Carlson 1995.

Study characteristics
Methods	Double‐blind, placebo‐controlled, repeat‐measures (across drug and dosage), cross‐over trial with 6 interventions: MPH at 10 mg twice/d MPH at 15 mg twice/d MPH at 20 mg twice/d desipramine alone desipramine + MPH placebo Phases: each child received placebo, desipramine, each of the 3 doses of MPH (10 mg, 15 mg, 20 mg) and combined desipramine and MPH (at the same 3 doses)
Participants	Number of participants screened: not stated Number of participants included: 16 (all boys) Number of participants followed up: 16 Number of withdrawals: 0 Diagnosis of ADHD: DSM‐IV (combined (62.5%), inattentive (12.5%), “in partial remission” (25%)) Age: mean: not reported (range 7.9‐12.10 years) IQ: mean not stated (range overall 81‐121; range verbal 74‐113, range performance 73‐126) MPH‐naive: 4 (25%) Ethnicity: white (87.5%), African American (12.5%) Country: USA Setting: inpatient ward Comorbidity: yes; major depressive disorder (68.75%), dysthymic disorder (31.25%). “All had ODD, CD or both” Comedication: yes Other sociodemographics: none Inclusion criteria Initial team diagnosis of ADHD, non‐bipolar major depressive disorder, dysthymic disorder or a combination thereof ≥ 7 years old WISC‐R, full‐scale IQ > 80 Exclusion criteria Medical contraindication to medications being investigated Family history of bipolar disorder in first‐ or second‐degree relatives Abnormal baseline laboratory values or ECG
Interventions	Participants were randomly assigned to different possible drug condition orders of MPH (10 mg, 15 mg and 20 mg), twice/d at 7:30 am and 11:30 am × 6 days, then 1‐day washout; the titrated therapeutic level (125 ng/mL to 225 ng/mL) of desipramine twice daily at 3:30 pm and 7: 30 pm x 3 weeks minimum before final measures taken; and placebo Mean MPH dosage: not stated Duration of each medication condition: 1 week Washout before trial initiation: 14 days Medication‐free period between intervention: 1 day Titration period: none Treatment compliance: not stated
Outcomes	ADHD symptoms ACTeRS: ADD/H General behaviour Humphrey's Teacher Self‐Control Rating Scale Inpatient Global Rating Scale Non‐serious AEs Subjective Treatment Emergent Symptom Scale: side effect ratings, collected weekly by nurse Somatic factor of the Inpatient Global Rating Scale: collected weekly by nurse CDRS‐R: Appetite and Sleep disturbance items collected weekly by research psychologist Cardiovascular side effects (daily morning BP and pulse rates + weekly ECG)
Notes	Sample calculation: not stated Ethics approval: not stated Key conclusion of trial authors “With regard to differential efficacy, the major findings of this study were that a combination of DMI [desipramine] and MPH (at 20 mg) was somewhat more effective than DMI or MPH alone for improving hyperactive, inattentive and oppositional defiant, and 'aggressive' behaviours across both school and unit settings. Efficacy was also demonstrated for MPH and DMI alone in school, but less so on the unit” Comment from review authors Small sample of 16 participants entering the trial seems heterogeneous and opportunistic rather than clearly defined, with a mixture of diagnoses including mood, ADHD and ODD/CD. This makes it difficult to believe that the results are reliable Exclusion of MPH non‐responders/children who have previously experienced AEs while taking MPH before randomisation: no Any withdrawals due to AEs: no Funding source: not stated Email correspondence with trial authors. Emailed first trial author to ask for outcome data in mean and SD format. Trial authors replied in July 2014 to say that they were unable to help us
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Not stated
Allocation concealment (selection bias)	High risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Medications were packaged in identical grey capsules (size 00) that were administered 4 times/d
Blinding of outcome assessment (detection bias) All outcomes	Low risk	For this protocol, all raters (including teachers, nurses, psychologist and physicians, except for the attending child psychiatrist, who controlled the desipramine dosage but did not rate the children), children and parents were blinded to all medication conditions
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated Selection bias (e.g. titration after randomisation → exclusion of MPH non‐responders or placebo responders): not stated
Selective reporting (reporting bias)	Unclear risk	Not protocol identified