEthics approval: approved by the Hunter Area Health Research Ethics Committee and the University of Newcastle Human Research Ethics CommitteeFunding/vested interests: supported by the Australian Rotary Health Research FundAuthors' affiliations: none declared Key conclusions of the study authors: the findings support the continued use of clonidine in combination with psychostimulant medication to reduce conduct symptoms associated with attention‐deficit/hyperactivity disorder. Treatment is well tolerated and unwanted effects are transient Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no. But patients had to have been treated with methylphenidate for a minimum of 3 months |
Hechtman 2011
Methods | A patient report about a boy, who gets very emotional, with frequent crying, marked irritability and many tantrums when treated with methylphenidate. MPH use for around a year |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 5 years oldIQ: > 70Sex: maleEthnicity: not statedCountry: CanadaComorbidity: oppositional defiant disorder and substantial learning disability in expressive and receptive languageComedication: not stated Sociodemographics: not stated |
Interventions | OROS MPH dosage: 54 mg (the dosage was titrated from 36 mg to 54 mg)Administration schedule: once dailyDuration of intervention: 1‐2 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: In late afternoon and early evening he became very emotional, with frequent crying, marked irritability and many tantrums. The emotional side effects subsided after he discontinued methylphenidate treatment |
Notes | Funding/vested interests: Dr Hechtman declares having sat on the advisory boards/been a consultant for Eli Lilly, GlaxoSmithKline, Ortho Janssen, Purdue Pharma, and Shire Canada Comments from the study authors: children with ADHD often have other comorbid conditions that need to be addressed and treated, as stimulant medication is not likely to correct everythingIt is still unclear what predicts preferential response to 1 or the other stimulant. This preferential response should be kept in mind, so when children don't respond well to methylphenidate, the first change in medication should be to amphetamines Supplemental information regarding diagnostic criteria, type of ADHD and intervention period received through personal correspondence with the author in August 2013 (Hechtman 2013 [pers comm]) |
Hemmer 2001
Methods | Comparative cohort study on seizure development during MPH treatment |
Participants | Number of participants screened: not statedNumber of participants included: 234 (stimulant: 205, control: 29)Number followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐III, DSM‐III‐R or DSM‐IV (subtype: not stated)Age: range: 3‐20 years oldIQ: not statedSex: 179 males, 55 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate dosage: 0.3‐1 mg/kg/dayAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Serious adverse events:Patient 1: first seizure occurred 6 weeks after initiation of MPH treatment. She experienced 2 episodes several hours apart characterised by unresponsiveness, chewing movements, and tonic eye deviation. Stimulants were not reintroduced. She had an initial normal EEG before MPH treatmentPatient 2: she was treated uneventfully with MPH for 12 months, and experienced an unprovoked 4‐minute generalised tonic‐clonic seizure 2 months after discontinuation of methylphenidate. Her EEG prior to stimulant treatment revealed generalised epileptiform dischargePatient 3: experienced a 2‐minute generalised tonic‐clonic seizure with focal onset (tonic rightward head deviation) 3 years after initiation of MPH. Carbamazepine was initiated, and later replaced by phenytoin. MPH was reinitiated and there were no further seizures for the subsequent 14 months. EEG prior to stimulant treatment revealed focal epileptiform discharge Patient 4: episode 10 months after MPH initiation. He was heard to fall and was found unresponsive with upward eye deviation for approximately 2 minutes. EEG prior to stimulant treatment revealed focal epileptiform discharge |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interest: supported by the Crown FamilyAuthors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: our data suggest that a normal EEG can be used to assign children to a category of 'minimal risk' for seizure. In contrast, an epileptiform EEG in neurologically normal children with ADHD predicts considerable risk for the eventual occurrence of seizure. The risk, however, is not necessarily attributable to stimulant use |
Hollis 2007
Methods | A patient report of acute and transient dyskinesia occurring within hours of taking modified release methylphenidate |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined/hyperactive‐impulsive/inattentive)Age: 7 years oldIQ: Wechsler Abbreviated Scale of Intelligence language skills in the average/high‐average range, and nonverbal skills in the high‐average/superior rangeSex: maleEthnicity: white BritishCountry: UKComorbidity: conduct disorder (with predominant aggression) Comedication: on both occasions, treatment with methylphenidate was temporally associated with a recent withdrawal of risperidone. Sociodemographics: parents separated before he was born. He has an older brother and 3 older half‐sisters, none of whom have had behaviour problems. His mother has fibromyalgia. There is no history of mental or movement disorders in the family |
Interventions | Methylphenidate type: modified release methylphenidate (Concerta XL)Trial 1: 36 mg, 12 hours after abruptly stopping daily risperidone (1.5 mg) Trial 2: 18 mg, after a reducing course of risperidone over 4 weeks, with 6 risperidone‐free days before treatment |
Outcomes | Non‐serious adverse events:Trial 1: dyskinesia, marked overactivity, distress, headache, fatigue, and vomiting within 8 hours of treatment Trial 2: dyskinesia, increased aggression, difficulty sleeping within 8 hours of treatment |
Notes | Key conclusions of the study authors:This report is the first of a dyskinesia occurring after a single first dose of methylphenidate in a previously stimulant‐naïve patient after neuroleptic withdrawal. It is also the first to link this effect with modified‐release methylphenidate. The dyskinesia described here consisted of both brief tic‐like movements and more sustained dystonic movements and posturing Supplemental information regarding diagnostic criteria received through personal email correspondence with the authors in October 2013 (Hollis 2013 [pers comm]) |
Holtkamp 2002
Methods | A patient report of growth impairment during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 7.6 years oldIQ: normalSex: maleEthnicity: not statedCountry: GermanyComorbidity: bronchial asthmaComedication: inhaled corticosteroids Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 0.75‐0.8 mg/kg/dayAdministration schedule: morning and noonDuration of treatment: 19 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Appetite loss (only in the first weeks of medicine) Growth impairment |
Notes | Funding/vested interests: not stated Key conclusions of the study authors: one may conclude that some children are at risk of serious growth decrement when treated with methylphenidate. The growth of children should thus be monitored carefully, even if there are no alarming gastrointestinal side effects from methylphenidate. We found that the determination of growth velocity was a sensitive marker for the evaluation of growth impairment in our patient |
Hong 2012
Methods | An 8‐week open‐label trial to investigate the independent and interaction effects of DAT1, DRD4,ADRA2A and NET1 on treatment response to methylphenidate in ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 112Number of participants followed up: 103Number of withdrawals: 9
Diagnosis of ADHD: DSM‐IV (subtype: combined (69, 61.6%), hyperactive‐impulsive (6, 5.4%), inattentive (29, 25.9%), not otherwise specified (8, 7.1%))Age: mean 9.1 (SD 2.1) yearsIQ: 107.4 SD 13.7Sex: not statedMethylphenidate‐naïve: 100%Ethnicity: AsianCountry: South KoreaComorbidity: ODD (15, 13.4%), anxiety disorder (12, 10.7%), enuresis (5, 4.5%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: immediate release and extended releaseMean methylphenidate dosage: 19.8 SD 8.2 mg/day (initial dose) and 29.1 SD 11.6 mg/day (final dose)Administration schedule: not statedDuration of intervention: 8 weeks Treatment compliance: 1 participant's parents were anxious about their child taking psychiatric medication, this participant discontinued prematurely |
Outcomes | ADHD‐RS (ADHD Rating Scale‐IV) which consists of 18 items, each item is rated from 0 (never or rarely) to 3 (very often). Rated by parents before and after 8 weeks of treatment
The study design did not include collection of side‐effect profiles, so possible reasons for dropping out were not systematically assessed Non‐serious adverse events: 2 of the 9 dropouts experienced loss of appetite after methylphenidate medication, and 1 also complained about insufficient effect. Another participant was documented to experience insomnia, and described to be hyperactive at the last visit before dropping out. The remaining dropouts are not accounted for |
Notes | Sample calculation: none
Ethics approval: institutional review board for human subjects at the Seoul National University HospitalFunding: Supported by the Jun Sang‐Bae Child and Adolescent Psychiatry Research Fund of the Korean Neuropsychiatric Association in 2009Vested interests/authors' affiliations: no conflicts of interest or financial ties Key conclusions of the study authors: genetic determinants of methylphenidate response consist of both the dopaminergic and noradrenergic gene polymorphisms, and efforts to predict response to methylphenidate should cover these 2 catecholaminergic systems and their multifaceted aspects of their interactions as well Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: all participants were methylphenidate‐naïve |
Hulvershorn 2012
Methods | A 4‐week before‐after study |
Participants | Number of participants screened: not statedNumber of participants included: 25Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: range 10‐14 years oldIQ: above 80Sex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate type: osmotic release oral systemMethylphenidate dosage: titrated to a therapeutic dose over 4 weeksAdministration schedule: morningDuration of intervention: 4 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Intermittent 'hot' feeling: n = 1Decreased appetite: n = 6Upset stomach: n = 4Felt jittery: n = 1Intermittent headaches: n = 1 Headache: n = 1 |
Notes | Sample calculation: not statedEthics approval: not statedFunding: Klingenstein Third Generation Foundation, Brain Behavior Research Trust (NARSAD), Indiana University Health Values Fund
Authors' affiliations: not stated Key conclusions of the study authors: we present preliminary data on corticolimbic functional connectivity (FC) abnormalities seen in highly irritable youth with ADHD. Open‐label methylphenidate was well tolerated and resulted in parent‐rated improvements in ER. Methylphenidate appears to impact FC between the amygdala, visual/insular cortices and pallidum Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information regarding ADHD diagnostic criteria, IQ and adverse effect data received through personal email correspondence with the authors in August 2013 (Hulvershorn 2013 [pers comm]) |
Ilgenli 2007
Methods | A 4 hours before‐after study of methylphenidate acute effect on QT intervals |
Participants | Number of participants screened: not statedNumber of participants included: 25Number of participants followed up: 22Number of withdrawals: 3Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 9.4, range 7‐15 years oldIQ: no intellectual disabilitySex: 11 males, 11 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate type: not statedMethylphenidate dosage:10 mgAdministration schedule: not statedDuration of intervention: 2 hours Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:ECG were taken 2 hours before and 2 hours after administration of methylphenidateQT dispersion was measured as the difference between maximum and minimum QT intervals QTc was calculated with the use of Bazett's formula |
Notes | Sample calculation: not statedEthics approval: yes, approved by the institutional ethical committeeFunding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: this study reveals that methylphenidate reduces QT dispersion during the acute period, shortly after its administration. Data support the reliability of this drug in terms of early arrhythmia Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information received through personal email correspondence with the authors in November 2013 (Ilgenli 2013 [pers comm]) |
Irmak 2014
Methods | A patient report of phobias and visual hallucinations during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 9 years oldIQ: WİSC‐R: performance IQ: 78, verbal IQ: 87Sex: maleEthnicity: not statedCountry: TurkeyComorbidity: Moebius syndromeComedication: none Sociodemographics: not stated |
Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: gradually titrated up to 1 mg/kgAdministration schedule: not statedDuration of treatment: not stated Treatment compliance: not stated |
Outcomes | Serious adverse events: Methylphenidate prescribed at initial ADHD diagnosis, then withdrawn following the onset of phobias and visual hallucinations as well as lack of improvement in attention problems |
Notes | Key conclusions of the study authors: dramatic occurrence of adverse effects in our patients suggests that there is an increased vulnerability to adverse effects of methylphenidate in patients with syndromes when compared to other ADHD patients Supplemental information regarding ADHD diagnosis, IQ and comedication received through personal email correspondence with the authors in June 2016 (Irmak 2016 [pers comm]) |
Işeri 2007
Methods | 30‐day prospective cohort study of methylphenidate |
Participants | Number of participants screened: 428Number of participants included: 20Number of participants followed up: 20Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: combined 100%)Age: mean 9.27 (SD 1.59), range: 6‐12 years oldIQ: normalSex: 20 malesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: ODD 35%Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: short‐actingMethylphenidate dosage: 0.6 mg/kg/dayAdministration schedule: not statedDuration of intervention: 30 days Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Severity (0: not a problem, 1: mild, 2: moderate, 3: severe) of 13 possible side effects rated by mothersAppetite status (0: not a problem, 1: mild, 2: moderate, 3: severe) rated by mothers before and after medication Height and weight were measured before and after treatment and BMI was calculated. The patients were instructed not to change diet or physical activity during the study |
Notes | Sample calculation: not statedEthics approval: approved by the institutional ethical committeeFunding: Gazi University Scientific Project Fund Key conclusions of the study authors: short‐acting methylphenidate does not affect leptin appetite at 0.6 mg/kg/day dose. Did not show significant difference between pre‐ and postleptin levels Comments from the study authors: limitations of the study: small sample size, short duration of the study, only 1 dose of methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: all participants were methylphenidate‐naïve Supplemental data regarding the vomiting and skin eruptions have not been possible to receive from the authors. We have tried to get in contact with them twice without success |
Jafarinia 2012
Methods | A 6‐week randomised, double‐blind, parallel group study with 2 arms: |
Participants | Number of participants screened: 55Number of participants included: 44Number of participants randomised to methylphenidate: 22Number of participants followed up: 19Number of withdrawals: 3Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean 9.7 (1.9) years (range 6‐17)Sex: 14 males, 6 femalesMethylphenidate‐naïve: 100%Ethnicity: 100% PersianComorbidity: noneComedication: not statedIQ: above 70Sociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Participants were randomly assigned to methylphenidate or bupropionMethylphenidate dosage range: 20‐30 mg/day depending on weight (20 mg/day for 30 kg and below and 30 mg/day for above 30 kg)Methylphenidate mean dosage at week 6: 25.5 mg/dayAdministration schedule: not statedDuration of intervention: 6 weeksTitration period: 3 weeks initiated after randomisation Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Side effects measured in both groups. 11 side effects were recorded during the course of the study |
Notes | Sample calculation: yesAny withdrawals due to adverse events: not statedEthics approval: yesFunding/vested interests: public funding Key conclusions of study authors: bupropion has a comparable safety and efficacy profile with methylphenidate in children and adolescents with ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: all participants were methylphenidate‐naïve Supplemental information requested from the authors twice in August 2013 with no answer |
Jensen 1999 (MTA)
Methods | The Multimodal Treatment Study of Children With ADHD (MTA) is a 14‐month multicentre, randomised, parallel clinical trial with 4 arms
In our review we will compare combined treatment with behavioural treatment (RCT) according to our protocol, and look at the medication treatment group as a cohort (observational) |
Participants | Titration period (Greenhill 2001)The 28 day RCT (COMB + MGT group) N = 289 (MGT: n = 144, COMB: n = 145), N completed = 256 N not finishing titration = 33. Out of the completers, 198 were assigned to an individually best dose of MPH for the 14‐month trial, the rest on other medication or no medication Main study (Jensen 1999): Number of patients screened: 4541, N included = 579, N randomised to MPH + behavioural treatment (COMB) = 145, MPH: 144, behavioural treatment (BEH): 144, N followed up in each arm: combined treatment (COMB): 142; MPH: 136; behavioural treatment (BEH): 141, number of withdrawals/dropouts in each arm: combined treatment: 3; MPH: 8; behavioural treatment: 3All the demographic data below is for the COMB, BEH, and MGT group:DSM‐IV diagnosis of ADHD (combined (100%))Age: mean: 8.4 years (range: 7‐9.9).IQ: mean 100.4Sex: m: 346, f: 87MPH‐naïve (177/2)Ethnicity: white: 60.3%, African American: 20.6%, Hispanic: 8.8%, others: 10.4%Country: USA and CanadaComorbidity: anxiety disorder 35.1%, conduct disorder 14.1%, oppositional‐defiant disorder 38.8%, affective disorder 3.5%, tic disorder 10.2%, mania/hypomania 3%)Comedication (not stated)Sociodemographics (130 families on welfare. The population range widely in SES). There were no significant differences in baseline demographics between the 3 groups10‐month follow‐up (MTA Group 2004) Number of patients followed up in each arm: MGT: 128, COMB: 138, BEH: 139Age: mean: 8.4 yearsSex: m: 322, f: 83There were no difference from the demographic characteristics of the originally randomised 579 MTA participants and the participants who were assessed in the 10‐month follow‐up. The only statistically significant difference among treatment groups was a trivial difference in age (MHT was 0.3 years older that BEH)3‐year follow‐up (Jensen 2007) Number of patients followed up in each arm: MPH: 115, combined: 127Age: mean: 11.7 years (range: 10‐13)Sex: m: 291, f: 78There were no significant differences in baseline characteristics between participants in the 36‐month assessment and those who were unable to follow8‐year follow‐up (Molina 2008) Number of patients followed up in each arm: MGT: 101, COMB: 119. 32.5% of the MTA sample were medicated over 50% if days in the past yearAge: mean: 16.8 years (range: 13‐16). At the 8‐year assessment, 55 MTA participants had turned 18 years. Only 30% of the sample still fulfilled an ADHD diagnosis. Participants lost to the 8‐year follow‐up, compared with those retained, were more often male, had younger mothers, had less educated parents, had lower parent income, and were more likely to have been on welfare at baseline10‐year follow‐up, blood pressure (Vitiello 2012) Number of participants followed up in each arm: MGT: 77, COMB: 93. A comparison of patients who were retained through year 10 (n = 346) and those who were not (n = 233) showed a lower proportion of males in the retained group. Furthermore the participants were divided into groups based on the following criteria: never medicated, currently medicated, previously medicated. For the currently medicated group, the number of participants were respectively 184, 184, 108, 50, and 12 for 24 months, 36 months, 72 months, 96 months and 120 months follow‐up. Medication use during the previous 30 days was the criterion for positive medication status)Growth studies: at 24 months assessment (Jensen 2004) For both growth outcomes on the originally assigned, randomised, treatment groups were collected, and furthermore naturalistic subgroups had been made. The naturalistic subgroups consisted of those who had been medicated at all the assessment points up to 24 months (medication use during the previous 30 days was the criterion for positive medication status) and those who had not been medicated at the assessment points. Patients with consistent use of medication (med/med): 255, patients with no use of medication (NoMed/NoMed): 139 COMB: n = 135 mGT, n = 120Growth studies: up to 36‐month assessment (Swanson 2007) Naturalistic subgroups were established based on the patterns of treatment with stimulant medication. If medication was used within a 30‐day period before the assessment medication status was positive (med) and otherwise negative (no med). If an individual's medication status changed at any assessment point, then they were placed in the inconsistently medicated group. Patients with Med, n = 70. At the baseline at 14‐, 24‐, 36‐month assessment points, respectively, the percentages of medicated children taking methylphenidate were the following: 85.4%, 79.7%, 76.8%, 73.5%. The naturalistic subgroups did not differ on initial size at birth (birth weight), age, parent or teacher ratings of ADHD symptoms, sex, expected adult size (mid‐parent size), welfare status, or maternal smokingInclusion criteria:
Exclusion criteria:
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Interventions | Titration period (Greenhill 2001)Mean MPH dose during titration period: COMB: 32.1 mg/d MGT: 28.9 mg/d. Medication management started with a 4‐day single‐blind, safety lead‐in period, during which participants were exposed to 3 progressively higher daily MPH doses given 3 times daily. This was followed by a 28‐day, double‐blind, daily, switch titration of methylphenidate hydrochloride, using 5 randomly ordered repeats each of placebo, 5 mg, 10 mg, and 15 mg or 20 mg. Cross‐site teams of experienced clinicians blindly reviewed graphs portraying parent and teacher ratings of responses to each of the 4 doses and by consensus selected each child's best dose Compliance: not stated. 29 of the 32 placebo responders had to go back to taking MPH during the maintenance period Main study (Jensen 1999) Participants were randomly assigned to MGT, COMB, or BEH. Mean MPH dosage during the main study: COMB 31.2 mg/d, MGT: 37.8 mg/d. Administration schedule: 3 times a day; breakfast, lunch and in the afternoon. Duration of intervention: 14 months. Treatment compliance: monthly pill counts, intermittent saliva measurements to monitor taking methylphenidate, and encouragement of families to make up missed visits. "the study achieved a high degree of adherence to protocol." NB: for participants not obtaining an adequate response to MPH during titration, alternate medications were titrated openly in the following order until a satisfactory one was found: dextroamphetamine, pemoline, imipramine, and if necessary, others approved by a cross‐site panel. Thus 256 participants successfully completed titration; of these, 198 of 289 participants were assigned to an individually titrated best dose of MPH. 26 were titrated to dextroamphetamine, 32 given no medication because of a robust placebo response10 months follow‐up (MTA Group 2004) Duration of intervention: 24 months (10 months follow‐up from the 14 months RCT)Treatment compliance: not stated. From end of treatment to the first follow‐up, the percentage of participants on medication decreased for COMB (87% vs 70%) and MPH (93% vs 72%) but increased for behavioural (23% to 38%)3‐year follow‐up (Jensen 2007) Duration of intervention: 3 years (36 months follow‐up from the 14 months RCT). Treatment compliance: not stated. At 36 months the percentage of participants on medication were 70% for the combined group, 72% for the MPH group and 45% for the behavioural intervention group8‐year follow‐up (Molina 2009) Duration of intervention: 8 years. Mean MPH dose: 44.93 mg10‐year follow‐up (Vitello 2012) Duration of intervention: 10 years. Treatment compliance: not stated. Mean MPH dosage: 54.3 mg |
Outcomes | Titration period (Greenhill 2001)
Main study (Jensen 1999)
Serious adverse events: Main study (Jensen 1999)
Non‐serious adverse events Main study (Jensen 1999)Participants had up to 8 additional sessions provided when needed to address clinical emergencies or instances of possible study attrition
Titration period (Greenhill 2001)
3‐year follow‐up (Molina 2007)
8‐year follow‐up (Molina 2009)
8‐year follow‐up, substance abuse (Molina 2009)The substance use outcomes were measured at all interviews beginning with the 24‐month assessment
10‐year follow‐up (Vitello 2012)
Growth (Jensen 2004, Swanson 2007)
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Notes | Sample calculation: yes power analysis, 576 participants were required Ethics approval: yes, approved by both local institutional review boards and the National Institutes of Health Office for Protection From Research Risk Exclusion of MPH non‐responders/children who have previously experienced adverse events on MPH: no Any dropouts due to adverse events: 4 patients were removed during the lead‐in (titration period) because of prohibitive side effects. 1 child with buccal movements, another with skin picking; a third with depression, crying, sleep delay, and appetite loss, and a fourth who was anorexic, listless, and emotionally constricted Comments from the study authors: Main Study (Jensen 1999)Recruitment, screening, and selection procedures aimed to collect a carefully diagnosed sample of impaired children with ADHD and a wide range of comorbid conditions and demographics characteristics representative of patients seen in clinical practice. The design did not include a no‐treatment or placebo group. More than 3/4 of participants given behavioural treatment were successfully maintained without medication throughout the study. Consequently, it should not be concluded that behavioural treatment interventions did not work. Combined treatment and medication management treatments were clinically and statistically superior to behavioural treatment and community care in reducing children's ADHD symptoms. For other areas of function (oppositional/aggressive behaviours, internalising symptoms, social skills, parent‐child relations, and academic achievement), few differences among our treatments were noted, and when found, were generally of smaller magnitude. The significantly lower total daily dose of methylphenidate in the combined treatment arm are noteworthy but not unforeseen. The importance of this finding is unclear, and a rigorous test of the question would likely require a different design Titration period (Greenhill 2001) Its short 28‐day duration also limited its generalisability to long‐term treatment. Rates of response to MPH ran between 70% to 80% within the expected range.The MTA titration study showed a steeper dose‐response curve for younger and lighter ADHD children. When ratings were collected under placebo‐controlled, double‐blind conditions, parents reported more adverse events than did teachers. For this reason, clinicians would be wise to collect MPH side effect ratings from parents in the afternoon and evenings10‐month follow‐up (Group 2004) At follow‐up, MGT participants' dose levels (in methylphenidate equivalents) were significantly higher than COMB participants. There interesting results suggest the possibility that early COMB interventions might allow reducing overall medication requirements during later periods, consistent with findings that other have reported3‐year follow‐up (Jensen 2007) By 36 months, none of the randomly assigned treatment groups differed significantly on any of the 5 clinical and functional outcomes. However, despite no significant group differences at the 36‐month assessment, substantial improvement was manifested by all of the groups. Because there were no untreated control groups and because all of the treatment groups were improved in terms of relevant symptomatology at 36 months compared to baseline, it is possible that all of the treatments worked, but at different rates of different time periods. It is interesting that both medication and educational services for 24 to 36 months were markers for poorer outcome at 36 months, suggesting that those who are doing poorly get more treatment yet still do not do as well as those for whom treatment is not considered essentialVitiello 2001 Comorbid anxiety, oppositional defiant disorder, or conduct disorder was not associated with statistically significant differences in MPH dose at end of titration or maintenance, number of medication changes, or time to first change. A short‐term response to placebo occurred in 32 children (of 256 who completed the double‐blind titration) but was maintained in only 3 patients in the long term.Conners 2001 It is clear that the treatment effect in the study depends on the choice of endpoint measure. The results highlight the fact that there is no 'one true outcome' for a randomised clinical trial because different measures may be sensitive to different forms of treatment8‐year follow‐up (Molina 2008) Across time (to the 8‐year follow‐up) 17.2% of the children were medicated at every assessment beginning with 14‐months reports10‐year follow‐up, (Vitiello 2012) This clinical trial was not specifically designed to evaluate cardiovascular function. The blood pressure and heart measurements were not conducted under double‐blind conditions, and the measurement methods varied across the clinical sites. Abnormal blood pressure values were not systematically confirmed over 3 separate assessments as required for a diagnosis of prehypertension or hypertension. The time of the day when measurements were made was variableImplications and applications for primary care providers (Jensen 2001) Behavioural treatments may help families actively cope with their child's disorder and make the necessary life accommodations to optimise family functioning, even when such treatments are not as effective as medication in reducing children's ADHD symptoms. Findings suggest that high quality treatments may have considerable impact on restoring AHDH children to normal or near‐normal functioning at home and in the classroom. Because essentially none of the ADHD children met the normal criteria that were met by 88% of comparison children drawn from the same classrooms at the study outset, the notion that ADHD is just normal behaviour labelled by uninformed parents or overwhelmed teachers appears not only implausible, but preposterousPelham 1999 The 2 major treatment modalities ‐ behavioural and pharmacological ‐ were assessed at different time points relative to the intensive phase of treatment. Specifically, the effects of the pharmacological treatments were assessed at post‐treatment while participants were actively medicated; in contrast, the effects of BEH were assessed following fading of therapist involvement. The intensive period of BEH ended in late December or early January, and endpoint measures were typically taken 4‐6 months later ‐ usually several months after the last planned, face‐to‐face therapeutic contact. This design aspect has numerous implications for interpretation of the findings. For example, we cannot state that the medication (MPH for the vast majority) had long‐term effects. Rather, the results simply demonstrate that effects of MPH given steadily for 14 months are the same at the end of the time as the beginning (indeed the correlations between drug effects at these 2 points of the study are very high). When differences in outcome between these groups (e.g. BEH and MGT) are analysed, it is likely that combined treatment for children whose parents and teachers continued the behavioural interventions they had been taught will have an outcome superior to MGT, while combined treatment, for those whose parents and teachers did not continue BEH will be equivalent to MGT alone (which would not be surprising, as functionally that would be what they were receiving)Growth 24‐month outcomes (Jensen 2004) The growth suppression effects could be related to a medication effect, with the continuously treated subgroup having slower growth than the untreated subgroup. Alternatively, the 'continuously treated subgroup', defined by unknown self‐selection factors, could have had a slower growth rate before the start of the study, which continued during the treatment and follow‐up phases on the MTA. Our data cannot make a determination of the validity of these alternative interpretations. At this first follow‐up, our observations were of the children in the MTA when they were between the ages of 9 and 11 years, which is before expected phase of accelerated growth in adolescence and before the expected age when growth slows and final height is approximated. The rate of growth as well as the length of the growth phase together determines ultimate (adult) height, and it is possible that the consistent treatment with medication may reduce the rate but lengthen the duration of growth, so final height would be delayed but not reduced. It is possible that the never‐medicated group was pared down to good responders and the medicated groups enriched with poor behavioural responders. In the analysis of 14‐ to 24‐month change scores, the 'Medication status' was significant for both height (Chi2 = 16.16, P < 0.001) and weight (Chi2 = 13.32, P < 0.004) Growth 36 months assessment (Swanson 2007)We did not document a decrease in relative size in the group of participants with a history of treatment before entry into the MTA protocol during subsequent treatment with stimulant medication over 3 years. However, this group (the consistently medicated naturalistic subgroup) was smaller than the stimulant‐naïve group (the newly medicated naturalistic subgroup at entry, suggesting that early treatment of children (before the ages of 7‐9 years) with stimulant medication may have produced a reduction of growth rate before entry into the MTA protocol Key conclusions of the study authors: Main study (Jensen 1999)For ADHD symptoms, our carefully crafted medication management was superior to behavioural treatment and to routine community care that included medication. Our combined treatment did not yield significantly greater benefits than medications management for core ADHD symptoms but may have provided modest advantages for non‐ADHD symptom and positive functioning outcomes Vitiello 2001 For most children, initial titration found a dose of MPH in the general range of the effective maintenance dose but did not prevent the need for subsequent maintenance adjustments. For optimal pharmacological treatment of ADHD, both careful initial titration and ongoing medication management are neededTitration period (Greenhill 2001) The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10‐50 mg/day) across participants, effect sizes on impairment and deportment, as well as dose‐related adverse events. With 3 times daily dosing, the MTA titration trial showed that significant stimulant medication effects on ADHD symptom reduction and drug‐related adverse events could be detected by parents and teachers using daily ratings under controlled conditions10‐month follow‐up (MTA Group 2004) The benefits of intensive medical intervention for ADHD extend 10 months beyond the intensive treatment phase only in symptom domains and diminish over time.3‐year follow‐up (Jensen 2007) By 36 months the earlier advantage of having had 14 months of the medication algorithm was no longer apparent, possibly due to age‐related decline in ADHD symptoms, changes in medication management intensity, starting or stopping medications altogether, or other factors not yet evaluated.24‐ and 36‐month assessment of delinquency and substance abuse (Molina 2007) Cause‐and‐effect relationships between medication treatment and delinquency are unclear; the absence of associations between medication treatment and substance use need to be re‐evaluated at older ages. Findings underscore the need for continuous monitoring of these outcomes as children with attention deficit/hyperactivity disorder enter adolescence. There were no statistically significant effects at the P < 0.05 level of randomly assigned treatment on individuals rate of change in delinquency between baseline and 36 months. Result suggests the possibility that increasing delinquency between 24 and 36 months was associated with an increase in substance use in the same time period. We did not find evidence of protective or adverse effects of medication treatment for ADHD in either study.8‐year follow‐up (Molina 2009) Type or intensity of 14 months of treatment for ADHD in childhood (at age 7‐9.9 years) does not predict functioning 6 to 8 years later. Rather, early ADHD symptom trajectory regardless of treatment type is prognostic. This finding implies that children with behavioural and sociodemographic advantage, with the best response to any treatment, will have the best long‐term prognosis. As a group, however, despite initial symptom improvement during treatment that is largely maintained after treatment, children with combined‐type ADHD exhibit significant impairment in adolescence. Innovative treatment approaches targeting specific areas of adolescent impairment are needed10‐year follow‐up blood pressure (Vitiello 2012) Stimulant treatment did not increase the risk for prehypertension or hypertension over the 10‐year period of observation. However, stimulant had a persistent adrenergic effect on heart rate during treatmentGrowth studies, 24‐month follow‐up (Jensen 2004) In the MTA follow‐up, exploratory naturalistic analyses suggest that consistent use of stimulant medication was associated with maintenance of effectiveness but continued mild growth suppressionGrowth studies, 3‐year follow‐up (Swanson 2007) Children with combined type attention‐deficit/hyperactivity disorder were, as a group, larger than expected from norms before treatment but showed stimulant‐related decreases in growth rates after initiation of treatment, which appeared symptomatic within 3 years without evidence of growth reboundPelham 1999
Comorbidity (Jensen 2001)Our findings suggest that ADHD children with and without ODD/CD and ANX differed on many baseline characteristics, outcomes, and response to treatment. Children with ANX tended to be more treatment‐responsive than ADHD + ODD/CD and even ADHD‐only participants Anxiety (March 2000) Contravening earlier studies, no adverse effects of anxiety on medication response for core ADHD or other outcomes in anxious or non‐anxious ADHD children was demonstrated. When treating ADHD, it is important to search for comorbid anxiety and negative affectivity and to adjust treatment strategies accordinglySwanson 2007 Long‐term benefits from consistent treatment were not documented; selection bias was not shown to account for the loss of relative superiority of medication over time; there was no evidence for 'catch‐up' growth; early treatment with medication did not protect against later adverse outcomes. We expect that these challenges to the field's views will contribute to future controversies about the long‐term outcomes in the MTASubstance use (Molina 2012) Our findings did not provide any evidence that ADHD medication protects from, or increases risk for, adolescent substance use or SUD. This finding held for recent medication and for days cumulatively treated with stimulants. Unmeasured confounders may have been operating because of the naturalistic follow‐up study design and we did not statistically control for psychopathology and functioning at the follow‐up assessment. The observed lack of associations between stimulant exposure over time and adolescent substance use/SUD do not discount the possibility that brain‐based changes in neural mechanisms underlying addiction vulnerability are occurring as a function of prolonged stimulant treatment. The substance use/SUD outcomes for the MTA should be considered in the context of several unique study features and limitations. All of the children in the MTA were diagnosed with the combined type of DSM‐IV ADHD, and generalisation of study results should generally not extend beyond this subtype. Our follow‐up assessments, which relied on self‐report and often with 2‐year windows, may have missed episodes of substance use, and rates may be underestimatedPelham 2000 75% of the children in the behavioural treatment group were maintained without medication for 14 months, and 64% did not meet diagnostic criteria for ADHD at 14 months based on the DISC interview (MTA Cooperative Group, 1999a, 1999b). Such findings highlight the fact that intensive behavioural treatments are a viable alternative to medication in treatment of ADHDComments from the review authors: The authors from the MTA study have written more than 70 articles describing different outcomes and challenges of the study. We have only included those found in our comprehensive literature search or others we found relevant to include looking through the articles reference lists. We have discussed whether to include the MTA study or not since not all of the patients randomised to medication (COMB + MGT group) received MPH. Those who did not have an adequate response to MPH were given other medication (e.g. dextroamphetamine, pemoline, imipramine, or no medication). Furthermore, some of the participants in the BEH group were also medicated during the 14‐month randomisation phase. For all other studies in the review, we have only included those with pure MPH receivers. Furthermore lots of the participants did not have an ADHD diagnosis at the follow‐up assessment. At 8‐year follow‐up only 30% of the remaining participants still had a diagnosis of ADHD. However, we have chosen to use the data from MTA since it is such a large and well‐known study. All of the MTA analyses will be part of the review as sensitivity analysesRegarding Molina 2012 (substance use): we have included/asked for additional data for this article, even though that the group that were medicated in the more group were only medicated for mean 2071.10 (SD 728.87) days out of the 8 years the follow‐up took place. The following articles from the MTA study have only been assessed by one review author: Pelham 2000, Carey 2000, Swanson and Hinshaw 2007, Galanter 2003, Hinshaw 1999, Molina 2013We sent several emails to the MTA group in order to get additional information and furthermore spoke orally to some of the authors. We did not get additional data |
Johnson 2013
Methods | A cohort stud of methylphenidate use for 6 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 96Number of participants followed up: 77Number of withdrawals: 9Diagnosis of ADHD: DSM‐IV (subtype: combined (82%), hyperactive‐impulsive (9%), inattentive (9%))Age: mean 8 (SD 2.6) years (range 4‐15)IQ: mean 92.7 (SD 15.9)Sex: 66 males, 11 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: IrelandComorbidity: oppositional defiant disorder: 60%, conduct disorder: 16%Comedication: paracetamol, salbutamol and steroid inhalers for asthma and ampicillin antibioticsSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: 45 participants took short‐acting methylphenidate. Otherwise not statedMethylphenidate dosage: mean 0.57 mg/kg/day (SD 0.19)Administration schedule: not statedTime points: not statedDuration of intervention: 1 year, however only data up to 6 weeks were reported here Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Barkley's Side Effect Rating Scale at 6 weeks, parent rated ‐ included decreased appetite, weight loss, headache, abdominal pain, irritability, sadness, insomnia, and tics |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: not statedEthics approval: granted by 8 local research ethics committeesFunding/vested interests: this study was funded by the Irish Health Research Board, DublinAuthors stated that there were no competing financial interests Key conclusions of the study authors: the study found an association between 2 CES1 SNP markers and sadness as a side effect of short‐acting methylphenidate Comments from the study authors: limitations: not cross‐over design; serum measures of methylphenidate were not obtained; study did not consider environmental factors impacting on CES1A1 function Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Jung 2007
