Table 1.
Published Blinded Studies of Stimulant Treatment of Attention-Deficit/Hyperactivity Disorder in Preschool Children
| Authors | Age Range (Mean ± SD) | N/n < 6 years | Procedure for ADHD Diagnosis | Intervention Medication/Dose | Study Design/Duration | Outcome Assessment (for ADHD and disruptive behaviors) | Study Outcome | Side Effects/Safety |
|---|---|---|---|---|---|---|---|---|
| Conners, 1975 | <6 years (57.7 ± 13.2 months) | 59/59 | Clinical interview, parent questionnaire | (MPH 11.8 mg/day (1.5 mg/kg/day) | Double-blind, 2 parallel groups (MPH, placebo)/6 weeks | Parent Behavior Rating Scale, Global Clinical Improvement Rating, measures of vigilance, seat activity & impulsivity | Significant clinical improvement (93% improved on MPH, 11.5% improved on placebo) as rated by the physician on the Global Clinical Improvement Rating, significant reduction in restlessness and disruptive behavior as rated by the parents on the Parent Behavior Rating Scale. Measures of vigilance, seat activity & impulsivity did not show significant difference between MPH and placebo | Minimal side effects, trend towards elevated blood pressure in the MPH group |
| Schleifer et al., 1975 | 40–58 months (49 ± months1) | 26/26 | Clinical interview | MPH 2.5–30 mg/day on a qd or bid schedule | Double-blind, crossover (placebo & MPH “optimal dose”)/4–6 weeks | Nursery school observation, Hyperactivity Rating Scale measures of reflectivity-impulsivity, field independence and motor impulsivity | Improvement based on caregiver report, no improvement on nursery school observation or psychological measures | Dysphoria, social withdrawal, poor appetite, difficulty getting to sleep |
| Barkely et al., 1984 | 48–119 months (60.8 ± 7.6 months) | 54/18 | Clinical interview, Conners' Rating Scale-Parent (CRS-P), WWPARS | MPH 0.15 mg/kg bid, 1.5 mg/kg bid | Double-blind, crossover (placebo & 2 MPH doses)/3 weeks | Mother-child interaction | Significant improvement in child compliance and off-task behavior with MPH, “normalizing” effect of MPH on mother-child interactions | More frequent side effects on high MPH dose than low dose or placebo |
| Barkley et al., 1985 | 5–9 years (89 months1) | 60/12 | Psychiatric assessment, CRS-P, Werry Weiss Peters Activity Rating Scale (WWPARS), Home Situations Questionnaire (HSQ) | MPH 0.3 mg/kg bid. 0.7 mg/kg bid | Double-blind, crossover (placebo & 2 MPH doses)/4 weeks | Mother-child interaction during free play and task periods | Child compliance and length of sustained compliance improved with the higher dose during the task period, drug effects did not differ during free play or across age levels | Greater number of side effects on MPH compared to placebo |
| Cunningham et al., 1985 | 4–6 years (68 months1) | 42/12 | Clinical diagnosis CRS-P | Single dose of MPH 0.15 mg/kg, 0.50 mg/kg | Double-blind, crossover (placebo & 2 MPH doses)/4 sessions | Videotaped observations during freeplay, co-operative task, and simulated school setting | ↓ actometer readings & ↑ on-task behavior during the simulated school setting, linear dose response, optimal ↓ in controlling and domineering interactions observed at 0.15 mg/kg dose with no incremental benefit on 0.50 mg/kg dose | Side effects were not monitored |
| Barkley, 1988 | 31–59 months (46.8 ± 6.7 months) | 27/27 | Clinical interview, CRS-P, WWPARS, HSQ | MPH 0.15 mg/kg bid, 1.5 mg/kg bid | Triple-blind, crossover (placebo & 2 MPH doses)/3 weeks | Mother-child interaction | ↑ rates of compliance and length of sustained compliance with maternal commands, and on task behavior on higher dose during the task period | Trend for more frequent side effects on MPH compared to placebo |
| Barkley, at al., 1988 | 5–12 years (8.5 ± 2.3 years) | 23/not specified | Semistructured parent interview, CRS-P or CRS- Teacher (CRS-T) | MPH 0.3 mg/kg bid, 0.5 mg/kg bid | Double-blind, crossover (placebo & 2 MPH doses)/3 weeks | Gordon Diagnostic System (GDS) for vigilance and impulse control, playroom observation during a restricted academic situation, CRS-P, CRS- T, HSQ, School Situations Questionnaire (SSQ) | 80% of the children responded positivly to MPH on parent and teacher ratings of hyperactivity and disruptive behaviors, and ↓ off-task and hyperacctivity ratings during playroom observation (restricted academic situation). Significant main drug effects for 16 of the 31 outcome measures, mostly on teacher ratings and observations during the restricted academic situation, both doses were equally effective | No difference in the number or severity of side effects. Two children discontinued the study due to development of tics in response to the medication and were excluded from the study analysis |
