Castellanos 1997.

Study characteristics
Methods	9‐week, double‐blind, cross‐over trial with 3 interventions for 3 weeks each: MPH dextroamphetamine placebo Trial was followed up by an open clinical follow‐up of 22 months
Participants	Number of participants screened: 64 Number of participants included: 22 (all boys) Number of participants followed up: 20 Number of withdrawals: 2 Diagnosis of ADHD: DSM‐III‐R Age: mean 9.4 years (range 6‐13) IQ: mean 98.8 MPH‐naive: not stated Ethnicity: white (80%), African American (10%), Asian (5%), Hispanic (5%) Country: USA Setting: outpatient clinic Comorbidity: Tourette’s disorder (95%), chronic motor tics (5%), CD (5%), ODD (30%), reading disorder (5%), overanxious disorder (5%), OCD (10%), enuresis (20%) Comedication: 4 received haloperidol Other sociodemographics: none Inclusion criteria DSM‐III criteria for Tourette’s disorder, with tics confirmed by a knowledgeable clinician ≥ 1 year before referral Symptoms of ADHD present in ≥ 2 settings Conners' hyperactivity factor scores from home teacher ≥ 2 SD > age norms Exclusion criteria Full‐scale IQ < 75 (WISC‐R) Evidence of medical or neurological disease Any other Axis I psychiatric disorder except OCD, CD or ODD, overanxious disorder and specific developmental disorders
Interventions	Participants were randomly assigned to 1 of the possible drug condition orders of MPH and placebo. MPH was increased weekly. For body weight > 30 kg, weekly MPH doses were 15 mg/dose, 25 mg/dose and 45 mg/dose twice/d. For weight ≤ 30 kg, 12.5: 25 mg/dose and 45 mg/dose, twice/d Mean MPH dosage: main cohort 1.20 mg/kg, 2nd cohort 0.69 mg/kg, 3rd cohort 1.22 mg/kg Administration schedule: twice/d: breakfast and lunch Duration of each medication condition: 3 weeks. 1st cohort underwent weekly increases in stimulant doses described as low, medium and high. 2nd cohort underwent increase described as low, medium and medium, and the 3rd cohort as low, high and high Washout before trial initiation: minimum 4 weeks Medication‐free period between interventions: 20 h Titration period: during the first 3 weeks of intervention Treatment compliance: no information
Outcomes	ADHD symptoms CTRS: completed by day programme teachers, weekly ratings Non‐serious AEs AEs Tic severity: Unified Rating Scale (Tourette Syndrome Association): variety, frequency, intensity, complexity and interference of motor and vocal tics based on observations by programme staff and derived by consensus at weekly meetings
Notes	Sample calculation: no Ethics approval: approved by NIMH Institutional Review Board Comments from trial authors Limitations Small sample size Drug dosage was not randomly assigned Allowed 4 participants to continue on a constant dose of haloperidol Exploration of different dose schedules As MPH undergoes much more rapid and complete metabolism than dextroamphetamine, we would expect blood level curves of the 2 stimulants to differ markedly Key conclusion of trial authors Substantial minority of comorbid participants had consistent worsening of tics while taking stimulants, although most experienced improvement in ADHD symptoms with acceptable effects on tics Comment from review authors Trial consists of a main trial of 12 boys followed by 2 smaller cohorts of, respectively, 6 and 4 boys Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Withdrawals due to AEs: yes, 1 on placebo Funding source: not stated Email correspondence with trial authors: January 2014. Corresponding author was not able to supply us with further information
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants were randomly assigned
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Capsule formulation prepared by a pharmacy
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	High risk	2 dropouts; their data are not included in subsequent analyses. One of these was dropped from the trial because of acute exacerbation of tics, and 1 because of excessively disruptive behaviour Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no
Selective reporting (reporting bias)	High risk	Yes; they seem to have reported only hyperactivity scores from CTRS