Methods | A open‐label cohort study of osmotic release oral system (OROS) methylphenidate use for 4 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 91Number of participants followed up: 83Number of withdrawals: 8Diagnosis of ADHD: DSM‐IV (subtype: 100% combined)Age: mean 8.46, range: 6‐12 years oldIQ: mean 96 (SD 15.17). All above 70Sex: 75 males, (90.4%), 8 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: KoreaComorbidity: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: osmotic release oral system (extended release)Methylphenidate dosage: start dosage was 18 or 36 mg based on the clinician's judgment and dosage was adjusted at each visit if necessaryAdministration schedule: once per day in the morning before 8:30Duration of intervention: 4 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: 79.5% showed ≥ 1 harmful effects of medication with most being mild. Not mentioned how these were measured |
Notes | Sample calculation: noEthics approval: yesFunding/vested interests: Janssen Korea Pharmaceuticals LTD Key conclusions of the study authors: OROS methylphenidate improves performance on common tests of cognitive function. A further long‐term follow‐up study of these effects in ADHD is warranted Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Karabekiroglu 2008
Methods | A retrospective cohort of methylphenidate use for 6 months |
Participants | Number of participants screened: not statedNumber of participants included: 90Diagnosis of ADHD: DSM‐IV diagnosis (subtype: not stated)Age: mean: 9.0, range: 5‐16 years old)IQ: above 70Sex: 59 males, 14 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: conduct disorder (16.7%); tics (23.3%); Tourette syndrome (10.5%); obsessive compulsive disorder (16.3%); pervasive developmental disorder (8.1%); learning disorder (26.7%); depression (9.2%)Comedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria: |
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 10‐30 mg/dayMean methylphenidate dosage: 17.6 (SD 4.95) mg/dayAdministration schedule: 2‐3 times/dayDuration of intervention: 6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Parents completed the Barkley Stimulant Side Effects Rating Scale (BSSERS) at baseline and on the 3rd, 7th, and 15th days of the medication |
Notes | Sample calculation: not stated
Ethics approval: not stated
Funding/vested interest: "This research had a naturalistic design. Therefore, a limited financial support, which was supplied by the authors, was needed." Key conclusions of the study authors: authors found significant decrease in appetite, and they suppose that some of the Barkley SES may represent both ADHD symptoms and methylphenidate adverse events Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: all participants were methylphenidate‐naïve Supplemental information regarding the IQ of the participants received through personal email correspondence with the authors in June 2016 (Karabekiroglu 2016 [pers comm]) |
Karaman 2010
Methods | A patient report of a 15‐year old boy with ADHD who developed pulmonary arterial hypertension (PAH) during OROS methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 15 years oldIQ: intellectual capacity within normal limitsSex: maleEthnicity: not statedCountry: TurkeyComorbidity: noComedication: noneMPH‐naïve: yes Sociodemographics: not stated |
Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: 54 mg/dayAdministration schedule: once daily, morningDuration of intervention: 18 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:On the 4th day of treatment: the patient began to experience occasional episodes of slight shortness of breath. Continued over several months. Not associated with either exercise or anxietyAt the 18th month of treatment: fainting. Normal weight. No sign of allergy, hypersensitivity, or sleep apnea. Mean pulmonary arterial pressure of 40 mmHg at rest, otherwise no pathological findings from extensive testing(Examination: clear lungs, no murmurs, rubs, or gallops, and otherwise unremarkable. Laboratory tests, including C‐reactive protein, thyroid and liver function tests, electrolytes. Blood gases, antinuclear antibodies, D‐dimers, chest X‐ray, ventilation‐perfusion scintigraphy, electrocardiography, respiratory function tests. Echography. Transthoracic echocardiogram: normal except for the mean pulmonary arterial pressure)No use of any other drug. No history of alcohol and substance use and no symptoms or signs of methylphenidate misuse (intravenous (IV) injection). The personal and family histories were also negative for pulmonary or cardiovascular diseases Discontinuation of OROS‐methylphenidate, 1 month: free of symptoms. Mean pulmonary arterial pressure of 28 mmHg |
Notes | Funding/vested interests/affiliations: no conflict of interests or financial ties to disclose. Key conclusions of study authors: this case shows that pulmonary arterial hypertension should be considered in patients who present with dyspnoea and a reduced exertion tolerance and who are known to use methylphenidate Comments from the study authors: using the Naranjo algorithm, the likelihood that OROS methylphenidate was responsible for precipitating pulmonary arterial hypertension in our patient was judged probable |
Karapinar 2014
Methods | A patient report of sudden hearing loss associated with methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 8 years oldIQ: > 70Sex: femaleEthnicity: not statedCountry: TurkeyComorbidity: noneComedication: none Sociodemographics: not stated |
Interventions | Methylphenidate type: RitalinMethylphenidate dosage: 10 mg/dayAdministration schedule: 5 mg twice dailyDuration of treatment: 4‐5 days Treatment compliance: yes |
Outcomes | Serious adverse events: About 24 hours after taking methylphenidate the patient began feeling loss of balance, nausea, vomiting. She was kept on the medication. After third dose, her symptoms became more severe. Clinical findings suggested sensorineural hearing loss associated with drug ototoxicity in the left ear. Methylphenidate treatment was discontinued, and the hearing loss treated. At the end of the 2‐month follow‐up period, her hearing in the affected ear showed no significant improvement. |
Notes | Key conclusions of the study authors: sensorineural hearing loss that occurred after the introduction of methylphenidate is a serious complication of the treatment, without resolution after discontinuation of the drug and administration of several treatments. The possibility of the development of irreversible sudden hearing loss should be borne in mind when patients are undergoing medical treatment of ADHD with methylphenidate |
Kazanci 2015
Methods | 2 patient reports of dyskinesia following a single dose of methylphenidate |
Participants | Case 1Diagnosis of ADHD: DSM 5Age: 8 years oldIQ: normalSex: maleEthnicity: not statedCountry: TurkeyComorbidity: noneComedication: noneSociodemographics: uneventful pregnancy and delivery history. Born from healthy, non‐consanguineous parents without any history of any psychiatric diseases, movement or muscle disorders Case 2 Diagnosis of ADHD: DSM 5Age: 6 years oldIQ: normalSex: maleEthnicity: not statedCountry: TurkeyComorbidity: noneComedication: noneSociodemographics: uneventful pregnancy and delivery history. Born from healthy, non‐consanguineous parents without any history of any psychiatric diseases, movement or muscle disorders |
Interventions | Case 1Methylphenidate type and dosage: methylphenidate IR 10 mg/dayMethylphenidate dosage: 5 mg twice dailyDuration of treatment: 3 hoursTreatment compliance: yes Case 2 Methylphenidate type and dosage: OROS methylphenidate 18 mg/dayAdministration schedule: not statedDuration of treatment: 2 hoursTreatment compliance: yes |
Outcomes | Case 1 Non‐serious adverse events: 3 hours after first dose of methylphenidate IR 5 mg: repetitive facial contortions and abnormal neck movement. The abnormal movements decreased during the following hours. Continuation of 5 mg methylphenidate immediate release twice daily. After 2 months further increase to 10 mg twice a day and no repetition of dyskinesia Case 2 Non‐serious adverse events: 2 hours after a single dose of OROS‐methylphenidate 18 mg: repetitive facial grimaces, lip smacking and protrusion of tongue. 2 hours later all symptoms have resolved. No treatment required. Continuation of 18 mg OROS‐methylphenidate. After 3 months, further increase to 27 mg OROS‐methylphenidate and no repetition of dyskinesia in the 8‐month follow‐up period |
Notes | Funding/vested interest: the authors report no conflicts of interest related to this article Key conclusions of the study authors: these side effects are assumed to occur due to individual drug sensitivities. Continuation of the methylphenidate treatment, despite dyskinetic side effects, may not cause any recurrent dyskinetic movements |
Kemner 2005 (FOCUS)
Methods | A 3‐week, prospective, open‐label, community‐based, multicentre, randomised, parallel study with 2 arms:
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Participants | Number of participants screened: not statedNumber of participants included: 1323Number of participants randomised to OROS‐MPH: 850Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐IV‐TR (subtype: combined (72%%), hyperactive‐impulsive (13%), inattentive (15%))Regarding the OROS‐MPH group:Age: mean 8.77, range 6‐12 years oldIQ: above 70Sex: 630 males, 219 femalesMethylphenidate‐naïve: 57.97%Ethnicity: white: 75.12%, African American: 14.74%, Asian: 0.71%, Hispanic: 6.72%, American Indian: 0.24%, others: 2.48%Country: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral systemWashout: more than 3 days or 5 half‐livesInvestigators were allowed to select starting dosesMean OROS‐MPH starting dose: 21.57 mgTitration: 2 weeks, after randomisationMean OROS‐MPH dose at week 3: 32.7 mg (12.1) / 1.01 mg/kg (0.45)Mean OROS‐MPH dose at week 3 for the African American patients: 32.8 mg (10.9)Mean OROS‐MPH dose at week 3 for the non‐African American patients: 32.7 mg (12.2)Administration schedule: once daily, in the morningDuration of intervention: 3 weeks Treatment compliance: 92% or higher |
Outcomes | Non‐serious adverse events:Blood pressure, heart rate, height and weight were recorded at baseline, week 2 and 3 Spontaneously reported adverse effects by patients, parents or investigators |
Notes | The FOCUS study: the Formal Observation of Concerta versUs Strattera, Phase IV studySample calculation: noEthics approval: yesFunding/vested interests: supported by funding from McNeil Consumer & Specialty Pharmaceuticals Key conclusions of the study authors: these results suggest greater ADHD symptom improvement with osmotic release oral system methylphenidate compared with atomoxetine Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, known methylphenidate non‐responders and methylphenidate‐optimal‐responders are excluded Supplemental information requested from the authors and YODA‐team in March and June 2014. No reply |
Khajehpiri 2014
Methods | A cohort study of methylphenidate use for 6 months |
Participants | Number of participants screened: not statedNumber of participants included: 71Number of participants followed up: 71Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 8.23, range: 4‐15 years oldIQ: not statedSex: 46 males (64.8%), 25 females (35.2%)Methylphenidate‐naïve: not statedEthnicity: not statedCountry: IranComorbidity: epilepsy 11.2%, neonatal jaundice 25.4%, seizure 4.2%, respiratory disease 2.82%, Down syndrome 2.82%, urinary tract infection 1.41%Comedication: methylphenidate plus risperidone: 23 (32.4%), methylphenidate plus other medications: 8 (11.3%)Sociodemographics: not stated Inclusion criteria All children under methylphenidate treatment alone or with other agents attending a university‐affiliated psychology clinic were screened regarding all subjective and objective adverse drug reactions (ADRs) of methylphenidateNo specific inclusion‐exclusion criteria regarding duration of methylphenidate treatment course, methylphenidate dose, and probable co‐administered medications for management of ADHD were used for patient selection |
Interventions | Methylphenidate type: not statedMean methylphenidate dosage/day: 20.5 (SD 9.6) mg (range 5‐40)Administration schedule: not statedDuration of intervention: < 1 month (2.8%) to ≥ 6 months (63.1%) Treatment compliance: 63.1% received methylphenidate for ≥ 6 months; 2.8% less than a month |
Outcomes | Type of adverse event/reaction/effect: ADRsMeasure method/instrument: face‐to‐face interview with patients or his/her parents at regular follow‐up office visits through a checklist of methylphenidate adverse reactions in relevant scientific literature and reviewing their brief office charts Serious adverse events: The WHO definition of a serious adverse reaction was used i.e. any adverse reaction resulting in death, life‐threatening situation, persistent or significant disability/incapacity, hospital admission, or prolonged hospital stay |
Notes | Sample calculation: noEthics approval: Tehran University Medical Ethics committeeFunding/vested interest: not stated Key conclusions of the study authors: our data suggested that although methylphenidate related adverse reactions were common in children with ADHD, they were mainly mild and non‐serious Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Khodadust 2012
Methods | A 6‐week randomised, double‐blind, parallel group study with 2 arms:
No control/no‐intervention group |
Participants | Number of participants screened: not statedNumber of participants included: 30Number of participants randomised to Ritalin: 15 and Stimdate: 15Number followed up in each arm: Ritalin: 14 and Stimdate: 14Number of withdrawals in each arm: Ritalin: 1 and Stimdate: 1Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined 100%)Age: Ritalin: 9.2 (0.5); Stimdate: 8.33 (0.5)IQ: above 70Sex: Ritalin: 12 males, 3 females; Stimdate: 15 femalesMethylphenidate‐naïve: noneEthnicity: 100% PersianComorbidity: noneComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Participants were randomly assigned to 2 methylphenidate preparations: Ritalin or StimdateFinal mean methylphenidate dose: Ritalin (29.2 (SD 9.1) mg), Stimdate (31.4 (SD 8.6) mg)Administration schedule: morning and noonDuration of intervention: 6 weeksTitration period: 4 weeks initiated after randomisation Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Nonserious adverse events checklist and telephone interviews asking about drug side effects were performed |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: none declared Key conclusions of the study authors: we recommend clinicians choose Ritalin or Stimdate according to the patient's preferences, sustained accessibility, primary response to treatment, and possible side effects encountered in course of treatment. This means that neither of these drugs has been proven to be superior to the other one Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes. See exclusion criteria 4 Supplemental information requested twice through email correspondence with the authors in June 2013. No reply |
Kim 2010
Methods | Single‐site, 6‐week, prospective, open‐label, flexible‐dose trial with osmotic release oral system methylphenidate (Concerta) monotherapy to examine OROS‐MPH effect on sleep in children with ADHD. Examination by physician at baseline, participants were seen at the first, second, fourth, and sixth weeks for repeated clinical evaluation and dosage titration |
Participants | Number of participants screened: not statedNumber of participants included: 27Number of participants followed up: 24Number of withdrawals: 3Diagnosis of ADHD: DSM‐IV (subtype: combined (66.7%), hyperactive‐impulsive (4.2%), inattentive (29.2%))Age: mean 8.2 (SD 1.4) yearsIQ: mean 105 (SD 11.5)Sex: 22 males, 2 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: South KoreaComorbidity: ODD: 2 (9.1%)Comedication: no medications that might influence clinical status or sleep characteristics were permittedSociodemographics: family history of ADHD: 4, 16.7% Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: the mean daily dose at week 6 was 29 (SD 6.8, range 18‐45) mg or 1.08 (SD 0.24) mg/kgAdministration schedule: once dailyDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Children's Depression Inventory, rated by parentsState Trait Anxiety Inventory (STAI), rated by parentsYale Global Tic Severity Scale, rated by parentsBarkley Side Effect Rating Scale, rated at 1st, 2nd, 4th and 6th week by parentsQuestions to parents about adverse events at each follow‐up visit (1st, 2nd, 4th and 6th week)Children's Sleep Habits Questionnaire (CSHQ), measured at week 6Height measured at week 1st, 2nd, 4th and 6th weekWeight measured at week 1st, 2nd, 4th and 6th weekBlood pressure measured at week 1st, 2nd, 4th and 6th weekHeart rate measured at week 1st, 2nd, 4th and 6th weekEKG measured at week 6Overnight polysomnography measured at week 6 Apnea and hypopnea, scored according to the recommended criteria of the American Academy of Sleep Medicine at week 6. Apnea was defined as an absence of oronasal airflow with minimal interval of 2 respiratory cycles. Hypopnea was defined as 50% air flow reduction or more for ≥ 2 respiratory cycles resulting in EEG arousals or oxygen desaturation (Z3%) |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interests: sponsored by Janssen Korea Key conclusions of the study authors: these results suggest that OROS MPH in open‐label treatment does not appear to impair sleep on either qualitative measures of sleep or sleep architecture and may improve some aspects (including sleep quality) Comments from the study authors: no significant effects were found on any laboratory tests and EKG. Another important finding indicated that children who experienced subjective sleep difficulties showed increased sleep onset latency, sleep onset delay, and bedtime resistance compared with those without sleep complaints during treatment Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no. All participants were methylphenidate‐naïve Supplemental information regarding outcome measures requested in February 2014. No reply |
Kim 2011
Methods | A 4‐week multicentre, open‐label before‐after study |
Participants | Number of participants screened: not statedNumber of participants included: 102Number of participants followed up: 97Number of withdrawals: 5Diagnosis of ADHD: DSM‐IV (subtype: combined (71.3%), hyperactive‐impulsive (5.9%), inattentive (23.8%))Age: mean 9.4 years (range 6‐12)IQ: above 75Sex: 94 males, 8 femalesMethylphenidate‐naïve: noneEthnicity: not statedCountry: KoreaComorbidity: oppositional defiant disorder (17.6%), anxiety disorder (17.6%), depression (9.8%), conduct disorder (2.9%), learning disorder (17.6%), others (5.9%)Comedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Prior to the study stabilised on immediate release methylphenidate (IR‐MPH) with a mean dose of 25 mg dailyThen osmotic release oral system methylphenidate (OROS‐MPH) dosage: 18 mg, 36 mg, or 54 mgThe participants were assigned to 1 of 3 OROS‐MPH doses based on their pre‐study dose of IR‐MPH. Participants receiving 5 mg of MPH‐IR 2‐3 times daily were assigned to the 18 mg once daily group; participants receiving 10 mg of MPH‐IR 2‐3 times daily were assigned to the 36 mg once daily group; and participants receiving 15 mg of MPH‐IR 2‐3 times daily or a total daily dose > 45‐60 mg were assigned to the OROS‐MPH 54 mg once daily group. Doses could be adjusted among these 3 levels at study visit 1 and 2 on days 7 and 14The dose of methylphenidate before entering the study was 10‐60 mg/day (mean 25.26 mg, the mean final doses of OROS‐MPH was 27.67 mg/dayAdministration schedule: once, morningDuration of intervention: 28 days Treatment compliance: 94.3% completed the 28 day study |
Outcomes | Non‐serious adverse events:All participants received a screening physical examination at baseline and on day 28. The participants' height and weight were also measuredAdverse events were documented at each visit by recording spontaneous reports of adverse events and asking parents/caregivers about the quality of their child's sleep, their children's appetite during the past week, and whether their children had experienced tics during the past week No serious adverse events were reported during the study |
Notes | Sample calculation: noEthics approval: approved by the Institutional Review Board for human participants at Seoul National University HospitalFunding: supported by Korean Jassen Pharmaceutical CompanyVested interest/authors' affiliations: none Key conclusions of the study authors: the results of this study indicated that an IR‐MPH regimen can be successfully changed to a once‐daily OROS‐MPH regimen without any serious adverse effects. The changes in parent/caregiver IOWA Conners ratings suggested that OROS‐MPH improved the control of symptoms after school, a finding that is consistent with the 12‐h duration of action of this medication. Because the therapeutic effect of OROS‐MPH is sufficiently longer than that of a twice daily dose of IR‐MPH, OROS‐MPH had significant positive effects on oppositional/defiant behaviour in addition to its effects on the core symptoms of ADHD. No significant differences between the 2 drugs were noted related to appetite loss and sleep disturbances. Tic symptoms significantly decreased after switching from IR‐MPH to OROS‐MPH Comments from the study authors: the investigators and participants were not blind to the treatment conditions Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes. The study excludes all patients who are hypersensitive to methylphenidate Supplemental information requested from the study authors in January 2014. No reply |
Kim 2014a
Methods | A review of the medical records of children and adolescents receiving MPH for ADHD between 2004 and 2011 |
Participants | Number of participants screened: not statedNumber of participants included: 157Number of participants followed up: 157Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: combined (71.3%), hyperactive‐impulsive (0.6%), inattentive (28.0%))Age: mean 8.9, range 5‐14 years oldIQ: 104.5 (SD 15.3), range 71‐143Sex: 134 males, 23 femalesMethylphenidate‐naïve: noneEthnicity: not statedCountry: KoreaComorbidity: ODD 30.6%, tic 17.8%, anxiety 11.5%, depressive disorder:4.5%, elimination disorder 2.5%Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: OROS‐MPH 52.2%, ER‐MPH 26.1%, combination 27.1%Mean methylphenidate dosage: 35.0 (SD 12.4 mg); 0.98 (SD 0.27) mg/kg/dayAdministration schedule: not statedDuration of intervention: ≥ 1 year; mean 28.8 months (SD 16.1); range 12‐88 months Treatment compliance: ≥ 80% |
Outcomes | Non‐serious adverse events: Weight and height Z score measured during the first and second year of MPH treatment |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: funded by the Korean Ministry of Education, Science and Technology Key conclusions of the study authors: these results suggest that methylphenidate could be related to weight and height deficit in Korean children and adolescents, although the effects were minor, and disappeared after the 1st year Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Kim 2014b
Methods | A naturalistic cohort study of methylphenidate use for 8 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 75Number of participants followed up: 57Number of withdrawals: 18Diagnosis of ADHD: DSM‐IV (subtype: combined (48%), hyperactive‐impulsive (12%), inattentive (24%), not specified (16%))Age: mean 9.7 (SD 2.8), range 6‐16 years oldIQ: not statedSex: 61 males, 14 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: KoreaComorbidity: 4 had oppositional defiant disorder, 5 had conduct disorder, 6 had anxiety disorder, 6 had learning disorder, 10 had depressive disorder, and 10 had mild to moderate intellectual disabilitiesComedication: not statedSociodemographics: yearly household income > USD 4000 = 23 (30.7%), USD 2000‐4000 = 20 (26.7%),< USD 2000 = 12 (16.0%), unknown = 20 (26.7%) Inclusion criteria: Children and adolescents aged 6‐16 with a DSM‐IV diagnosis of ADHD, with no baseline physical or laboratory abnormalities; were able to comply with the study visitation schedule and express a voluntary wish to withdraw from the trial |
Interventions | Methylphenidate type: osmotic release oral system (OROS)Mean methylphenidate dosage: 36.3 (SD 15.5) mg/dayAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Children who withdrew from the study because of adverse events |
Notes | Sample calculation: noEthics approval: not statedFunding/vested interests: the authors declare that they have no conflict of interest, and the organisation that sponsored the research had no part in the writing of the manuscript Key conclusions of the study authors: methylphenidate treatment for ADHD was associated with both symptom alleviation in children with ADHD and improvement in parental depressive mood and quality of life, suggesting that the effects of treatment could go beyond symptom improvement in ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Kim 2015a
Methods | A cohort study of methylphenidate use for 12 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 86Number of participants followed up: 37Number of withdrawals: 49Diagnosis of ADHD: DSM‐IV (subtype: inattentive, hyperactive‐impulsive or both)Age: mean 8IQ: > 70Sex: 34 males, 3 femalesMethylphenidate‐naïve: 2‐month washout period prior to studyEthnicity: not statedCountry: KoreaComorbidity: noneComedication: noneSociodemographics: none Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: immediate release or extended releaseMean methylphenidate dosage: 22.23 (SD 8.93) mg/0.70 (SD 0.20) mg/kgAdministration schedule: not statedDuration of intervention: 12 weeks Treatment compliance: 43% completed 12 week programme |
Outcomes | Non‐serious adverse events: All participants were evaluated for adverse events during each visit, and an interview with their care providers was conducted |
Notes | Sample calculation: noEthics approval: study approved by Institutional Review Board of Guro Hospital, Korea University Medical CenterFunding/vested interests: financial support from Jun Sang‐Bae Child and Adolescent Psychiatry Research Grant from the Korean Foundation of Neuropsychiatric Research Key conclusions of the study authors: HF and RMSSD suggested that parasympathetic dominance in ADHD can be changed by methylphenidate treatment Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested twice from the study authors in May and June 2016 with no reply |
Kim 2015b
Methods | A prospective, multicentre, open‐label cohort study of 116 children with ADHD treated with OROS methylphenidate for 12 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 143Number of participants followed up: 116Number of withdrawals: 27Diagnosis of ADHD: DSM‐IV (subtype: combined (36.2%), hyperactive‐impulsive (5.2%), inattentive (33.6%), NOS (25%))Age: mean 9.4, range: 6‐18 years oldIQ: mean 108.9 (SD 16.0)Sex: 100 males, 16 femalesMethylphenidate‐naïve: 89.7%Ethnicity: not statedCountry: KoreaComorbidity: depression (5.2%), anxiety (7.7%), tic disorder (7.7%), ODD (10.3%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Mean methylphenidate dosage: average daily dose increased from 19.20 (SD 3.11) mg/d (0.64 (SD 0.18) mg/kg per day) at week 1 to 34.13 (SD 13.80) mg/d (1.03 (SD 0.3318) mg/kg per day) at the end of 12 weeks of dosingAdministration schedule: not statedDuration of intervention: 12 weeks Treatment compliance: 12 patients dropped out because of medication non‐compliance |
Outcomes | 8 participants dropped out because of adverse events (29.6%) |
Notes | Sample calculation: noEthics approval: yesFunding: this study has been sponsored by Janssen, KoreaVested interests/authors' affiliations: the authors have no conflicts of interest to declare. Key conclusions of the study authors: treatment with OROS‐MPH was associated with symptomatic functional changes that were moderately correlated; therefore, symptomatic functional outcomes appear to be partially overlapped but distinct domains. Consequently, functional measures should be incorporated as important outcome measures in future treatment studies; the importance of treatments targeting functional improvement should be emphasised in the treatment of children with ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding adverse events requested through personal email correspondence with the authors in June 2016 with no reply |
Klein 2004
Methods | Randomised controlled trial parallel study comparing:
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Participants | Number of participants screened: 332Number of participants included: 129Number of participants randomised to each arm: MPH = 34; MPH + MPT = 34; MPH + ACT = 35Number of withdrawals in each arm: MPH: 10; MPH + MPT: 6; MPH + ACT: 6Diagnosis of ADHD: DSM‐III‐RAge: mean 8.2 (SD 0.8) years (range: 7.0‐9.9)IQ: mean WISC IQs were full scale, 109.5 (SD 14.5); verbal, 108.5 (SD 4.0); and performance, 108.7 (SD 15.0)Sex: 93% males, 7% femalesMethylphenidate‐naïve: 79.6%Ethnicity: 84% white, 13% African American, 2% Hispanic, and 1% otherCountry: USA and CanadaComorbidity: 55 (53.4%) ODD, 31 (30%) had 1‐2 symptoms of CD. 17 (16.5%) had an anxiety disorder (simple phobia, overanxious disorder, separation anxiety disorder), 4 (3.9%) had major depressionComedication: not stated Sociodemographics: 84 (81.2%) children lived with both parents, 13 (12.6%) with 1 parent (in all but one instance, the mother), and 6 (5.8%) with their mother and stepfather. Mean socioeconomic status was 2.5 SD 0.9 (range 1‐5) (Myers 1968). There were no significant difference in baseline demographics between the 2 groups Inclusion criteria
Exclusion criteria
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Interventions | Participants were randomly assigned to methylphenidate (MPH), methylphenidate and multimodal psychosocial treatment (MPH + MPT) or methylphenidate and attention control psychosocial treatment (MPH + ACT). Participants were balanced for ethnicity, sex, IQ, and oppositional defiant disorder. Assignment was done in blocks of 4 to enable group treatment componentsMean methylphenidate dosage: year 1: MPH = 35.8 (SD 8.5) mg, MPH + MPT = 35.6 (SD 9.4) mg, MPH + ACT = 38.4 (SD 8.5) mg. Year 2: MPH = 38.0 (SD 12.6) mg, MPH + MPT = 41.0 (SD 11.2) mg, MPH + ACT = 38.4 (SD 8.3) mgAdministration schedule: 8 am, noon, 4 pmDuration of intervention: 2 yearsTitration period: 5 weeks duration before randomisation Treatment compliance: the percentage of positive Ritalin acid assays was 87%, without differences between groups. Medication compliance was addressed by counting returned pills |
Outcomes | Non‐serious adverse events: Children's Depression Inventory (CDI) (Kovacs 1992)Piers‐Harris Children's Self‐Concept Scale (Amato 1984) Before every visit, teachers were called to obtain information about the child's school performance. The sessions were used to assess vital signs (weight, height, pulse, blood pressure), side effects (reported by parent and child), and the child's overall condition |
Notes | Sample calculation: not statedEthics approval: not statedFunding: supported by NIMH grants RO1 MH44848 (H.A.) and RO1 MH44842 (L.H.).Vested interests: Dr Klein is a member of the ADHD Advisory Board of Shire Pharmaceutical Co. Key conclusions of the study authors: in stimulant‐responsive young children with ADHD without learning and conduct disorders, there is no support for academic assistance and psychotherapy to enhance academic achievement or emotional adjustment. Significant short‐term improvements were maintained over 2 years Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
Kordon 2011
Methods | A prospective, open‐label, single arm, non‐interventional cohort study of osmotic release oral system (OROS) methylphenidate use for 12 weeks after abrupt switching from immediate release (IR) methylphenidate |
Participants | Number of participants screened: 616Number of participants included: 598 (ITT population)Number of participants followed up: 579Number of withdrawals: 110 (18.4%)
Diagnosis of ADHD: ICD‐10 (subtype: F90.0 (63.5%), F90.1 (37%), F90.8 (2%), F90.9 (2.8%), F98.8 (9.9%)).
Age: mean 10.9, range 6‐17 years oldIQ: not statedSex: 507 males, 91 femalesMethylphenidate‐naïve: 8.8%Ethnicity: not statedCountry: GermanyComorbidity: 33.3% (subtype: conduct disorder (23.4%), oppositional defiant disorder (16.6%), anxiety disorder (3.8%), obsessive compulsive disorder (1.5%), substance abuse (0.8%)Comedication: not statedSociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate starting dose: 29.5 SD 12 mg/day (range: 18‐108 mg/day, median 36 mg/day)Methylphenidate final dose: 33.5 SD 13.2 mg/day (range: 18‐108 mg/day, median 36 mg/day)Administration schedule: once dailyDuration of intervention: 12 weeks Treatment compliance: 0.8% of ITT non compliant |
Outcomes | 3 visits in clinic: baseline, after 1 month of treatment, after 3 months of treatment, or on premature terminationAdverse events: World Health Organization ‐ Adverse Reactions Terminology (WHO‐ART). Rated throughout the study. Spontaneous reporting. ITT safety population included only those who had ≥ 1 post‐baseline efficacy measurementSleep quality and appetite: rated at each visit using a 5‐point scale (1 = very good, 5 = very bad)Vital signs: blood pressure and heart rate. Measured at every visit Body weight: measured at baseline and after 3 months of treatment |
Notes | Sample calculation: noEthics approval: independent ethics committee (Freiburg, Germany)Funding/vested interests: editorial assistance funded by Janssen‐CilagAuthors' affiliations: BS is employed by Janssen‐Cilag, KR is a consultant working for GEM, and paid by Janssen‐Cilag Key conclusions of the study authors: in this naturalistic setting, transitioning from IR‐MPH to OROS‐MPH, in patients who showed previously insufficient response and/or poor tolerability, was successful. OROS methylphenidate was generally safe and well tolerated. Children/adolescents with ADHD who were switched from IR methylphenidate to OROS methylphenidate experienced clinically relevant improvements in symptoms, HRQoL and social functioning Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: unclear Supplemental information requested from the study authors twice in July 2014 with no reply |
Kratochvil 2002
Methods | A randomised, open‐label, parallel, cohort study of
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Participants | Number of participants screened: 319Number of participants included: 228Number randomised to methylphenidate: 44Number followed up: 25Number of withdrawals: 19Diagnosis of ADHD: DSM‐IV (subtype: combined (77.3%), inattentive (22.7%))Age: mean 10.4 (SD 2.1) years oldIQ: > 70Sex: 44 malesMethylphenidate‐naïve: not statedEthnicity: white: 81.8%, others: 18.2%Country: USA and CanadaComorbidity: ODD 59.1%, major depressive disorder 13.6%, elimination disorder 11.4%Comedication: not stated, but other psychoactive medication not permittedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: initial dose 5 mg 1‐3 times daily with an ascending dose titration based on the investigator's assessment of clinical response and tolerabilityMean methylphenidate dosage: 0.85 SD 0.53 mg/kg pr day, or 31.3 SD 18.7 mg/dayMedian dose: 0.74 mg/kg/day or 27.5 mg/day. Total daily dose was not to exceed 60 mgAdministration schedule: 1‐3 times daily, based on clinical response and tolerabilityDuration of intervention: 10 weeksTreatment compliance: not stated Washout period prior to treatment ‐ duration not specified |
Outcomes | Non‐serious adverse events At weekly visits: ECG, liver function, blood count, urinalysis, open‐ended questions |
Notes | Sample calculation: yes, but sample size and power computations were performed to answer questions specific to the relapse‐prevention portion of the study which followed the open‐label period described in this paperEthics approval: yesFunding/vested interest: study funded by Eli Lilly and CoAuthors' affiliations: the authors are either employees or paid consultants and/or investigators of Eli Lilly. The employees are also shareholders Key conclusions of the study authors: the results of this study provide preliminary evidence that the magnitude and profile of symptom reduction associated with atomoxetine administration and its tolerability are comparable to that observed with methylphenidate Comments from the study authors: in our trial, investigators had latitude in the frequency and timing of methylphenidate dosing, and methylphenidate outcomes might have been different had all methylphenidate‐treated patients been required to receive fixed dosing on a thrice‐daily basis. A relatively large proportion of patients in both groups withdrew from the study early. No single reason appears to have accounted for this, but this could limit the interpretability of the results. The groups were not well matched for gender. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information regarding IQ received through personal email correspondence with the authors in June 2014 (Kratochvil 2014 [pers comm]) |
Kraut 2013
Methods | A database study of methylphenidate use |
Participants | Number of participants screened: not statedNumber of participants included: 2,150,362Diagnosis of ADHD: ICD‐10 German Modification (subtype: not stated)Mean age: not stated, range: 3‐17IQ: not statedSex: not statedEthnicity: not statedCountry: GermanyComorbidity: yesComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | 8 participants dropped out due to adverse events |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interests/authors' affiliations: AAK received funding from Sanofi Pasteur MSD for the annual conference of the German Society of Epidemiology in 2010. The present work is unrelated to the funding mentioned. TB served in an advisory or consultancy role for Bristol Myers‐Sqibb, Develco Pharma, Lilly, Medice, Novartis, Shire, Viforpharma; YES‐Pharma. He received conference attendance support and conference support or received speaker's fee by Lilly, Janssen McNeil,Medice, Novartis and Shire. He is/has been involved in clinical trials conducted by Lilly and Shire. The present work is unrelated to the above grants and relationships. RTM received research funding from Sanofi PasteurMSD and Bayer‐Pharma. The mentioned funding is unrelated to the present work. EG is running a department that occasionally performs studies for pharmaceutical industries with the full freedom to publish. The companies include Mundipharma, Bayer‐Pharma, Stada, Sanofi‐Aventis, Sanofi‐Pasteur, Novartis, Celgene and GSK. In the past, EG has been consultant to Bayer‐Schering, Nycomed, Teva and Novartis. The present work is unrelated to the stated relationships. IL, CL, UP, and FP declare no competing interests Key conclusions of the study authors: children starting methylphenidate treatment had a high prevalence of pre‐existing psychiatric comorbidities which may affect methylphenidate prescribing. Cardiovascular and other comorbidities were generally rare, but require attention as they were more common among those who received methylphenidate than in the control group Supplemental information requested through personal email correspondence with the authors in June 2016. Data were not available |
Lahat 2000
Methods | A cohort study of bone density in children with ADHD treated with methylphenidate for a mean of 13 (SD 4) months with a mean daily dose of 10 mg (SD 2.5) mg |
Participants | Number of participants screened: 20Number of participants included in the methylphenidate group: 10Number of participants followed up: 9Number of withdrawals: 1Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 8.9 (SD 1.6) years oldIQ: not statedSex: 20 malesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: IsraelComorbidity: not statedComedication: noneSociodemographics: not statedThere were no significant difference in baseline demographics between the 2 groups except for the use of methylphenidate Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 0.5 mg/kgMean methylphenidate dosage: 10 (SD 2.5) mg, range 7.5‐12.5 mgAdministration schedule: not statedDuration of intervention: 12‐24 months, mean 13 (SD 4) months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Abnormal levels of:
Weight and height measured |
Notes | Sample calculation: not statedEthics approval: approved by the ethics committee of our medical centre.Funding/vested interests/authors' affiliations: not stated. On a more recent publication by Lahat, he was listed as working for Teva Pharmaceutical Industries Ltd., Teva Israel, Netanya, Israel Key conclusions of the study authors: in conclusion, our data do not support a significant effect of methylphenidate on bone mineral density turnover in children when used for 1‐2 years. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information from the study authors requested twice with no reply |
Lakic 2012
Methods | A cohort study of the influence of methylphenidate treatment on the occurrence of tics and exacerbation of pre‐existing tics |
Participants | Number of participants screened: not statedNumber of participants included: 68Diagnosis of ADHD: DSM‐TR‐IV (subtype: not stated)Age: range 7‐15 years oldIQ: > 70Sex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: SerbiaComorbidity: tic disorder 9.7%Comedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria: |
Interventions | Methylphenidate type: sustained‐releaseMethylphenidate dose range: 18‐36 mg/day (individualised dose)Administration schedule: not statedDuration of intervention: > 6 weeks, up to 6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Assessment of the occurrence of tics at the time of diagnosis, start of therapy and during methylphenidate treatment. Furthermore, monitoring (type, intensity, duration) of pre‐existing tics during methylphenidate treatment |
Notes | Sample calculation: not statedEthics approval: not statedFunding: no fundingAuthors' affiliations: not stated Key conclusions of the study authors: tics as a side effect of sustained‐release methylphenidate treatment in our patients was predominantly motor, of mild intensity and transient in nature, and did not require cessation of therapy Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental outcome data and information about IQ and funding were received through personal email correspondence with the authors in October 2013 (Lakic 2013 [pers comm]) |
Lamberti 2015
Methods | An observational prospective study of immediate‐release methylphenidate and cardiovascular effects |
Participants | Number of participants screened: not statedNumber of participants included: 54Number of participants followed up: 54Number of withdrawals: 0Diagnosis of ADHD: DSM‐5 (subtype: not stated)Age: mean 12.14 (SD 2.6) years (range 6‐19)IQ: not statedSex: 51 males, 3 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: ItalyComorbidity: no cardiovascular, pulmonary, or endocrine disordersComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate: immediate release (IR‐MPH)Methylphenidate dosage: 10‐60 mg according to the participant's weightMean methylphenidate dosage: 18.5 mg/dayAdministration schedule: each treatment condition was administered 7 days, 2‐3 times daily, at breakfast (approximately 7:30 am), at lunch (approximately 12:30 pm), and in some cases, early afternoon (approximately 3:30 pm)Duration of intervention: 4 weeks Treatment compliance: 100% |
Outcomes | For each patient, 2 standard 12‐lead ECGs were obtained at a paper speed of 25 mm/second with the same instrument (Cardioline delta 3 plus), on the same day and under similar conditions. The first (predose) ECG examination was performed before the administration of the first daily dose of IR‐MPH; the second (postdose) ECG was executed 2 hours after drug intake, simultaneously with the serum peak of methylphenidate Non‐serious adverse events Treatment with immediate‐release methylphenidate was associated with a slight increase of systolic and diastolic BP |
Notes | Sample calculation: not statedEthics approval: the study was approved by the local ethics committeeFunding/vested interests: none Key conclusions of the study authors: this study underlines the relative cardiac safety of IR‐MPH in childhood, even if stimulants may exert a cardiovascular effect on BP and HR. However, particular caution should be exercised by physicians in prescribing these drugs to patients with a genetic predisposition to arrhythmias. It might be useful to carry out an ECG examination in all patients starting methylphenidate therapy Comments from the study authors: the most important limitation of this study includes the lack of a long‐term follow‐up. More studies are needed to confirm the cardiovascular safety during long‐term therapy Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Langevin 2012