| Speltz et al., 19882 | 51 months | 1/1 | Clinical interview, CRS-T | Dextroamphet-amine (DEX) 2.5 mg bid DEX 5 mg bid and Day Program | Double-blind time series (placebo & 2 DEX doses in counter- balanced order)/11 weeks | Daily observations of 15-minute work periods and 20-minute free play for frequency of on-task behavior, and teacher ratings of aggressive and disruptive behaviors and reports of side effects | ↓ off-task and aggressive behavior on DEX compared to placebo Behavior gains maintained at follow up 2 years later | ↓ whining, listlessness, solitary play, stomachache ↓ appetite, more frequent during 5 mg bid dose |
| Fischer & Newby, 1991 | 2–17 years (8.9 ± 2.9 years) | 161/not specified | Semistructured parent interview, CRS-P, CRS-T, Child Behavior Checklist (CBCL), Teacher Rating Form (TRF) | MPH 0.2 mg/kg & 0.4 mg/kg BID | Double-blind crossover (placebo & 2 MPH doses)/3 weeks | CRS-P, CRS-T, HSQ SSQ, reaction time, GDS viligance task | Significant positive medication response on parent and teacher ratings of hyperactivity and laboratory measures of viligance and off-task behaviors, higher dose was most effective | No side effects reported |
| Mayes et al., 19943 | 2–13 years (7.1 years1) | 69/14 | Clinical interview | MPH 7.5–30 mg/day on a tid schedule | Double-blind, ABA (placebo & MPH “optimal dose”)/3 weeks | Conners' 10-item ADHD Parent Rating Scale | 79.4% improved on MPH based parent ratings on the Conners' scale | 50.7% experienced side effects irritability, ↓ appetite, lethargy |
| Musten et al., 1997; Firestone et al., 1998 | 48–70 months (58.1 ± 8.2 months) | 31/31 | Diagnostic Interview for Children and Adults-Parents (DICA-P), Swanson, Nolan and Pelham checklist (SNAP), CRS-P, attention task | MPH 0.3 mg/kg bid, 0.5 mg/kg bid | Double-blind, crossover (placebo & 2 MPH doses)/3 weeks | Parent-child interaction tasks, CRS-P, GDS Delay and Vigilance Tasks | ↑ attention and on-task during laboratory observation, ↓ impulsivitiy and hyperactivity as rated by parents on the CRS-P, no improved in compliance to parent requests | 10% experienced severe side effects: social withdrawal, sadness, ↑ number & ↑ severity of side effects with the higher dose |
| Handen et al., 19994 | 48–71 months (58.9 ± 8.2 months) | 11/11 | Clinical interview, Preschool Behavior Questionaire (PBQ), CRS-P | MPH 0.3 mg/kg/dose & 0.6 mg/kg/dose qd to tid | Double-blind, crossover (placebo & 2 MPH doses)/3 weeks | CRS-T, PBQ, direct behavior observation | 72.7% improved on MPH based on at-least 40% reduction in teacher ratings of hyperactivity and inattention, significant improvement on clinic-based observations of activity level and level and compliance, more improvement on the higher dose | 45% experienced side effects (social withdrawal and irritability); side effects more frequent at the higher dose |
| Short et al., 2004 | <6 years (63 months1) | 28/28 | Diagnostic Interview Schedule for Children-Parent (DISC-P) or clinical interview, Conners' Abbreviated Symptoms Questionnaire (CASQ), ADHD Rating Scale (ADHD-RS) | MPH 5 mg, 10 mg, 15 mg bid or mixed amphetamine salts (MAS; Adderall) 5 mg, 10 mg & 15 mg qd | Double-blind, crossover (placebo & 2 or 3 MPH or MAS doses)/3–4 weeks | ASQ ADHD-RS, HSQ | Improved parent and teacher ratings of ADHD on either stimulant by at least 1 SD in 82% of the children and by 2 SD in 50% of the children. Clinical ratings of normalized behavior on best dose in 82% of the children | ↓ appetite, crying & rebound effects |
| Chacko et al., 2005 | 5–6 years (6.1 ± 0.57 months) | 36/14 | Structured parent interview, parent and teacher Disruptive Behavior Disorder rating scales | MPH 0.3 mg/kg & 0.6 mg/kg bid and Behavior Modification System in a Summer Treatment Program | Double-blind, crossover (placebo & 2 MPH doses)/8 weeks | Point system, classroom rules, productivity and accuracy of class work | Improved classroom behavior for following rules and noncompliance and class work completion on both MPH doses compared to placebo, little incremental improvement in classroom measures on the higher MPH dose compared to the lower MPH dose. 28% children improved with classroom behavioral intervention & showed no incremental benefit of MPH | ↓ appetite |
| Greenhill et al., 2006 | 3–5.5 years (53 ± 8 months) | 165/165 | Clinical assessment for DSM-IV diagnosis of ADHD, unanimous consensus by the panel of investigators, CRS-P, CRS-T | MPH 1.25 mg, 2.5 mg, 5.0 mg, 7.5 mg tid | Double-blind, crossover (placebo & 4 MPH doses) after 10 weeks of parent training/5 weeks | Swanson, Kotkin, Atkins, M-Flynn, and Pelham (SKAMP), Conners, Loney and Milch (CLAM) rating scales | Significant ↓ in parent- and teacher-rated ADHD symptoms on the 3 higher doses | ↓ appetite stomachache, and sleep difficulties, ↑ rates of social withdrawal and lethargy, ↑ growth velocity, 8.3% discontinued due to MPH side effects |
1
SD not provided.
2
Individualized weekly parent training sessions, classroom behavior management program and social skills training group were also administered concurrently.
3
Included inpatient or outpatient preschool and school age children with autism, other developmental disorders or no developmental disorders.
4
Included preschool children with mental retardation.
ADHD = attention-deficity/hyperactivity disorder; MPH = methylphenidate.