Buitelaar 1995.

Study characteristics
Methods	Randomised, cross‐over trial with 3 interventions: pindolol MPH placebo Phases: Phase 1: 4‐week treatment block Phase 2: 2‐week drug‐free interval Phase 3: 4‐week treatment block First 32 participants were randomly assigned to interventions 1‐3 in the first treatment block, and to intervention 1 or 2 in the second treatment block. Next 20 participants were randomly assigned to intervention 2 or 3 in the first treatment block, and to intervention 2 or 3 in the second treatment block
Participants	Number of participants screened: not stated Number of participants included: 52 (46 boys, 6 girls); however, because of an incomplete block design, only 46 were treated with MPH and 31 were treated with placebo in first or second treatment block Number of participants followed up: 52 Number of withdrawals: 0 Diagnosis of ADHD: DSM‐III‐R (subtype not stated) Age: mean 9.3 years (range 6‐13) IQ: mean 94.2 MPH‐naive: 100% Ethnicity: not stated Country: the Netherlands Setting: outpatient clinic Comorbidity: CD (38%); depressive disorder, dysthymia or major depressive disorder (15%); anxiety disorder, overanxious disorder or avoidant disorder (42%); psychomotor epilepsy (2%) Comedication: antiepileptic medication (carbamazepine) at a fixed dosage (2%) Other sociodemographics: none. 20% were from families of high socioeconomic status, 50% of middle socioeconomic status and 30% of low socioeconomic status (on the Hollingshead Index). No significant difference in baseline characteristics were noted between groups of children treated with MPH, pindolol or placebo Inclusion criteria ADHD according to DSM‐III‐R criteria Scores in the clinical range on both the CBCL and CTRS, Hyperactivity factors Deficits in attention performance on a reaction time task or a continuous performance task in neuropsychological testing No previous treatment with psychotropic medication Clinical indication for drug treatment Exclusion criteria Diagnosis of tic disorder or pervasive developmental disorder Family history of tic disorder Contraindications to treatment with blockers such as cardiac disease, in particular, conduction abnormalities and bradycardia, hypotension, obstructive pulmonary disease and insulin‐dependent diabetes
Interventions	Participants were randomly assigned to possible drug condition orders of 40 mg pindolol, 20 mg MPH and placebo Fixed dosage: 10 mg MPH, twice daily (approximately 0.6 mg/kg/d) Administration schedule: morning and noon Duration of each medication condition: 4 weeks Washout before trial initiation: no (medication‐naive) Medication‐free period between interventions: 2 weeks Titration period: yes. After randomisation, during the first 3 days of a treatment period, participants received 1 morning dose (10 mg MPH, 20 mg pindolol or placebo). After completion of endpoint assessment, medication was tapered off (3 days with 1 morning dose) Treatment compliance: good to very good in 96% of children. 2 children had poor compliance under MPH treatment as the result of side effects
Outcomes	ADHD symptoms 10‐Item Abbreviated Conners' Rating Scale: rated by parents, teachers and a psychologist 93‐Item CPRS 39‐Item CTRS Parents and teachers completed ratings at baseline, at week 2 and at endpoint of each treatment period. The psychologist completed ratings at baseline and at endpoint of each treatment period. Furthermore, ACRS was rated 30 min after drug administration Non‐serious AEs Adverse effects checklist (encompassing 20 possible side effects, modified from the Stimulant Drug Side Effects Rating Scale, rated by parents after 2 and 4 weeks of treatment Treatment‐emergent adverse effects were further assessed systematically at endpoint by research psychiatrist Pulse and BPs were recorded at each clinical visit
Notes	Sample calculation: yes; for comparison of pindolol with MPH (50 participants) Ethics approval: yes; approved by the Committee for Research on Human Subjects of Utrecht University Hospital Comments from trial authors Interim analysis of side effects indicated that pindolol was associated with significantly more intense AEs when compared with placebo and MPH. Consequently, pindolol was dropped from the trial design, and the next 20 participants were included in a randomised MPH‐placebo cross‐over design Trial was limited by use of fixed dosage, with exclusive focus on behavioural symptoms ‐ not on improvement in neuropsychological measures of information processing, and with an incomplete and unbalanced block design Key conclusions of trial authors Beta‐blocker pindolol appeared to be modestly effective in the treatment of behavioural symptoms of children with ADHD. Data suggest some utility for pindolol in treating hyperactivity and conduct problems in children with ADHD, but safety concerns about troubling side effects clearly limit use of pindolol in ADHD Only strong levels of response could be predicted by baseline characteristics. Severity of disorder based on clinical judgement and improvement after a single dose of MPH are found to be important contributors to response prediction Comments from review authors Trial designed to compare usage of pindolol and MPH Few participants Trial design changed during the trial because of AEs. Phase 2 changed intervention from pindolol versus MPH to MPH versus placebo Phase 1: given the relatively small sample sizes, effects of single treatments (i.e. MPH vs placebo, and pindolol vs placebo) were not robust enough to reach conventional levels of statistical significance Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no; only medication‐naive participants Any withdrawals due to AEs: no; however, in 4 participants, dosages of MPH had to be adjusted in the first 2 weeks of the trial because of increased agitation, restlessness and insomnia. 2 participants remained on 5 mg of MPH for 4 weeks, whereas dosage for the other 2 participants could be gradually increased to 10 mg MPH in the last 2 weeks Funding source: not stated Email correspondence with trial authors: January to March 2014. Requested but did not receive from trial authors supplemental efficacy and safety data and information regarding randomisation, allocation concealment and blinding
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomly assigned, not further described
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, not further described. MPH and placebo were administered in identical‐looking tablets
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 participants from the MPH group had bad compliance but were included in the analyses, as an ITT analysis was planned Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): no, but design of trial changed during the course of the trial because of AEs
Selective reporting (reporting bias)	Unclear risk	Protocol not identified