Methods | A controlled before‐after study of methylphenidate use for ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 10Number of participants included as cases: 5 and controls: 5Number of participants followed up: 10Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV TM (subtype: combined (80%); inattentive (20%))Age: mean 8.13 years (range 7‐9)IQ: normalSex: 8 males, 2 femalesMethylphenidate‐naïve: not statedEthnicity: white (90%), African‐Canadian (10%)Country: CanadaComorbidity: 20% ODD, 10% seasonal affective disorderComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: immediate‐release or moderate‐releaseMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: 6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Sleep quality and numbers of hours of sleep |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests/authors' affiliations: this study was supported by a grant from the University of Alberta (Killam Research Fund) Key conclusions of the study authors: the principal results support the study's hypothesis and show a significant baseline difference (P = 0.008) between the nocturnal movements of the ADHD children and those of the control children Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Larrañaga‐Fragoso 2015
Methods | A cohort study of methylphenidate use for 9 months |
Participants | Number of participants screened: not statedNumber of participants included: 14Number of participants followed up: 14Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean 11 (SD 2.79) years (range: 7‐17)IQ: not statedSex: 6 males, 8 femalesMethylphenidate‐naïve: 100%Ethnicity: 100% whiteCountry: SpainComorbidity: noneComedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: unknownMethylphenidate dosage: unknownAdministration schedule: unknownDuration of intervention: 9 months Treatment compliance: unknown |
Outcomes | Ocular examination before and after cycloplegia was performed at each visit, including Pentacam imaging of the anterior chamber Visual acuity, sphere, spherical equivalent refraction, intraocular pressure, and cup:disk ratio |
Notes | Sample calculation: not statedEthics approval: clinical research ethics committeeFunding/vested interests: not stated Key conclusions of the study authors: methylphenidate does not seem to affect refraction in most children with ADHD. After 9 months of treatment, however, there was a reduction in the anterior chamber depth, which has been described as a powerful predictor of angle closure glaucoma. Further investigation of the potential ocular side effects of methylphenidate is warranted Comments from the study authors: this study is limited by the small sample size and short follow‐up period. Further studies are warranted, because the decrease in ACD observed in this study may be a risk factor for the development of angle closure glaucoma Supplemental information regarding comorbidity received through personal email correspondence with the authors in June 2016 (Larrañaga‐Fragoso 2016 [pers comm]). The authors were not able to supply us with information regarding IQ, ADHD subtype, methylphenidate dosage and type |
Lee 2007
Methods | A cohort of methylphenidate use for 3 weeks plus 1 week baseline |
Participants | Number of participants screened: not statedNumber of participants included: 119Number of participants followed up: 110Number of withdrawals: 9Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 8.5 (SD1.6) years (range 6‐13)IQ: > 70Sex: 107 males, 12 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: South KoreaComorbidity: oppositional behaviours (14.8%), conduct behaviours (2.3%), obsessive‐compulsive behaviours (0.8%), generalised anxiety symptoms (7.8%), depressive symptoms (12.5%), learning problems (18.8%)Comedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: osmotic release oral sytem (OROS)Mean methylphenidate dosage: 0.87 mg/kg (SD 0.33)Administration schedule: dailyDuration of intervention: 3 weeks Treatment compliance: 2 participants discontinued trial due to protocol non‐compliance |
Outcomes | Non‐serious adverse events
1 respondent withdrew from trial during first week of trial on 18 mg OROS because of decreased appetite of moderate severity while another participant withdrew in the same period because of insomnia of mild severity |
Notes | Sample calculation: yesEthics approval: not statedFunding/vested interests: funded by Janssen Korea Key conclusions of the study authors: these data provide support for the benefit of the once daily methylphenidate preparation Concerta, in the treatment of Korean children with ADHD. Children were initiated safely in this short‐term trial, and its effectiveness was evident in the behavioural, as well as neuropsychological measurements Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Lee 2009
Methods | A prospective 12‐week, open‐label, multicentre study to examine optimal dosage of osmotic release oral system methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 144Number of participants followed up: 88Number of withdrawals: 56Diagnosis of ADHD: not stated (subtype: not stated)Age: mean 9.43, range 6‐18 years oldIQ: 109.7 (SD 16.1)Sex: 77 males, 11 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: KoreaComorbidity: oppositional defiant disorder (n = 12), tic disorder (n = 9), depressive disorder (n = 3), and anxiety disorder (n = 6)Comedication: not statedSociodemographics: not stated Exclusion criteria
|
Interventions | Methylphenidate type: osmotic release oral system (OROS) extended releaseMethylphenidate dosage: 18 mg or 27 mg (depending on clinical judgment)Mean methylphenidate dosage: 0.99 mg/kg (SD 0.29) at 12 weeks (n = 88)Administration schedule: not statedDuration of intervention: 12 weeks plus 9‐week initial titration Treatment compliance: not stated |
Outcomes | Of the 144 participants enrolled in the study, 8 dropped out due to adverse events (28.6%) during the titration phase |
Notes | Sample calculation: not statedEthics approval: approved by the Institutional Review Boards of all 7 sitesFunding/vested interests: this study was supported by Janssen Korea Ltd. The authors have no financial conflicts of interest Key conclusions of the study authors: high response time (RT) among Korean children with ADHD on a computerised continuous performance attention test RT variability may predict poor response to MPH treatment in children with ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information requested twice from the study authors regarding supplemental data on adverse events with no answer |
Lee 2012
Methods | A cohort study of methylphenidate use in children with ADHD for 4 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 93Number of participants followed up: 63Number of withdrawals: 30Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (84.1%), hyperactive‐impulsive (not stated), inattentive (not stated))Age: mean 8.58 (SD 1.61) yearsIQ: mean 96.39 (SD 17.01)Sex: 56 males, 7 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: KoreaComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: osmotic release oral system (OROS) or Metadate‐CDMean methylphenidate dosage: 1.0 (SD 0.25) mg/kg. Initial doses for OROS‐MPH 18 mg and Metadate‐CD 10 mg; dose range and maximum dose for OROS‐MPH was 0.4‐1.8 mg/kg and 72 mg and for Metadate‐CD was 0.6‐1.5 mg/kg and 60 mg)Administration schedule: dailyDuration of intervention: 4 weeks Treatment compliance: the children and caregivers were visited weekly to review whether medication was taken as prescribed |
Outcomes | Non‐serious adverse events
|
Notes | Sample calculation: irrelevant
Ethics approval: the study protocols were reviewed and approved by each site's Institutional Review Board
Funding/vested interests: Yeungnam University research grants in 2009. No conflicts of interest statement Key conclusions of the study authors: methylphenidate had negative impacts on sleep among young ADHD children, but different preparations and doses did not affect the result Comments from the study authors: data yielded by a sleep diary, which relies on the validity of parents' observations, may not be an accurate representation of reality. Used a flexible titration method and did not divide the participants into parallel groups from the beginning. Lack of blinding. More than 30% did not complete the procedure. Comments from the review authors: participants were dropped from the study if they violated the study protocol by failing to take the prescribed medicine more than twice a week, or if they presented with serious adverse effects such as seizures or hallucinations Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested from the study authors in August 2014. Email sent twice but no answer received |
Lee 2014
Methods | A cohort study of medication‐related adverse events in children and adolescents reported to the US Food and Drugs Administration (FDA) from 2007 to 2012 |
Participants | Number of patients screened: not statedNumber of participants included: 4055Diagnosis of ADHD: not statedAge: mean 10.2 years (range: 1‐17)IQ: not statedSex: not statedEthnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria: All patient reports submitted to the FDA Adverse Event Reporting System (FAERS) between 1 January 2007 and 27 August 2012 for children (1‐11 years) and adolescents (12‐17 yrs)Exclusion criteria: none stated |
Interventions | Methylphenidate type: not statedMean methylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Type of adverse event: all adverse events and adverse events with serious outcomes. The description of the adverse events is coded based on a 'preferred term' from the Medical Dictionary for Regulatory Activities (MedDRA) terminology |
Notes | Sample calculation: noEthics approval: not reportedFunding/vested interests/authors' affiliations: no Key conclusions of the study authors: our findings highlight the high‐risk medications and the corresponding adverse events commonly reported in children and adolescents. Information from this analysis can be used to prioritise drugs and adverse events that might be investigated in future studies of drug safety in children Comments from the study authors: our findings are consistent with other studies that have used data from spontaneous reporting systems to examine the adverse events in children Supplemental information regarding data and IQ requested through personal email correspondence with the authors in June 2016 (Schumock 2016 [pers comm]). The authors were not able to retrieve the information |
Lewis 2012
Methods | A patient report of a paediatric patient with glaucoma receiving methylphenidate treatment for 8 years |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 10 years oldIQ: within normal limitsSex: femaleCountry: USAComorbidity: primary open angle glaucoma. Physical examination within normal limitsComedication: latanoprost 0.005% eye drops twice daily Sociodemographics: not stated |
Interventions | Methylphenidate type: extended releaseMethylphenidate dosage: 18 mg/day titrated to 54 mg/day over 6 monthsAdministration schedule: once dailyDuration of treatment: 8 years Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsNo exacerbation of glaucoma:Before methylphenidate treatment: after treatment for glaucoma, the patient's intraocular pressure was brought to a stable range between 16 mmHg and 19 mmHg in both eyes During methylphenidate treatment: ophthalmic examination every 6 months showed intraocular pressure consistently in the 16‐19 mmHg range bilaterally |
Notes | Key conclusions of the study authors: this report concluded stimulant medication (methylphenidate) should not be withheld in patients with glaucoma as long as intraocular pressure (IOP) remains well controlled Comments from the study authors: the actual risk associated with adrenergic medications in patients with open angle glaucoma is negligible, and there are no studies proving adverse effects on IOP in normal or open angle eyes Supplemental information regarding IQ received through personal email correspondence with the authors in March 2014 (Lewis 2014 [pers comm]) |
Li 2011
Methods | An 8‐week, randomised, double‐blind, parallel study with 2 interventions:
|
Participants | Number of participants screened: 136Number of participants included: 72Number of participants randomised to methylphenidate: 36Number followed up: 34Number of withdrawals: 2Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 9.2, range 3‐13 years oldIQ: almost all above 70Sex: 23 males, 13 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: ChinaComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: not statedMean methylphenidate dosage: 1 mg/kg/dayAdministration schedule: not statedDuration of intervention: 8 weeks Treatment compliance: not stated |
Outcomes | Serious adverse events:
Non‐serious adverse events:
|
Notes | Sample calculation: noEthics approval: all research procedures were permitted by the medical ethics committee of Provincial Hospital Affiliated to Shandong UniversityFunding/vested interests: grants from the Chinese Medicine Administration Bureau of Shandong ProvinceAuthors' affiliations: not stated Key conclusions of the study authors: compared to methylphenidate, Ningdong granule is effective and safe for ADHD children in the short term, increases the homovanillic acid concentration in sera to regulate dopamine metabolism, and promises to be an alternative medication, safely and effectively Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information received through personal email correspondence with the study authors in April 2013 (Li 2013 [pers comm]) |
Lyon 2010
Methods | A cross‐over trial with 2 interventions:
10 children with ADHD and TD were given dexmethylphenidate on 1 visit and no medication on another (day 2 and 3), using a random cross‐over design |
Participants | Number of participants screened: 51Number of participants included: 13Number of participants followed up: 10Number of withdrawals: 3Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (50%), inattentive (50%))Age: mean 12.7 years old, range 8‐16 years oldIQ: mean 104, range 85‐118Sex: 9 males, 1 femaleMethylphenidate‐naïve: not statedEthnicity: white 70%, African American 0%, Asian 0%, Hispanic 30%, others 0%Country: USAComorbidity: Tourette's 100%Comedication: 70%Sociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Participants were randomly assigned to 1 of 2 possible drug condition orders of (0.15 mg/kg) methylphenidate and placeboMean methylphenidate dosage: 7.5 mg/dayAdministration schedule: once a dayDuration of each medication condition: 1 dayWashout prior to study initiation: not statedMedication‐free period between intervention: not statedTitration period: none Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsThe Safety Monitoring Uniform Report Form (SMURF) (Greenhill et al. 2004) was administered by one of the investigators on day 1, and after TSP procedures on days 2 and 3 Adverse events were generally mild. 7 (70%) participants experienced ≥ 1 minor adverse event during the study. The most common adverse events possibly related to study drug were drowsiness or sedation (20%) and stomach discomfort (20%) |
Notes | Sample calculation: not statedEthics approval: all study procedures were approved by the institutional review boards (IRB) at the University of Wisconsin‐Milwaukee and New York University Langone Medical Center Key conclusions from study authors: preliminary results suggest that dexmethylphenidate does not appear to enhance tic suppressibility in children with ADHD and TD. First, there was a clear tic‐reduction effect, and not exacerbation, with a 1‐time dose of dexmethylphenidate compared to no medication in these children. Second, youths with TD and ADHD appear to be able to suppress their tics with a behavioural reward comparable to youths with TD without ADHD Comments from the study authors: some limitations of the study design need to be taken into account. First, our sample size was small and participants were recruited from a specialised clinic. Thus, findings may not generalise to non‐specialty settings. Second, 70% of participants were receiving medication for TD, anxiety, OCD, or asthma, and our results might have differed if the participants were not receiving concomitant medication. Third, investigators, parents, and participants were not blind to medication status, because medication was administered openly Comments from the review authors: ADHD outcome data are only available for 7 participants ('data from 3 participants were unusable as a result of computer malfunction') Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Maayan 2009
Methods | A cohort study of long‐acting methylphenidate use for 4 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 11Number of participants followed up: 8Number of withdrawals: 3Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (91%), hyperactive‐impulsive (9%))Age: mean 5.1, range: 4‐5 years oldIQ: above 70Sex: 9 males, 2 femalesMethylphenidate‐naïve: 100%Ethnicity: white 27%, Hispanic 73%Country: USAComorbidity: ODD 9%Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: long actingMethylphenidate dosage: 10‐30 mg/day, mean 17.73 mg/dayAdministration schedule: morningDuration of intervention: 4 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsDecreased appetite was experienced by 7 participants (64%) following treatment initiation. 5 out of these 7 participants continued to report decreased appetite for the duration of the studyDifficulty sleeping occurred in 3 participants (27%)Emotional lability and gastrointestinal pain were reported by 2 participants (18%) These adverse events were resolved by the end of the study. 1 participant who terminated the study early experienced moderate levels of insomnia, vomiting, decreased appetite, and stomach pain, and another who also terminated early experienced moderate irritability |
Notes | Sample calculation: noEthics approval: the study was approved by the New York State Psychiatric Institute Columbia University Institutional Review Board (IRB) and was conducted in accordance with the ethical standards of the 1975 Declarations of Helsinki as revised in 2000 (World Medical Association).Funding/vested interests/authors' affiliations: Novartis Pharmaceuticals Corporation provided the study medication. No financial support was received from Novartis. Dr Maayan receives grant support from Eli Lilly and Pfizer. Dr Greenhill received support from Novartis and has an consultant arrangement with Pfizer. He has been awarded research contract to study Risperidon by Johnson and Johnson and has been awarded an investigator‐initiated grant to study aripiprazole by Otsuka Key conclusions of the study authors: long‐acting methylphenidate was safe and effective for the treatment of ADHD in the 4‐ and 5‐year‐olds participating in this study. Rates of adverse events were higher than previously reported in methylphenidate trials of school‐aged children. 10‐mg/day doses failed to achieve response in the 5 children who could not tolerate higher doses Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
MacDonald 2005
Methods | A cross‐over study of 5 children, 4 boys, 1 girl all aged 10‐14 years old Volunteers participated in 13 sessions |
Participants | Number of participants screened: 14Number of participants included: 5Number of participants followed up: 5Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 12, range 10‐14IQ: not statedSex: 4 males, 1 femaleMethylphenidate‐naïve: noneEthnicity: not statedComorbidity: not statedComedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: individual maintenance dose as taken by participant prior to study enrolment, range 10 mg twice/day to 30 mg thee times/dayAdministration schedule: morningDuration of intervention: ≥ 1 year Treatment compliance: not stated |
Outcomes | No relevant outcomes |
Notes | Sample calculation: noEthics approval: Human Subjects Institutional Review Board at Western Michigan University, Kalamazoo, MI
Funding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: 3 of 5 participants reliably chose methylphenidate more often than placebo. Differences between the number of methylphenidate, placebo, and neither choices across participants were significant (P < 0.01) Comments from the study authors: relevant clinical effects were not observed under methylphenidate compared to placebo conditions. Although the questionnaires used in this study have been used to measure subjective effects in children, the psychometric integrity of these instruments has not been determined in these populations. In addition, the reading level of the children may have affected the manner in which the subjective effects were evaluated, such that the participants may not have fully understood the items on the questionnaires Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Machado 2010
Methods | A patient report of a 6‐year old girl developing acute choreoathetoid movements induced by methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 6 years oldIQ: above 70Sex: femaleEthnicity: not statedCountry: USAComorbidity: psychomotor developmental delay, discrete macrocephalus, congenital mild ataxia, and hyperactivity. Otherwise healthyComedication: none Sociodemographics: her parents were first‐degree relatives. No family history of neurological disease |
Interventions | Methylphenidate type: extended releaseMethylphenidate dosage: 18 mg/dayAdministration schedule: once daily in the morning Duration of treatment: single dose |
Outcomes | Serious adverse events: After single dose extended‐release methylphenidate 18 mg: choreoathetoid movements of orofacial muscles, arms, and legs, with transient dystonic postures of the right arm |
Notes | Key conclusions of the study authors: we believe that the immediate response ensuing chlorpromazine prescription argues in favor of a specific role for dopamine receptor antagonists in methylphenidate‐induced chorea Comments from the review authors: the author is not sure that the girl fulfilled criteria E of the ADHD diagnosis (DSM‐IV). The author only saw the girl once in the emergency unit Supplemental information regarding diagnosis and IQ received through personal email correspondence with the authors in October 2013 (Machado 2013 [pers comm]) |
Maia 2008
Methods | 8‐week open clinical trial |
Participants | Number of participants screened:159Number of participants included: 120Number of participants followed up: 39Number of withdrawals: 6
Diagnosis of ADHD: DSM‐IV (subtype: combined (67.7%))Age: mean 12.17 (SD 2.67)IQ: mean 89.11 (SD 16.07)Sex: 36 males, 3 femalesMethylphenidate‐naïve: noneEthnicity: European‐Brazilian (31), other (8)Country: BrazilComorbidity: oppositional defiant disorder (48.4%), anxiety disorder (29%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Patients switched from equivalent dose of immediate release methylphenidate to methylphenidate SODAS. The mean methylphenidate‐IR dose at baseline was 0.68 (SD 0.24) mg/kg/day and the mean methylphenidate‐SODAS dose prescribed at baseline was 0.7 (SD 0.25) mg/kg/dayMethylphenidate type: spheroidal oral drug absortion system (SODAS)Methylphenidate dosage: 20‐40 mgMean methylphenidate dosage: 0.7 (SD 0.25) mg/kg/dayAdministration schedule: once dailyDuration of intervention: 8 weeks Treatment compliance: the treatment adherence was checked by direct inquiring patients on compliance at week 4 and 8 |
Outcomes | Serious adverse events:
Barkley Side Effect Rating Scale (SERS) Non‐serious adverse events: Barkley Side Effect Rating Scale (SERS)SNAP‐IVEfficacy and side events were rechecked at week 4 and 8 using respectively the total, inattentive, hyperactive/impulsive scores of the SNAP‐IV and the total score of the SERS |
Notes | Sample calculation: no
Ethics approval: yes
Funding: Novartis
Vested interest/authors' affiliations: none Key conclusions of the study authors: results suggested that switching from immediate release methylphenidate to methylphenidate SODAS did not affect stabilisation of ADHD symptoms in most patients. Methylphenidate prescription in patients with previous cardiovascular conditions must be extremely careful Comments from the review authors: the additional data received from the authors do not provide the numbers of adverse events in the paediatric population Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Man 2015
Methods | A cohort study of methylphenidate and the risk of trauma |
Participants | Number of participants screened: 17,381Number of participants included: 4934Number of participants followed up: not statedNumber of withdrawals: not stated
Diagnosis of ADHD: ICD‐9‐CM (subtype: not stated)
Age: mean age at commencement of observation 6.9 years. Range 6‐19
IQ: not stated
Sex: 4309 males (87%), 625 females (13%)
Methylphenidate‐naïve: not statedEthnicity: not statedCountry: Hong KongComorbidity: acute reaction to stress (1.46%), adjustment disorder (1.42%), anxiety disorder (1.64%), autism spectrum disorder (12.7%), disturbance of conduct not elsewhere classified (2.39%), disturbance of emotions specific to childhood and adolescence (10.9%), specific delays in development (12.2%), other psychiatric comorbidities (8.84%)Comedication: no atomoxetine ‐ not otherwise statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: all formulations, standard and extended releaseMethylphenidate dosage: median daily dosage: 20 mg, IQR of daily dosage: 20 mg (all), 20 mg(male), 15 mg (female)
Administration schedule: not statedDuration of intervention: median length of prescription 70 days Treatment compliance: not stated |
Outcomes | Trauma‐related ED admission Non‐trauma related ED admission |
Notes | Sample calculation: with reference to the equation developed by Musonda 2006, an IRR of 0.9 with 80% power (2‐sided 95% CI) could be detected with a minimum of 4062 trauma‐related ED admissionsEthics approval: not statedFunding: funding received from the Research Grants Council (RGC, Hong Kong) under grant agreement number 781913 for the study (Effects of Attention Deficit Hyperactivity Disorder pharmacotherapy on hospital accident and emergency admission due to injury‐related events (ATHAN))
Vested interests: Dr Chan reports grants from Janssen (a division of Johnson & Johnson), BMS, Pfizer, The Research Grant Council (RGC, Hong Kong), received for other work. Dr Coghill reports grants and personal fees from Shire and Vifor; personal fees from Janssen‐Cilag, Lilly, Novartis, Flynn Pharma, Medice, and Oxford University Press, received for other work. Dr Douglas reports personal fees from GSK and Gilead, received for other work. Prof ICK Wong reports grants from the Research Grants Council (RGC, Hong Kong) (during the study) and grants from Shire, Janssen‐Cilag, Eli Lily, the European Union FP7 programme, received for other work. The other authors have indicated they have no financial relationships relevant to this article to discloseAuthors' affiliations: Dr Coghill reports grants and/or personal fees from Shire, Janssen‐Cilag, Novartis, Flynn Pharma, and Medice; and Prof I.C.K. Wong was a member of the National Institute for Health and Clinical Excellence ADHD Guideline Group and the British Association for Psychopharmacology ADHD Guideline Group and acted as an advisor to Shire. The other authors have indicated they have no potential conflicts of interest to disclose Key conclusions of the study authors: our study findings support the hypothesis that methylphenidate is associated with a reduced risk of trauma‐related ED admission in children and adolescents of both genders Comments from the study authors: this outcome has important clinical, resource utilisation, and public health implications. Trauma prevention should be considered in the broader clinical assessment of methylphenidate risks and benefits aside from the traditional consideration of improving academic performance |
Mayes 1994
Methods | A cohort study of 69 children with attention deficit hyperactivity disorder (ADHD) who underwent blind methylphenidate trials |
Participants | Number of participants screened: not statedNumber of participants included: not statedNumber of participants followed up: 69Number of withdrawals: not statedDiagnosis of ADHD: DSM‐IIIR (subtype: hyperactive‐impulsive (100%))Age: mean 7.1 years old, range 22 months‐13 yearsIQ: mean 86, range 23‐136Sex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: 36 had ADHD alone (with or without a learning disability) and 33 had additional neurodevelopmental disordersComedication: not statedSociodemographics: not stated Exclusion criteria
|
Interventions | MPH was prescribed three times daily (8 am, noon, 4 pm) with a starting dose of 0.3 mg/kg rounded to the nearest 2.5 mg. MPH was trialled using an ABA design (A = no medication, B = MPH). Days per MPH dosage was a minimum 3 days (mean of 6 days) and no medication minimum of 6 days (mean 11 days). MPH was increased by 2.5 mg or 5 mg per dose until a response was achieved. The total mean days per MPH dosage was 8 days, mean days no medication 9 days. Doses for responders 50/69 ranged from a dosage of 2.5 mg to 10 mg. The dosage given to the 19/69 who did not respond or did not complete the trial (6/69) were not reported |
Outcomes | Non‐serious adverse events An adverse event was defined as being reported on ≥ 2 methylphenidate days (i.e. at the response dosage for responders or at the highest dosage for non‐responders) and not reported on ≥ 2 methylphenidate‐free days |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: not stated Key conclusions of the study authors: the results confirm and add to the research literature indicating that ADHD children who are of preschool age and/or who have co‐existing neurological disorders may benefit from methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information has not been able to retrieve from authors due to lack of email address |
McCarthy 2009
Methods | A retrospective cohort study of methylphenidate, dexamphetamine and atomoxetine use |
Participants | Number of participants screened: approximately 3 millionNumber of participants included: 5351Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: not stated (subtype: not stated)Age: mean not stated, range: 2‐21 years oldIQ: not statedSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: UKComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Serious adverse events:5 deaths:
|
Notes | Sample calculation: not stated
Ethics approval: ethics approval for the study was granted by the Independent Scientific Advisory Commitee for the Medicines and Healthcare products Regulatory Agency (MHRA) database research
Funding/vested interests: the School of Pharmacy has received an education grant from Janssen Cilag for professional continued development courses. No specific funding was obtained for the conduct of this study. Ian Wong was funded by a UK Department of Health Public Health Career Scientist Award to investigate the safety of psychotropic drugs in children. Eric Taylor and CK Wong were members of the NICE guideline committee for the diagnosis and management of ADHD in children, young people and adults. The other authors have no conflict of interests relevant to the content of this study Key conclusions of the study authors: in this study, it was not possible to demonstrate an increase in the risk of sudden death associated with methylphenidate, dexamphetamine or atomoxetine. Although it was not an initial aim of this study, an increase in the risk of suicide was observed, particularly in the younger teenager category Comments from the study authors: clinicians should identify patients at increased risk for cardiovascular events and those patients at increased risk for suicide, particularly males with co‐morbid conditions, and monitor them appropriately Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
McCracken 2016
Methods | An 8‐week double‐blind randomised controlled trial |
Participants | Number of participants screened: 323Number of participants included: 69Number of participants followed up: 61Number of withdrawals: 8Diagnosis of ADHD: DSM‐IV (subtype: combined (46%), hyperactive‐impulsive (3%), inattentive (48%))Age: mean 10.1 (SD 2.0) years (range: 7‐14)IQ: mean 101.5 (SD 13.3)Sex: 46 males (66.7%), 23 females (33.3%)Methylphenidate‐naïve: not stated. The participants received placebo only the first 4 weeks of the trial before starting methylphenidate treatmentEthnicity: white 73.9%, Black 14.5%, Asian, Pacific Islander 5.8%, Hispanic 14.5%, others 5.8%Country: USAComorbidity: oppositional defiant disorder 24 (35%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: dexmethylphenidateMean methylphenidate dosage: 16.0 (SD 3.9) mg (range 5‐20)Administration schedule: once dailyDuration of intervention: 4 weeks Treatment compliance: not stated |
Outcomes | Side effects were measured via a structured instrument, using a modification of the Physical Symptom Checklist and open‐ended clinician inquiry |
Notes | Sample calculation: not statedEthics approval: yesFunding: supported by National Institute of Mental Health (NIMH) grantsVested interests/authors' affiliations: Dr Bilder has received consulting income or honoraria from EnVivo Pharmaceuticals, Forum Pharmaceuticals, Lumos Labs, Maven Research, Neurocog Trials Inc., OMDUSA, LLC, Snapchat, Takeda‐Lundbeck, and ThinkNow Inc. He has received research support from the National Institute of Mental Health, the John Templeton Foundation, and Johnson and Johnson. Dr Piacentini has received grant or research support from the National Institute of Mental Health, Pfizer Pharmaceuticals through the Duke Clinical Research Institute CAPTN Network, Psyadon Pharmaceuticals, and the Tourette Association of America. He has received financial support from the Petit Family Foundation and the Tourette Syndrome Association Center of Excellence Gift Fund. He is a co‐author of the Child OCD Impact Scale‐Revised (COIS‐R), the Child Anxiety Impact Scale (CAIS), the Parent Tic Questionnaire (PTQ), and the Premonitory Urge for Tics Scale (PUTS) assessment tools, all of which are in the public domain therefore no royalties are received. He has received royalties from Guilford Press and Oxford University Press. He has served on the speakers' bureau of the Tourette Association of America, the International Obsessive Compulsive Disorder Foundation, and the Trichotillomania Learning Center. Dr McGough has received consultant honoraria from Neurovance; research support from Purdue; material research support for investigator initiated studies from NeuroSigma and Shire; book royalties from Oxford University Press; and DSMB honoraria from Sunovion. He has provided expert testimony for Shire. Dr McCracken has received consultant honoraria from Dart Neuroscience and Think Now, Inc. Drs. Loo, Sturm, Cowen, Walshaw, Levitt, Del'Homme, and Mr Cho report no biomedical financial interests or potential conflicts of interest Key conclusions of the study authors: combination medication treatment showed consistent evidence for clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and alpha2A agonists. Adverse events were generally mild to moderate, and combination treatment showed no differences in safety or tolerability Comments from the study authors: this design allows us to compare the medication conditions by comparing all participants and time‐points for which that condition occurred, after adjusting for overall drift. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
McLaren 2010
Methods | A patient report of acute dystonia following withdrawal of methylphenidate treatment in the context of multiple high dose drug treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 11 years oldIQ: no mental retardationSex: maleEthnicity: not statedCountry: USAComorbidity: bipolar disorderComedication: aripiprazole, 15 mg, twice daily. Lithium carbonate, 600 mg and 300 mg at night. Clonidine, 0.2 mg, twice daily Sociodemographics: not stated |
Interventions | Extended‐release OROS methylphenidate dosage: 108 mg dailyAdministration schedule: not statedDuration of treatment: 4 years prior to withdrawal in hospital. The last 6 months the dose had not been changed. Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsAcute dystonia after discontinuation of OROS methylphenidateThe patient experienced spasmodic muscular contractions of his jaw. The staff noticed a forceful jaw closure, contraction, and tension, and the patient had difficulties opening his mouth. Intramuscular diphenhydramine at 50 mg was administered intramuscularly, and the patient could open his mouth within 30 minutes and with no further dystonia |
Notes | Funding/vested interest/authors' affiliations: none declared Key conclusions of the study authors: need for vigilance regarding development of acute dystonic reactions when discontinuing methylphenidate whilst using concomitant antipsychotic drugs Comments from the review authors: the patient was on extremely high doses, not normally given to patients of this age, of all of the medication that he was on i.e. extended‐release OROS methylphenidate 108 mg (twice the recommended maximum dose), aripiprazole 15 mg twice daily (also in excess of double the normal maximum dose), lithium 900 mg daily (very high for a child of 11 years) and clonidine 0.2 mg (around double the maximum recommended dose) Supplemental information regarding patients diagnostic criteria and IQ received through personal email correspondence with the authors in October 2013 (McLaren 2013 [pers comm]) |
Miller‐Horn 2008
Methods | A retrospective cohort study of patients with ADHD attending a clinic over a 2‐year period taking methylphenidate |
Participants | Number of participants screened: 516Number of participants included: 150Number of participants followed up: 137Number of withdrawals:1363 took MPH, of which 40 (29.2% of whole sample) took extended release methylphenidate and 23 (16.8%) took immediate release methylphenidate.Diagnosis of ADHD: DSM‐IV (subtype: combined 121 (88.3%), hyperactive‐impulsive 4 (2.9%), inattentive 12 (8.8%))Age: males: mean 9.9 (SD 3), range 4‐19 years old; females: 10.9 (SD 3.4), range 4‐17 years oldIQ: not statedSex: 109 males, 28 femalesMethylphenidate‐naïve: 65%Ethnicity: not statedCountry: USAComorbidity: 87 (64%) (type: oppositional defiant disorder/conduct disorder (16%), seizures (15%), learning disabilities (14%), PDD 13%, sleep disturbances (9%), mental retardation/cerebral palsy (7%), chronic headaches (6%), Tourette's (6%), obsessive compulsive disorder/depression (6%))Comedication: all patients were on monotherapy for medications used in the treatment of ADHD; however, some of the patients were currently being treated for comorbid conditionsSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: osmotic release oral system (OROS) and immediate releaseOROS‐methylphenidate dosage: mean 34.2 (SD 13.6) mg/day (range 18‐54)IR‐methylphenidate dosage: mean 23.3 (SD 14.8) mg/day (range 5‐60)Administration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Retrospective database analysis. The database contained information on side effects. No other information regarding measurement available |
Notes | Sample calculation: not statedEthics approval: approved by the Institutional Review Board at St. Christopher's Hospital for Children in PhiladelphiaFunding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: atomoxetine showed a significantly lower incidence of headaches than amphetamine/dextroamphetamine XR, amphetamine/dextroamphetamine or OROS‐methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested twice in June 2014 with no reply |
Mino 1999
Methods | A patient report on methylphenidate‐induced psychosis in an adolescent with hyperkinetic disorder |
Participants | Diagnosis of ADHD: DSM‐III‐R and later ICD‐10 (subtype: not stated)Age: 16 years oldIQ: around 70Sex: femaleEthnicity: not statedCountry: JapanComorbidity: conduct disorder and secondary neurotic symptomsComedication: not at the time when the patient took methylphenidate Sociodemographics: lives with parents and stepsister |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mg for 3 weeks, reduced to 5 mg for 1 weekAdministration schedule: once daily, morningDuration of intervention: 1 month Treatment compliance: not stated |
Outcomes | Serious adverse events: 3 weeks after starting on methylphenidate (10 mg/day), the mother reported by telephone that the patient seemed depressed. Dose of methylphenidate was reduced to 5 mg/day. A week later the patient visited the clinic. The therapist diagnosed her condition as a depressive state and discontinued methylphenidate. 6 weeks after discontinuation of methylphenidate she was diagnosed with schizophrenic‐like psychotic state, due to symptoms of delusions of reference and persecution, delusional mood, silly smile and thought block. There was no evident hallucination. The patient took antipsychotic medication for 2 months, and her psychotic symptoms disappeared. |
Notes | Key conclusions of the study authors: we discuss this case as an example of methylphenidate‐induced psychosis Comments from the study authors: we suggest that there are 2 types of methylphenidate psychosis: the first being hallucination dominant type and the second, delusion dominant type. This patient report address the second one Comments from the review authors: another article written in Japanese by the same authors found in our search. The abstracts of the 2 articles were identical, and the Japanese full‐text has therefore not been translated Funding/vested interests/authors' affiliations: not stated |
Mize 2004
Methods | A patient report of headache and mild depression during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 12 years and 3 months oldIQ: 124Sex: maleEthnicity: not statedCountry: USAComorbidity: none statedComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: Ritalin slow releaseMethylphenidate dosage: 20 mg/dailyAdministration schedule: not statedDuration of treatment: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Headache and symptoms of mild depression |
Notes | Key conclusions of the study authors: 10 sessions of haemoencephalograph appear to have produced significant change in attention Comments from the review authors: the study shortly comments that the boy has headache and symptoms of mild depression when taking methylphenidate (20 mg/daily) Funding/vested interest/authors' affiliations: not stated |
Mohammadi 2004
Methods | A 6‐week, parallel group, randomised trial with 2 arms:
|
Participants | Number of participants screened: not statedNumber of participants included: 32Number of participants randomised to methylphenidate: 16Number of participants followed up: 11Number of withdrawals: 5Diagnosis of ADHD: DSM‐IV (subtype: combined (100%))Age: mean 8.87 years (range 6‐14)IQ: > 70Sex: 11 males, 5 femalesMethylphenidate‐naïve: 100%Ethnicity: 100% PersianCountry: IranComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: not statedMethylpenidate dosage: 1 mg/kg/dayAdministration schedule: not statedDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Headaches were observed more often in the methylphenidate group |
Notes | Sample calculation: yesEthics approval: not statedFunding: the study was supported by a grant from Tehran University of Medical SciencesVested interests/authors' affiliations: not stated Key conclusions of the study authors: the results suggest that theophylline may be a useful for the treatment of ADHD. In addition, a tolerable side‐effect profile is one of the advantages of theophylline in the treatment of ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no. All participants were newly diagnosed |
Mohammadi 2009
Methods | 42 days double‐blind, parallel, randomised clinical trial with 2 arms: |
Participants | Number of participants screened: not statedNumber of participants included: 60Number of participants randomised to Ritalin: 30; Stimdate: 30Number of participants followed up in each arm: Ritalin: 24; Stimdate: 30Number of withdrawals in each arm: Ritalin: 6; Stimdate: 0Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age (Ritalin): mean 9.21 years (range 6‐15)Age (Stimdate): mean 9.29 years (range 6‐15)Sex (Ritalin): 23 males, 7 femalesSex (Stimdate): 22 males, 8 femalesMethylphenidate‐naïve: not statedEthnicity: 100% PersianComorbidity: not statedComedication: not statedIQ: > 70Sociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Participants were randomly assigned to Ritalin or StimdateMethylphenidate type: extended release (Ritalin) or Extended release (Stimdate)Mean methylphenidate dosage: 25 mg/day. Titrated to the highest dose level; 1 mg/kg/day Ritalin or Stimdate, or a maximum of 40 mg/dayAdministration schedule: orally twice daily 7.30‐8.00 am and 12:00 to 1:00 pmDuration: 42 days Treatment compliance: not stated |
