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: 2411 Number included in methylphenidate group: 1426 Number followed up in methylphenidate group: 1414 Number of withdrawals in methylphenidate group: 12 Diagnosis 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 known Sex: 1247 (87.4%) males, 179 (12.6%) females Methylphenidate‐naïve: not stated Ethnicity: not stated Country: Italy Comorbidity: oppositional defiant disorder (34.4%), conduct disorder (4.2%), depression (3.6%), anxiety (11.1%), learning disorder (35.9%) Comedication: not stated Sociodemographics: 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‐TR Exclusion criteria: Given the naturalistic design, no a priori exclusion criteria were applied
Interventions	Methylphenidate type: immediate release Methylphenidate dosage: 0.3‐0.6 mg/kg/dose/day Mean methylphenidate dosage: 18.3 mg/day Administration schedule: 2‐3 times a day Duration 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: no Ethics approval: yes Funding/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])