Gadow 1995.

Methods	A randomised, placebo‐controlled, double‐blind, cross‐over trial with 2 interventions: Methylphenidate in 2‐3 dosages Placebo Phases: Washout if medications prior to trial 8 week RCT with 2 weeks in each arm Open‐label follow‐up at 24 months
Participants	Number of participants screened: not stated Number of participants included: 34. Participants were randomly assigned to different orders of the 3 dosages Number of participants followed up: 12‐months follow‐up: 30; 18 months follow‐up: 26; 24 months follow‐up: 26 Number of withdrawals: 8 Diagnosis of ADHD: DSM‐III‐R (subtype: not stated) Age: mean: 8 years and 10 months, range: 6.1‐11.9 years old IQ: mean: 105.9 (SD 13.7) Sex: 31 males, 3 females Methylphenidate‐naïve: 71% Ethnicity: white: 85%, African American: 3%, Asian: 3%, Hispanic: 9% Country: USA Comorbidity (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 problems Comedication: 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 Meet DSM III‐R diagnostic criteria for ADHD Either chronic motor tic disorder or Tourette disorder ADHD had to be a primary reason for seeking clinical services In general, be above the cutoff on 2‐3 parent‐ and teacher completed hyperactivity and/or ADHD behaviour rating scales Written signed statement from the parents consenting to their child's participation Exclusion criteria Dangerous to self or others Tics as the major clinical management concern Psychosis IQ below 70 Seizure disorder, major organic brain dysfunction or major medical illness Contraindications to medication (other than tics) Pervasive developmental disorder
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 analyses Administration schedule: 2‐3 times daily at morning and noon, approximately 3.5 hours apart, 7 days a week Duration of each medication condition: 2 weeks Washout prior to study initiation: methylphenidate: 1 week, antipsychotic: 3 weeks, clonidine: 2 weeks Medication‐free period between intervention: none Titration period: none Treatment 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 RCT Side Effect Checklist (SSEC), 13 items, rated by parents on Saturday and Sunday and rated by teacher twice a week Global Tic Rating Scale (GTRS), rated by parents on Saturday and Sunday and rated by teacher twice a week Motor 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 week Tourette Syndrome Unidentified Rating Scale, rated every second week Global Tic Rating Scale (GTRS) (only assessed in 22 patients), rated every second week Shapiro Tourette Syndrome Severity Scale (OBS! Only assessed in 22 patients), rated every second week Motor 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 week Weight, assessed every second week Heart rate, assessed every second week Blood pressure, assessed every second week During the 24‐months follow‐up Physician evaluations All rated at MED (right after RCT) 6 months, 12 months, 18 months, and 24 months Yale Global Tic Severity Scale (YGTSS) Shapiro Tourette Syndrome Severity Scale 3 subscales from the Tourette Syndrome Unified Rating scale Total number of tics Number of tics observed in 2 minutes of quiet conversation with the physician The LeWitt Disability Scale which assesses tics and the symptoms of comorbidities The Global Tic Rating Scale (GTRS) Blood pressure Heart rate Pulse Weight Parents' ratings Based on the last 2 weeks and rated at MED (right after RCT) 6 months, 12 months, 18 months, and 24 months Stimulant Side Effect Checklist (SSEC) GTRS
Notes	Sample calculation: yes Any withdrawals due to adverse events: no Ethics approval: no information Funding: 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 Health Vested 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