Outcomes | No usable data |
Notes | Sample calculation: noEthics approval: not statedFunding/vested interest: not stated Key conclusions of the study authors: based on the results of this study, no significant difference was observed between the 2 medications, and it seems both drugs behave in a similar way. In addition, Stimdate appears to be effective and well tolerated for ADHD in children and adolescents in Iran Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental data regarding side effects requested from the study authors twice in November 2013 with no reply |
Mohammadi 2010
Methods | A 6‐week, parallel group, double‐blind, randomised clinical trial with 2 arms:
|
Participants | Number of participants screened: 65Number of participants included: 40Number of participants randomised to methylphenidate: 20Number of participants followed up: 19Number of withdrawals: 1.Diagnosis of ADHD: DSM‐IV (subtype: combined (100%))Age: mean 9.25, range 6‐14 years oldIQ: > 70Sex: 13 males, 7 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: IranComorbidity: noneComedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: RitalinMethylphenidate dosage: 20‐30 mg/day depending on weight (20 mg/day for < 30 kg and 30 mg/day for > 30 kg)Mean methylphenidate dosage. At week 6: 25.50 mg (SD 5.10)Titration period: 3 weeks after randomisationDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Side effects checklist that comprises 20 side effects including psychic, neurologic, autonomic and other side effects, administered by a child psychiatrist on days 7, 21 and 42Body weight and vital signs were measured at baseline and weeks 1, 2, 4 and 612‐lead ECG and physical examinations were evaluated at baseline and week 6 Haematology tests were collected at baseline and weeks 2, 4 and 6; serum chemistry and urinalysis were evaluated at baseline and week 6 |
Notes | Sample calculation: not statedEthics approval: yesFunding: the study was supported by a grant from Tehran University of Medical Sciences.Vested interests/authors' affiliations: not stated Key conclusions of the study authors: the results of this study indicate that amantadine significantly improved symptoms of ADHD and was well tolerated and it may be beneficial in the treatment of children with ADHD. Nevertheless, the present results do not constitute proof of efficacy Supplemental information requested from the study authors twice in July and August 2013 with no reply |
Mohammadi 2012a
Methods | An 8‐week double‐blind parallel‐group randomised controlled trial with 2 arms:
|
Participants | Number of participants screened: not statedNumber of participants included: 60Number randomised to methylphenidate + placebo: 32 and methylphenidate + melatonin: 28Number followed up in the methylphenidate + placebo group: 24Number of withdrawals in the methylphenidate + placebo group: 8 Methylphenidate + placebo group Diagnosis of ADHD: ICD‐10 (subtype: combined (100%))Age: mean 8.83 years old (range 7‐12)IQ: above 70Sex: 17 males, 7 femalesMethylphenidate‐naïve: 100% were newly diagnosedEthnicity: not statedCountry: IranComorbidity: noComedication: noSociodemographics: level of family income: low (58.8%), average (23.6%), high (17.6%)Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: RitalinMethylphenidate dosage: 1 mg/kgAdministration schedule: not statedDuration of intervention: 8 weeks Treatment compliance: not stated |
Outcomes | Sleep Disturbance Scale for Children (SDSC) sleep questionnaires and appetite questionnaires were completed by mothers at baseline, week 2, 4, and 8Height, weight were measured by a dietitian at baseline and week 8. Weight was measured with minimal clothing and height without shoes in standard position3‐day food records were completed by mothers at baseline and week 8 Stimulant drug side effects questionnaires were completed by mothers at week 8 (methylphenidate + placebo, n = 18) |
Notes | Sample calculation: not statedAny withdrawals due to adverse events: not statedEthics approval: yesFunding/vested interests: the study was financially supported by Research Deputy of Tehran University of Medical SciencesAuthors' affiliations: not stated Key conclusions of study authors: melatonin with methylphenidate can partially improve symptoms of sleep disturbance by circadian cycle modification. However, it did not seem to reduce the attention deficiency and hyperactivity behaviour of ADHD children Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental data received through personal email correspondence with the authors in July 2013 (Mohammadi 2013 [pers comm]) |
Mohammadi 2012b
Methods | A a single‐centre randomised, double‐blind, parallel‐group clinical trial of methylphenidate use for 6 weeks |
Participants | Number of patients screened: 53Number included: 46Number randomised to methylphenidate: 23, buspirone: 23Number followed up in each arm: methylphenidate: 20 and buspirone: 20Number of withdrawals in each arm: methylphenidate: 3 and buspirone: 3Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (100%))Age: mean: 9.70 (SD 3.18), range: 6‐14 years oldIQ: above 70Sex: 13 males, 7 femalesMethlphenidate‐naïve: 100% (n = 20)Ethnicity: not statedCountry: IranComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: immediate release (Ritalin)Mean methylphenidate dosage: 20‐30 mg/day depending on weight (20 mg/day for < 30 kg and 30 mg/day for > 30 kg)Administration schedule: not statedDuration of intervention: 6 weeks Treatment compliance: not stated |
Outcomes | Adverse effects were systematically recorded at each visit (baseline, 3 weeks, and 6 weeks) using a checklist (not otherwise specified) that comprised 20 side effects |
Notes | Sample calculation: not statedEthics approval: the study was approved by the Institutional Review Board (IRB) of Tehran University of Medical Sciences (grant No: 8643)Funding/vested interests: this study was supported by a grant from Tehran University of Medical Sciences (grant no: 8643)Any withdrawals due to adverse events: noAuthors' affiliations: not stated Key conclusions of the study authors: the results of this study suggest that administration of buspirone has no comparable efficacy in comparison with methylphenidate in the treatment of ADHD. Nevertheless, in our study, those in the buspirone group experienced fewer adverse events than the methylphenidate group in particular regarding decreased appetite, headache and insomnia Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information requested from the authors twice through email correspondence in June 2016. No reply |
Montañés‐Rada 2012
Methods | An 8‐week prospective, open‐label cohort study of participants receiving 8 hours extended release methylphenidate |
Participants | Number of patients screened: 60Number included: 40Number followed up: 40Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean: 13.6 years old (range: 10‐16)IQ: above 100Sex: 30 males, 10 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: SpainComorbidity: ODD: 75%, anxiety disorder: 10%, Gilles de la Tourette syndrome: 2.5%, no comorbidity: 20%Comedication: not statedSociodemographics: low socioeconomic status: 37.5%, medium socioeconomic status: 50%, high socioeconomic status: 12.5% Inclusion criteria:
Exclusion criteria: |
Interventions | Methylphenidate type: Medikinet (50% extended release and 50% immediate release methylphenidate)Methylphenidate dosage: 40‐50 mg/dailyAdministration schedule: twice daily. A fixed dose of 30 mg at breakfast (8:30 am) and either 10 mg (n = 34) or 20 mg (n = 6) in the afternoon (3:00 pm)Duration of intervention: 8 weeks (1 month of titration) Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Insomnia, spontaneous reported |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: HB Pharma Key conclusions of the study authors: at week 8, 63% of the participants reached complete remission, and 27.5% reached partial remission. Scores in all subscales of Eyberg, Conners (parents and teachers) were reduced till the level of normal population (except for the conduct subscale of the teacher rated) in a statistical significant level. Due to insomnia, 2 patients reduced the afternoon dose of 50/50‐ER/IR‐MPH from 20 mg to 10 mg and 3 patients changed the 20 mg 50/50‐ER/IR‐MPH afternoon dose to 10 mg IR‐MPH Comments from the study authors: our sample is representative of patients with moderate and severe symptomatology Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: see inclusion criteria 4‐6 Supplemental information regarding ADHD diagnostic criteria and IQ received through personal email correspondence with the authors in November 2013 (Montañes‐Rada 2013 [pers comm]) The publications on this study were received from the pharmaceutical company HB Pharma in June 2013 (Fischer 2013 [pers comm]) |
Montiel‐Nava 2002
Methods | A 6‐week randomised parallel trial with 2 arms:
No placebo or no‐intervention group |
Participants | Number of participants screened: not statedNumber of participants included: 24Number randomised to methylphenidate: 12 and parent training: 12Number followed up in methylphenidate‐arm: not statedNumber of withdrawals in methylphenidate‐arm: not statedDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 7.16 years old (range: 6‐10)IQ: mean: 92.25 (SD 15.64).Sex: total sample: 16 males, 8 females (not stated for the methylphenidate group)Methylphenidate‐naïve: 100%Ethnicity: Marabinos (from Northwestern Venezuela)Country: VenezuelaComorbidity: academic, oppositional and various behavioural problemsComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mg/daily at the start of the titration periodAdministration schedule: morning and noonDuration of intervention: 6 weeks, including 4 weeks of titration (after randomisation) Treatment compliance: not stated |
Outcomes | A checklist of adverse effects were used, telephone interview with parent, once weekly during the 4‐week titration period |
Notes | Sample calculation: noEthics approval: not statedFunding/vested interests: not statedAuthors' affiliations: not stated Key conclusions of the study authors: to our knowledge this is the first article describing the effectiveness of methylphenidate and parent training in Venezuelan children diagnosed with ADHD. It should be considered as a preliminary study, that supports the thesis of positive effects of psychosocial and psychopharmacological interventions in children with ADHD. There was no difference in the effectiveness of the 2 types of treatment Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no (only inclusion of methylphenidate‐naïve children) Supplemental information regarding ethics approval, funding, type of methylphenidate, number of males and females in the methylphenidate group, and adverse event data were not possible to receive through personal email correspondence with the authors. Emails sent twice without reply |
Moungnoi 2011
Methods | A retrospective, descriptive cohort study of methylphenidate use for long‐term administration and its impact on growth at 6 months, 1 years, 2 years, 3 years, 4 years, and 5 years' follow‐up |
Participants | Number of participants screened: not statedNumber of participants included: 96Number of participants followed up: 6 participants followed up to 5 yearsNumber of withdrawals: more than 50% by 3rd year of follow‐upDiagnosis of ADHD: DSM‐IV (subtype: combined, 100%)Age: mean 8.62 years old (SD 1.70)IQ: not statedSex: 75 males, 21 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: ThailandComorbidity: not statedComedication: not stated, but children who received other medication continuing more than 3 months were excludedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: short acting methylphenidateMean methylphenidate dosage: 6 months= 0.44 mg/kg/day, 1 year = 0.48 mg/kg/day, 2 years = 0.48 mg/kg/day, 3 years = 0.49 mg/kg/day, 4 years = 0.41 mg/kg/day and 5 years = 0.42mg/kg/dayAdministration schedule: not statedDuration of intervention: ≥ 1 year Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Height and weight, observer, beginning of short‐acting methylphenidate medication, 6 months, 1‐, 2‐, 3‐, 4‐, 5‐year follow‐up |
Notes | Sample calculation: yes. Margin of error 5%, estimated prevalence of ADHD 3.5‐5%, CI 95% = sample size 51‐73Ethics approval: yes, Ethics Committee of the Queen Sirikit National Institute of Child HealthFunding/vested interests: noneAuthors' affiliations: none Key conclusions of the study authors: prolonged medication with short‐acting methylphenidate showed minimal impact on growth only at the first 6 months; however, growth could catch up in the adolescent period Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Munk 2015
Methods | A patient report of cardiac arrest following myocardial infarction during methylphenidate treatment |
Participants | Diagnosis of ADHD: ICD‐10Age: 11 years oldIQ: unknownSex: maleEthnicity: not statedCountry: DenmarkComorbidity: Tourette syndromeComedication: none Sociodemographics: not stated |
Interventions | Methylphenidate type and dosage: 54 mg/dayAdministration schedule: not statedDuration of treatment: approximately 2 years Treatment compliance: yes |
Outcomes | Serious adverse events: Cardiac arrest following exercise without any prior complaints about chest discomfort or shortness of breath. A week before the event, he had a short episode of tachycardia. The examination showed that the myocardial infarction was of an older date (more than weeks) due to thinning of the myocardium and an adversely remodeled left ventricle. A pacemaker was inserted and methylphenidate treatment was discontinued |
Notes | Key conclusions of the study authors: the present case demonstrates that myocardial infarction can happen due to methylphenidate exposure in a cardiac healthy child, without any other cardiovascular risk factors Comments from the study authors: the boy has been very thoroughly examined and the only thing that stands out is the methylphenidate treatmentFunding/vested interest/authors affiliations: the authors declare that there is no conflict of interests regarding the publication of this paper Supplemental information regarding IQ and comedication received through personal email correspondence with the authors in April 2016 (Munk 2016 [pers comm]). Not possible to retrieve information regarding ADHD subtype |
Na 2013
Methods | A 12‐week, open‐label, multicentre, phase 4 study of osmotic release oral system (OROS) methylphenidate use |
Participants | Number of patients screened: not statedNumber of participants included: 121Number of participants followed up: 103Number of withdrawals: 18Diagnosis of ADHD: DSM‐IV (subtype: combined (17.4%), hyperactive‐impulsive (0.8%), inattentive (70.2%))Age: mean: 13.8 years old (range: 12‐18)IQ: above 70Sex: 93 males, 28 femalesMethlphenidate‐naïve: not statedEthnicity: KoreanCountry: KoreaComorbidity: oppositional defiant disorder: 24%, conduct disorder: 5%, tic disorder: 4.1%, depressive disorder: 4.1%, social phobia: 1.7%, generalised anxiety disorder: 2.5%, enuresis: 1.7%, encopresis: 1.7%)Comedication: noSociodemographics not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: osmotic‐release oral system (OROS)Methylphenidate dosage: dose titration was allowed for up to 6 weeks (starting doses were 18 mg/day (if body weight < 30 kg) and 27 mg/day (if body weight equal to or higher than 30 kg), maximum allowed daily dose was 72 mg or 1.4 mg/kg)Mean methylphenidate dose at endpoint: 54.53 (SD 12.33, range 27‐72) mg/day or 0.99 (SD 0.21) mg/kg/dayAdministration schedule: once a day, between 6:30 and 9:00 amDuration of intervention: 12 weeksWashout before study initiation: ≥ 6 months Treatment compliance: not stated, but participants were required to take ≥ 70% of the study medication during the study period |
Outcomes | Non‐serious adverse events:Vital signs, body weight, and adverse events (both by general inquiry to patients and parents and by clinician rated checklist) were measured at every visit (day 0 (baseline) and at weeks 1, 3, 6, and 12) The study‐specific adverse events checklist consisted of 61 methylphenidate‐specific questions (Items from the Symptom Rating Scale (Barkley 1990) and the Pittsburg Side‐Effects Rating Scale (Pelham 1993) were included) Chemistry tests were performed at screening and at week 12 |
Notes | Sample calculation: not statedEthics approval: yes, the study was approved by the institutional review board of each study siteFunding: this study was supported by grants from the Johnson & Johnson family of companies. The Johnson & Johnson family of companies was involved in the study design and approved the reportVested interests: disclosure statement "No competing financial interests exist". Key conclusions of the study authors: OROS methylphenidate was effective in enhancing learning skills in adolescents with ADHD. Furthermore, clinicians should supplement the subjective report on adverse events from patients or their parents with a more drug‐specific checklist to obtain drug side effects more effectively. As there are some differences in the patterns of adverse events reported by patients and their parents, it is generally recommended that clinicians obtain information from both parties when possible Comments from the review authors: safety data comparing patients, parents and clinicians as raters from Lee 2013 concerns only 47 participants, whereas efficacy data and supplemental safety data from Na 2013 concerns 121 participants Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, see exclusion criteria no. 1 (hypersensitivity to methylphenidate HCL) Supplemental information regarding safety data received through personal email correspondence with the authors in August 2014 (Lee 2014 [pers comm]) |
Niederhofer 2009
Methods | A patient report of dosage reduction of methylphenidate treatment by addition of atomoxetine. Adverse effects of methylphenidate are reported |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 11 years oldIQ: 97Sex: maleEthnicity: not statedCountry: ItalyComorbidity: not statedComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 20 mg/dayAdministration schedule: not statedDuration of intervention: 2 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Methylphenidate 20 mg/day: depressed mood and appetite loss Dosage‐reduction to 10 mg/day: improved the depressed mood |
Notes | Key conclusions of study authors: the reported case mainly shows that the combination between atomoxetine and methylphenidate helped reducing the dose of methylphenidate and thus, probably the side effects while showing beneficial clinical effectsFunding/vested interests/authors' affiliations: not stated Supplemental information regarding ADHD type received through personal email correspondence with author in July 2013 (Niederhofer 2013 [pers comm]) |
Niederhofer 2011
Methods | A patient series describing adverse effects (xerostomia, aggression and emotional instability) among children taking methylphenidate |
Participants | Case with xerostomia, n = 1Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 11 years oldIQ: 97Sex: maleEthnicity: not statedCountry: ItalyComorbidity: not statedComedication: not statedSociodemographics: not stated Cases with aggression (n = 1) and emotional instability (n = 1) Diagnosis of ADHD: DSM‐IV (subtype: combined)Ages: 10 and 11 years oldIQ: above 70Sex: 2 malesEthnicity: not statedCountry: ItalyComorbidity: noComedication: not statedSociodemographics: not stated |
Interventions | Case with xerostomiaMethylphenidate type: not statedMehylphenidate dosage: 40 mg/dayAdministration schedule: not statedDuration of intervention: 1 weekTreatment compliance: not stated Cases with aggression and emotional instability Methylphenidate type: not statedMethylphenidate dosage: 20 mgAdministration schedule: not statedDuration of intervention: 2 monthsTreatment compliance: not stated |
Outcomes | Non‐serious adverse events: Xerostomia, aggression and emotional instability |
Notes | Key conclusions of study author: methylphenidate is first‐line agent for ADHD, if monotherapy is sufficientFunding/vested interests/authors' affiliations: none declared Supplemental information regarding ADHD subtype and duration of intervention received through personal email correspondence with author in July 2013 (Niederhofer 2013b [pers comm]) |
Nymark 2008
Methods | A patient report of serious cardiomyopathy during methylphenidate treatment |
Participants | Diagnosis of ADHD: ICD‐10 (subtype: not stated)Age: 18 years oldIQ: above 70Sex: maleEthnicity: not statedCountry: NorwayComorbidity: obesity (BMI = 40)Comedication: quetiapine fumarate (900 mg/day) for 17 months Sociodemographics: not stated |
Interventions | Methylphenidate type: extended release (Concerta)Methylphenidate dosage: 54 mg/dayAdministration schedule: once dailyDuration of intervention: 11 months Treatment compliance: not stated |
Outcomes | Serious adverse events: 11 months of MPH treatment: hypoxia and dyspnoea. On investigation, signs of liver‐, renal‐, and heart‐failure were found. Noradrenalin infusion was started. Echocardiography showed dilated left ventricle and an ejection fraction (EF) of 25%. Liver function improved, noradrenalin and dobutamine were tapered, but 3 days after admission a new echocardiography showed an EF of 10%. Intensified treatment including intra‐aortic balloon pump (IABP) was instituted. Cardiac function improved, and 3 weeks later the IABP was disconnected. EF at this point was 15%. The patient was denied heart transplantation due to various cofactors. 7 months later: his clinical status was improved, function class II (New York Heart Association) with an EF estimated by echocardiography to 30%‐35% |
Notes | Funding/vested interests/authors' affiliations: not stated Key conclusions of study authors:the investigation concluded with a probable relationship between the patient's cardiomyopathy and the use of methylphenidate |
Park 2013
Methods | A cohort study of methylphenidate use for 2 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 96Number of participants followed up: 96Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (62.5%), hyperactive‐impulsive (5.2%), inattentive (27.1%), NOS (5.2%))Age: mean: 8.70 (SD 1.41) years old (range: 6‐12)IQ: not statedSex: 79 males, 17 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: KoreaComorbidity: tic disorder: 10.4%, anxiety disorder: 8.3%, oppositional defiant disorder: 9.4%, enuresis: 6.3%, depression: 1.0%Co‐medication: noSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: osmotic release oral system (OROS) methylphenidateMethylphenidate dosage: children weighing less than 30 kg were treated with 18 mg per day, and children weighing more than 30 kg were treated with 27 mg/dayAdministration schedule: not statedDuration of intervention: 2 weeks Treatment compliance: not stated |
Outcomes | Barkley Symptom Rating Scale: a 17‐item list of methylphenidate‐related adverse event symptoms, rated from 0 (nothing) to 9 (severe) for symptoms during the past 2 weeks. Any negative sign, symptom, syndrome, or new illness that appeared or worsened after treatment began was counted as a treatment‐emergent adverse event |
Notes | Sample calculation: noEthics approval: approved by the institutional review board (IRB) for human subjects at the Seoul National University Hospital and other hospitalsFunding/vested interests: the authors declare that there are no conflict of interest. The study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111523) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, Republic of Korea (20110023888)Authors' affiliations: Seoul National University College of Medicine Key conclusions of the study authors: ADHD participants with the A/a genotype at the NTF3 rs6332 polymorphism showed the highest 'proneness to crying' and 'nail biting' item scores, followed by those with the G/a genotype and those with the G/G genotype (P = 0.047 and P = 0.017, respectively). These data provide preliminary evidence that genetic variation in the NTF3 gene is related to susceptibility to emotional side effects in response to methylphenidate treatment in Korean children with ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Perera 2010
Methods | This study prospectively analysed an outpatient treatment programme for children with ADHD. Methylpenidate use for 6 months |
Participants | Number of participants included: 102Diagnosis of ADHD: DSM‐IV (subtype: combined (100%))Age: mean 6.92 years old (range 4‐12)IQ: above 90Sex: 90 males,12 femalesEthnicity: not statedCountry: Sri LankaComorbidity: oppositional defiant disorder, conduct disorder, specific learning disorder and tic disorder (numbers not stated)Comedication: 19 (18.3%) children were also taking other medication on a regular basis. These were anticonvulsants in 15 (14.4%) and anti‐asthmatic drugs in 4 (3.9%)Sociodemographics: not stated Inclusion criteria: Data used for this article is confined to those children who consistently attended clinics and completed 6 months of treatment/interventionExclusion criteria:
|
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 2.5‐40 mg dailyAdministration schedule: not statedDuration of intervention: 6 months Treatment compliance: data used for this article is confined to those children who consistently attended clinics and completed 6 months of treatment |
Outcomes | Non‐serious adverse events: A 7 item checklist of known side effects of methylphenidate. Parents responded by indicating 'present' or 'absent', which was recorded on a weekly basis, in the first 4 weeks. Loss of appetite, social withdrawal, restlessness, abdominal pain, headache, poor sleep, and sadness |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interest: noAuthors' affiliations: none Key conclusions of the study authors: close involvement of parents in monitoring outcome of treatment of ADHD helps to focus on aspects of care relevant to them Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, children with ADHD found to be unsuitable for treatment with methylphenidate were excluded Supplemental information regarding IQ, comorbidity and methylphenidate dosage received through personal email correspondence with the authors in June 2016 (Perera 2016 [pers comm]) |
Peyre 2012a
Methods | A non‐randomised longitudinal study of methylphenidate use for up to 3 months |
Participants | Number of participants screened: not statedNumber of participants included: 173Number of participants followed up: 136Number of withdrawals: 37Diagnosis of ADHD: DSM‐IV (subtype: combined (69.12%), hyperactive‐impulsive (8.09%), inattentive (22.79%))Age: mean 10.74 (SD 2.74)IQ: > 70Sex: 90% males, 10% femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: FranceComorbidity: conduct disorder (7.35%); ODD (50%); anxiety (32.35%); major depressive (22.06%); bipolar (1.47%); learning (33.09%)Comedication: noneSociodemographics: not stated Inclusion criteria Children and adolescents younger than 18 years who were eligible for MPH treatment for DSM‐IV ADHD and had parents able to speak and understand French. A subsample with complete data were re‐evaluated after optimal adjustment of MPHExclusion criteria Mental retardation (IQ < 70) and chronic neurological disease |
Interventions | Methylphenidate type: multiple‐dose immediate release or prolonged‐action once‐daily formulations (Ritaline LAR or ConcertaRMean methylphenidate dosage: 0.82 mg/kg/day (SD 0.22)Administration schedule: not statedDuration of intervention: 15 days to 3 months Treatment compliance: not stated |
Outcomes | Adverse effects were elicited through systematic questions (first about adverse events in general and then with a list of frequent adverse events) and medical chart review |
Notes | Sample calculation: noEthics approval: local ethics committee (Comite de Protection des Personnes Pitie‐Salpetriere)Funding: supported by grants from a Programme Hospitalier de Recherche Clinique (PHRC AOR 03006) and the Institut National de la Sante et de la Recherche Medicale (INSERM AAP‐RRC‐09).Vested interests: the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of the article Key conclusions of the study authors: Child Behavior Checklist‐Dysregulation Profile (CBCL‐DP) was associated neither with poorer response to methylphenidate nor with more side effects. There were no differences in cognitive performance between participants with and without CBCL‐DP |
Pierce 2010
Methods | An open‐label, randomised, multicentre study evaluating the pharmacokinetic properties of dl‐methylphenidate after single, multiple fixed, and escalating doses of MTS (methylphenidate transdermal system) and osmotic release oral sytem (OROS) methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 71Diagnosis of ADHD: DSM‐IV (subtype: not stated) Children Number randomised to OROS: 11Number randomised to MTS: 24Number of withdrawals: 0Age: mean 9.5 years (range 6‐12)IQ: not statedSex: 19 males, 16 femalesMethylphenidate‐naïve: not statedEthnicity: white (25.7%), African American (74.3%)Country: USAComorbidity: not statedComedication: not statedSociodemographics: not statedAdolescents Number randomised to OROS: 11Number randomised to MTS: 25Number of withdrawals: 0Age: mean 14.1 years (range 13‐17)IQ: not statedSex: 19 males, 17 femalesMethylphenidate‐naïve: not statedEthnicity: white (47.2%), African American (52.8%)Country: USAComorbidity: not statedComedication: not statedSociodemographics: not statedInclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate transdermal system dosage: 10 mg in single dose phase and 15 mg, 20 mg, or 30 mg in the multiple escalating phaseOsmotic release oral system methylphenidate dosage: 18 mg in single dose phase and 27 mg, 36 mg, and 54 mg in the multiple escalating phaseAdministration schedule: once dailyDuration of intervention: 4 weeks for the whole trial, with the 4 different phases having varying duration Treatment compliance: not stated |
Outcomes | Non‐serious adverse events
|
Notes | Sample calculation: noEthics approval: approved by the institutional review boardFunding: ShireVested interests/authors' affiliations: Dr Pierce is an employee of Shire Pharmaceutical Development Ltd. Dr Katic receives or has received research support, acted as a consultant, and/or served on a speakers' bureau for Forest, GlaxoSmithKline, Lundbeck, Merck, Novartis, Sanofi‐Aventis, Sepracor, Shire, Somerset, and Wyeth. Ms Buckwalter is an employee of Shire Pharmaceuticals Inc. Mr Webster at the time of the study was an employee of Aptuit Ltd, a contract research organisation subcontracted to conduct work on behalf of Shire Pharmaceutical Development Ltd. Key conclusions of the study authors: overall, after single and multiple fixed or escalating doses of MTS or OROS methylphenidate, systemic exposure to the predominantly active d‐methylphenidate was greater in children compared with adolescents. As a result of drug accumulation on repeated dosing, systemic exposure to d‐methylphenidate in children after multiple escalating doses was 1.4‐ to 1.6‐fold higher for MTS compared with OROS; however, in adolescents, systemic exposure was similar for both formulations. Plasma concentrations of l‐MPH were approximately half those of d‐MPH across both age groups after single and multiple doses of MTS. In contrast, plasma concentrations of l‐MPH were negligible after single and multiple doses of OROS MPH. Reported AEs included those that are typical for oral methylphenidate treatment, with the exception of generally mild application site irritations associated with transdermal delivery of methylphenidate Comments from the study authors: no participants exhibited a DRS score higher than 2 (definite erythema, readily visible minimal oedema, or minimal popular response) immediately before the removal of the patch after 1 or 28 days. No participant had an experience of discomfort and pruritus scale score higher than 1 (mild discomfort) Comments from the review authors: it was the investigator who decided whether an adverse events was clinically significant or not Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
Polanczyk 2007
Methods | A pharmacogenomic study of children and adolescents consecutively evaluated during 2 years in the ADHD outpatient clinic |
Participants | Number of participants screened: 457Number of participants included: 137Number of participants followed up: 106Number of withdrawals: 31Diagnosis of ADHD: DSM‐IV (subtype: combined (58.5%), hyperactive‐impulsive (5.7%), inattentive (26.4%))Age: mean 10.3 years old (range: not stated)IQ: mean: 100.4Sex: 82 males, 24 femalesMethylphenidate‐naïve: 100%Ethnicity: European‐Brazilian (100%)Country: BrazilComorbidity: conduct disorder (16.0%), oppositional defiant disorder (51.9%), mood disorder (9.4%), anxiety disorder (23.6%)Comedication: yes (9.4%)Sociodemographics: not stated Inclusion criteria:
Exclusion criteria: Not stated |
Interventions | Methylphenidate type: immediate releaseMean methylphenidate dosage: 0.5 mg/kg (baseline) and 0.65 mg/kg at 1 monthAdministration schedule: 8 am and 12 pm, with extra dose at 5‐6 pm for those needing evening coverage. Dosages of short‐acting methylphenidate were augmented until no further clinical improvement was detected or until there were limited adverse effectsDuration of intervention: 3 months (1 month for 106 participants, 3 months for 89) Treatment compliance: data were excluded from 2 children because of irregular use of methylphenidate |
Outcomes | Barkley Side Effect Rating Scale measured by child psychiatrists at baseline,1 and 3 months. Data not reported |
Notes | Sample calculation: no
Ethics approval: yes
Funding/vested interests: the ADHD program received research support from the pharmaceutical companies: Bristol Myers‐Squibb, Eli Lilly and Company, Janssen‐Cilag, and Novartis Pharmaceuticals. The study was supported by grant 471761/03‐6 from Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico, Programa de Apoio a Núcleos de Excelência, and Hospital de Clínicas de Porto Alegre Key conclusions of the study authors: the study documented the effect of the G allele at the ADRA2A ‐1291 C > G polymorphism on the improvement of inattentive symptoms with methylphenidate treatment in children and adolescents with ADHD. Our findings provide clinical evidence for the involvement of the noradrenergic system in the modulation of methylphenidate action Comments from the study authors: regarding adverse events, a mixed‐effects model analysis demonstrated effects of treatment over time on the Barkley Side Effect Rating Scale scores, as expected (n = 106; F2,201.2=5.4; P=.005). However, neither an effect for the presence of the G allele (n = 106; F1,107.6=0.15; P=.69) nor an interaction effect between the presence of the G allele and treatment over time (n = 106; F2,201.2=0.71; P=.49) on the Barkley Side Effect Rating Scale scores was found during the 3 months of methylphenidate use Comments from the review authors: no data presented on side effects apart from the paragraph above Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Porfirio 2011
Methods | A patient report of visual hallucinations during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 7 years at diagnosis, 11 years at occurrence of hallucinationsIQ: above 70Sex: maleEthnicity: not statedCountry: ItalyComorbidity: K‐SADS‐PL excluded any psychiatric comorbidities (at age 11)Comedication: not stated Sociodemographics: mother presented with affective seasonal disorder and binge eating disorder |
Interventions | Methylphenidate type: oral immediate‐releaseMethylphenidate dosage: 0.5 mg/kg twice daily (30 mg/day)Duration of treatment: 3 years with discontinuation of medication during summer time each year Treatment compliance: not stated |
Outcomes | Serious adverse events:3 years after start of MPH treatment: an episode of complex visual hallucinations (dramatic scenes appearing before going to sleep, sometimes during the day after methylphenidate‐ingestion). Normal physical and neurological examinations. Standard laboratory work‐up and drug screening were within normal limits. Normal visual acuity. Sleep electroencephalography (EEG) revealed no abnormalities and no evidence of epileptic activity. K‐SADSPL excluded any psychiatric comorbiditiesDiscontinuation: complete resolution of hallucinations 24 months follow‐up period: no further hallucinations occurred |
Notes | Key conclusions of the study authors: although the pathogenetic mechanism is unclear, the occurrence of hallucinations may be explained by a chronic increase in synaptic dopamine. Clinicians should be aware of this possible rare adverse manifestation occurring at therapeutic doses Comments from the study authors: because methylphenidate is a widely used, well studied and safe pharmacological agent, clinicians who prescribe methylphenidate should be aware of this possible rare adverse manifestation occurring at therapeutic dosesFunding/vested interest/authors' affiliations: not stated Supplemental information regarding IQ received through personal email correspondence with the authors in October 2013 (Curatolo 2013 [pers comm]) |
Poulton 2003
Methods | A retrospective cohort study of growth data |
Participants | Number of participants screened: not statedNumber of participants included: 19Number of participants followed up: 6 months: 19, 18 months: 13, 30 months: 6, 42 months: 4Number of withdrawals: 6 months: 0, 18 months: 6, 30 months: 13, 42 months: 15Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: range 3.1‐11.4 years oldIQ: > 70Sex: 17 males, 2 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: AustraliaComorbidity: not statedComedication: clonidineSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10‐40 mg/dayMean methylphenidate dosage: 1.0 (SD 0.24) mg/kg per day, median 27.5 mgAdministration schedule: not statedDuration of intervention: 6‐42 months Treatment compliance: many patients were taking less than the prescribed dose of stimulant medication, ceasing or reducing medication at weekends or during school holidays, but precise details were not available |
Outcomes | Non‐serious adverse events:
Both measures without shoes and outdoor clothing |
Notes | Sample calculation: no
Ethics approval: no
Funding/vested interest: none Key conclusions of the study authors: stimulant medication is associated with a decrease in height and weight SD scores during the first 6‐30 months with a characteristic pattern on the growth chart Comments from the study authors: all children were started on dexamphetamine initially but were changed on to methylphenidate if the response was suboptimal or they experienced adverse effects. When weight loss occurred the parents were asked to reduce or omit the medication whenever possible and to encourage the child to eat more Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding data received through personal email correspondence with the authors in November 2013 (Poulton 2013 [pers comm]) |
Poulton 2012
Methods | A clinic‐based, prospective, cohort study with up to 3 years of follow‐up |
Participants | Number of participants screened: not statedNumber of participants included: 21Number of participants followed up: 19Number of withdrawals: not stated
Diagnosis of ADHD: DSM‐IV (subtype: combined (76%), inattentive (19%),
hyperactive (5%))Age: mean 7.54, range 4.99‐9.04 years oldIQ: > 70Sex: 18 males, 3 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: AustraliaComorbidity. not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 24.3 mg/day (6.2 mg/day) at 6 monthsAdministration schedule: not statedDuration of intervention: up to 36 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:
Growth: height, weight, and BMI z scores measured at baseline, 6 months, 18 months, 30 months. All measurement were made without shoes or outdoor clothing
Height was measured to the nearest 1 mm using a wall mounted stadiometer
Weight was measured to the nearest 0.1 kg using electronic scales BMI were corrected for age and sex by conversion to z scores based on Centers for Disease Control and Prevention (CDC) reference data |
Notes | Sample calculation: yes
Ethics approval: yes
Funding: the research was supported by the Australian Woman and Children's research Foundation (OZWAC) and by the Nepean Medical Research Foundation
Vested interests/authors' affiliations: the authors declare that they have no competing interests Key conclusions of the study authors: stimulant medication was associated with early fat loss and reduced bone turnover. Lean tissue including bone increased more slowly over 3 years of continuous treatment than would be expected for growth in height. There was long‐term improvement in the proportion of central fat for height. This study shows that relatively minor reductions in weight on stimulant medication can be associated with long‐term changes in body composition. Further study is required to determine the effects of these changes on adults Comments from the review authors: the study describe children both on dexamphetamine treatment and methylphenidate treatment. We have received separate data on the methylphenidate group from the study authorsExclusion of MPH non‐responders/children who have previously experienced adverse events on MPH: no Supplemental information regarding data received through personal email correspondence with the authors in October 2013 (Poulton 2013b [pers comm]) |
Ramasamy 2014
Methods | A patient report of testicular failure possibly associated with chronic use of methylphenidate |
Participants | Diagnosis of ADHD: DSM III‐RAge: 20 years oldIQ: an exact number cannot be discerned but it is likely that the participant exhibits a normal IQ without any sort of disabilitySex: maleEthnicity: LatinoCountry: USAComorbidity: noneComedication: none Sociodemographics: family history was unremarkable |
Interventions | Methylpenidate type: not statedMethylphenidate dosage: varied with ageAdministration schedule: not statedDuration of treatment: approximately 17 years with voluntary cessation a few years ago Treatment compliance: not stated |
Outcomes | Serious adverse events: The patient's complaint was initially delayed puberty. He complained of high‐pitched voice, lack of libido, low energy level, chronic fatigue and poor erectile function. The results of laboratory tests were consistent with the patient's idiopathic testicular failure and warranted further exploration of the link between chronic methylphenidate use and effects on reproductive parameters |
Notes | Key conclusions of the study authors: the patient described in our case study seemed to exhibit characteristics related to the effects of chronic use of methylphenidate on development of human reproductive function. The unknown effects of methylphenidate are currently being studied, but as can be seen, one should exercise caution and patients should be followed closely when prescribing methylphenidate Comments from the study authors: because the developmental changes that occurred in the participant occurred over a number of years of treatment with methylphenidate, there is very little information about the patient's condition and how it developed during that period of time Comments from the review authors: this case has been included although the patient is 20 years old since he had been taking methylphenidate for approximately 17 yearsFunding/vested interest/authors' affiliations: no competing interests were disclosed Grant information: Ranjith Ramasamy is an NIH K12 Scholar supported by a Male Reproductive Health Research Career (MHRH) Development Physician‐Scientist Award (HD073917‐01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program Supplemental information regarding ADHD diagnosis and type, comorbidity and comedication received through personal email correspondence with the authors in April 2016 (Pranav 2016 [pers comm]) |
Rappaport 2004
Methods | A patient report of side effects during methylphenidate treatment in a 14‐year‐old boy with ADHD and a number of other co‐morbid conditions |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 14 years oldIQ: 80‐85Sex: maleEthnicity: LatinoCountry: USAComorbidity: PTSD, bipolar disorder, attachment disorder, language‐based learning disorderComedication: olanzapine Sociodemographics: working single mother, sporadic contact with father. Patient and his siblings were intermittently exposed to domestic violence |
Interventions | Both IR and ER MPH trieddosage: not statedAdministration schedule: not statedtime points: not statedDuration of treatment: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:
While taking immediate release methylphenidate (Ritalin): loss of appetite While taking extended release methylphenidate (Concerta): nausea and vomiting |
Notes | Key conclusions of the study authors: the patient's course and symptoms are illustrative of the maladaptive sequelae of untreated ADHD, complicated by a language‐based learning disorder.
