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 measures Number of participants screened: 840 Number of participants included: 351 Number of participants followed up: 214 at 6 months, 190 at 12 months, 77 at 24 months Nnumber of withdrawals: 137 at 6 months, 161 at 12 months, 274 at 24 months Diagnosis of ADHD: DSM‐IV (subtype: not stated) Age: mean 10.41, range 6‐17 years old IQ: not stated Sex: 305 males, 346 females Methylphenidate‐naïve: 100% Ethnicity: not stated Country: Italy Comorbidity: not stated for methylphenidate subgroup Comedication: not stated Sociodemographics: not stated Patients with outcomes on weight Number of participants screened: 840 Number of participants included: 840 Number of participants followed up: 296 at 6 months, 184 at 12 months, 55 at 24 months Nnumber of withdrawals: 137 at 6 months, 161 at 12 months, 274 at 24 months Diagnosis of ADHD: DSM‐IV (subtype: not stated) Age: mean 10.41, range 6‐17 years old IQ: not stated Sex: 305 males, 346 females Methylphenidate‐naïve: 100% Ethnicity: not stated Country: Italy Comorbidity: not stated for methylphenidate subgroup Comedication: not stated Sociodemographics: not stated Number 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 months The rest of the demographic data regarding the sample were described together with the atomoxetine group, and therefore this data are not extracted Patients with outcomes on height Number of participants screened: 840 Number 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 months The 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 ADHD Patients from the Campania Region Number of patients screened: 8, number included: 8, number followed up: 5, number of withdrawals:3 The rest of the demographic data regarding the sample were described together with the atomoxetine group, and therefore this data are not extracted Patients 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 MPH Number included: 34 number followed up: 34, number of withdrawals: 10 DSM‐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 child Article on adverse events Number of patients screened: not stated, number included: 1098 followed up: 931 number of withdrawals: 167 Subtype: (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 onwards To 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 setting Exclusion 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 tolerability Treatment compliance: adherence to treatment was not evaluated. But participants with compliance problems were excluded Regarding 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 reactions Arrhythmia Non‐serious adverse events: BP and HR were assessed monthly ECG 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 cardiologist Liver status assessed every sixth month at the follow‐up Suicidal thoughts assessed every sixth month at the follow‐up Convulsion assessed every sixth month at the follow‐up BMI assessed every sixth month at the follow‐up Height 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 33 Any 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 visits Sample 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 ISS Funding/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 events Authors' affiliations: authors declare no financial interests Key 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 analyses Comments 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 ADRs Comments 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 outcomes Exclusion of MPH non‐responders/or children who have previously experienced adverse events on MPH: no Supplemental 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])