Funding/vested interest/authors' affiliations: not stated Supplemental information regarding ADHD diagnosis and IQ received through personal email correspondence with the authors in November 2013 (Rappaport 2013 [pers comm]) |
Rapport 1996
Methods | Patient report of 2 6‐year‐old dizygotic twins with ADHD and ODD treated with methylphenidate |
Participants | ADHD diagnosis: DSM‐III‐R at time of examination. Authors state that both would have achieved the then new DSM‐IV diagnoses of ADHD combined type at the time of publication.Age: 6 years oldIQ: 100 and 93Sex: 2 girls, dizygotic twinsEthnicity: mixed white/JapaneseCountry: USAComorbidity: ODD (100%)Comedication: not stated Sociodemographics: low socioeconomic status |
Interventions | Methylphenidate type: immediate release methylphenidateMethylphenidate dosage: 4 doses: 5 mg (0.29 mg/kg), 10 mg (0.58 m/kg), 15 mg (0.87 mg/kg), 20 mg (1.16 mg/kg), placebo. Both children received each of the 4 methylphenidate dosesAdministration schedule: administration "was intentionally counterbalanced to allow for direct contrasts between no‐dose and moderate dose conditions (placebo vs 10 mg), low and high dose conditions (5 mg vs 15 mg) and identical high dose conditions (20 mg) between the 2 childrenDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | None of the active treatment conditions (methylphenidate and attentional training) resulted in higher frequency or greater severity of complaints compared to baseline Non‐serious adverse events:Measures: Side Effects Rating Scale (SERS)
|
Notes | Funding/vested interest: not stated Key conclusions of the study authors: brief mention should be made of the relative absence of emergent symptoms found in the present study. Although side effects are frequently reported in children undergoing psychostimulant trials (often as a function of increasing dosage), severity is typically mild, and it is advisable to gauge both frequency and severity against a placebo control owing to the high base rate of physical complaints reported by children with ADHD |
Rashid 2007
Methods | A patient report of intensified somatic hallucinations during dose increase of methylphenidate treatment at the hospital |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: unknown)Age: 10 years oldIQ: > 70Sex: maleEthnicity: unknownCountry: USAComorbidity: chronic pattern of somatisationComedication: unknownMethylphenidate‐naïve: no. OROS methylphenidate, 36 mg/day, ≥ 2 years Sociodemographics: history of several foster placements, now adopted |
Interventions | Methylphenidate dose: regular‐release methylphenidate, 10 mg, twice daily, then titrated to regular‐release methylphenidate, 15 mg, twice daily, 2 days Treatment compliance: not stated |
Outcomes | Serious adverse events:HallucinationsRegular‐release methylphenidate, 10 mg, twice dailyRegular‐release methylphenidate, 15 mg, twice daily, 2 days: somatic hallucinationsDiscontinuation of methylphenidate: complete resolution of the psychotic phenomena within 2 days Follow‐up 1 year later: no unexplained somatic complaints |
Notes | Funding/vested interest: no financial relationships to discloseAuthors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: here we describe a case of a 10‐year‐old boy with ADHD with a chronic pattern of somatisation, which evolved into overt somatic hallucinations with an increase in the methylphenidate dose. This pattern of somatisation was retrospectively recognised as partial somatic hallucinations Supplemental information regarding ADHD diagnostic criteria and IQ received through personal email correspondence with the authors in October 2013 (Rashid 2013 [pers comm]) |
Remschmidt 2005
Methods | A 21‐day multicentre, open‐label study of osmotic release oral system (OROS) methylphenidate in children and adolescents with ADHD switched from immediate release (IR) methylphenidate followed by a 12‐month follow‐up |
Participants | Number of participants screened: not statedNumber of participants included in the main study: 105Number of participants followed up: 101Number of withdrawals: 4Number of participants included in the follow‐up: 89Number of participants followed up: 56Number of withdrawals: 33Diagnosis of ADHD: DSM‐IV (subtype: combined (69.5%), hyperactive‐impulsive (7.6%), inattentive (22.8%))Age: range 6‐16 years oldIQ: not statedSex: 90 males, 15 femalesMethylphenidate‐naïve: noneEthnicity: not statedCountry: UK and GermanyComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria:
|
Interventions | Methylpenidate type: osmotic release oral systemMethylphenidate dosage: 18 mg, 36 mg, or 54 mg. 11.9% received 18 mg; 54.4% received 36 mg, and 33.7% received 54 mg at the end of the 21‐day main studyAdministration schedule: once daily, morningDuration of intervention: main study: 21 days, follow‐up: 12 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Reports of any adverse events, sleep and appetite patterns, and tics were reported by parents/caregivers up to day 21, and at months 2, 4, 6, 8, 10 and 12 |
Notes | Sample calculation: not statedEthics approval: independent Ethics Committees in each country reviewed the study protocolFunding/vested interest: this company‐initiated study was supported by a grant from Janssen‐Cilag GmbH Key conclusions of the study authors: children and adolescents can effectively and safely be switched from IR‐methylphenidate to OROS‐methylphenidate with improved symptom control and compliance Comments from the study authors: current international guidelines recommend the use of long‐acting stimulant preparations over short‐acting stimulants for the management of ADHD. The results of this study provide further support for this recommendation. These data cannot necessarily be generalised to unselected children and adolescents in clinical practice who may not be responsive to methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information requested from the review authors in June 2014 with no reply |
Ririe 1997
Methods | A patient report on unexpected interaction of methylphenidate (Ritalin) with anaesthetic agents |
Participants | Diagnosis of ADD/ADHD: DSM‐IV (subtype: not stated)Age: 6 years oldIQ: > 70Sex: maleEthnicity: not statedCountry: USAComorbidity: history of William's syndrome and supravalvar aortic stenosisComedication: only during anaesthesia: midazolam 20 mg + 10 mg, ketamine 60 mg,Glycopyrrolat IV 0,1 mg, midazolam IV 5 mg Sociodemographics: living at home with parents |
Interventions | Immediate release methylphenidate (Ritalin) dosage: 10 mg/dayAdministration schedule: twice dailyDuration of treatment: 2 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Difficulty with conscious sedation. No previous problems with sedation. Despite additional oral doses of sedatives the child remained alert and unable to lie still, until intravenous sedative drugs were given. After discharge, the child developed nausea, vomiting, lethargy and dehydration, which led to hospitalisation |
Notes | Funding/vested interest/authors' affiliations: Novartis Key conclusions of the study authors: there could be a potential risk of unwanted interactions between methylphenidate and anaesthetic agents. Based on the observations from the patient report, a more detailed and systematic investigation of methylphenidate in patients undergoing anaesthesia or sedation is warranted Comments from the study authors: no previous problems with anaesthesia. The child had no apparent limitations of activity and no cardiac symptoms. We believe that the stimulant effect of methylphenidate may have played a major role in antagonising the sedative effect of the oral midazolam in the clinically recommended doses. The stimulant effect of methylphenidate makes it potentially very difficult to attain a desirable level of sedation without requiring large and potentially unsafe doses of sedative drugs or administration of general anaesthesia. The gastrointestinal side effects of methylphenidate, particularly decreased appetite and nausea and vomiting, may be aggravated by many of the drugs used for sedation or general anaesthesia Supplemental information regarding intellectual function and diagnostic criteria received through personal email correspondence with the authors in October 2013 (Ririe 2013 [pers comm]) |
Sabuncuoglu 2007
Methods | 3 patient reports of hyperactivity and irritability during switch from risperidone to methylphenidate |
Participants | Case 1Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 5 years oldIQ: no developmental delaySex: maleEthnicity: not statedCountry: TurkeyComorbidity: ODDComedication: noneSociodemographics: not stated Case 2 Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 6 years oldIQ: 70‐90Sex: femaleEthnicity: not statedCountry: TurkeyComorbidity: borderline intellectual functioningComedication: noneSociodemographics: not statedCase 3 Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 15 years oldIQ: > 90Sex: femaleEthnicity: not statedCountry: TurkeyComorbidity: ODD and learning disorderComedication: noneSociodemographics: not stated |
Interventions | Case 1: immediate release methylphenidate dosage: 15 mg/day. Administration schedule: not stated. Duration of treatment: not stated. Treatment compliance: not stated Case 2: immediate release methylphenidate dosage: 15 mg/day. Administration schedule: not stated. Duration of treatment: not stated. Treatment compliance: not stated Case 3: immediate release methylphenidate dosage: 18 mg/day. Administration schedule: once, morning. Duration of treatment: not stated. Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Case 1: methylphenidate introduced 2 days after abrupt discontinuation of risperidone 1 mg/day (8 months) and produced agitation, irritability, vigilance, and violent behaviour. No dyskinetic movements. Methylphenidate was discontinued and the adverse events disappeared. After a 6‐week long drug‐free period, methylphenidate was reintroduced at 15 mg/day. No adverse events were observed Case 1: methylphenidate introduced after discontinuation of risperidone 1 mg/day (2 years) and produced a near manic state, irritability, agitation, racing thoughts, and distractibility. No dyskinetic movements. Methylphenidate was discontinued and the adverse events disappeared. After a couple of months methylphenidate was reintroduced at 15 mg/day and was well‐tolerated Case 1: methylphenidate introduced after a 1‐week medication free interval after treatment with risperidone 1 mg, and produced irritability, agitation and discomfort. Methylphenidate was discontinued and the adverse events disappeared. The patient did not retry the medication |
Notes | Funding/vested interest/authors' affiliations: not stated Key conclusions of the study authors: this report of 3 patients draws attention to a unique condition that arises in switching from atypical antipsychotic to stimulant medication. A drug‐free interval is recommended in switching from risperidone to methylphenidate Comments from the study authors: the severity of adverse events correlated well with methylphenidate administration, ceased upon discontinuation of treatment and, interestingly, readministration of methylphenidate after an interval was associated with no adverse events in the first and second patient Supplemental information regarding IQ received through personal email correspondence with the authors in October 2013 (Sabuncuoglu 2013 [pers comm]) |
Sahin 2014
Methods | A study of methylphenidate use for 2 months |
Participants | Number of patients screened: not statedNumber of participants included: 30Number of participants followed up: 30Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: combined (46.7%), hyperactive‐impulsive (10%), inattentive (43.3%))Age: mean 9.54 (SD 2.83), range 6‐18 years oldIQ: > 70Sex: 24 males, 6 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: disruptive behaviour disorder (DBD): 17, anxiety disorder: 5, learning disability: 3, enuresis/encopresis: 3, tic disorder: 2Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
|
Interventions | Methylphenidate type: osmotic release oral system (OROS)Mean methylphenidate dosage: 0.70 (SD 0.20) mg/kg/day (0.64 (SD 0.16) mg/kg/day in the 1st month and 0.76 (SD 0.25) mg/kg/day in the 2nd month)Administration schedule: not statedDuration of intervention: 2 months Treatment compliance: 100% |
Outcomes | Non‐serious adverse events:
|
Notes | Sample calculation: noEthics approval: yesFunding: sponsored by Ondokuz Mayis University project number PYO.TIP.1904.12.013.Vested interests/authors' affiliations: none of the authors report conflicts of interest Key conclusions of the study authors: leptin and brain‐derived neurotrophic factor (BDNF) were not associated with poor appetite and/or weight loss due to methylphenidate treatment. However, ghrelin and adiponectin might be biomolecules that play a role in underlying neurobiological mechanisms of methylphenidate‐related appetite or weight loss. Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Saieh 2004
Methods | A patient report of hospitalisation due to hypertension during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 8 years oldIQ: normalSex: maleEthnicity: not statedCountry: ChileComorbidity: not statedComedication: not stated Sociodemographics: maternal family history of hypertension |
Interventions | Methylphenidate type: RitalinMethylphenidate dosage: 0.32 mg/kgAdministration schedule: not statedDuration of treatment: 6 months Treatment compliance: not stated |
Outcomes | Serious adverse events:72‐hour hospitalisation, emergency unit:Abdominal pain for 4 days prior to hospitalisation, intermittent accentuation (hours), no other symptomsSecondary hypertension: persistent hypertension (158/88 ‐ 170/105, pulse: 78‐98 bpm). Normal physical examination. Normal eye fundus and normal cardiological examination. Discontinuation of methylphenidate: hypertensive treatment only necessary for 24 hours. Normal blood pressure after 1 week |
Notes | Key conclusions of the study authors: we want to draw attention to our experience of a patient who had hypertension, which was clearly related to the administration of MPH, and which disappeared when MPH was discontinued Comments from the study authors: unfortunately, only a few relevant publications and no national studies on the subject exist, so we do not know exactly the extent of this problem, although from anecdotal experience of verbal communication the incidence of tachycardia and hypertension appear to be low. Prospective studies should be performed to find the true incidence of complications with the use of methylphenidate and thus further establish careful and appropriate control of MPH‐treated patients to avoid these complicationsFunding/vested interest/authors affiliations: no affiliations to pharmaceutical companies stated Supplemental information regarding ADHD diagnostic criteria, IQ, type and dose of MPH, and duration of hospitalisation received through personal email correspondence with the authors in October and December 2013 (Saieh 2013 [pers comm]) |
Sangal 2006
Methods | A 7‐week randomised, double‐blind, cross‐over trial of:
|
Participants | Number of participants screened: 107Number of participants included: 85Number of participants followed up: 75Number of withdrawals: 10Diagnosis of ADHD: DSM‐IV (subtype: combined (67.9%), hyperactive‐impulsive (2.4%), inattentive (29.8%))Age: mean 10.1 (SD 2.0), range 6 to 14 years oldIQ: not statedSex: 64 (males, 21 females)Methylphenidate‐naïve: 43.5%Ethnicity: white: 72.9%, others: 27.1%Country: USAComorbidity: ODD (48.2%); conduct disorder (3.5%); anxiety/agoraphobia (1.2%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMean methylphenidate dosage: 42.29 mg/day (range 15 to 60), or 1.12 mg/kg per dayAdministration schedule: 3 time pointsDuration of treatment: 7 weeksMedication‐free period between intervention: 10‐20 days Treatment compliance: measured by pill counts at visits in 7‐12 day intervals, ranging from 87.5% to 100% |
Outcomes | Non‐serious adverse events
|
Notes | Sample calculation: yesEthics approval: yesFunding: this research was funded by Eli Lilly and Company, which markets atomoxetine. Some patients received doses that were off‐labelVested interests/authors' affiliations: this was an industry supported study sponsored by Eli Lilly. The data were analysed by statisticians at Eli Lilly, including Dr Sutton, one of the authors. The manuscript was written as a combined effort of all authors. Dr Sangal has received research support from Eli Lilly, Merck, Organon, Cephalon, and Novartis. Dr Owens has received research support from Cephalon, Sanofi‐ Aventis, Johnson & Johnson, Sepracor, and Eli Lilly; is a member of the speakers' bureau for Eli Lilly; is a consultant for Cephalon; and is an advisory board member for Cephalon, Pfizer, and Eli Lilly. Drs. Sutton, Allen, Schuh, and Kelsey are employees of Eli Lilly Key conclusions from study authors: patients receiving atomoxetine twice daily had shorter sleep‐onset latencies, relative to methylphenidate 3 times daily, based on objective actigraphy and polysomnography data Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information requested from the study authors twice in January/February 2014. No reply received |
Santosh 2006
Methods | 2 separate retrospective cohort studies (only study 2 is used here due to polypharmacy) |
Participants | Number of participants screened: not statedNumber of participants included: 52 (ADHD: 25, ADHD + ASD: 27)Number of participants followed up: 52Number of withdrawals: not stated
Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 11.08 years oldIQ: mean 89.56Sex: ADHD group 80% males, 20% females. ADHD + ASD group 88.89% males, 11.11% femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: UKComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
|
Interventions | Methylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: range of follow‐up was between 1 and 6 months, mean: 87 days Treatment compliance: not stated |
Outcomes | Non‐serious adverse events Pre‐ and post‐treatment: routine ratings using the side effects module of the Treatment Outcome Rating Scale |
Notes | Sample calculation: noEthics approval: not statedFunding/vested interests: both the pilot study and current development and deployment of the DENEM™ system have been supported by an award from Guys' and St Thomas' Charity
Authors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: both studies presented here support previous findings from smaller studies that show children with autism and ADHD can respond as well to stimulants as children with ADHD alone. Although randomised controlled trials remain the gold standard for efficacy studies, systems like this that allow clinicians to continue rigorous and consistent monitoring for many years have a valuable role to play. Furthermore, such monitoring systems which now exist electronically can easily accumulate large data sets and reveal details about long‐term effectiveness and long‐term side effects of medication that are unlikely to be discovered in short‐term trials Comments from the review authors: the article describes 2 studies. Some of the participants in the first study are not receiving MPH but dexamphetamine instead, and for this reason the first study is excluded from our review. The second described study is included Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information and data have not been possible to retrieve through personal email correspondence with the authors in February‐June 2014 |
Schertz 1996
Methods | A retrospective study examining predictors of weight loss in children with ADHD treated with methylphenidate or dextroamphetamine sulfate |
Participants | Number of participants screened: not statedNumber of participants included: 60 (total)Number of participants included in methylphenidate group: 32Number followed up: 60Number of withdrawals: 0Diagnosis of ADHD: DSM‐III‐R (subtype: not stated)Age: mean 7.5 years old (range: 3.6‐15.5)IQ: no mental retardationSex: 29 males, 3 femalesMethylphenidate‐naïve: 0Ethnicity: white 77%, African American 10%, Asian: 3%, Hispanic: 10%Country: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: not statedMean methylphenidate dosage: 25.5 mg or 1 mg/kg/dayAdministration schedule: not statedDuration of intervention: mean duration 11.2 months (range 6‐20 months) Treatment compliance: not assessed |
Outcomes | Weight and body mass index (BMI) were the 2 measures of adiposity used. Weight was expressed in terms of z scores derived from US normative data |
Notes | Sample calculation: noEthics approval: not statedFunding: not statedVested interests/authors' affiliations: not stated Key conclusions of the study authors: pretreatment weight, adjusted for age, gender and height is a significant predictor of weight loss in children with ADHD treated with either methylphenidate or dextroamphetamine sulphate. In contrast, pretreatment age, duration of treatment, and weight‐adjusted dose were not found to be significant predictors Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information regarding height and weight for the methylphenidate group requested from the authors by email correspondence in January 2014. No reply |
Schmidt 2002
Methods | A retrospective cohort study analysing the EEGs of 124 children and adolescents treated with methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 124Number of participants followed up: 124Number of withdrawals: 0Diagnosis of ADHD: ICD‐10 (subtype: F90.0, predominantly inattentive type (64,5%), F90.1, predominantly hyperactive type (35,5%))Age: mean 10.3: years old (range 6.1‐17.1)IQ: 4% were intellectually disabledSex: 113 males, 11 femalesMethylphenidate‐naïve: both methylphenidate naïve and not methylphenidate naïve participants included in the studyEthnicity: not statedCountry: GermanyComorbidity: nocturnal enuresis (4%), mild intellectual disability (4%), mixed disorders of conduct and emotions (3.2%), absence epilepsy (0.8%), focal epilepsy (1.6%), developmental anomaly or developmental delay (0%), no comorbidity (64.5%)Comedication: 94.4% of the sample did not use another type of medicine apart from methylphenidate. 2.4% used anticonvulsant, and 0.8% were treated with different medicinesSociodemographics: not stated Inclusion criteria:
Exclusion criteria: None stated |
Interventions | Methylphenidate type: RitalinMean methylphenidate dosage: 0.5‐1.0 mg/kgAdministration schedule: not statedMean duration of intervention: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:EEG (according to the German guidelines) measures by medical staff and under supervision from one of the authors (a doctor). A total of 4 categories were formed to evaluate the EEG:
|
Notes | Sample calculation: noEthics approval: yesFunding/vested interest: no fundingAuthors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: whether or not methylphenidate medication influences the occurrence of epileptic seizures remains unsettled. Given the data from this study, we would conclude that an EEG during therapy with methylphenidate is not necessary. Before commencing a planned methylphenidate therapy, however, an EEG should be performed. Comments from the review authors: there were several parameters from the EEG assessment in the article. However since we in the review have chosen to analyse it according to EEG changes yes/no we have only used the 4 categories that the authors formed Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding funding, ethics approval received through personal email correspondence with the authors in December 2013 (Sinzig 2013 [pers comm]). Not able to get separate data on the participants without intellectual disability |
Schulz 2010
Methods | A multicentre, randomised, cross‐over trial with 2 interventions:
Phases: 2 phases of 1 week each. All participants were treated with Ritalin LA |
Participants | Number of participants screened: 159Number of participants included: 150Number of participants followed up: 145Number of withdrawals: 5Diagnosis of ADHD: DSM‐IV (subtype: combined (67.3%), hyperactive‐impulsive (6%), inattentive (26.7%))Age: mean 9.7 (SD 1.6) years old (range 6‐12)IQ: not stated, but patients not meeting minimum intelligence requirements were excludedSex: 112 males, 38 femalesMethylphenidate‐naïve: 0%Ethnicity: white: 95.3%, African American: 1.3%, Asian: 2%, others: 1.3%Country: GermanyComorbidity: not clear, see exclusion criteria 1Comedication: not clear, see exclusion criteria 8Sociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: Ritalin LA (extended release)Mean methylphenidate dosage: 20 mg or 40 mgAdministration schedule: not statedDuration of intervention: 14 days Treatment compliance: not stated |
Outcomes | Serious adverse events:No deaths or serious adverse events occurred in the study Non‐serious adverse events: A total number of 36 patients (24%) experienced a total of 64 adverse events, 33 of which were considered to be related to study medicationNo mentioning of how the adverse events were measured |
Notes | Sample calculation: noEthics approval: yes, Central Ethics Committee University FreiburgFunding/vested interest: sponsored by Novartis Pharma GmbH, GermanyAuthors' affiliations: several authors have received funding from medical companies Key conclusions of the study authors: all of the clinical rating scales showed consistently no difference between the 2 breakfast conditions. The clinical efficacy of Ritalin LA is not influenced by breakfast and works independently of food intake Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
Schwartz 2004
Methods | A patient report of stuttering priapism associated with withdrawal from sustained‐release methylphenidate |
Participants | Diagnosis of ADHD: DSM‐ IV‐TR (subtype: inattentive)Age: 15 years oldIQ: not statedSex: maleMethylphenidate naïve: yesEthnicity: whiteCountry: USAComorbidity: not statedComedication: no Sociodemographics: not stated |
Interventions | Methylphenidate type: osmotic release oral system, OROS (Concerta)Methylphenidate dosage: begun at 27 mg/day Monday through Saturday with drug holiday on Sunday, then increased to 36 mg/day, followed by 7 days where medication was not taken, then a dose increase to 54 mg/dayAdministration schedule: once daily, in the morningDuration of treatment: 2 months Treatment compliance: not stated |
Outcomes | Serious adverse events:Intermittent painful priapism beginning on the second drug holiday (the Sunday after the dosage was increased to 36 mg/day). 5‐10 episodes lasting up to an hour were experienced for at least half of the week with a pain score of 5/10. With the increase dose of 54 mg/kg the duration and pain associated with episodes increased When the patient was weaned off methylphenidate, the symptoms resolved and had not re‐occurred at either 2 weeks or 6 months follow‐up |
Notes | Funding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: it is likely that withdrawal from OROS methylphenidate was the cause of this adolescent boy's priapism Comments from the study authors: it is possible that this adverse event is underreported due to embarrassment about discussing the problem Supplemental information regarding IQ and ADHD diagnosis received through personal correspondence with the authors in September 2013(Schwartz 2013 [pers comm]) |
Shang 2015
Methods | A cohort study of methylphenidate use for 24 weeks |
Participants | Number of participants screened: 174Number of participants included: 160Number included in the methylphenidate group: 80Number of participants followed up: 66Number of withdrawals: 14Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean: 9.64 (SD 2.42) years old (range: 7‐16)IQ: mean: 106Sex: 70 males, 10 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TaiwanComorbidity: not statedComedication: noSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: osmotic release oral system (OROS)Mean methylphenidate dosage: 27.83 mg/day (SD 12.44)Administration schedule: once dailyDuration of intervention: 24 weeks Treatment compliance: assessed by pill count and interview, results not reported |
Outcomes | Non‐serious adverse events:Safety measures, including decreased appetite, vomiting, insomnia, somnolence, dizziness, stomachaches, headaches, palpitations, and dry mouth, were assessed at each visit by open‐ended questions during a clinical interview firstStructured interview listing all the potential adverse effects at each visit Vital signs and body weight monitored at each visit |
Notes | Ethics approval: yes. The Research Ethics Commitee of National Taiwan University Hospital approved this study prior to implementationFunding/vested interest: noAuthors' affiliations: SSG, CYS and HYL were on the speakers' bureau for Janssen‐Cilag and Eli‐Lilly & Co., Taiwan Key conclusions of the study authors: both drugs are associated with significant improvement in symptoms while also being safe Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding comorbidity and treatment compliance requested through personal email correspondence with the authors in June 2016. No reply |
Shibib 2009
Methods | A report of 4 cases of psychosis during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined 100%)Age: 14, 8, 10, and 14 years oldIQ: above 70Sex: 1 female, 3 malesEthnicity: not statedCountry: UKComorbidity: conduct disorder (Case 4)Comedication: no, and no use of illicit substances Sociodemographics: not stated |
Interventions | Case 1Methylphenidate type: extended release (Equasym XL)Methylphenidate dosage: gradually increased to 30 mg over 4 weeksAdministration schedule: once dailyDuration of treatment: 1 month titration, hereafter 4 months treatmentTreatment compliance: not stated Case 2 Methylphenidate type: immediate release (Ritalin)Methylphenidate dosage: gradually increased from 5 mg once daily to 10 mg twice dailyAdministration schedule: once/twice dailyDuration of treatment: 7 daysTreatment compliance: not statedCase 3 Methylphenidate type: immediate release and extended release (Concerta XL)Methylphenidate dosage: immediate release: gradually increased to 15 mg daily. Extended release: 36 mg, later increased to 54 mg dailyAdministration schedule: immediate release: not stated. Extended release: once dailyDuration of treatment: immediate release: not stated. Extended release: 3 weeksTreatment compliance: because compliance became an issue treatment with immediate release methylphenidate was stopped, and extended release methylphenidate was initiated. No information about compliance during treatment with extended release methylphenidateCase 4 Methylphenidate type: extended release (Concerta XL)Methylphenidate dosage: 18 mgAdministration schedule: not statedDuration of treatment: 24 hoursTreatment compliance: because compliance became an issue treatment with immediate release methylphenidate was stopped, and extended release methylphenidate was initiated. No information about compliance during treatment with extended release methylphenidate |
Outcomes | Serious adverse events: Case 1Psychosis. Visual hallucinations. ParanoidDiscontinuation: symptoms resolved spontaneously Case 2 Psychosis. Auditory and visual hallucinations. SuspiciousDiscontinuation: symptoms resolved spontaneouslyCase 3 Psychosis. Suspicious. Auditory hallucinationsDiscontinuation: symptoms resolved spontaneouslyReadministration of extended release methylphenidate (low dose) as an adjunct to atomoxetine, 5 weeks: "completely uncharacteristic behaviour", throwing furniture, making "silly" noises, and irritability. "Being unable to feel himself"Discontinuation: this behaviour resolved spontaneously within 72 hoursReadministration of immediate release methylphenidate (15 mg, twice daily): no psychotic symptoms reportedCase 4 Psychosis. Suspicious. Paranoid ideation. Denied any hallucinatory experiences although he was observed to be responding to possible auditory hallucinationsDiscontinuation: symptoms resolved spontaneouslyRe‐challenged with immediate release methylphenidate (10 mg 3 times daily): well toleratedNon‐serious adverse events Case 1Extended release methylphenidate gradually increased to 30 mg over 4 weeks: loss of appetite Case 3 Immediate release methylphenidate gradually increased to 15 mg daily: poor appetite |
Notes | Key conclusions of the study authors: psychosis is an important, unpredictable side effect of stimulant medication. Symptoms resolve with discontinuation of treatment. Reemergence of ADHD symptoms are rapid and re‐challenge is often indicated Comments from the study authors: it would be advisable for all professionals involved in the care and treatment of patients with ADHD to receive mental health training to aid the early recognition and appropriate management of such side effectsFunding/vested interest/authors' affiliations: not stated Supplemental information regarding ADHD diagnostic criteria, ADHD subtype, and IQ received through personal email correspondence with the authors in August‐October 2013 (Shibib 2013 [pers comm]) |
Shin 2016
Methods | Self‐controlled patient series analysis of cardiovascular events associated with methylphenidate treatment in children and young people with ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 1224Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: ICD‐10 (subtype: not stated)Age: under 17 or 17IQ: not statedSex: 75‐80% malesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: KoreaComorbidity: the prevalence of comorbidities varied across adverse events. Depressive episode was the most common comorbidity (n = 15, 29% in participants with myocardial infarction), though only 9 (13.4%) participants with ischaemic stroke had this condition. In contrast, mental retardation occurred in 12 (18%) participants with an ischaemic stroke, while only 2 (5%) with heart failure had this condition comedication: antidepressants and antipsychotics were often co‐prescribed (15‐27%)Sociodemographics: not stated Inclusion criteria:
Exclusion criteria: None stated |
Interventions | Methylphenidate type: not describedMean methylphenidate dosage: not stated Mean duration of methylphenidate exposure: 0.5 years for all events except heart failure, which was 0.3 years |
Outcomes | All data used were obtained from secondary electronic records for the study participants. This study had both comparative cohort data and non‐comparative cohort data Non‐serious adverse events: These were all patients aged ≤ 17 years who had at least one recorded diagnosis of ADHD (ICD‐10 code F90), had started taking methylphenidate (ATC (Anatomical Therapeutic Chemical) code N06BA04), and had an incident cardiovascular adverse event with a recorded diagnosis during the study period (1 January 2008 and 31 December 2011) |
Notes | Ethics approval: this study was approved by the institutional review board of the Korea Institute of Drug Safety and Risk Management, Seoul. Obtaining informed consent from the study population was waived by the boardFunding: this research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors. EER was supported by an NHMRC fellowship (GNT1110139). NP was supported by an NHMRC early career fellowship (GNT1035889)Vested interests: all authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work Key conclusions of the study authors: our self‐controlled patient series study suggests an increased risk of cardiac events associated with methylphenidate use Comments from the study authors: methylphenidate exposure in children/young people with a diagnosis of ADHD is associated with arrhythmia and potentially with myocardial infarction in specific time periods of use. With the increased use of drugs for ADHD globally, the benefits of methylphenidate should be carefully weighed against the potential cardiovascular risks of these drugs in children and adolescents Inclusion of methylphenidate responders only or exclusion of children who have previously experienced adverse events on methylphenidate: no |
Shyu 2015
Methods | A case‐control study |
Participants | Number of patients screened: for ADHD group: 146,063. Control group: 1,000,000Number included: 146, 098Number included as cases (MPH): 73,049 and controls (no intervention): 73,049Number followed up in each arm: MPH: 73,049 and C: 73,049Number of withdrawals in each arm: 73,014 were excluded from the ADHD group. No data on control groupDiagnosis of ADD: DSM‐?/ICD‐? diagnosis of ADHD (combined (%), hyperactive‐impulsive (%), inattentive (%)).Age: cases (mean 9.4 years, SD 3.3), controls (mean 9.6 years, SD 3.8)IQ: no dataSex: cases: 14,742 females, 58,302 males. Controls: 20,057 females, 52,992 malesMPH‐naïve: no dataEthnicity: no dataCountry: TaiwanComorbidity (type: %): cases: ODD/conduct disorder (11.1%), PDD (8.7%), tic disorders (6.6%), intellectual disability (14.2%), psychotic disorder (1.7%), and schizophrenia (0.9%)Controls: ODD/conduct disorder (0.3%), PDD (0.3%), tic disorders (0.9%), intellectual disability (0.9%), psychotic disorder (0.2%), and schizophrenia (0.1%)Comedication (no/yes) no dataSociodemographics (e.g. double or single parent family, low, middle or upper class). No data Inclusion criteria 1. Diagnosed with ADHD between January 1999 and December 20112. Was a part of the National Health Insurance Research Database of Taiwan (NHIRD‐TW)Exclusion criteria 1. Were diagnosed with ADHD before 31 December 19992. Had a diagnosis of psychotic disorders that preceded the diagnosis of ADHD3. Born after 31 December 1999 |
Interventions | Methylphenidate type: no dataMPH dosage: no dataAdministration schedule: no dataDuration of intervention: medical records followed from January 2000 to December 2011 Treatment compliance: no data |
Outcomes | Outcomes were defined as having diagnoses of schizophrenia spectrum disorders, including schizophrenia, schizophreniform disorder, schizoaffective disorder (ICD‐9‐CM code 295.X), delusional disorder (ICD‐9‐CM code 297.X), brief psychotic disorder and psychotic disorder NOS (ICD‐9‐CM code 298.X). Diagnoses of schizophrenia spectrum disorders and date of diagnosis were identified based on the insurance status, and outpatient and hospitalisation claims databases. Having a diagnosis of any psychotic disorder (ICD‐9‐CM code 295.X, 297.X or 298.X) and schizophrenia (ICD‐9‐CM code 295.X) were set as 2 different outcomes and were analysed separately Serious adverse events: "Compared to ADHD patients who were never exposed to MPH, MPH use among ADHD patients significantly increased the risk of developing any psychotic disorder (aHR 1.20, 95% CI 1.04 to 1.40). However, MPH use did not significantly increase the specific risk of developing schizophrenia (aHR 1.16, 95% CI 0.94 to 1.42) among patients with ADHD" |
Notes | Sample calculation: no dataEthics approval: no dataFunding: supported by the Chang Gung Memorial Hospital Research ProjectVested interests/authors' affiliations: the authors declare no conflicts of interest Key conclusions of the study authors: compared to ADHD patients who were never exposed to MPH, MPH use among ADHD patients significantly increased the risk of developing any psychotic disorder; however, it did not significantly increase the specific risk of developing schizophrenia |
Silva 2004
Methods | Open‐label cohort study to determine efficacy of a single daily dose of dexmethylphenidate (d‐MPH) in 22 children with ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 22Number of participants followed up: 20Number of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 8.7 years old (range 6‐12)IQ: not statedSex: 17 males, 5 femalesMethylphenidate‐naïve: n = 18Ethnicity: white 54%, African American 23%, Hispanic 23%Country: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria
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Interventions | Methylphenidate type: dexmethylphenidate (d‐MPH)Mean methylphenidate dosage: the starting dose was 2.5 mg/day and titrated to up to a maximum 30 mg/day based on clinical effect and tolerability over 8 weeks. The mean daily dose was 16.0 mg/dayAdministration schedule: once daily in the morningDuration of treatment: not stated Treatment compliance: was confirmed by tablet and bottle counts |
Outcomes | Non‐serious adverse events Participants were seen at least weekly and monitored for adverse events. Apart from nightmares, data were only recorded for adverse events when reported by ≥ 2 participants |
Notes | Sample calculation: not statedEthics approval: approved by Institutional Review BoardFunding/vested interest: supported by Celgene Corporation and the NIHAuthors' affiliations: New York University, 4 Rivers Clinical Research and Celgene Corporation (4/8 authors) Key conclusions of the study authors: a single daily dose of d‐MPH is safe and effective in controlling ADHD symptoms alleviating the need for midday dosing. Patients who failed prior therapy including dl‐MPH may respond to d‐MPH. A controlled study to confirm these data are warranted Comments from the study authors: in controlled clinical trials, d‐MPH was at least as efficacious and safe as dl‐MPH, at half the dose. In contrast to dl‐MPH it was effective on objective measures 6 hours post‐dose Comments from the review authors: although the only outcome which was measured into the extension period after the 8‐week trial was adverse events, only data up to the end of the 8‐week trial are reported. This study examines the efficacy of d‐MPH, which is not identical to standard methylphenidate (i.e. d‐ and l‐ isomers) Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, see exclusion criteria 1 Supplemental information regarding data requested from the authors in April 2014. No reply received |
Sobanski 2013
Methods | A cohort study of methylphenidate use for 6‐12 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 381Number of participants followed up: 347Number of withdrawals: 34
Diagnosis of ADHD: ICD‐10 (subtype: combined (64.8%), hyperactive‐impulsive (32.3%), inattentive (2.6%))Age: mean 14.0 years old (range: 12‐17)IQ: not statedSex: 307 males, 74 femalesMethylphenidate‐naïve: 7.3%Ethnicity: not statedCountry: GermanyComorbidity: speech and language disorders and learning disabilities (8.9%), depressive disorders (3.1%) and anxiety disorders (2.4%). Asperger's syndrome (1%) tic disorders (1.3%)Comedication: yes, 42 patients (11%) (type: not stated)Sociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: Medikinet retard (50% extended‐release component)Mean methylphenidate dosage: 35.7 (SD 15.1, range 5‐120) mg/d, and at end point 0.7 (SD 0.3, range 0.2‐2.8) mg/kg of the body weightAdministration schedule: all patients received Medikinet retard in the morning, 16% received a second dose at lunchtime and 4% on a pro re nata basisDuration of intervention: the median observational period for the treatment with Medikinet retard was 70 days Treatment compliance: not stated |
Outcomes | Adverse events were assessed by spontaneous report during the clinical interview at each visit (at T1 and T2) |
Notes | Sample calculation: noEthics approval: yesFunding/vested interest/authors affiliations: the study was funded by Medice. Esther Sobanski has received consulting income and research support from Eli Lilly, Medice, Novartis and Shire and research support from the German Research Foundation, German Ministry of Education and Research. She receives royalties from books by Medizinisch Wissenschaftliche Verlagsgesellschaft and Dansk Psykologisk Forlag. Manfred Dopfner received consulting income and research support from Lilly, Medice, Shire and Vifor and research support from the German Research Foundation, German Ministry of Education and Research. He receives royalties from books and psychological tests published by Hogrefe, Beltz and Huber. Claudia Ose has received an unrestricted educational grant for statistical and administrative support from Medice. Roland Fischer is the medical director of Medice Key conclusions of the study authors: the findings suggest that pharmacologically treated adolescents with ADHD and insufficient symptom reduction and/or treatment adherence benefit from switching to Medikinet retard and that it is well tolerated when given in clinical routine care Comments from the study authors: adverse events were assessed by spontaneous reports but not by the use of structured measures possibly resulting in underreporting. Most patients that were included in the study had an indication for a medication switch. Thus, the study does not allow for conclusions about general effectiveness or superiority of Medikinet retard compared to alternative medications Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information on adverse events requested through personal email correspondence with the authors in July 2014 (Sobanski 2014 [pers comm]). Authors not able to provide further information |
Song 2012
Methods | A 12‐week, multicentre, open‐label trial of osmotic release oral system (OROS) methylphenidate in Korean children with ADHD |
Participants | Number of participants screened: not statedNumber of participants included: 143Number of participants followed up: 116Number of withdrawals: 27Diagnosis of ADHD: DSM‐IV (subtype: combined 35.4%, hyperactive‐impulsive 6.3%, inattentive 34.3%, not specified 24.5%)Age: mean 9.36 years old (range 6‐18)IQ: mean 108Sex: 121 males, 22 femalesMethylphenidate‐naïve: 89.5%Ethnicity: 100% AsianCountry: KoreaComorbidity: tic disorder 7%, anxiety disorder 3.9%, depression 4.1%, oppositional defiant disorder/conduct disorder 27.3%Comedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Mean methylphenidate dosage: 30.05 mg/dayAdministration schedule: once daily, in the morningDuration of intervention: 12 weeks Treatment compliance: not stated |
Outcomes | Barkley Side Effects Rating Scale |
Notes | Sample calculation: not statedEthics approval: yes. Approved by the institutional review boards for all participating centresFunding/vested interest: supported by Janssen Korea Key conclusions of the study authors: optimal mean dose of OROS‐methylphenidate was significantly different by age groups. Higher doses was needed in older aged groups than younger groups. Effectiveness and tolerability of OROS‐methylphenidate in symptoms of ADHD sustained for up to 12 weeks Comments from the study authors: positive bias may have resulted from enrolment of only participants who could tolerate OROS‐methylphenidate and experienced efficacy during the dose titration period. Our findings may not be generalised to long‐term effects of methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through email correspondence with the authors in May 2014. No reply |
Spencer 1992
Methods | A cohort study of methylphenidate use for 14.2 (SD 10.7) months |
Participants | Number of participants screened: not statedNumber of participants included: 29Number followed up: 29Number of withdrawals: not statedDiagnosis of ADHD: DSM‐III‐R (subtype: not stated)Age: mean 7.8 SD 2.4IQ: not statedSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria: 1. DSM‐III‐R diagnosis of ADHD |
Interventions | Methylphenidate type: immediate releaseMean methylphenidate dosage: 31.4 (SD 17.6) mg (1 mg/kg SD 0.5)Administration schedule: not statedDuration of intervention: 14.2 (SD 10.7) months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Assessment of growth deficits: simple growth deficit, percent deficit, change in cumulative frequency percentiles, percent change, standardised height deficit, deficits in growth velocity Malnutrition index |
Notes | Sample calculation: not stated
Ethics approval: not stated
Funding/vested interest: not stated
Authors' affiliations: not stated Key conclusions of the study authors: although there were statistically significant weight deficits in children treated with both desipramine and methylphenidate compared with normal controls, only those treated with methylphenidate sustained height deficits that attained statistical significance Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through personal email correspondence with the authors in September and October 2013. No reply |
Steele 2006
Methods | An open‐label, 8‐week, multicentre, randomised, parallel trial with 2 arms:
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Participants | Number of participants screened: 187Number of participants included: 147Number randomised to OROS‐methylphenidate: 73 and IR‐methylphenidate: 74Number of participants followed up: OROS‐methylphenidate: 61; IR‐methylphenidate: 62Number of withdrawals: OROS‐methylphenidate: 12; IR‐methylphenidate: 12Diagnosis of ADHD: DSM‐IV (subtype: combined (79.3%), hyperactive‐impulsive (2.1%), inattentive (18.6%)Age: mean: not stated (range: 6‐12)IQ: above 70Sex: 121 males, 24 femalesMethylphenidate‐naïve: not statedEthnicity: white: 86.9%, African American: 3.4%, Asian: 0.7%, others: 9.0%Country: CanadaComorbidity: oppositional defiant disorder (40.7%), conduct disorder (0.7%), anxiety (4.1%)Comedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system and immediate release methylphenidate (patients were randomly assigned)Mean daily dose of OROS‐methylphenidate: 37.8 (SD 11.9) mg (1.17 (SD 0.52) mg/kg; range 18‐54 mg)Mean daily dose of IR‐methylphenidate: 33.3 (SD 13.2) mg (1.03 (SD 0.46) mg/kg; range 10‐70 mg)Administration schedule: OROS‐methylphenidate once daily in the morning and IR‐methylphenidate 2‐3 times dailyDuration of intervention: 8 weeksTitration period: 4 weeks initiated after randomisationWashout: at study entry, patients on stimulant or non‐stimulant medication to treat ADHD underwent a minimum 3‐day washout Treatment compliance: the percentage of participants who missed any dose during the trial: IR‐methylphenidate (84%) and OROS‐methylphenidate (56%) |
Outcomes | Non‐serious adverse events: Adverse events, physical examination, vital signs, and body weight, height |
Notes | Sample calculation: yes (130 participants)Ethics approval: yesFunding/vested interest: this research was supported by Janssen‐Ortho Inc., CanadaAuthors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: once‐daily OROS‐methylphenidate is significantly more effective than usual care with IR‐methylphenidate based on multiple outcome measures including remission rate Exclusion of methylphenidate non‐responders: yes, known non‐responders excluded (see exclusion criteria 1)Supplemental information requested through email correspondence with the authors in September 2013. No reply |
Stein 2002
Methods | A comparative cohort study of 32 non‐medicated ADHD male adolescents, 35 ADHD male adolescents receiving methylphenidate, and 77 controls (no ADHD) |
Participants | Number of participants screened: 150Number of participants included: 95 (non‐medicated: 32; medicated: 35; controls: 77)Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐III (subtype: not stated)Age: mean: non‐medicated: 13.06 years; medicated: 13.26 years old (range not stated)IQ: not statedSex: 144 malesMethylphenidate‐naïve: non‐medicated group had not been receiving any medication for the treatment of ADHD for ≥ 6 months prior to the studyEthnicity: Jewish‐Ashkenazi (European descent) 46%, Jewish‐Sepharadi (Middle Eastern descent) 54%Country: IsraelComorbidity: not statedComedication: noSociodemographics: not stated Inclusion criteria: Exclusion criteria:
Controls:
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Interventions | Methylphenidate type: immediate releaseMean methylphenidate dosage: 18 mg/dayAdministration schedule: once or twice/day (morning/noon)Duration of intervention: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Questionnaires on sleep |
Notes | Sample calculation: noEthics approval: the Israel Ministry of Education and the principals of the 2 participating schools approved the study. Written informed consent was obtainedFunding/vested interests: not stated Key conclusions of the study authors: the study did not find a greater severity of sleep disturbances among non‐medicated male adolescents diagnosed with ADHD in childhood compared to control participants. Sleep disturbance among male students receiving methylphenidate treatment was significantly greater compared with the non‐medicated group Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through personal email correspondence with the authors in April 2014. No reply |
Stevens 2010
Methods | A cross‐sectional study of youths treated with high‐dose osmotic release oral system (OROS) methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 17Diagnosis of ADHD: DSM‐IV (subtype: combined 11, inattentive 6)Age: mean 16.2 years old (range 11‐20)IQ: not statedSex: 13 males, 4 femalesMethylphenidate‐naïve: noEthnicity: white 88%, Native American 12%Country: USAComorbidity: depressive spectrum disorders 47%, pervasive developmental disorders 41%, oppositional defiant disorder 41%, bipolar spectrum disorders 29%, fetal alcohol syndrome 12%Comedication: bupropion (n = 10), SSRIs (n = 8), lithium (n = 5), alpha‐2 agonists (n = 4), atypical antipsychotics (n = 3), lamotrigine (n = 3), trazodone (n = 2), SNRIs (n = 1), oxcarbazepine (n = 1), tricyclic antidepressants (n = 1)Sociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Mean methylphenidate dosage: 169 mg/day SD 31 (range: 126‐270)Administration schedule: not statedDuration of intervention: not stated, but ≥ 2 weeks stabilised on same dose Treatment compliance: not stated |
Outcomes | Heart rate, systolic blood pressure, and diastolic blood pressure measured No adverse events or adverse cardiovascular outcomes were reported |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interest: the data analysis of this research was funded by institutional funds from the Pediatric Psychopharmacology Unit at Massachusetts General HospitalAuthors' affiliations: George is a speaker for McNeil, Shire, Novartis and Lilly, consultant for McNeil and Shire. Wilens receives grant support from Abbott, McNeil, Lilly, Merck and Shire, is a speaker for Lilly, McNeil, Novartis and Shire, is a consultant for Abbott, McNeil, Lilly, NIH, Novartis, Merck and Shire Key conclusions of the study authors: high‐dose OROS methylphenidate used in combination with other medications, was not associated with either unusually elevated plasma methylphenidate concentrations or with clinically meaningful changes in vital signs Comments from the review authors: requirement to be stabilised on OROS methylphenidate de facto excludes patients with poor or adverse response Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: see above Supplemental information regarding data requested through email correspondence with the authors in June 2014. No reply |
Strandell 2007
Methods | A series of spontaneously reported cases of suicidal and self‐damaging behaviour from VigiBase |
Participants | Number of cases reported: 116Diagnostic criteria not stated, nor subtypeAge(range): 5‐17 years oldIQ: not statedSex: not statedEthnicity: not statedCountry: not statedComorbidity: 78 were depressed, otherwise not statedComedication: in 33 cases methylphenidate and atomoxetine were co‐reported. 17 depressed patients were on antidepressants, and 42 were on antidepressants (without depression) ‐ (not clear if they were on atomoxetine or methylphenidate) Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Serious adverse events:Depression suicidalIntentional overdoseIntentional self‐injuryNon‐accidental injurySuicidal tendencySuicideSuicide attempt Thoughts of self‐harm |
Notes | Ethics approval: not statedFunding/vested interest/authors' affiliations: not stated Key conclusions of the study authors: the number of reports with suicidal behaviour in children and adolescents raises concern. The reports do not only imply possible suicidal behaviour: young patients actually commit suicide Comments from the review authors: this case‐series is based on a database of spontaneously reported adverse events. Therefore, some of these cases might have been reported in other case‐reports Supplemental information, specifically asking for full‐text article and additional information, requested through email correspondence with the authors in November 2013. No reply |
Su 2015
Methods | A multicentre, prospective, single‐arm, open‐label study on methylphenidate use for 8 weeks with extended observation for up to 24 weeks |
Participants | Number of participants screened: 248Number of participants included: 239Number of participants followed up: 205Number of withdrawals: 34Diagnosis of ADHD: DSM‐IV (subtype: combined 61.1%, predominantly inattentive type: 34.3%, predominantly hyperactive‐impulsive type: 3.8%, not specified: 0.8%)Age: mean: 9.2 (SD 2.02) years old (range 6‐16)IQ: not statedSex: 203 male, 36 femalesMethylphenidate‐naïve: all the children were psychotropic drug naïve or had received anti‐ADHD drugs (including OROS‐methylphenidate, atomoxetine, monoamine oxidase inhibitors, clonidine, other α2‐adrenergic receptor agonists, tricyclic antidepressants, theophylline, and bishydroxycoumarin) for 6 months or longer before the trial with the treatment course not more than 1 month or were currently having effective immediate release methylphenidate treatmentEthnicity: Asian 94.6%, other 5.4%Country: ChinaComorbidity: not statedComedication: recorded, but not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: 18 mg/day, 36 mg/day and 54 mg/dayAdministration schedule: for methylphenidate‐naïve dose participants: adjustment phase for 3 weeks, optimal dosage treatment for 5 weeks. For non‐naïve participants: 18 mg/day for previous 5 mg 2‐3 times a day, 36 mg/day for previous 10 mg 2‐3 times a day and 54 mg/day for previous 15 mg 2‐3 times a day or higherDuration of intervention: 8‐24 weeks Treatment compliance: most patients (> 90%) in the full analysis set had compliance between 80% and 120%, during the 8‐ and 24‐week treatment periods |
Outcomes | Safety and tolerability were monitored throughout the study by the evaluation of the incidence and type of treatment emergent adverse events and changes in clinical laboratory test results, vital signs, sleep status, tics, appetite, height, and weight |
Notes | Sample calculation: noneEthics approval: approved the institutional review board of Peking University sixth Hospital and other independent ethics committees at all sitesFunding/vested interests: sponsored by Xi'an Janssen Pharmaceutical Ltd, and supported by the Major State Basic Research Development Program of China. YW has served on advisory boards of Xi'an Janssen Pharmaceutical Ltd and Eli Lilly & Company. JZ and JQ are full‐time employees of Xi'an Janssen Pharmaceutical Ltd. Key conclusions of the study authors: most of the children experienced symptom relief with no severe adverse events. The OROS‐methylphenidate at the dosage levels of 18 mg, 36 mg, and 54 mg once daily was generally well tolerated in Chinese children with ADHD between the ages of 6‐16 years Comments from the study authors: an open‐label, non‐comparator, non‐randomised study design is a major limitation for this study. No blinded trained clinician raters collected the study data. Also, the outcome measures were mainly based on the parent reports. As the role of measurement in ADHD makes school settings critical, hence, the data of ADHD symptom expression in school settings are not presented. To further improve this situation, we recommend the incorporation of direct evaluations from teachers/instructors in the follow‐up studies in China Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through personal email correspondence with the authors in May 2016. No reply |
Sudarmadji 2009
Methods | A double‐blind, randomised parallel trial of methylphenidate use for 2 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 841 group randomised to 5 mg methylphenidate daily, other group to 10 mg methylphenidate daily (number of participants in each group not stated)Number followed up in each arm: not statedNumber of withdrawals in each arm: not statedDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean not stated (range: 6‐14)IQ: above 70 (attending elementary school)Sex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: IndonesiaComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria: None stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 5 mg or 10 mgAdministration schedule: once dailyDuration of intervention: 2 weeks Treatment compliance: not stated |
Outcomes | No description of measures |
Notes | Sample calculation: not stated
Ethics approval: not stated
Funding/vested interests: not stated
Authors' affiliations: not stated Key conclusions of the study authors: treatment with 5 mg methylphenidate was more effective compared with 10 mg methylphenidate to improve the attention, decrease hyperactivity and increase the cognitive function. The side effects of 5 mg/daily methylphenidate were milder compared with 10 mg/daily Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information was attempted to be retrieved through contact with the authors in July 2014. We were not able to find contact information on any of the authors |
Tang 2010
Methods | A patient report of stool and urinary incontinence during treatment with osmotic release oral system (OROS) methylphenidate |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 8 years oldIQ: above 70Sex: maleEthnicity: not statedCountry: TaiwanComorbidity: noComedication: no Sociodemographics: not stated |
Interventions | Methylphenidate type: immediate and extended releaseMethylphenidate dosage: immediate release, 10 mg. OROS 18 mg/day then 36 mg/dayAdministration schedule: immediate release, each morning. OROS methylphenidate, once dailyDuration of intervention: immediate release methylphenidate, 2 weeks. OROS methylphenidate, 2 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsSide effects reported by the mother:Immediate release methylphenidate 10 mg: no side effectsOROS methylphenidate 18 mg/day: no side effects OROS methylphenidate, 36 mg/day: double incontinence. Stool incontinence (every day, frequent during daytime) and urinary incontinence (almost every day). The double incontinence completely resolved after the discontinuation of OROS methylphenidate 36 mg |
Notes | Key conclusions of study authors: the causality in this case might be dose‐related, and careful monitoring is highly suggested Comments from the authors: the Adverse Drug Reaction Probability score in this patient was 7, denoting a probable adverse reaction caused by OROS methylphenidate 36 mg. Because of ethical considerations, this patient did not undergo re‐challenge with OROS methylphenidate Funding/vested interests/authors' affiliations: not stated |
Tasdelen 2015
Methods | A prospective cohort study of methylphenidate use |
Participants | Number of participants screened: not statedNumber of participants included: 22Number of participants followed up: 17Number of withdrawals: 5Diagnosis of ADHD: DSM‐IV (subtype: combined (100%))Age: mean 9.59 years old (range: 7‐12)IQ: mean: 102 (SD 10)Sex: 17 males, 5 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: not statedComedication: noSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS) 36‐54 mgMean methylphenidate dosage: 0.9 mg/kg/dayAdministration schedule: not statedDuration of intervention: mean 7 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Several adverse events (loss of appetite, abdominal pain, irritability, tingle, headache, nausea, insomnia and tics) were observed in 12 out of 22 patients receiving OROS methylphenidate. Not stated how these adverse events were reported or measured |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interests: noneAuthors' affiliations: none Key conclusions of the study authors: behaviour and cognitive functionality are recovered simultaneously using OROS‐methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no, all patients were newly diagnosed and methylphenidate naïve Supplemental information regarding IQ and specific adverse events received through personal email correspondence with the authors in June 2016 (Tasdelen 2016 [pers comm]) |
Tekin 2015
Methods | A patient report of focal dystonic reaction during MPH treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 15 years oldIQ: not knownSex: femaleEthnicity: not statedCountry: TurkeyComorbidity: noneComedication: none Sociodemographics: uneventful pregnancy and delivery. Family members had no history of psychiatric or movement disorders |
Interventions | Methylphenidate type: modified‐releaseMethylphenidate dosage: 27 mg/dayAdministration schedule: not statedDuration of treatment: 9 days Treatment compliance: not stated |
Outcomes | Serious adverse events: After 9 days of methylphenidate treatment: involuntary extensor muscular contraction of right hand and wrist, tension and severe pain. The dystonic reaction subsided after biperiden and diazepam administration. No opportunity for re‐challenge, because the patient refused to take methylphenidate again |
Notes | Key conclusions of the study authors: clinicians should consider acute dystonia as a rare adverse event that might emerge during modified release methylphenidate treatment Comments from the study authors: to our knowledge, this is the first reported case of focal dystonia after initiation of methylphenidate in a drug‐naïve otherwise healthy attention‐deficit/hyperactivity disorder (ADHD) patient. The patient had a history of similar adverse effects due to immediate‐release methylphenidate. Therefore, acute dystonic reaction was considered to be due to methylphenidate treatment. Naranjo Adverse Drug Reaction Probability Scale score was 5Funding/vested interests/authors' affiliations: the authors have no financial relationships or conflicts of interest to disclose. There was no financial support relevant to the articleEthics approval: the patient and the patient's mother gave written informed consent for the publication of this patient report Supplemental information regarding ADHD diagnosis and any comedication received through personal email correspondence with the authors April 2016 (Soyata 2016 [pers comm]). No information regarding the patient's IQ was available |
Thorell 2009
Methods | A cross‐sectional study of children on stimulant treatment studying positive and negative effects |
Participants | Number of participants screened/questionnaires sent out to: 132Number of participants included/returned questionnaires: 79Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 13.14 years old (range 9‐17)IQ: above 70, except for 2 children with mild mental retardationSex: 62 males, 17 femalesMethylphenidate‐naïve: noneEthnicity: not statedCountry: SwedenComorbidity: Aspergers (7.6%), Tourette syndrome (13.9%), obsessive‐compulsive disorder (2.5%), mild mental retardation (2.5%), oppositional defiant disorder/conduct disorder (2.5%)Comedication: noSociodemographics: not stated Inclusion criteria:
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Interventions | Methylphenidate type: 96% were taking methylphenidate and 4% amphetamineDosage: not statedAdministration schedule: not statedDuration of intervention: mean 3.12 years (range: 6 months to 12 years) Treatment compliance: most children knew how it felt to be off medication. Only 8% of the parents in the present study indicated that the child never forgot to take his or her medication |
Outcomes | Non‐serious adverse events Children's and parents questionnaire of negative events (4‐point Likert‐type scale), parent and self‐reported |
Notes | Sample calculation: none reportedEthics approval: yes, the study was approved by the local ethics committeeFunding: the study was supported by a grant from Majblommans RiksförbundVested interests/authors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: Swedish children treated with stimulants generally experienced positive treatment effects in many areas, especially in the school setting, and a majority wished to continue taking their medication. There was, however a small group of children who reported a relatively large number of negative effects. Few differences between parents and children were found for positive effects, although parents reported higher levels of negative effects Comments from the study authors: excluding the children with comorbid diagnoses did not make any significant changes in the results. The 4 participants not taking methylphenidate and who were mentally retarded are excluded from the data Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding adverse event data for patients taking methylphenidate without intellectual disability (n = 75) received through personal email correspondence with the authors in October 2013 (Thorell 2013 [pers comm]) |
Tomás Vila 2010a
Methods | A patient report of visual hallucinations during methylphenidate treatment |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 10 years oldIQ: above 70Sex: maleMPH‐naïve: noEthnicity: not statedCountry: SpainComorbidity: none statedComedication: not stated Sociodemographics: lives with his grandmother |
Interventions | Methylphenidate type: 50% immediate release and 50% extended releaseMethylphenidate dose: 30 mg/day (1 mg/kg/day)Administration schedule: not statedDuration of treatment: 2 weeks Treatment compliance: not stated |
Outcomes | Serious adverse events:After 2 weeks of 50% immediate release and 50% extended release methylphenidate: visual hallucinations (insects on hands, feet, abdomen and thorax) with associated itching, initiated 2 hours after ingestion and ceased 5 hours afterDiscontinuation of methylphenidate and initiation of risperidone: no visual hallucinations No readministration of methylphenidate due to ethical reasons |
Notes | Key conclusions of the study authors: this is the first patient report of visual hallucinations caused by 50% immediate release, 50% extended release methylphenidate, which is no wonder when you consider that the preparation has been marketed recentlyFunding/vested interests/authors' affiliations: not stated Supplemental information regarding diagnostic criteria and IQ received through personal email correspondence with the authors in September 2013 (Tomás 2013 [pers comm]) |
Tomás Vila 2010b
Methods | A multicentre 3‐month cohort study that investigates the impact of methylphenidate treatment on sleep |
Participants | Number of participants screened: not statedNumber of participants included: 114Number of participants followed up: 114Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: combined (54.5%), hyperactive‐impulsive (6.3%), inattentive (39.3%))Age: mean 8.8 years old (range 4‐15)IQ: normal intelligenceSex: 79% males, 27% femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: SpainComorbidity: not statedComedication: noSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type and mean dosage: immediate release methylphenidate, mean dose: 18.5 mg (n = 42). Intermediate release‐methylphenidate, mean dose: 23.3 mg (n = 34). Extended release‐methylphenidate, mean dose: 32.9 mg (n = 38)Administration schedule: not statedDuration of intervention: minimum 3 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events Spanish abbreviated (18 questions chosen) version of the Paediatric Sleep Questionnaire (PSQ) rated by neuro‐paediatricians |
Notes | Sample calculation: not statedEthics approval: not statedFunding/authors' affiliations: the authors declare no conflicts of interest Key conclusions of the study authors: the results of the study suggest that methylphenidate does not have a negative impact on sleep in patients with ADHD and comorbid sleep disorders. Methylphenidate improves the quality of sleep in those patients Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding ADHD diagnostic criteria and IQ received through personal email correspondence with the authors in October 2013 (Tomás 2013b [pers comm]) |
Trugman 1988
Methods | A patient report of cerebral arteritis during methylphenidate treatment |
Participants | Diagnosis of ADHD: ICD‐9 (unspecified hyperkinetic syndrome)Age: 12 years oldIQ: not statedSex: maleEthnicity: not statedCountry: USAComorbidity: not statedComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mgAdministration schedule: twice dailyDuration of treatment: 5‐12 years of age (7 years) Treatment compliance: not stated |
Outcomes | Serious adverse events:Right hemiparesis, 7 years following daily consumption of methylphenidateAphasia Non‐serious adverse events: Headaches, intermittently before onset of stroke |
Notes | Key conclusions of the study authors: cerebral arteritis and infarction were caused by chronic oral methylphenidate use. The CSF profile and angiogram support the diagnosis of inflammatory arteritis, yet laboratory evaluation revealed no identifiable cause. In the 6 years since the stroke, while not on methylphenidate there has been no evidence of active central nervous system or systemic vasculitis Comments from the study authors: given its pharmaceutical similarity to amphetamine, the association of methylphenidate with cerebral vasculitis is not unexpected, yet has not been previously reported. Physicians who prescribe methylphenidate for long‐term use should be aware of this potential complication and specifically question patients regarding symptoms of cerebral ischaemia, including headache Supplemental information regarding diagnostic criteria received through personal email correspondence with the authors in September 2013 (Trugman 2013 [pers comm]) |
Tzang 2012
Methods | A prospective observational study for 48 weeks. Patients categorised into 4 groups based on occurring treatment:
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Participants | Number of participants screened: not statedNumber of participants included: 757Number of participants included in each group: IR methylphenidate: 265, OROS methylphenidate: 293, IR and OROS methylphenidate: 129, controls (no intervention): 70Number of participants followed up in each arm: IR methylphenidate: 265, OROS methylphenidate: 293, IR and OROS methylphenidate: 129, controls: 70Number of withdrawals in each arm: IR methylphenidate: 0, OROS methylphenidate: 0, IR and OROS methylphenidate: 0, controls: 0Diagnosis of ADHD: DSM‐IV (combined (58.52%), hyperactive‐impulsive (4.76%), inattentive (36.72%))Age: mean 10.05 (SD 2.65) years old (range: 6‐18 years)IQ: not statedSex: 607 males, 150 femalesMethylphenidate‐naïve: not statedEthnicity: white (0%), African American (0%), Asian (100%), Hispanic (0%), others (0%)Country: TaiwanComorbidity: oppositional defiant disorder (21.80%), conduct disorder (1.85%), anxiety disorder (3.04%), depressive disorder (0.40%), tic disorder (2.64%), Tourette disorder (1.59%), somatisation (5.15%), others (7.40%)Comedication: 6.61%Sociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: immediate release (IR) and osmotic release oral system (OROS)Methylphenidate dosage: not statedAdministration schedule: OROS‐methylphenidate once a day, other groups not statedDuration of intervention: 48 weeks Treatment compliance: not stated |
Outcomes | The frequency of adverse effects was determined using a symptom checklist that included the following items: decreased appetite, nausea, somnolence, insomnia, headache, dizziness, abdominal pain, and stomachache at 12, 24, 36, and 48 weeks |
Notes | Sample calculation: no informationEthics approval: not statedFunding/vested interests/authors' affiliations: supported by Janssen‐Cilag, Taiwan Key conclusions of the study authors: OROS methylphenidate treatment at the adequate dosage can achieve higher remission and recovery rates, produce greater functional improvement, and result in better treatment adherence that IR methylphenidate treatment Supplemental information requested through email correspondence with the authors in December 2013 and January 2014. No reply |
Tølløfsrud 2006
Methods | A patient report of death caused by heart failure (acute dilated cardiomyopathy) during methylphenidate treatment |
Participants | Diagnosis of ADHD: ICD‐10 (subtype: not stated)Age: 17 years oldIQ: no intellectual disabilitySex: maleEthnicity: not statedCountry: NorwayComorbidity: Tourette's syndromeComedication: none Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 15 mgAdministration schedule: 3 times dailyDuration of treatment: 10 years Treatment compliance: not stated |
Outcomes | Serious adverse events: Heart failure resulting in death |
Notes | Key conclusions of the study authors: heart failure leading to death, possibly caused by methylphenidate treatment Comments from the study authors: dilated cardiomyopathy can be a rare side effect of methylphenidate useFunding/vested interest/authors' affiliations: none Supplemental information regarding ADHD diagnosis and IQ received through personal email correspondence with the authors in November 2013 (Tølløfsrud 2013 [pers comm]) |
Valdizán Usón 2004
Methods | A 12‐month cohort study |
Participants | Number of participants screened: not statedNumber of participants included: 170Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐IV‐TR (subtype: not stated for the total sample. Subtype for the sample with polysomnography data: combined (40%), hyperactive‐impulsive (9%), inattentive (57%))Age: mean 8 years old (range not stated)IQ: above 70Sex: 121 males, 27 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: SpainComorbidity: immunological diseases (33.3%)Comedication: no medication for sleep initiationSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 10‐40 mg/day, adjusted as neededAdministration schedule: morning and noonDuration of intervention: 12 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsReports of side effectsComplete blood testThyroid hormones and cortisol levels Nocturnal polysomnography (n = 46), initiated at 10 pm and disrupted at 7 am. Evaluated parameters: sleep efficiency, total registered time, latency time of sleep initiation, number of awakenings, total time of sleep and efficiency, duration of each phase and latency time of REM sleep |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interest: not statedAuthors' affiliations: not stated Key conclusions of the study authors: it is more likely that the ADD subgroup continues in the adult age and, although as a minority, immunological disorders and/or epileptiform paroxysms are associated. The effect of methylphenidate may be observed by seriated recording of digitalised cortical bioelectrical activity, with synchronic course to the clinical response Comments from the review authors: EEG was conducted every 6th month, but the methylphenidate treatment was paused 24 hours before, so we cannot use these data Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding ethics approval, funding, protocol, patient demographics, and data not possible to receive through personal email correspondence with the authors. Emails sent several times in December 2013. No reply |
Valdizán Usón 2013
Methods | A cohort (observational, retrospective, non‐interventional, multicentre) study of methylphenidate use for 1 month, 3 months, 6 months, and 1 year |
Participants | Number of participants screened: not statedNumber of participants included: 680Number of participants followed up: 680 (safety population), 561 (4‐16 years old)Number of withdrawals: not statedDiagnosis of ADHD: DSM‐IV TR (subtype: combined (64.9%), hyperactive‐impulsive (5%), inattentive (30.05%))Age: mean 9.497 SD 2.538 (under 6 years old: mean: 5.27, range: not stated; 6‐16 years old: mean 9.77, range: 6‐16)IQ: above 80Sex: 454 males, 105 females (under 6 years old: 31 males, 3 females; 6‐16 years old: 423 males, 102 females)Methylphenidate‐naïve: 0%Ethnicity: not statedCountry: SpainComorbidity: anxiety disorder (13.01%), oppositional defiant disorder (23.35%), learning disorder (50.09%), conduct disorder (30.30%), depressive disorder (5.35%), tics (6.95%). Other associated symptoms were substance abuse (0.36%), apathy (9.68%) and anhedonia (4.36%), developmental coordination disorder (12.66%), pervasive developmental disorder (10.52%), and generalised epilepsy (1.78%)Comedication: yes (under 6 years old: 10 (29.41%); 6‐16 years old: 114 (21.63%))Sociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: immediate releaseMean methylphenidate dosage: mean starting dose: 16.72 mg/day, mean dose at 1‐month follow‐up: 18.76 mg/day; mean dose at 6‐month follow‐up: 20.58 mg/day; mean dose at 1‐year follow‐up: 22 mg/day. Administration schedule: not statedDuration of intervention: medical records for the years 2002‐2006 (mean = 10.01 months) Follow‐up after 1 month, 6 months and 1 year Treatment compliance: not stated |
Outcomes | A year after treatment information on adverse events was obtainedSafety outcomes included adverse events and serious adverse events reported, and their recurrence, duration, and relationship with the study drug Obtained by a single questionnaire ‐ presence or absence and number of adverse events per patient |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interest: the authors report no conflicts of interest in this work Key conclusions of the study authors: good efficacy and safety results were found for immediate‐release methylphenidate in patients with ADHD Comments from the study authors: a limitation of the study is that even when favorable results were found overall in reduction of the number of symptoms and a significant global improvement, these results are only preliminary due to the limited numbers of patients included Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information received through personal email correspondence with the authors in July 2014 (Valdizán 2014 [pers comm]) |
Van der Oord 2007
Methods | A 4‐week pseudorandomised, placebo‐controlled, cross‐over study investigating the additional value of short‐term intensive multimodal behaviour therapy to optimally titrated methylphenidate Follow‐up 4.5 to 7.5 years after treatment |
Participants | Number of participants screened: not statedNumber of participants included in methylphenidate group: 23; included in methylphenidate + multimodal behaviour therapy: 27Number of participants followed up in methylphenidate group: 21Number of withdrawals in methylphenidate group: 2Diagnosis of ADHD: DSM‐IV/I (subtype: combined (n = 31), hyperactive‐impulsive (n = 3), inattentive (n = 16))Age: mean 9.6 years oldIQ: 96.81Sex: not statedMethylphenidate‐naïve: 100%Ethnicity: white: 89%, others: 11%Country: NetherlandsSetting:Comorbidity: oppositional defiant disorder/conduct disorder 61.9%, oppositional defiant disorder 46%, conduct disorder 4%Comedication: noSociodemographics: most parents medium to high education level Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 5 mg, 10 mg, and 20 mg in titration periodAdministration schedule: 7:30 am, 12:30 pmDuration of intervention: 4 week pseudo randomised cross‐over design, 1 week medication‐free, 5 weeks optimal dose Treatment compliance: high, weekly phone calls to parents and teachers |
Outcomes | The MTA Side Effect Rating Scale was used to assess side effects |
Notes | Sample calculation: yes (power calculation)Ethics approval: not statedFunding: not statedVested interest/authors' affiliations: not stated Key conclusions of the study authors: no evidence was found for the additive effect of multimodal behaviour therapy next to optimally titrated methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding data on adverse events received through personal email correspondence with the authors in January 2014 (Van der Oord 2014 [pers comm]) |
Varley 2001
Methods | A retrospective chart review |
Participants | Number of participants screened: 555Number of participants included: 517Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 11 years old (range not stated)IQ: not statedSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: not statedComorbidity: ticsComedication: noSociodemographics: not stated Inclusion criteria: Exclusion criteria: |
Interventions | Methylphenidate type: not statedMean methylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsRetrospective review of medical records. It was recorded whether the participants did or did not have a reported history of tic emergence in the course of pharmacologic treatment in that clinic. 8.3% (31 of 374) of participants treated with methylphenidate developed tics |
Notes | Sample calculation: noEthics approval: not statedFunding/vested interest: supported by a National Institutes of Health Biomedical Research Support Grant, 1991Authors' affiliations: not stated Key conclusions of the study authors: tics was not related to dose nor treatment length, and may not be related to stimulants Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through personal email correspondence with the authors in April 2014. No reply |
Vashi 2011
Methods | A patient report on allergic contact dermatitis caused by methylphenidate transdermal system |
Participants | Diagnosis of ADHD: DSM‐IV (subtype: not known)Age: 9 years oldIQ: above 70Sex: femaleEthnicity: not statedCountry: USAComorbidity: noneComedication: not stated Sociodemographics: not stated |
Interventions | Methylphenidate type: transdermal systemMethylphenidate dosage: not knownAdministration schedule: not statedDuration of intervention: 8 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Allergic contact dermatitis: after 8 months of using a methylphenidate patch the patient presented with pruritic dermatitis. She had itchy, burning, red lesions. Symptoms began on her hip at the area of patch placement, then progressively spread to her arms, legs, abdomen, and backMethylphenidate discontinued: symptoms lasted for 2 months. First and second patch test. Re‐tested with methylphenidate patch: 9 days after the first test the patient presented with recall reaction, characterised by a return of the original pruritic dermatitis to her entire back, similar to the eruption that had occurred months previously after therapeutical use of methylphenidate patch Avoidance of methylphenidate patches: symptom‐free |
Notes | Key conclusions of study authors: this is the first reported case of allergic contact dermatitis caused by methylphenidate present within the transdermal system Supplemental information regarding diagnosis and IQ received through personal email correspondence with first author in August 2013 (Vashi 2013 [pers comm]) |
Verret 2010
Methods | A comparative cohort study assessing the impact of methylphenidate on physical functioning and gross motor performance |
Participants | Number of participants screened: not statedNumber of participants included: 70Number included in each group: ADHD + methylphenidate: 24, ADHD no methylphenidate: 19Number followed up in each group: ADHD + methylphenidate: 24 and ADHD no methylphenidate: 19Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (94.3%), hyperactive‐impulsive (5.7%)Age: mean not stated (range: 7‐12)IQ: not statedSex: 70 males, 0 femalesMethylphenidate‐naïve: the ADHD no methylphenidate group: 19Ethnicity: not statedCountry: CanadaComorbidity: ADHD + methylphenidate group: opposition or anxiety (29%), anxiety, opposition or obsessive‐compulsive disorder (13%); ADHD no methylphenidate group: opposition or anxiety (37%)Comedication: noSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMethylpheniate dosage: not statedAdministration schedule: not statedDuration of intervention: average 24 months (range 5‐72 months) Treatment compliance: not stated |
Outcomes | Non‐serious adverse events Anthropometric and vital measures (height, weight, BMI, resting heart rate and blood pressure) |
Notes | Sample calculation: noEthics approval: yes, Research Ethics Committee of the Riviere‐des‐Prairies HospitalFunding/vested interest: none statedAuthors' affiliations: none stated Key conclusions of the study authors: fitness level of children with ADHD using medication or not, including body composition, flexibility and muscular endurance was similar to that of the control group. The only difference was observed for BMI which was lower in children with ADHD using medication. Both groups of children with ADHD presented significantly lower scored for locomotion skills Comments from the study authors: in this study, it was not possible to obtain precise data for dosage of medication. Because of this methodological issue, the impact of dosage and time of prescription on growth parameters could not be established Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Vincent 1990
Methods | A retrospective cohort study of medical records |
Participants | Number of participants screened: not statedNumber of participants included: 31Number of participants followed up: 31Number of withdrawals: 0Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: mean 12.9 (SD 0.8) years old (range not stated)IQ: not statedSex: 25 males, 6 femalesMethylphenidate‐naïve: 0%Ethnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria: |
Interventions | Methylphenidate type: not statedMean methylphenidate dosage: 34 (SD 14) mg/day or 0.75 (SD 0.29) mg/kg/dayAdministration schedule: not stated.Duration of intervention: 15 participants received methylphenidate for 6‐12 months, 9 participants for 1‐4 years, 7 participants for 5‐7 years (range: 6 months to 6 years and 11 months) Treatment compliance: not stated |
Outcomes | Non‐serious adverse events Weight and height: participants were measured in indoor clothing and stocking feet on a platform scale twice, 6‐12 months apart (mean: 221 SD 57 days) by treating physician. Weight to nearest 0.1 kg, height to nearest cm. Initial measurements were randomly distributed throughout the year so as to eliminate any seasonal effects. Expected height and weight obtained from National Center for Health Statistics |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interest: not statedAuthors' affiliations: not stated Key conclusions of the study authors: the results of this retrospective study suggest that methylphenidate use at customary doses does not noticeably impair adolescent growth velocities over 6‐12 months treatment Comments from the study authors: analysis of age, gender, dose, and other characteristics on the basis of length of treatment was not feasible because of sample size Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through email correspondence with the authors in September and October 2013. No reply |
Walitza 2007
Methods | A prospective study analysing genomic damage in children with ADHD (initial sample size 38 children) before and 1 (30 children), 3 (21 children), and 6 (8 children) months after initiation of methylphenidate therapy. In addition a group of 9 children receiving chronic methylphenidate treatment were investigated |
Participants | Prospective groupNumber of participants screened: not statedNumber of participants included: 38Number of participants followed up: 1 month: 30, 3 months: 21, 6 months: 8number of withdrawals: 1 month: 8, 3 months: 17, 6 months: 30Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean: 10 years old (range: 4.9‐17.0)IQ: above 70Sex: 29 males, 9 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: GermanyComorbidity: not statedComedication: noSociodemographics: not stated Chronic group Number of participants screened: not statedNumber of participants included: 9Diagnosis of ADHD: DSM‐IV‐TR (subtype: not stated)Age: mean 11.2 years old (range 7.1‐16.0)IQ: above 70Sex: 9 males, 0 femalesMethylphenidate‐naïve: 0%. All treated previously 6 months to 2 yearsEthnicity: not statedCountry: GermanyComorbidity: yes, 4 patients received additional medicine, but diseases not specifiedComedication: yes, 4 patients; 1 received valproic acid and 3 received risperidoneSociodemographics: not statedBoth groups Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not stated Mean methylphenidate dosage: prospective group: 0.54 mg/kg/day (5‐40 mg/day) increasing to 0.74 mg/kg/day (15‐45 mg/day) by the end of the trial. Chronic methylphenidate users: 0.83 mg/kg/dayAdministration schedule: not statedDuration of intervention: 1‐6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsVital signsECGMicronucleus analysis (in peripheral lymphocytes): blood samples (7.5 mL each) were collected 1 day before, and 1, 3, and 6 months after methylphenidate treatment. The micronucleus scoring was carried out by a single scorer 6 times for each sample in blinded mannerClinical laboratory values: white and red blood cell count, electrolytes, transaminases measuredThe measure for genomic damage was the frequency of micronuclei, a subset of chromosomal aberrations, in peripheral lymphocytes, obtained from blood samples No abnormal parameters were observed except slightly reduced values of total iron, without signs of hypochromic microcytic anaemia, which occurred in some patients before and during the treatment, independent of micronucleus deviation |
Notes | Sample calculation: not statedEthics approval: approved by the ethics committee of the University of Würzburg (study no. 140/03)Funding/vested interests: partially funded by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft; KFO 125/1‐1) and from the Interdisciplinary Center for Clinical Research (IZKF N‐5 (1)) and was performed independent of financial or other support by companies producing or selling methylphenidateAuthors' affiliations: the authors declare they have no competing financial interest Key conclusions of the study authors: the concern regarding a potential increase in the risk of developing cancer later in life after long‐term methylphenidate treatment is not supported. The study did not find any alteration in the number of micronucleated cells after methylphenidate treatment at 3 follow‐up intervals (up to 6 months) Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: 2 withdrew after 1 month of treatment due to lack of effect Supplemental information regarding information on whether any of the children had intellectual disability received through personal email correspondence with the authors in October 2013 (Stopper 2013 [pers comm]). Also asked for vital signs and ECG in August 2014 (Stopper 2014 [pers comm]). The author no longer has access to this |
Walitza 2009
Methods | A prospective study (both cohort study: the drug naïve group, and cross‐sectional study: the chronically treated group) analysing genomic damage in 3 different group of children:
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Participants | Drug‐naïve groupNumber of participants screened: not statedNumber of participants included: 26Number of participants followed up: 3 months: 17, 6 months: 11Number of withdrawals: 3 months: 9, 6 months: 15Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 8.6 years old (range 5‐16)IQ: above 70Sex: 20 males, 6 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: GermanyComorbidity: not statedComedication: not statedSociodemographics: not stated Chronically methylphenidate‐treated group Number of participants screened: not statedNumber of participants included: 21Number of participants followed up: not statedNumber of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean: 11.4 years old (range 9‐16)IQ: above 70Sex: 16 males, 5 femalesMethylphenidate‐naïve: none. All but 1 treated more than 12 months with methylphenidateEthnicity: not statedCountry: GermanyComorbidity: yes, but not specifiedComedication: 4. 1 also took atomoxetine, 1 sulthiame, and 2 risperidoneSociodemographics: not statedBoth groups Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not stated Mean methylphenidate dosage: after 3 months: 0.46 (SD 0.22) mg/kg/day. After 6 months: 0.46 (SD 0.24) mg/kg/day. Chronically treated group: 0.80 (SD 0.31) mg/kg/dayAdministration schedule: not statedDuration of intervention: 6 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse eventsVital signs, blood pressure, pulse, ECG Blood test to detect haematological abnormality. Micronucleus analysis (measure of genomic damage): blood sampling and sampling of buccal mucosa cells: baseline, 3, and 12 months after initiation of treatment. Only 1 blood sample/buccal mucosa sample at a certain point of time for the chronic group |
Notes | Sample calculation: not statedEthics approval: approved by the ethics committee of the University of Würzburg (study no. 124/06)Funding/vested interest: this study (124/06) was funded by grants from the IZKF Wuerzburg (Interdisciplinary Clinical Center of the University of Wuerzburg), project N5‐1, and supported by a grant from the Deutsche Forschungsgemeinschaft (KFO 125)Authors' affiliations: during the course of this study, HS was asked to serve as an independent consultant for Novartis Pharmaceutical Company. Consulting occurred after this study was finished (all data evaluated) and did not influence any aspect of this study. The other authors declare no potential conflicts of interest Key conclusions of the study authors: in this study, we did not find any alteration in the number of micronucleated cells in the group of chronically treated (> 12 months) children compared to the ADHD group before treatment initiation. We also did not find any elevation after initiation of methylphenidate treatment at 2 follow‐up intervals at 3 and 6 months after treatment initiation. This is the result from both investigated tissues, peripheral blood lymphocytes and buccal mucosa cells. Therefore, no induction of genomic damage in ADHD patients due to methylphenidate therapy was detectable, supporting our previous study (124/06) Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: 2 withdraw after 1 month of treatment due to lack of effect Supplemental information regarding the children's intellectual function received through personal email correspondence with the authors in October 2013 (Stopper 2013 [pers comm]), and mean and SD on measure of genomic damage received in March 2014 (Stopper 2014b [pers comm]) |
Wang 2007
Methods | A multicountry, multicentre, randomised, double‐blind, 8‐week study in children and adolescents with ADHD to test the hypothesis that atomoxetine is non‐inferior to methylphenidate on conventional ADHD symptom measures |
Participants | Number of participants screened: 361Number of participants included: 166 includedNumber of participants followed up: 152Number of withdrawals: 14Diagnosis of ADHD: DSM‐IV (subtype: combined (57.2%), hyperactive‐impulsive (3.6%), inattentive (39.2%))Age: 9.9 (SD 2.3) yearsIQ: not statedSex: 134 males (80.7%), 32 females (19.3%)Methylphenidate‐naïve: 74.7%Ethnicity: Asian (91.6%), Hispanic (8.4%)Country: China (n = 242), Korea (n = 60), Mexico (n = 28)Comorbidity: ODD (17.5%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 0.2‐0.6 mg/kg/dayAdministration schedule: morning and lunchDuration of intervention: 8 weeksTreatment compliance: the study completion rate was high 91.6% Titration: treatment titrated from 0.2mg/kg/day to 0.4 mg/kg/day on Day 5 and either maintained or titrated upward or downward within the range 0.2‐0.6 mg/kg/day |
Outcomes | Non‐serious adverse eventsTolerability measures ‐ assessment of treatment emergent adverse events via open‐ended questionsMonitoring of vital signs ‐ ECG and clinical laboratory tests (chemistries, haematology and urinalysis)6 patients (3.6%) discontinued due to:
|
Notes | Sample calculation: yes, approximately 330 patients between the 2 armsEthics approval: not statedFunding: not statedVested interest/authors' affiliations: not stated Key conclusions of the study authors: atomoxetine was non‐inferior to methylphenidate in improving ADHD symptoms based on response rates. Treatment‐emergent adverse effects experienced significantly more frequently in the atomoxetine group compared with the methylphenidate group Supplemental information requested through personal email correspondence with the authors in January 2014 with no reply |
Wang 2011
Methods |
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Participants | Number of participants screened: not statedNumber of participants included: 50Number of participants followed up: 30Number of withdrawals: 20Diagnosis of ADHD: DSM‐IV diagnosis (subtype: combined (48%), hyperactive‐impulsive (22%), inattentive (30%))Age: mean 7.56, range 6‐12 years oldIQ: above 70Sex: 40 males, 10 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: TaiwanComorbidity: noneComedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 5‐15 mg/dayMean methylphenidate dosage: 10.62 mg/daily at 1 month, 14.15 mg/daily at 3 months and 12.84 mg/daily at 6 months.Administration schedule: not statedDuration of intervention: 24 weeks Treatment compliance: the drug compliance at each visit was confirmed to the reports of patients' parents and the remnant drug |
Outcomes | Non‐serious adverse eventsNo reporting of adverse events 3 patients discontinued prematurely due to decreased appetite and weight loss |
Notes | Sample calculation: noEthics approval: approved by the Institutional Review Board of Chang Gung Memorial HospitalFunding: the study was funded by the Chang‐Gung Memorial Hospital Research ProjectVested interests/authors' affiliations: the authors have no conflicts of interest to declare Key conclusions of the study authors: DHEA (dehydroepiandrosterone), but not the cortisol basal level, may be a biological laboratory marker for ADHD, particularly for performance on the CPT. Both the causal relationship between DHEA and ADHD and the role of DHEA in treating ADHD require further investigation Supplemental information received through personal email correspondence with the authors in December 2013 (Wang 2013 [pers comm]) |
Warshaw 2010
Methods | Methylphenidate transdermal system use for 7 weeks. 4 weeks dose optimisation followed by 3 weeks on optimised dose. Follow‐up visit 30 days after last dose |
Participants | Number of participants screened: 309Number of participants included: 305Number of participants followed up: 260Number of withdrawals: 45Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 9.1, range: 6‐12 years oldIQ: not statedSex: 215 males, 90 femalesMethylphenidate‐naïve: not statedEthnicity: white (77.7%), African American (11.5%), Asian (0.7%), Hispanic (23.9%), others (10.2%)Country: USAComorbidity: not statedComedication: only medication non concomitant with central nervous system effectsSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: transdermal systemMethylphenidate dosage: 10, 15, 20, 30 mgMean methylphenidate dosage: 20.1 mgAdministration schedule: MTS 9 hours per dayDuration of intervention: 7 weeks Treatment compliance: 260 (84.1%) completed the study |
Outcomes | Non‐serious adverse events:Safety was assessed at each clinic visit (baseline, at weeks 1 through 5, week 7, and week 11) by evaluating adverse events reported spontaneously; analysing changes in vital signs, and conducting physical examinations. Dermal reactions were classified as an adverse event when pharmacologic treatment for the reaction was required Experience of Discomfort scale, Transdermal System Adherence scale, and Dermal Response Scale |
Notes | Sample calculation: not statedEthics approval: yesFunding: the study was funded by Shire Development, Inc., Wayne, PennsylvaniaVested interests/authors' affiliations: Dr Warshaw has served as a consultant to Shire. Dr Squires is a full‐time employee of Shire and a stock shareholder in Johnson & Johnson, Pfizer, and Shire. Dr Li was a full‐time employee of Shire at the time of the study and is now an employee of Cerexa, Inc, Oakland, California. Dr Civil is a full‐time employee of Shire. Dr Paller has served as a consultant to Shire Key conclusions of the study authors: the results of this study indicate that dermal reactions with methylphenidate use were predominantly mild to moderate. Dermal reactions appeared to be of an irritant contact dermatitis form; they dissipated rapidly with time and most resolved with continued treatment. Overall, less than 1% of participants manifested sensitisation to methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental data requested through personal email correspondence with the authors in May 2016 but none were available |
Weber 2003
Methods | A retrospective cohort study investigating the side effects of methylphenidate in children |
Participants | Number of participants screened: 73Number of participants included: 57Number of participants followed up: 45Number of withdrawals: 12Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 11.1, range 7.2‐18.0 years oldIQ: range 85‐115Sex: 42 males, 3 femalesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: GermanyComorbidity: anxiety, depression, disturbance in attention, antisocial behaviour and aggressive behaviourComedication: not statedSociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type: not statedMean methylphenidate dosage: 16.8 mgAdministration schedule: not statedDuration of intervention: mean 2.7 years, range 0.2‐12.3 years Treatment compliance: questions regarding compliance were included in the mailed questionnaire; however, no results are reported |
Outcomes | Non‐serious adverse events German version of Barkley Side Effects Rating Scale (17 items), parent rated every sixth week |
Notes | Sample calculation: not stated
Ethics approval: not necessary at the time the study were carried out
Funding/vested interests: no funding
Authors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: the application of methylphenidate in therapy of attention deficit disorder and the interpretation of side effects of methylphenidate is a multimodal task. Adverse effects are not correlated with daily doses, age, the severity of body complaints and the presence of neuroticism and extraversion. The children with more side effects showed more emotional comorbidity Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding diagnostic criteria, ethics approval, funding, ratings and drug naïvety received through personal email correspondence with the authors in December 2013 (Weber 2013 [pers comm]) |
Weiss 2007
Methods | A 5‐11 week randomised, double‐blind, cross‐over comparison of
6‐month open‐label extension period on MLR‐methylphenidate |
Participants | Cross‐over phaseNumber of participants screened: 110Number of participants included: 90Number of participants followed up: 79Number of withdrawals: 11Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 11.0, range 6.4‐17.5 years oldIQ: above 80Sex: 74 males, 16 femalesMethylphenidate‐naïve: 59%Ethnicity: white: 83%, African American: 6%, Asian: 4%, others: 7%)Country: CanadaComorbidity: oppositional defiant disorder (37.5%)Comedication: noneSociodemographics: not stated Open‐label phase Number of participants included: 76Number of participants followed up: 61Number of withdrawals: 15Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 11.0, range 6.4‐16.8 years oldIQ: above 80Sex: 62 males, 14 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: CanadaComedication: noneSociodemographics: not statedInclusion criteria
Exclusion criteria
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Interventions | Cross‐overMethylphenidate type: long duration multi‐layer release methylphenidate or immediate release methylphenidateMean methylphenidate dosage: MLR‐MPH: 32.0 (SD 8.4) mg; IR‐MPH: 32.5 (SD 8.6) mgAdministration schedule: MLR‐MPH: once daily in the morning. IR‐MPH: twice daily, morning and noonDuration of each medication condition: 2 weeks on a stable doseWashout: 1 week baseline medication washout periodTitration period: initial daily dose was based on body weight. Daily dose was titrated in 10‐mg increments over a period of 2‐3 weeks at weekly clinical visits. Titration was halted if the dose was not tolerated, or if the investigator‐rated CGI‐I scale was rated 1‐2. There were 2 weeks of observation on this stable dose Treatment compliance: not stated |
Outcomes | Non‐serious adverse events Cross‐overClinical assessment of Side Effects (CASE). The scale consist of 26 possible adverse events. Teacher and parent rated by telephone interview before next clinical visit. Side effects, including sleep quality, were assessed on daily basis Open‐label 3 follow‐up visits at 2, 4 and 6 months. CASE; teacher and parent rated by telephone interview just before next clinical visit The 4 cases that dropped out due to side effects dropped out because of the following events:Long‐duration multi‐layer release methylphenidate
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Notes | Sample calculation: yesEthics approval: the study protocol and consent form were approved by the Research Ethics Committees at each siteFunding: Purdue PharmaVested interests/authors' affiliations: the study was sponsored by Purdue Pharma (Canada). Dr Weiss is a consultant for Eli Lilly, Janssen‐Ortho, Novartis, Purdue Pharma and Shire. Dr Hechtman is a consultant for Eli Lilly, Janssen‐Ortho, Novartis, Purdue Pharma and Shire. Drs. Hechtman, Jain, Quinn, and Weiss are on the advisory board for Purdue Pharma. Dr Turgay is a consultant for the same company. Mr. Donnelly, Mr. Reiz, Mr. Harsanyi, and Dr Darke are employees of Purdue Pharma. The other authors have no financial relationships to disclose Key conclusions of the study authors: clinical implications of the study results include that once daily, MLR‐MPH is an effective treatment for ADHD that produces equivalent improvements to twice‐daily dosing of IR‐MPH in home and school situational behaviour, while maintaining a favourable side‐effect profile and a prolonged duration of effect Comments from the study authors: a large portion of participants were previous methylphenidate responders, which may have reduced any chance of finding differences. As participants received active medication in both phases if the study, higher effect sizes could be expected because of investigators' and participants' expectation, although this would more closely approximate the clinical situation than a comparison placebo Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information regarding protocol, data for CASE, adverse events on the 4 dropouts, and data on all periods received through personal email correspondence with study funder, Purdue Pharma in August 2013 (Harsanyi 2013 [pers comm]) |
Wigal 2011
Methods | A double blind, double‐dummy randomised cross‐over study with osmotic release oral system (OROS) methylphenidate and immediate release methylphenidate given with 5 different breakfast conditions |
Participants | Number of participants screened: not statedNumber of participants included: 32Participants were randomly assigned to 1 of 6 possible drug condition ordersNumber of participants followed up: 30Number of withdrawals: 1Diagnosis of ADHD: DSM (subtype: not stated)Age: mean 10.1 (SD 1.5), range 7‐12 years oldIQ: not statedSex: 26 males, 5 femalesMethylphenidate‐naïve: noneEthnicity: white: 67.7%, African American: 1%, Hispanic: 3%, others: 6%Comorbidity: not statedComedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Participants were randomly assigned to 1 of 5 possible drug condition orders of equivalent to OROS MPH 18 mg, 36 mg and 54 mg and IR MPH 5 mg, 10 mg and 15 mg based on pre‐study established doses.Group 1
Mean MPH dosage: not stated. Administration schedule: not stated. Duration of each medication condition: not stated. Washout prior to study initiation: not stated. Medication‐free period between intervention: not stated. Titration period: not stated Treatment compliance: not stated |
Outcomes | Non‐serious adverse events Vital signs measured pre‐dose, then every 1.5‐2.5 h until 11.5 h postdose |
Notes | Sample calculation: not statedEthics approval: not stated, but UC Irvine Institutional Review Board approved consent proceduresFunding/vested interest/authors' affiliations: Sharon Wigal on a number of drug company advisory boards. Suneel Gupta is a full‐time employee of Impax Pharmaceuticals and previously worked for a number of drug companies. Lynne Starr and Erica Everin are employees of a drug company. The study was sponsored by ALZA corporation. Ortho‐McNeil Janssen Scientific Affairs funded an editorial on the study Key conclusions of the study authors: the results of this study demonstrate that in children with ADHD administering OROS methylphenidate with or without food produces similar PK and PD profiles Comments from the review authors: despite lack of information about ADHD diagnostic criteria, the article is included ‐ because it reports data on serious adverse events (n = 0), deaths (n = 0). This means, that only data regarding serious adverse events should be extracted. Wrong NCT‐number reported Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information received through personal email correspondence with the authors in August 2014. No answer received |
Wigal 2013
Methods | 4‐6 weeks open‐label treatment (dose optimisation), cross‐over, and 2‐week double‐blind with 2 interventions:
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Participants | Number of participants screened: 45Number of participants included: 44Number of participants followed up: 39Number of withdrawals: 6Diagnosis of ADHD: DSM‐IV diagnosis of ADHD (subtype: combined (70.5%), hyperactive‐impulsive (2.3%), inattentive (27.3%))Age: mean 8.8, range 6‐12 years oldIQ: not statedSex: 32 males, 12 femalesMethylphenidate‐naïve: noneEthnicity: white (79.5%), Black/African American (9.1%); Asian (6.8%); other (4.5%)Country: USAComorbidity: elimination disorder (9.1%); oppositional defiant disorder (18.2%); specific phobias (4.5%)Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Participants were randomly assigned to different sequences of methylphenidate and placeboMethylphenidate type: liquid formulation of extended release methylphenidateMean methylphenidate dosage: 32.8 mg/dayAdministration schedule: 4 times dailyDuration of each medication condition: 1 weekWashout prior to study initiation: yes (1 day for stimulants)Medication‐free period between intervention: noTitration period: 3 weeks initiated before randomisation Treatment compliance: 2 withdrawals of assent/consent, 2 adverse events, 1 lack of efficacy, 1 lost to follow‐up |
Outcomes | ADHD symptoms‐ SKAMP, ADHD‐RS (open‐label phase) Non‐serious adverse events 42 participants (93.3%) experienced a treatment‐emergent adverse event3 (6.7%) participants with severe (affect lability, aggression, and initial insomnia) and 2 (4.4%) participants had to discontinue medication (affect lability and aggression)Open‐label phase: decreased appetite (55.6%), abdominal pain upper (42.2%), affect lability (26.7%), initial insomnia (22.2%), insomnia (17.8%), and headache (17.8%) Other AEs reported in ≥ 5% of the participants during the open phase: vomiting, diarrhoea, logorrhea, aggression, dizziness, irritability, fatigue, upper respiratory tract infection, cough, and flushingDouble‐blind phase: 11 (24.4%) participants had a AE while receiving NWP06 and 5 (11.1%) participants had a AE while receiving placebo |
Notes | Sample calculation: noEthics approval: yes Key conclusions from study authors: NWP06 resulted in significant improvements in the SKAMP‐combined score at 4 hours post‐dose as compared with placebo in the completers. This study shows that NWP06 significantly improved ADHD symptoms in school‐aged children and was well tolerated Comments from the study authors: "This study of NWP06 allowed inclusion of patients who were either treatment naïve or had previously been treated with stimulants" "Subjects were required to have been in need of pharmacological treatment for ADHD" "Our population more closely reflects a real‐world population and provides a more rigorous test of the study drug."Comments from the review authors: laboratory school environment, and lack of the ADHD‐RS. Race/ethnicity doesn't reflect a real‐world population Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not clear Supplemental information requested from study authors in August 2014. No reply |
Wigal 2015
Methods | A multicentre study of 4 phases: screening, double‐blind (1 week placebo controlled), open‐label (11 week dose optimisation), and a 30 day safety follow‐up |
Participants | Number of participants screened: 280Number of participants included: 230Number of participants followed up: 200Number of withdrawals: not statedDiagnosis of ADHD: DSM‐ IV‐TR (subtype: combined (61%), inattentive (33%))Age: mean 10.8 years (range 6‐18)IQ: > 80Sex: 154 males, 76 femalesMethylphenidate‐naïve: 148Ethnicity: white: 68.7%, African American: 23%, Asian:1.3%, others: 7%Country: USAComorbidity: ODD 22, enuresis 14Comedication: not statedSociodemographics: unknown Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: extended releaseMethylphenidate dosage: 10‐60 mg/dayMethylphenidate dosage during 11 weeks open‐label titration phase: 30 mg (27.7%), 40 mg (25.2%), 50 mg (17.8%), 20 mg (16.8%), 60 mg (8.9%), 15 mg (2.0%), 10 mg (1.5%)Administration schedule: once daily, in the morning, no later than 10 amDuration of intervention: 11‐12 weeks Treatment compliance: not stated |
Outcomes | Vital signs, physical examination, ECG, clinical laboratory evaluations, C‐SSRS, and AEs were collected at each visit |
Notes | Sample calculation: not stated
Ethics approval: the study protocol, amendments, and informed consent were reviewed and approved by an Institutional Review Board for each study site
Funding: this research was funded by Rhodes Pharmaceuticals LPVested interests/authors' affiliations: Dr Wigal has been an advisory board and speakers bureau member/consultant for Eli Lilly, Ironshore, Neos, NextWave, Noven, NuTec, Pfizer, Purdue, Rhodes Pharmaceuticals LP, Shionogi, Shire, and Tris and has received grant and research support from Eli Lilly, Forest, Ironshore, the National Institutes of Health, NextWave, Noven, NuTec, Purdue, Rhodes Pharmaceuticals LP, Shire, Sunovion, and Tris. Dr Nordbrock is a consultant for Rhodes Pharmaceuticals LP Dr Adjei and Dr Kupper are employees of Rhodes Pharmaceuticals LP Dr Childress has received research support from Shire, Novartis, NextWave, Lilly, Forest Research Institute, Johnson & Johnson, Sepracor, Otsuka, Sunovion, Pfizer, Shionogi, Noven, Ironshore, Rhodes, Theravance, Neurovance, Neos, Arbor, Tris, and Purdue. She has received consulting fees or honoraria from Ironshore, Pfizer, Shionogi, Rhodes, Shire, Novartis, and Neos; support for travel from Ironshore, Pfizer, Shire, Novartis, and NextWave; writing assistance on projects from Shire, Novartis, NextWave, Pfizer, Ironshore, and Arbor; and payment for lectures from Shire, Novartis, and Pfizer. Dr Greenhill has received research support from the National Institute on Drug Abuse/National Institutes of Health and Shire and is on the advisory board for BioBehavioral Diagnostics Key conclusions of the study authors: dose‐related improvements in ADHD‐RSIV scores that exceeded those of placebo were observed in patients treated with methylphenidate‐MLR. No new safety signals were noted Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Wiguna 2012
Methods | 12‐week open, prospective, non‐randomised trial using a pre‐test and post‐test design |
Participants | Number of participants screened: not statedNumber of participants included: not statedNumber of participants followed up: 21Number of withdrawals: not stated
Diagnosis of ADHD: DSM‐IV/ICD‐10 (subtype: combined (71.4%), inattentive (28.6%))Age: mean 8.52, 7‐10 years oldIQ: mean 110.14Sex: 17 males, 4 femalesMethylphenidate‐naïve: 100%Ethnicity: IndonesianComorbidity: noneComedication: noneSociodemographics: low to average socioeconomic status Inclusion criteria
Exclusion criteria
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Interventions | Participants were assessed before and after methylphenidate‐treatmentMethylphenidate type: long actingMethylphenidate dosage: 20 mgAdministration schedule: dailyDuration of intervention: 12 weeks Treatment compliance: not stated |
Outcomes | Weight, height, pulse, blood pressure and interim history: every 2 weeks |
Notes | Sample calculation: yesEthics approval: yesFunding: not statedVested interests/authors' affiliations: not stated Key conclusions of the study authors: findings of this pilot study are important in that it demonstrated, with stimulant treatment, significant neurochemical changes ‐ thought to reflect functional improvement and improved neuroplasticity ‐ in the prefrontal cortices of children with ADHD |
Wilens 2005
Methods | A multicentre, open‐label, cohort study of methylphenidate osmotic release oral system (OROS) use for 24 months |
Participants | Number of participants screened: 436Number of participants included: 407Number of participants followed up: 289 (12 months), 229 (24 months)Number of withdrawals: 118 (12 months), 178 (24 moths)Diagnosis of ADHD: DSM‐IV (subtype: combined (75.5%), hyperactive‐impulsive (5.9%), inattentive (18.4%), not determined ( 0.2%))Age: mean 9.2, range 6‐13 years oldIQ: not statedSex: 338 males, 69 femalesMethylphenidate‐naïve: noneEthnicity: white: 86%, African American: 5.7%, Asian: 0.7%, Hispanic:4.4%, others: 3.2%Country: USAComorbidity: tics (11.8%)Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: extended release (OROS)Methylphenidate dosage: 18 mg/day, 36 mg/day, or 54 mg/dayMean methylphenidate dosage: 35 mg at study entry, 41 mg at the end of 12 months, and 44.2 mg at month 21/24Administration schedule: once dailyDuration of intervention: 21 to 24 months Treatment compliance: 86.4% |
Outcomes | Non‐serious adverse eventsGrowth (weight, height), rated objectively by observer at monthly visits for the first 12 months and then at 15, 18, 21, and 24 monthsCardiac (heart rate, blood pressure), rated objectively by observer at monthly visits for the first 12 months and then at 15, 18, 21, and 24 monthsSleep quality, tics, rated subjectively by parents at monthly visits for the first 12 months and then at 15, 18, 21, and 24 monthsLaboratory tests (urinalysis, haematology/complete blood counts, electrolytes, and liver function tests) were performed at baseline, at 6 and 12 months, and at the end of the study (21/24 months) At 12 months, 28 (6.9%) discontinued study medication prematurely because of adverse events. At 21/24 months, 38 discontinued study medication prematurely because of adverse events. From final: there was a 26% increase in mean daily dose over the study period, with most of the increase occurring during year 1. In general, treatment was well tolerated, with 31 (7.6%) participants discontinuing because of adverse events. Comparison of the baseline characteristics of participants discontinuing the study compared with those continuing with treatment for 21/24 months did not reveal any significant differences between the 2 groups for ADHD subtype, teacher and parent/caregiver IOWA Conners inattention/overactivity and oppositional/defiant baseline scores, previous stimulant exposure, presence of comorbidity, specific comorbidity, race, sex, or type of school classroom |
Notes | Sample calculation: noEthics approval: reviewed and approved by the institutional review board of participating centres prior to initiation of the studyFunding: supported by McNeil Consumer & Specialty PharmaceuticalsVested interests/authors' affiliations: all authors work for different medical companies Key conclusions of the study authors: sustained effectiveness of OROS methylphenidate was maintained for up to 24 months with minimal effects on growth, tics, vital signs, or laboratory test values, as demonstrated by stable IOWA Conners ratings and sustained improvements in peer interaction and Global Assessment Scale scores Comments from the study authors: the prospective trial was terminated by the sponsor (concomitant with US FDA approval) between 21 and 24 months of participation for administrative reasons that were not related to safety or effectiveness. Therefore, although data were available for a minority of participants at 24 months (n = 56), we refer to the final end point as 21/24 months Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes. Included children had participated in previous controlled studies and were methylphenidate responders |
Wilens 2006
Methods | A 2‐week randomised, double‐blind, 15‐centre, parallel trial with 2 arms:
Preceded by a 4 week open‐label dose titration phase and followed by a 8 week open‐label follow‐up |
Participants | Number of participants screened: not statedNumber of participants included: 220 in the 4 week dose titration phaseNumber of participants randomised to methylphenidate: 87 and placebo: 90Number followed up in the methylphenidate group: 71Number of withdrawals in methylphenidate group: 16Number followed up: 171 (total)Number completed follow‐up: 135Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean: 14.6 years old (range 13‐18)IQ: not statedSex: 142 males, 35 femalesMethylphenidate‐naïve: not stated, but ADHD treatment naïve (n = 24)Ethnicity: white (75.1%), African American (13.6%), others (11.3%)Country: USAComorbidity: noComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Participants were randomly assigned to OROS‐methylphenidate or placeboMean methylphenidate dosage: 0.84 mg/kgAdministration schedule: once dailyDuration of intervention: 2 weeksTitration period: 4 weeks initiated before randomisation. All participants initiated therapy at 18 mg/day, and clinical response was measured after 1 week. If response to treatment was inadequate, as per the a priori study definition, the dose was titrated upward (in 18 mg increments) at 1 week intervals for up to 4 weeks, with the maximum dose being 72 mg/dayTreatment compliance: not stated 8‐week open‐label follow‐up on individualised dosage |
Outcomes | ADHD symptomsADHD‐RS, clinician and parent rated, completed at baseline and weekly during double blind phase Serious adverse events Serious adverse events were reported in only 1 participant during the open‐label dose titration phase of the study. While being treated with OROS, 18 mg/daily, a 16‐year‐old female participant with a history of depression and suicidal ideation threatened suicide on the third day of medication use after an argument with her mother. A decision was made to discontinue study medication, and the symptoms resolvedNo serious adverse events were reported during the double‐blind phaseNon‐serious adverse events Heart rate and blood pressure, recorded by a clinician weekly throughout whole studyECG at screening and at the end of the double‐blind phase of the studySpontaneous reports to the investigator of adverse events were recorded at weekly visitsSafety assessments made at monthly visit and every 2 weeks between monthly visits during the follow‐upHeight and weight were assessed at baseline and at weeks 4 and 8 in the follow‐up studyNo participants experienced clinically important effects on ECG‐indexes, heart rate or blood pressure during the study |
Notes | Sample calculation: yesEthics approval: yes, approval of the study design was obtained from the institutional review boards for all participating centres before initiation of the study Key conclusions of the study authors: in adolescents, once‐daily OROS methylphenidate significantly reduced ADHD symptoms and was well tolerated using dosages up to 72 mg/daily. Adolescents required, on average, a higher absolute dose but a lower weight‐adjusted dose (mg/kg) of OROS than was previously reported in children. The incidence of adverse events was not related to dose Comments from the study authors: participants were titrated to their individualised dosage before the double‐blind phase of the study may have biased the results toward a positive response in the double‐blind phase. The short duration of the double‐blind phase also may have decreased the likelihood of detecting potential rare adverse events. The rates of adverse events reported for OROS have been underestimated, because participants entering this study phase were already stabilised on an affective tolerated dosage of medication Supplemental information requested through email correspondence with the authors in December 2013 and January 2014. No reply |
Wilens 2008
Methods | An open‐label, 5‐week, dose optimisation period followed by a randomised, double‐blind, 8‐centre, 3‐way, 3‐week, cross‐over trial with 2 interventions:
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Participants | Number of participants screened: 148Number included in open‐label dose‐titration: 128Number randomly assigned to 1 of 3 possible drug orders: 120Number followed up for safety: 127 and for efficacy: 117Number of withdrawals: 2 Characteristics of the 127 followed up for safety Diagnosis of ADHD: DSM‐IV (combined or hyperactive‐impulsive (92,1%))Age: mean 8.8 (SD 1.84), range 6‐12 years oldIQ: above 80Sex: 84 males, 43 femalesMethylphenidate‐naïve: not statedEthnicity: white (62.2%/63.2%), African American (not stated/15.4%), Asian (not stated)Country: USAComorbidity: not allowedComedication: not statedSociodemographics: not statedCharacteristics of the 117 followed up for efficacy Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: 8.8 (SD 0.2), range 6‐12 years oldIQ: above 80Sex: 75 males, 42 femalesMethylphenidate‐naïve: not statedEthnicity: white (63.2%), African American (15.4%), Asian (0%), others (21.4%)Country: USAComorbidity: not allowedComedication: not statedSociodemographics: not statedInclusion criteria:
Exclusion criteria:
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Interventions | Participants were randomly assigned to 1 of 3 possible drug orders of (4 and 6 hours) methylphenidate and placeboMean methylphenidate dosage: 10 mg patch (n = 15), 15 mg patch (n = 34), 20 mg patch (n = 32), and 30 mg patch (n = 36)Administration schedule: once daily in the morning, patch worn for 9 h daily, and 4 or 6 h for the cross‐over assessmentsDuration of each medication condition: 1 dayWashout: noneTitration period: 5 weeks before randomisation Treatment compliance: not stated |
Outcomes | ADHD symptomsSKAMP, teacher, rated at randomisation (week 5) and 2 hrs after patch application end of treatment (week 6, 7, and 8) Quality of life ADHD Impact Module‐Child (AIM‐C) ‐ Child Impact Scale and Family Impact Scale, rated at baseline and randomisation (week 5) and end of study (week 8)Non‐serious adverse events Vital signs were evaluated at screening, baseline, and on weeks 1 to 8 (erythema, oedema, papules, and vesicles, discomfort, haematology, urinalysis, and electrocardiographic measures were completed at screening, baseline, and weeks 5 and 8)No clinically meaningful changes from baseline were observed in vital signs, ECG, urinalysis, and haematological results, or physical examinationsAdverse events were recorded from the time informed consent was signed until 30 days (week 12) after the last drug treatment |
Notes | Sample calculation: yesEthics approval: yes, institutional review board at each site approved the study Comments from the study authors: important to note that participants who failed to respond to psychostimulants in the past and those with conduct disorder were excluded from the study. The results of this study therefore should not be extrapolated to these patient populations. From Manos: the lack of placebo comparison has the potential to confound the findings of this study. The relatively short study duration (about 2 months) may not be enough time to capture some emerging changes in HRQoLKey conclusions from study authors: all of the efficacy measures indicated that 4‐ and 6‐hour wear times improved ADHD symptoms Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes, participants with a history of failing to respond to psychostimulant treatment were also excluded Supplemental information requested from the authors twice in August 2014. No reply |
Williams 2008
Methods | A cohort study of methylphenidate use for 4 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 51Number of participants followed up: 33Number of withdrawals: not statedDiagnosis of ADHD: DSM‐IV (subtype: combined: 58.8%, inattentive: 37.3%, hyperactive‐impulsive: 3.9%).Age: mean 13.79 (SD 2.33, range 8‐17) years oldIQ: above 80Sex: 51 malesMethylphenidate‐naïve: 51%Ethnicity: not statedCountry: AustraliaComorbidity: not statedC‐medication: no participant was taking concurrent medications known to affect the CNSSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: immediate releaseMean methylphenidate dosage: 24.1 mg/day (range 10‐60 mg/day).26 medication naïve titrated to maximum effective dose (0.4‐1.3 mg/kg) in a week with 10 mg increments then kept on a stable dose for a week. 25 had 3 day washout then resumed optimal methylphenidate dose after baseline testingAdministration schedule: methylphenidate given 60 minutes before testingDuration of intervention: 4 weeks Treatment compliance: not stated |
Outcomes | No adverse events were reported |
Notes | Sample calculation: not statedEthics approval: not statedFunding: an Australia Research Council (ARC) Linkage Grant with industry partner Brain Resource Company (BRC) (Grant no. LP0349079) supported this work. LMW holds a competitive, peer‐reviewed Pfizer Senior Research Fellowship. We acknowledge the support of the Brain Resource International Database (under the auspices of the Brain Resource Company) for data acquisition and processing. All scientific decisions are made independent of any BRC commercial decisions via the independently operated scientific division, BRAINnetVested interests/authors' affiliations: DP, HK, and SC have no conflicts of interest to declare. As an industry partner on the ARC‐linkage grant that supported this research (Grant no. LP0349079), BRC contributed to the salary of DFH as research officer on this grant for 2003‐2005. MK uses BRC computerised cognitive tests in private practice. LMW and CRC hold a few private shares in BRC (1% of the company value), and CRC holds a number of share options in the BRC. EG is the chief executive officer of BRC. However, scientific decisions are made independent of the BRC operations, and access to the Brain Resource International Database for scientific purposes is coordinated via an independent scientific network BRAINnet Key conclusions of the study authors: methylphenidate normalised neural activity and produced some improvement of emotion recognition but had no impact on negative mood. Disruptions to emotional brain function may be improved with methylphenidate Supplemental information received through personal email correspondence with the authors in August 2014 (Williams 2014 [pers comm]) |
Williamson 2011
Methods | 2 patient reports of resolution of enuresis when treated with methylphenidate |
Participants | Case 1Diagnosis of ADHD: DSM‐IV (subtype: combined)Age: 9 years oldIQ: normalSex: femaleEthnicity: not statedCountry: USAComorbidity: primary nocturnal enuresisComedication: noSociodemographics: not stated Case 2 Diagnosis of ADHD: DSM‐IV (subtype: inattentive)Age: 11 years oldIQ: normalSex: maleEthnicity: not statedCountry: USAComorbidity: primary nocturnal enuresisComedication: noSociodemographics: not stated |
Interventions | Case 1Methylphenidate type: extended release (Concerta)Methylphenidate dosage: 54 mgAdministration schedule: once dailyDuration of intervention: not statedTreatment compliance: not stated Case 2 Methylphenidate type: extended release dexmethylphenidate (Focalin XR)Methylphenidate dosage: 10 mgAdministration schedule: once dailyDuration of intervention: not statedTreatment compliance: not stated |
Outcomes | Non‐serious adverse events: Case 1Cessation of enuresis occurred immediately after initiating the stimulant Case 2 On days taking stimulant, no enuresis occurred. On days when not taking stimulant, enuresis did occur |
Notes | Key conclusions of study authors: our patient series add to the existing literature of associations between ADHD and enuresis Comments from the study authors: information was gathered only from parents. We did not obtain collateral information from teachers or any other sources Funding/vested interests/authors' affiliations: this work was supported by the University of Alabama's Research Grants Committee. The authors report no conflicts of interest |
Winsberg 1982
Methods | A non‐randomised, double‐blind cross‐over trial with fixed doses of methylphenidate given twice a day for a week each in the following schedule:
|
Participants | Number of participants screened: not statedNumber of participants included: 25Participants were administered successive 5 1‐week treatment conditions of fixed oral dose given twice dailyNumber of participants followed up: 20Number of withdrawals: 5Diagnosis of ADHD: DSM‐III (subtype: not stated)Age: mean 9.27, range 6.7‐12.1IQ: mean 98.2 (14.2)Sex: 25 malesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Participants were administered successive 5 1‐week treatment conditions of fixed oral doses given twice daily according to the following order: placebo 1; 0.25 mg/kg; 0.50 mg/kg; 1.00 mg/kg; placebo 2Methylphenidate type: not statedDuration of intervention: 5 weeksWashout: not statedTitration period: none Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Treatment‐emergent side effects, weight, blood pressure measured at the end of each treatment period (after 1 week intervention). Blood pressures were obtained 2 hours following the administration of the oral dose |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests/authors' affiliations: not stated Key conclusions from study authors: teacher and parents ratings showed increased improvement in social behaviour as a function of methylphenidate dose. No drug effects were obtained on cognitive performance. Methylpenidate plasma concentrations were significantly associated with oral dose and with measures of social behaviour. No relationship was found with cognitive behaviour. Side effects at the largest dose were severe enough to require discontinuation of treatment for 5 children, but were relatively mild for the rest of the children Supplemental information requested through personal email correspondence with authors in September 2013. Not able to get supplemental information regarding data on side effects, and therefore we cannot use the data in the meta‐analyses but only report them as part of a weighted mean (Hungund 2013 [pers comm]) |
Winterstein 2009
Methods | A 10 year retrospective cohort design evaluating the cardiac safety of methylphenidate and amphetamine salts |
Participants | Number of participants screened: 2,131,953Number of participants included: 30,576Number of participants included in methylphenidate arm: 18,238Number of participants followed up: 18,238Number of withdrawals: 0Diagnosis of ADHD: ICD‐9 (subtype: not stated)Age: mean 8.5‐9.2, range: 3‐20 years oldIQ: not statedSex: 13332 males, 4906 femalesMethylphenidate‐naïve: 100%Ethnicity: white: 44‐48.2%, African American: 31.6‐34.7%, Hispanic: 14.4‐15.5%Country: USAComorbidity: circulatory disease (3.5%)Comedication: bronchodilators 15.5‐16.3%, antidepressants 14‐16.4%, antipsychotics 8.2%Sociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: not stated Treatment compliance: not stated |
Outcomes | Serious adverse events:Data assembled from the Florida Medicaid fee‐for‐service programmeCardiac event defined as a first emergency department (ED) visit for cardiac disease or symptoms: myocardial infarction, stroke, hypertensive disease (excluding malignant causes), angina, aortic or thoracic aneurysm, arrhythmias, syncope, or tachycardia or palpitation ED visits were chosen as clinical end point because they occur more frequently than hospital admissions or cardiac death and provided the best power to detect even subtle difference between drugs |
Notes | Sample calculation: noEthics approval: not statedFunding: funded in part by the Florida Department of Health, Agency for Healthcare AdministrationVested interests/authors' affiliations: Dr Gerhard was in part funded by a grant from the Agency for Healthcare Research and Quality Key conclusions of the study authors: exposure to methylphenidate and amphetamines salts showed similar risk for cardiac ED visits Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information requested through personal email correspondence with the authors in January 2014 with no reply |
Witt 2008
Methods | Open‐label parallel design study of methylphenidate or dexamphetamine use for 3 months |
Participants | Number of participants screened: 84Number of participants included: 63Number of participants randomised to methylphenidate: 34Number of participants followed up in the methylphenidate group: 25Number of withdrawals: 9
Diagnosis of ADHD: DSM‐IV (subtype: combined (48%), hyperactive‐impulsive (4%), inattentive (44%), not specified (4%))Age: mean 8.9 (SD 1.9), range 6‐12 years oldIQ: not statedSex: 16 males, 9 femalesMethylphenidate‐naïve: 100%Ethnicity: white: 64%, African American: 32%, Hispanic: 4%Country: USAComorbidity: not statedComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: Concerta (n = 24), Ritalin LA (n = 1)Methylphenidate dosage: n = 3, 8 mg Concerta/day; n = 11, 27 mg Concerta /day; n = 7, 36 mg Concerta/day; n = 3, 54 mg Concerta/day; n = 1, 30 mg Ritalin LA/dayAdministration schedule: first 4 weeks comprised weekly dose titration assessment with clinician using standardised parent/teacher rating scales to ensure adequate dose given. Thereafter, monthly reviews of medication, with adjustment of dose, as needed time points: once daily doseDuration of intervention: 90 days Treatment compliance: 96% |
Outcomes | Serious adverse events:Cytotoxic damage to cells cultured from blood samples Non‐serious adverse events: Other adverse events have been recorded, but the data are not available. AEs recorded include insomnia, syncope, loss of appetite, and a worsening of ADHD symptoms |
Notes | Sample calculation: the target enrollment of 30 participants in each group was based on the projected number of participants needed to detect a doubling of any of the cytogenetic endpoints with ≥ 90% power at a 0.05 level of significance. Posthoc power analyses with actual sample sizes confirmed that, even with less‐than‐target enrollment, the power was ≥ 90% for detecting a doubling of each of the 3 cytogenetic endpoints within each treatment group because the variability of each endpoint was smaller than anticipated
Ethics approval: this study protocol was reviewed and approved by the institutional review boards of both Duke University Medical Center and the National Institute of Environmental Health Sciences
Funding/vested interests/authors' affiliations: Dr Kollins received research support and/or honoraria/ consulting fees from the following sources during the conduct of this study: Athenagen, Eli Lilly, Psychogenics, Pfizer, New River Pharmaceuticals, Shire Pharmaceuticals, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and Environmental Protection Agency. Dr Chrisman received honoraria and was on the speakers' bureaus of Shire Pharmaceuticals and McNeil‐PPC. The other authors report no conflicts of interest Key conclusions of the study authors: the present study found no evidence of changes in any of the 3 cytogenetic endpoints examined in the lymphocytes of children treated with methylphenidate or mixed amphetamine salts based products continuously for 3 months. Our results add to a growing body of evidence that therapeutic levels of methylphenidate do not induce chromosomal damage in humans Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no, only methylphenidate‐naïve patients included Supplemental data on adverse events requested from the study authors. Answer received in July 2014: data are not available (Witt 2014 [pers comm]) |
Woolley 2003
Methods | A patient report of obsessive‐compulsive disorder (OCD) emerging during methylphenidate treatment |
Participants | Diagnosis of ADHD: ICD‐10 (subtype: not stated)Age: 11 years oldIQ: normalSex: maleEthnicity: not statedCountry: UKComorbidity: obsessive‐compulsive disorderComedication: Risperidone (1 mg/day) Sociodemographics: not stated |
Interventions | Methylphenidate type: immediate releaseMethylphenidate dosage: 40 mg/dayAdministration schedule: not statedDuration of treatment: more than 15 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Obsessions and compulsions with anxiety (DSM‐IV diagnosis of OCD). Washing his hands excessively, accompanied by checking rituals, reassurance seeking, and emetophobia. When methylphenidate was withdrawn the OCD symptoms decreased rapidly but increased when methylphenidate was reintroduced |
Notes | Key conclusions of the study authors: obsessive‐compulsive disorder (OCD) may emerge with stimulant treatment for attention deficit hyperactivity disorder (ADHD). We report a case of OCD worsening with methylphenidate treatment but not with dexamphetamineFunding/vested interest/authors affiliation: not stated Supplemental information regarding ADHD diagnosis and IQ received through personal email correspondence with the authors in October 2013 (Heyman 2013 [pers comm]) |
Yalcin 2012
Methods | 2 patient reports of methylphenidate use and development of dysphonic symptoms |
Participants | Case 1Diagnosis of ADHD: DSM‐IVAge: 10 years oldIQ: normalSex: maleCountry: TurkeyComorbidity: noneComedication: noneSociodemographics: living in metropolitan area with high school student mother who doesn't work and university graduate father who works as sergeant in the army, and older sister Case 2 Diagnosis of ADHD: DSM‐IVAge: 11 years oldIQ: normalSex: maleCountry: TurkeyComorbidity: specific learning disorder and social anxietyComedication: not statedSociodemographics: fourth child of high school graduate father who works as official and elementary school graduate mother |
Interventions | Case 1Immediate release methylphenidate dosage: 5 mgAdministration schedule: twice a dayDuration of intervention: 2 weeksTreatment compliance: not stated Case 2 OROS methylphenidate dosage: 18 mg/dayAdministration schedule: morningDuration of intervention: 2 weeksTreatment compliance: not stated |
Outcomes | Non‐serious adverse events: Case 1Disturbance of voice quality, hoarseness and bifurcation‐strain and over vibration of voice observed by teacher and family. The symptoms began on the first day of methylphenidate treatment. Hoarseness and reduction in the voice amplitude was evident during the first psychiatric controlDrug‐free days: no symptoms observed by parents or during the psychiatric control.Methylphenidate administration in the clinic: hoarseness. 3 hours after ingestion: voice quality returned to normal. Physical and endoscopic examination: laryngitis or other organic conditions causing hoarseness were not observedDiscontinuation of methylphenidate and administration of atomoxetine: no important side effects Case 2 Significant appetite loss, drowsiness, disturbance of voice and hoarseness. Disturbance of voice and hoarseness occurred every day since the first day on the medication. The symptoms started shortly after the single morning dose and decreased gradually until dinner time and disappeared before bedtimeDrug‐free days: no symptoms. Otolaryngology consultation: no organic pathology was detected with respect to clinical and endoscopic observationDiscontinuation of methylphenidate and prescription of atomoxetine: no symptom of hoarseness or disturbance of voice quality |
Notes | Funding/vested interest/authors' affiliations: the authors reported no conflict of interest related to this article Key conclusions of the study authors: 2 male children developed disturbances in voice quality and hoarseness associated with MPH use, which required drug discontinuation Comments from the study authors: according to the Naranjo 1981 classification, +5 point was calculated (+5‐8 possibly related side effect) for the hoarseness and impairment of voice quality associated with methylphenidate for these patients Supplemental information regarding IQ and ADHD diagnostic criteria received through personal email correspondence with the authors in March 2013 (Yalcin 2013 [pers comm]) |
Yalcin 2014
Methods | A cohort study of osmotic release oral system (OROS) methylphenidate use for 60 days |
Participants | Number of participants screened: not statedNumber of participants included: 40Number of participants followed up: 33Number of withdrawals: 7Diagnosis of ADHD: DSM‐IV (subtype: combined (54.54%), hyperactive‐impulsive (18.18%), inattentive (27.27%)Age: mean 9.20 years (range 6‐12)IQ: not statedSex: 33 malesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: oppositional defiant disorder: 9.09%; enuresis: 6.06%Comedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria |
Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: 18 mgAdministration schedule: fixed daily dose (no titration)Duration of intervention: 60 days Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Weight and height before and after methylphenidate. Mothers rated severity of methylphenidate associated adverse reactions (sleep problems, headache, tics, loss of appetite,abdominal pain, weight loss, sadness, mouth dryness, nausea, vomiting, fears, irritability, skin eruption and others): 0, not a problem; 1, mild; 2, moderate; 3, severe. Before and after medication appetite status of the children was rated by the mothers |
Notes | Sample calculation: not statedEthics approval: Gazi University Medical Faculty, Ethics CommitteeFunding/vested interests: this research was not supported by university funds or any drug company Key conclusions of the study authors: this is the first study which directly aims to determine methylphenidate's effect on serum active ghrelin levels. Further research with higher methylphenidate doses and/or other stimulants such as atomoxetine and amphetamine should be done as ghrelin is also associated with obesity, alcohol and drug addiction and reward system pathologies, which are also closely related to attention deficit hyperactivity disorder Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no, 100% were methylphenidate‐naïve |
Yang 2004
Methods | A 16 week, open‐label methylphenidate treatment study |
Participants | Number of participants screened: not statedNumber of participants included: 25Number of participants followed up: 19Number of withdrawals: 6Diagnosis of ADHD: DSM‐IV (subtype: combined (100%))Age: mean 8.7 (SD 1.7) years (range: 6 years and 4 months ‐ 11 years and 10 months)IQ: full intelligence quotients available from 10 participants (mean 100, range 86‐129). The other 9 participants were estimated to be normalSex: 14 males, 5 femalesMethylphenidate‐naïve: not statedEthnicity: 100% AsianCountry: TaiwanComorbidity: noneComedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: not statedMethylphenidate dosage: 10 mg/day (starting dose, bodyweight < 30kg) or 20 mg/day (starting dose, bodyweight ≥ 30 kg)Mean methylphenidate dosage: 18.95 (SD 7.56, range 10‐35) mg/day, equivalent to 0.61 mg/kg of bodyweight (SD 0.15, range 0.38‐0.87 mg/kg)Administration schedule: twice daily, mornings before school and at 1 pmTitration period: 3 weeksDuration of intervention: 16 weeks Treatment compliance: 4 noncompliant |
Outcomes | The study does not mention any measuring of adverse events. However it is reported, that 2 participants dropped out due to intolerable medication side effects |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interests: not statedAuthors' affiliations: Department of Psychiatry, Kaohsiung Medical University Hospital and Department of Psychiatry, Chung Shan Medical University Hospital, Taiwan Key conclusions of the study authors: the methylphenidate treatment demonstrated improvement in domains of classroom/home behaviours and academic performance, but showed minimal change on neuropsychological functioning in Taiwanese ADHD children. The finding of academic gain was unexpected, which might be due to the greater interest in achievement and better compliance to cultural expectations by Taiwanese versus Western students, which translated into more rapid improvement in academic performance Comments from the study authors: limitations of the study: the present study was conducted in a naturalistic manner, without a placebo controlled or contrast group and without blinding. The diagnoses were made by clinicians, without the benefit of standardised diagnostic instruments administered by a blind clinician. The exclusion criterion dyslexia was not tested Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no |
Yang 2012
Methods | A single‐blind (rater blinded) randomised parallel trial comparing:
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Participants | Number of participants screened: not statedNumber of participants included: 262Number of participants randomised to methylphenidate: 130Number of participants followed up: 85Number of withdrawals: 39Diagnosis of ADHD: DSM‐IV (subtype: inattentive (42%), combined (56.5%), hyperactive/impulsive (1.2%)Age: mean 9.64 (SD 1.95), range 7‐14 years oldIQ: above 70, mean 102.99 (15.01)Sex: 129 males, 23 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: ChinaComorbidity: oppositional defiant disorder (n = 44), conduct disorder (n = 2)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: started at 18 mg/daily and could be increased each week to 36 mg/daily and then 54 mg/daily according to the patients responseMean methylphenidate dosage: not statedAdministration schedule: not statedDuration of intervention: titration + 4‐6 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: 15 dropped out of the methylphenidate group due to adverse events |
Notes | Sample calculation: yesEthics approval: yesFunding: Xian‐Janssen Pharmaceutical Ltd.Vested interests/authors' affiliations: Xian‐Janssen, Eli Lilly Key conclusions of the study authors: the results imply that both OROS‐methylphenidate and atomoxetine could improve EF in ADHD children Comments from the study authors: there are a number of methodological limitations in the current study. First, we did not include a group that received placebo; therefore, there might have been a bias in the results for the potential placebo effect when we estimated the effect of each medication. The relatively small sample size in the atomoxetine group may have underestimated its therapeutic effect. Further, the slight differential effect between OROS‐methylphenidate and atomoxetine treatment groups might also have been a type I error. We excluded youths with significant current psychiatric co‐morbidity, restricting the generalisation the findings to more co‐morbid, clinically relevant populations Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information requested from the study authors in May 2014. No reply |
Yatsuga 2014
Methods | A cohort study of methylphenidate use for 3 months |
Participants | Number of participants screened: not statedNumber of participants included:, 50Number of participants followed up: 50Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV TR (subtype not stated)Age: mean 9.7 years (SD 2 years 8 months) (range: 6‐16)IQ: mean 93.15Sex: 50 malesMethylphenidate‐naïve: 100%Ethnicity: not statedCountry: JapanComorbidity: noneComedication: noneSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: 18/27 mg (0.5‐1.2 mg/kg/day)Administration schedule: not statedDuration of intervention: 3 months Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: In all, 7 children reported some kind of adverse effect: 2 children reported headache, 3 children had appetite loss, 3 children had sleeplessness and 1 child reported appetite loss and sleeplessness |
Notes | Sample calculation: not stated
Ethics approval: ethics committee of Graduate School of Medical Sciences, Kumamoto University
Funding/vested interests/authors' affiliations: Grant‐in‐Aid for Scientific Research (B) and Challenging Exploratory Sports, Science and Technology (MEXT) of Japan (KAKENHI:grant number 24300149 and 23650223 to A.T). Partially supported by Grant in Aid for Scientific Research from Japan‐U.S. Brain Research Cooperation Program (grant number 210201 to A.T) as well as the Research Grants from the University of Fukui to AT. The funding organisations had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or in preparation, review or approval of the manuscript. No authors have financial or personal relations that could pose a conflict of interest
Any withdrawals due to adverse events: none Key conclusions of the study authors: this study showed no relation between the COMT genotype and methylphenidate adverse effects Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: none indicated |
Yildiz 2010
Methods | An 8‐week, open‐label, prospective, parallel study with 2 arms:
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Participants | Number of participants screened: not statedNumber of participants included: 90Number of participants randomised: OROS‐MPH: 50 and IR‐MPH: 40Number of participants followed up: OROS‐MPH: 47 and IR‐MPH: 36Number of withdrawals: OROS‐MPH: 3 and IR‐MPH: 4Diagnosis of ADHD: DSM‐IV (subtype: combined (IR‐MPH: 75.0%, OROS‐MPH: 80.9%), inattentive (IR‐MPH: 25.0%, OROS‐MPH: 19.1%))Age: mean 9.7 SD 1.8, range 7‐15 years old (IR‐MPH: 9.3 SD 1.3 and OROS‐MPH: 10.0 SD 2.1)IQ: above 80. WISC‐R total IQ: IR‐MPH: 99.9 SD 14.2 and OROS‐MPH: 99.5 SD 10.9Sex: IR‐MPH: 28 males, 8 females. OROS‐MPH: 41 males, 6 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: TurkeyComorbidity: specific learning difficulties (IR‐MPH: 22.2%, OROS‐MPH: 23.4%)Comedication: not statedSociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Dosage the first 4 weeks: IR‐MPH: 10 mg/day. OROS‐MPH: 18 mg/dayAfter the fourth week: IR‐MPH: 10 mg/day (n = 16) or 20 mg/day (n = 20) and OROS‐MPH: 18 mg/day (n = 22) or 36 mg/day (n = 25)Duration of intervention: 60 days Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: Based on Side Effects of Stimulant Medications for Screening Scale developed by Turgay, there are 16 side effects for psychostimulants. Parents filled out the form for each side effects based on a 4‐point Likert scale (0: none, 1: rare, 2: moderate, 3: severe) in 4th and 8th week |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interests: not stated Key conclusions of the study authors: OROS‐methylphenidate was found to be as effective as IR‐methylphenidate in the treatment of behavioural symptoms in Turkish children with ADHD. These results demonstrated that both drugs were effective and well tolerated in the treatment of Turkish children with ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes |
Yildiz 2011
Methods | A 14‐week parallel, randomised, open‐label trial (first 2 weeks screening phase) with 2 arms:
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Participants | Number of participants screened: not statedNumber of participants included: 12Number of participants followed up: 11Number of withdrawals: 1Diagnsosis of ADHD: DSM‐IV‐TR (subtype: combined (66.7%), inattentive ( 33.3%)).Age: mean 10.16, range 8‐14 years oldIQ: none with mental retardationSex: not statedMethylphenidate‐naïve: not statedEthnicity: not statedCountry: TurkeyComorbidity: oppositional defiant disorder: 7, learning disorder: 6Comedication: participants taking concomitant psychoactive medications were excluded from the studySociodemographics: not stated Inclusion criteria
Exclusion criteria
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Mean methylphenidate dosage: 1.07 mg/kg/dayAdministration schedule: morning dose, once dailyDuration of intervention: 12 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:Weight, height, pulse, systolic, diastolic blood pressure, AST, ALT, EEG, ECG, observer, beginning and end point (12 weeks)Self‐reported medication related adverse events 18 item list, parent/children, at 4, 8 and 12 weeks 1 child discontinued the study due to chest pain and palpitations |
Notes | Sample calculation: noEthics approval: approved by the Local Independent Ethics CommitteeFunding/vested interests: not statedAuthors' affiliations: Department of Child and Adolescent Psychiatry, Kocaeli University, Izmit, Turkey Key conclusions of the study authors: treatment responses were not significantly different between the 2 study groups. OROS‐methylphenidate led to a significantly greater reduction in teacher T‐DSM‐IV‐S scores. OROS‐methylphenidate was more effective than atomoxetine on Stoop‐5 time and number of corrections. Significant decrease in the percentage of perseverative errors on WCST in the OROS‐methylphenidate group was seen. In the OROS‐methylphenidate group, patients most frequently reported anorexia, nervousness, insomnia, headache, nausea and weight loss. When all the results are considered, although both drugs can be considered effective in ADHD treatment, more remarkable improvement is provided by OROS‐methylphenidate based on the rates across informant and neuropsychological evaluation |
Yilmaz 2013
Methods | A patient report of methylphenidate‐induced acute orofacial and extremity limb dyskinesia |
Participants | Diagnosis of ADHD: DSM‐IVAge: 7 years oldIQ: above 70Sex: maleEthnicity: TurkishCountry: TurkeyComorbidity: epilepsyComedication: sodium valproate Sociodemographics: not stated |
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 18 mgAdministration schedule: once daily in the morningDuration of treatment: 1 dose Treatment compliance: good |
Outcomes | Serious adverse events: Involuntary movements started about 5 hours after taking methylphenidate. Lip‐licking, lip‐smacking and tongue‐rolling movements. Dyskinetic tongue movements inside and outside the mouth and involuntary bilateral arm swinging while sitting and standing. Opening and closing his fingers without complete extension. Occasional repetitive movements of the feet, such as beating them against each other while sitting. About 15 hours after methylphenidate intake both hand‐mouth movements and excessive mobility had significantly resolved. Dyskinetic symptoms had completely disappeared on the second day of hospitalisation, and the patient was discharged |
Notes | Funding/vested interest/authors' affiliations: authors declare that there are no potential conflicts of interest Key conclusions of the study authors: this case is reported to emphasise the potential side effects of methylphenidate, individual differences in drug sensitivities, and drug‐receptor interactions via different mechanisms Comments from the study authors: antiepileptic therapy may increase the sensitivity to the side effects of methylphenidate Supplemental data received through personal email correspondence with the authors in December 2013 (Yilmaz 2013 [pers comm]) |
Yu 2010
Methods | A patient report of 4 boys with attention‐deficit/hyperactivity disorder who developed vasculopathy during treatment with psychostimulants. 3 received treatment with methylphenidate |
Participants | Diagnosis of ADHD: ICD‐9/ICD‐10 (subtype: not stated)Age: 11, 12, 16 years old (mean: 13)IQ: no mentally retardedSex: 3 malesEthnicity: whiteCountry: USAComorbidity: case 2 (suspected bipolar disorder)Comedication: case 1 (Adderall); case 2 (Abilify and Lamictal, later on they were discontinued and Seroquel was added) Sociodemographics: not stated |
Interventions | Case 1 First methylphenidate attempt:Extended release methylphenidate dosage: 54 mg/daily (Concerta). Comedication: Adderall. Administration schedule: not stated. Duration of treatment: 2 years. Treatment compliance: not stated Second methylphenidate attempt: Immediate release‐/dex‐ and extended release‐methylphenidate dosage: Concerta 90 mg/daily and Focalin 20 mg/daily. Administration schedule: not stated. Duration of treatment: 9 months. Treatment compliance: not statedTotal duration of psychostimulant treatment: 9 yearsCase 2 Immediate‐ and extended release methylphenidate dosage: long acting Ritalin: 30 mg/daily and Focalin 2.5 mg/dailyAdministration schedule: not statedDuration of current treatment: 4 yearsTotal duration of psychostimulant treatment: 5 yearsTreatment compliance: not statedCase 4 Extended release/dex‐ and immediate release/dex methylphenidate dosage: Focalin XR 20 mg/daily, Focalin IR 10 mg/dailyAdministration schedule: twice daily, XR in the morning, and IR in the afternoonDuration of treatment: 1 yearTotal duration of psychostimulant treatment: 7 yearsTreatment compliance: not stated |
Outcomes | Non‐serious adverse events: Case 1Tachycardia at age 11 while taking Concerta, 54 mg/dailyVasculopathy at age 16. Hands and feet were a continuous blue color which increased in frequency in cold weather. Diagnosed with decreased circulation but not Raynaud's syndrome. Occured when the Concerta dose was increased from 54 mg/daily to 90 mg/daily in 3 months with the same Focalin dose (10 mg/daily) Case 2 Vasculopathy. First diagnosed with Raynaud's syndrome with finger pain and colour changes during a neurology consultation at age 10. At age 12 had diffuse erythema of both earlobes, the fingers of both hands, and the toes of the left footTics at age 10 ‐ not clear if these were present prior to ADHD treatmentCase 4 Vasculopathy. After taking Focalin for a year, he developed persistent curling of the toes of both feet. In addition, he had reddish and purple colour changes in his hands and feet with cold exposure that lasted for 20 min. No associated pain and only rare paresthesia. At age 10 toes 2, 3, and 4 of both feet were held in a flexed position ('curled toes'), and there was skin discoloration and excoriation |
Notes | Funding/vested interest: noneAuthors' affiliations: Drs Ronald and Elizabeth Weller are co‐owners of the Children's Interview for Psychiatric Syndromes (and the parent's version) and have received annual royalties from copyright ownership of this diagnostic interview. Dr Elizabeth Weller was the principal investigator for a grant from GlaxoSmithKline to investigate the tolerability and efficacy of lamotrigine in children and adolescents diagnosed with bipolar disorder Key conclusions of the study authors: these patient reports raise the concern that adverse effects in the peripheral vascular system of children and adolescents may be associated with psychostimulant treatment Comments from the review authors: none of the patients had their psychostimulants decreased or discontinued. Due to the severe nature of their ADHD symptoms, these patient could not stop or reduce their psychostimulant treatment to determine whether their vascular symptoms would improve Supplemental information received through personal email correspondence with the authors in October 2013 (Yu 2013 [pers comm]) |
Zarinara 2010
Methods | A 6‐week double‐blind, parallel‐group randomised clinical trial with 2 arms:
No control/no‐intervention group |
Participants | Number of participants screened: 60Number of participants included: 38Number randomised to methylphenidate: 19Number of participants followed up in the methylphenidate group: 18Number of withdrawals in the methylphenidate group: 1 MPH group Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (100%))Age: mean 9.57 years old (range 6‐13)IQ: above 70Sex: 13 males, 6 femalesMethylphenidate‐naïve: 100% (newly diagnosed)Ethnicity: Persian (100%)Country: IranComorbidity: not statedComedication: not statedSociodemographics: not statedInclusion criteria:
Exclusion criteria:
|
Interventions | Methylphenidate type: not statedMethylphenidate dosage: 20‐30 mg/day depending on weight (20 mg/day for < 30 kg and 30 mg/day for > 30 kg)Methylphenidate titration: 3 weeks (week 1: 10 mg/day twice daily; week 2: 20 mg/day twice daily; and week 3: 30 mg/day for children > 30 kg 3 times daily)Duration of intervention: 6 weeks inclusive titration Treatment compliance: not stated |
Outcomes | Adverse effects checklist (20 possible adverse events), rated by a child psychiatrist on days 7, 21, 42. Body weight and vital signs assessed at baseline, week 1, 2, 4, 6. 12‐lead ECG and physical examination at baseline and week 6 |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interests/authors' affiliations: this study was supported by a grant from Tehran University of Medical Sciences Key conclusions of the study authors: the results suggest that venlafaxine may be useful for the treatment of ADHD. In addition, a tolerable side‐effect profile is one of the advantages of venlafaxine in the treatment of ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding data requested through personal communication with the authors in August 2013. No reply |
Zelnik 2015
Methods | A naturalistic study of osmotic release oral system (OROS) methylphenidate use for ≥ 1 year |
Participants | Number of participants included: 128Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean: not stated (range 7‐17)IQ: patients with intellectual disabilities were excludedSex: 83 males, 40 femalesMethylphenidate‐naïve: not stated, but all were newly diagnosedEthnicity: not statedCountry: IsraelComorbidity: anxiety 27.2‐46.8%, depression 1.2‐9.7%, all psychiatric comorbidities 48.1%‐74.5%Comedication: noSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: group I: lower dose OROS + short acting formulation; group II: OROSMean methylphenidate dosage: group I: 0.83 SD 0.21 mg/kg; group II: 1.06 SD 0.29 mg/kgAdministration schedule: group I: not stated; group II: OROS once dailyDuration of intervention: ≥ 1 year Treatment compliance: not stated |
Outcomes | In the present study data were retrospectively collected of all the patients that were treated with OROS methylphenidate and characterised the clinical characteristics of those who tolerated it well in comparison with those that better tolerated lower doses of OROS methylphenidate together with shorter acting methylphenidate, offering them a more potent level during school hours while lessening the effect during the afternoon and evening hours |
Notes | Sample calculation: not statedEthics approval: yesFunding/vested interest: noAuthors' affiliations: none Key conclusions of the study authors: while OROS methylphenidate and other long‐acting methylphenidate formulations prove beneficial for most children and adolescents with ADHD, some patients (mostly those with psychiatric comorbidities) might sometimes better tolerate a lower OROS methylphenidate dose combined with short‐acting methylphenidate formulation. Additional larger‐scale prospective studies are required to validate our preliminary observation Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated |
Zeni 2007
Methods | A cohort study of methylphenidate use for 1 month |
Participants | Number of participants screened: 111Number of participants included:106Number of participants followed up: not statedNumber of withdrawals: 5Diagnosis of ADHD: DSM‐IV (subtype: combined (58.5%), hyperactive‐impulsive (7.5%), inattentive (26.4%))Age: mean 10.26, range 4‐17 years oldIQ: not statedSex: 82 males, 24 femalesMethylphenidate‐naïve: 100%Ethnicity: 100% European‐BrazilianCountry: BrazilSetting: outpatient clinicComorbidity: conduct disorder (16%), oppositional defiant disorder (51.9%), mood disorders (9,4%), anxiety disorders (23.8%)Comedication: noneSociodemographics: not stated Inclusion criteria
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Interventions | Methylphenidate type: short actingMean methylphenidate dosage: 0.5 mg/kg/dayAdministration schedule: not statedDuration of intervention: 1 month Treatment compliance: 2 patients excluded due to irregular use of methylphenidate |
Outcomes | Non‐serious adverse eventsBarkley SERS:
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Notes | Sample calculation: noEthics approval: yesFunding/vested interest: governmental agencies: Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico (CNPq, Brazil); Grant number: 471761/03‐6; Grant sponsor: Programa de Apoio a Nucleos de Excelencia (PRONEX, Brazil); Grant sponsor: Hospital de Clınicas de Porto Alegre Key conclusions of the study authors: no significant association was detected between polymorphisms of dopaminergic (DRD4, DAT1) and serotonergic genes (HTR1B, HTR2A, and 5‐HTT) on the response nor side effects to the treatment with methylphenidate Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no, 100% were methylphenidate‐naïve Supplemental information received through personal email correspondence with the authors in September 2016 (Zeni 2016 [pers comm]) |
Zhang 2010
Methods | A case‐control study of methylphenidate use for 2‐4 years |
Participants | Number of participants screened: not statedNumber of participants included: 175Number included as cases: methylphenidate 126; controls (no intervention) 29Number followed up in each arm: methylphenidate 46; controls 2Number of withdrawals in each arm: methylphenidate 98; controls 27Diagnosis of ADHD: DSM‐IV (subtype: combined (74.65%), hyperactive‐impulsive (8.9%), inattentive (16.43%))Age: mean 7.42 years old (range 6‐9.8)IQ: not statedSex: 126 males, 20 femalesMethylphenidate‐naïve: not statedEthnicity: not statedCountry: ChinaComorbidity: oppositional defiant disorder (39.73%), conduct disorder (4.79%), learning disorder (8.22%), tics (4.79%)Comedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: immediate releaseMean methylphenidate dosage: 0.27‐0.64 mg/kgAdministration schedule: 2 time points (mornings and afternoons)Duration of intervention: 2‐4.8 years Treatment compliance: not stated |
Outcomes | Non‐serious adverse events:
Height
Weight BMI |
Notes | Sample calculation: not statedEthics approval: not statedFunding/vested interest: not statedAuthors' affiliations: Department of Paediatrics, First Affiliated Hospital, Sun Yat‐sen University, Guangzhou, P. R. China Key conclusions of the study authors: methylphenidate inhibits linear growth of children, but it is correlated to methylphenidate treatment length; there was no influence on weight; there was no differences on BMI Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: not stated Supplemental information requested through personal email correspondence with the authors in June 2014. Email sent twice but no answer received |
Zheng 2011
Methods | A 6‐week multicentre, prospective, naturalistic, open‐label, pilot study evaluating the effectiveness and safety of osmotic release oral system (OROS) methylphenidate |
Participants | Number of participants screened: not statedNumber of participants included: 1447Number of participants followed up: 1154Number of withdrawals: 293Diagnosis of ADHD: DSM‐IV (subtype: combined (56.8%), hyperactive‐impulsive (9.8%), inattentive (28.5%), unidentified type (3.4%))Age: 9.53 (SD 2.35) years old (range 6‐16)IQ: not statedSex: 1219 males, 228 femalesMethylphenidate‐naïve: not stated (no current methylphenidate treatment: 1304 (90%))Ethnicity: Asian (97.8%), others (2.2%)Country: ChinaComorbidity: noComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: 18, 36 or 54 mg once daily at the discretion of investigators. However, the recommended dosing strategy is: methylphenidate‐naïve: 18 mg; currently receiving 5 mg immediate release methylphenidate 2‐3 times a day: 18 mg OROS methylphenidate; currently receiving 10 mg immediate release methylphenidate 2‐3 times a day or a total daily dose of 40 mg immediate release methylphenidate: 36 mg OROS methylphenidate; and currently receiving 15 mg immediate release methylphenidate 2‐3 times a day or a total daily dose of > 45‐60 mg: 54 mg OROS methylphenidateDoses of OROS methylphenidate could be adjusted between a total daily dose range of 18 and 54 mg after 14 days of treatment by the investigator on the basis of safety and efficacy. At the end of the study 96.8% participants received an OROS methylphenidate dose of 18 mg, 3.1% 36 mg and 0.1% 54 mgDuration of intervention: 6 weeks Treatment compliance: 93.4% of the patients showed good compliance (defined as more than 80% adherence to the prescribed regimen) |
Outcomes | Non‐serious adverse eventsBlood pressure, pulse rate measurement, adverse event review were conducted by the investigator at baseline, week 2, 4 and 6 Parents rated the participant's sleep quality and were asked about the presence of motor and/or verbal tics at baseline, week 2, 4 and 6 |
Notes | Sample calculation: not statedEthics approval: not statedFunding: funded by Xi'an Jassen Pharmaceutical Ltd, China Key conclusions of the study authors: this open‐label, naturalistic study provides further evidence of effectiveness and safety of OROS methylphenidate in school‐aged children under routine practice Comments from the study authors: since the patients in this study only received 6‐weeks OROS methylphenidate treatment, the long‐term adverse events such as influence on growth and weight can not be observed. This is a limitation of this study because ADHD patients need long‐term treatment Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: yes Supplemental information requested through email correspondence with the first author in September 2013. No reply |
Zheng 2015
Methods | A 12‐week, prospective, multicentre, open‐label, self‐controlled clinical study of methylphenidate use for 12 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 153Number of participants followed up: 123Number of withdrawals: 30Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 9.2 (SD 1.5) years old (range 6‐12)IQ: 85 or moreSex: 108 males, 20 femalesMethylphenidate‐naïve: 90.4%Ethnicity: Han (96.9%), others (3.1%)Country: ChinaComorbidity: not statedComedication: noneSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral system (OROS)Methylphenidate dosage: during the optimised treatment phase (weeks 3‐12), 73.5% children received OROS methylphenidate 18 mg once daily and 26.5% received 36 mg once daily (weeks 7‐12)Administration schedule: once dailyDuration of intervention: 12 weeks Treatment compliance: the mean course of OROS methylphenidate treatment was 80.1 days and total compliance was 93.6% |
Outcomes | Children had a general physical and blood examination (if required) before initiating OROS methylphenidate. Blood pressure, pulse rate, concomitant medications, adverse events (AEs), and treatment review were conducted at baseline and at each visit. A total of 149 patients were included in the safety analysis set |
Notes | Sample calculation: not statedEthics approval: yes
Funding/vested interest: the study presented in this report was supported by Xi'an Janssen Pharmaceutical Ltd.
Authors' affiliations: Ms. Jian‐Min Zhuo and Dr Sheng‐Nan Xie are full‐time salaried employees of Xi'an‐Janssen Pharmaceutical Ltd. Drs. Yi Zheng, Hong‐Yun Gao, Zhi‐Wei Yang, Fu‐Jun Jia, Fang Fang, and Rong Li have served on advisory boards of Xi'an Janssen Pharmaceutical Ltd., and Eli Lilly and Company Key conclusions of the study authors: in conclusion, this open‐label study suggests that the OROS methylphenidate improves academic and cognitive performance in Chinese school‐aged children with ADHD. The treatment was safe and generally well‐tolerated over the period of 12 weeks Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: see exclusion criteria 4 |
Çetin 2015
Methods | A randomised, open‐label parallel study of methylphenidate or atomoxetine use for 6 months |
Participants | Number of participants screened: not statedNumber of participants included: 145Number of participants randomised to methylphenidate: 73Number of participants followed up on methylphenidate: 61Number of withdrawals: 12
Diagnosis of ADHD: DSM‐IV‐TR (subtype: combined (91.8%), inattentive (8.2%))Age mean: 9.47 (SD 2.32) years oldIQ: above 90Sex: 9 males (86.9%), 8 females (13.1%)Methylphenidate‐naïve: 100%Ethnicity: not statedCountry: TurkeyComorbidity: noneComedication: not statedSociodemographics: not stated Inclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: osmotic release oral systemMean methylphenidate dosage: 0.73 (SD 0.22) mg/kg/dayAdministration schedule: not statedDuration of intervention: 6 months Treatment compliance: not stated |
Outcomes | The adverse effects and tolerability of medications were evaluated using a questionnaire including 12 questions about anorexia, insomnia, stomachache, nervousness, headache, weight loss, rash, obsessions, sedation, epistaxis, tics and others, in addition to open ended questionsThe rate of adverse effects observed was 31.1% (n = 19) in the OROS‐methylphenidate groupTreatment was stopped in 5 patients because of the adverse effects Non‐serious adverse events:
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Notes | Sample calculation: not statedEthics approval: yes, the study protocol was approved by local Ethics Committee
Funding/vested interests/authors' affiliations: not stated Key conclusions of the study authors: OROS‐methylphenidate and atomoxetine had similar efficacies and adverse effect profiles in the treatment of ADHD Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: all participants were methylphenidate‐naïve |
Özcan 2004
Methods | A cohort study comparing time domain heart rate variability in non‐ADHD controls and ADHD cases treated with methylphenidate for 12 weeks |
Participants | Number of participants screened: not statedNumber of participants included: 73Number included as cases (ADHD): 42Number included as controls (non‐ADHD): 31 ADHD group Number of participants followed up: 42Number of withdrawals: 0Diagnosis of ADHD: DSM‐IV (subtype: not stated)Age: mean 11.1 years old (range 6‐15)Sex: 34 males, 8 femalesIQ: above 70Country: TurkeySetting:Ethnicity: not statedMethylphenidate‐naïve: not statedComorbidity: not statedComedication: noSociodemographics: not statedInclusion criteria:
Exclusion criteria:
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Interventions | Methylphenidate type: not statedMean methylphenidate dosage: 10 mg (2 x 5 mg)Administration schedule: not statedDuration of treatment: 12 weeks Treatment compliance: not stated |
Outcomes | Non‐serious adverse events: heart rate variability |
Notes | Sample calculation: not stated
Ethics approval: yes
Funding/vested interests: not stated
Authors' affiliations: no affiliations to pharmaceutical companies stated Key conclusions of the study authors: methylphenidate decreased the time domain HRV parameters in ADHD group. Therefore, close cardiac follow‐up is necessary for the detection of side effects of methylphenidate especially in patients who are under risk for developing cardiac arrhythmias and in patients using methylphenidate together with drugs affecting central nervous system Exclusion of methylphenidate non‐responders/children who have previously experienced adverse events on methylphenidate: no Supplemental information regarding IQ has not been possible to receive through personal email correspondence with the authors. Emails sent twice to several of the authors |
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Data on adverse events from published systematic review on methylphenidate versus placebo or no intervention (Storebø 2015), National Summary of Product Characteristics, and from the present review
Adverse event | Randomised clinical trials: methylphenidate group (from Storebø 2015) | Randomised clinical trials: placebo or no intervention group (from Storebø 2015) | National Summary of Product Characteristics (UK, USA, DK) | Non‐comparative cohort studies and cohort studies from randomised trials (present review) | Non‐comparative cohort studies (present review) | Non‐comparative cohort studies from randomised trials (present review) |
Serious adverse events | 1.90% (95% CI 1.10% to 3.20%; 9 studies, 919 participants) | 2.80% (95% CI 1.70% to 4.80%; 9 studies, 613 participants) | No information | 1.20% (95% CI 0.70% to 2.00%; 51 studies, 162,434 participants) | 1.10% (95% CI 0.60% to 2.00%; 32 studies, 159,761 participants) | 1.60% (95% CI 1.00% to 2.30%; 18 studies, 2661 participants) |
Non‐serious adverse events | 51.4% (95% CI 41.9% to 60.9%; 21 studies, 1861 participants) | 38.3% (95% CI 30.3% to 47.0%; 21 studies, 1271 participants) | No information | 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants) | 47.1% (95% CI 35.6% to 58.9%; 36 studies, 13,035 participants) | 62.1% (95% CI 44.4% to 77.1%; 13 studies, 943 participants) |
Headache | 11.6% (95% CI 8.80% to 13.3%; 17 studies, 1642 participants) | 9.40% (95% CI 7.10% to 12.4%; 17 studies, 1082 participants) | 1% to 10% | 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants)a | 9.90% (95% CI 7.00% to 13.9%; 57 studies, 10,929 participants | 24.3% (95% CI 18.0% to 32.1%; 33 studies, 2540 participants) |
Anxiety | 6.50% (95% CI 1.20% to 29.2%; 3 studies, 356 participants) | 12.4% (95% CI 8.30% to 18.0%; 3 studies, 240 participants) | 1% to 10% (UK and DK); no information (USA) | 18.4% (95% CI 11.3% to 28.7%; 22 studies, 1287 participants)a | 10.2% (95% CI 5.30% to 18.9%; 8 studies, 938 participants | 27.9% (95% CI 17.8% to 40.8%; 14 studies, 349 participants |
Sleep difficulty | 8.00% (95% CI 5.80% to 11.1%; 13 studies, 1417 participants) | 8.30% (95% CI 6.40% to 10.7%; 13 studies, 999 participants) | 1% to 10% | 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants)a | 14.3% (95% CI 11.2% to 18.2%; 51 studies, 9073 participants | 25.4% (95% CI 18.2% to 34.4%, 31 studies, 2434 participants) |
Irritability | 6.40% (95% CI 3.70% to 10.8%; 11 studies, 1038 participants) | 3.50% (95% CI 1.40% to 8.60%; 11 studies, 778 participants) | 1% to 10% | 17.2% (95% CI 11.5% to 25%; 35 studies, 4792 participants)a | 15.5% (95% CI 10.2% to 22.7%; 21 studies, 3298 participants | 20.6% (95% CI 7.90% to 44.1%; 14 studies, 1494 participants) |
Tics | 2.30% (95% CI 1.00% to 5.20%; 7 studies, 684 participants) | 5.50% (95% CI 3.70% to 8.10%; 7 studies, 476 participants) | No information | 6.40% (95% CI 4.50% to 8.90%; 39 studies, 1980 participants)a | 5.60% (95% CI 3.80% to 8.10%; 29 studies, 1601 participants) | 10.6% (95% CI 5.30% to 19.9%; 10 studies, 379 participants) |
Drowsiness | 7.30% (95% CI 2.40% to 20.2%; 4 studies, 510 participants) | 6.70% (95% CI 2.60% to 16.2%; 4 studies, 310 participants) | 1% to 10% | 9.50% (95% CI 5.20% to 16.6%; 17 studies, 1146 participants)a | 7.50% (95% CI 3.10% to 17.2%; 7 studies, 644 participants) | 11.3% (95% CI 5.00% to 23.3%; 10 studies, 502 participants) |
Sadness | 5.70% (95% CI 1.30% to 21.9%; 4 studies, 382 participants) | 4.20% (95% CI 0.90% to 16.9%; 4 studies, 318 participants) | No information | 16.8% (95% CI 9.40% to 28.3%; 21 studies, 1802 participants)a | 13.1% (95% CI 6.60% to 24.1%; 9 studies, 626 participants) | 20.6% (95% CI 8.10% to 43.1%; 12 studies, 1176 participants) |
Fatigue | 4.80% (95% CI 2.30% to 9.90%; 6 studies, 471 participants) | 6.50% (95% CI 4.30% to 9.60%; 6 studies, 387 participants) | 1% to 10% | 5.70% (95% CI 3.00% to 10.4%; 17 studies, 2182 participants) | 5.60% (95% CI 2.80% to 10.9%; 5 studies, 673 participants) | 7.80% (95% CI 5.80% to 10.5%; 12 studies, 1509 participants) |
Abdominal pain | 11.5% (95% CI 7.70% to 16.8%; 13 studies, 1406 participants) | 7.60% (95% CI 5.00% to 11.5%; 13 studies, 935 participants) | 0% to 10% | 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants)a | 7.60% (95% CI 5.70% to 10.0%; 46 studies, 9229 participants) | 16.3% (95% CI 11.6% to 22.4%; 33 studies, 2521 participants) |
Decreased appetite | 17.3 (95% CI 12.3% to 24.2%; 16 studies, 1751 participants) | 4.30% (95% CI 2.40% to 7.40%; 16 studies, 1211 participants) | 1% to 10% | 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants)a | 28.8% (95% CI 23.0% to 33.5%; 57 studies, 9662 participants) | 39.7% (95% CI 27.0% to 54.0%; 27 studies, 1967 participants) |
Vomiting | 5.70% (95% CI 4.00% to 8.00%; 11 studies, 1140 participants) | 5.10% (95% CI 3.5% to 7.4%; 11 studies, 776 participants) | 1% to 10% | 7.30% (95% CI 3.70% to 13.4%; 20 studies, 2731 participants)a | 7.10% (95% CI 2.80% to 17.0%; 11 studies, 1528 participants) | 7.20% (95% CI 3.30% to 15.1%; 9 studies, 1203 participants) |
Nausea | 7.50% (95% CI 6.10% to 9.30%; 11 studies, 1174 participants) | 5.20% (95% CI 3.80% to 7.10%; 11 studies, 821 participants) | > 10% | 7.60% (95% CI 5.30% to 10.6%; 41 studies, 5612 participants)a | 8.00% (95% CI 7.00% to 9.10%; 22 studies, 3921 participants) | 10.4% (95% CI 5.80% to 17.9%; 19 studies, 1691 participants) |
Decreased weight | 6.30% (95% CI 3.80% to 10.3%; 6 studies, 472 participants) | 2.40% (95% CI 1.00% to 5.70%; 6 studies, 387 participants) | 1% to 10% | 8.70% (95% CI 4.80% to 15.3%; 26 studies, 5182 participants)a | 6.60% (95% CI 3.10% to 13.3%; 17 studies, 4855 participants) | 16.6% (95% CI 8.70% to 30.6%; 9 studies, 327 participants) |