The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials

Figures & data

Table 1 Risk of bias

Risk of bias question	12–18 months				18–36 months			36 months +
	Buitelaar et al^Citation47	Gillberg et al^Citation48	The MTA^Citation50	So et al^Citation51	Jensen et al^Citation52	The MTA^Citation24	Volpe et al^Citation49	Molina et al^Citation53
Was the method of randomization adequate?	✓	✓	✓	✓	✓	✓	?	✓
Was the treatment allocation concealed?	✓	✓	✓	✓	✓	✓	?	✓
Was the patient blinded to the intervention?	✓	✓	–	–	–	–	–	–
Was the care provider blinded to the intervention?	✓	✓	–	–	–	–	–	–
Was the outcome assessor blinded to the intervention?	✓	✓	–	✓	–	–	✓	–
Was the drop-out rate described and acceptable?	✓	✓	✓	✓	✓	✓	✓	✓
Were all randomized participants analyzed in the group to which they were allocated?	✓	✓	✓	✓	✓	✓	✓	✓
Free of suggestion of selective outcome reporting?	✓	✓	✓	?	–	–	✓	–
Similarity of baseline characteristics?	✓	✓	✓	✓	✓	✓	✓	✓
Cointerventions avoided or similar?	?	?	✓	–	–	–	?	–
Compliance acceptable?	✓	✓	✓	–	✓	–	?	–
Timing of the outcome assessments similar?	✓	✓	✓	✓	✓	✓	✓	✓
Total risk of bias score	11	11	9	7	7	6	6	6

Notes: ✓ = yes; – = no; ? = unclear.

Abbreviation: MTA, multimodal treatment of children with attention-deficit hyperactivity disorder (ADHD).

Figure 1 The study selection process.

Abbreviation: ADHD, attention-deficit hyperactivity disorder.

Table 2 A summary of study characteristics and results

Citation and location	Age, numbers (N)	Intervention	Duration	Outcome measures	Results
Buitelaar et al^Citation47 Europe Israel South Africa Australia	Age: treatment group mean age 10.7 years (SD 2.4); placebo group mean age 11.0 years (SD 2.0) N= 163	Atomoxetine initiated at 0.5 mg/kg/day, then titrated to between 1.2 and 1.8 mg/kg/day according to clinical response	6 months double-blind continuation of treatment following a 12-month double-blind treatment phase	ADHD rating scale CGI-S CHQ CDRS-R CPRS-R: S CTRS-R: S MASC	Atomoxetine was superior to placebo in preventing symptom relapse (P = 0.008) Some patients randomized from Atomoxetine to placebo did not relapse during 6-month follow up
The MTA Cooperative Group^Citation50 USA	Age: 7–9 years N = 579	Multicomponent Beh; Med Mgt; Beh + Med Mgt; Community care Medication at start of study 198: methylphenidate (average initial dose 30.5 mg/day) 26: dextroamphetamine 32: no medication due to robust placebo response during titration Medication at end of study 212: methylphenidate 30: dextroamphetamine 4: pemoline 3: imipramine 1 : bupropion 1 : haloperidol 28: no medication	14 months	SNAP–ADHD symptoms (Teacher and Parent Inattention and Hyperactivity-Impulsivity Subscales); SNAP-Oppositional/Aggressive Symptoms (Teacher and Parent Oppositional Defiant Disorder subscale) SSRS-Social Skills (Teacher and Parent Social Skills Subscale) SSRS-anxiety and depression (Teacher and Parent Internalizing Subscale) Parent child relationship questionnaire WIAT	All four groups showed significant improvement. Those in the Med Mgt and Med Mgt + Beh showed significantly greater improvement than Beh or Community care alone
Gillberg et al^Citation48 Sweden	Age 6–11 N = 62	Amphetamine sulfate 3-month titration phase: 5 mg twice daily up to max daily dose of 45 mg Mean dose at beginning of double-blind treatment phase was 17 mg/day (range 5–35 mg/day) = 0.52 mg/kg (range 0.2–1.1 mg/kg/)	15 months	Conners’ Teacher Rating Scale Conners’ Parent Rating Scale The Birleson Depression Self-Rating Scale	Conners’ Parent and Teacher Scales declined for adherent medication users (P = 0.02) Depressed mood; no differences detected between groups
So et al^Citation51 Hong Kong	Age: 8 years (mean) N = 86	Combined treatment n = 45 Medication only n = 41 Medication: Immediate Release Methylphenidate Start dose 5 mg once or twice daily, titrated up to maximum dose of 60 mg per day	6-month treatment phase with a 12-month follow up	DISC-IV-P Hong Kong WISC HKT-SpLD SWAN Rating Scale PTA	At 6 months, the combined group treatment arm was significantly more effective than medication alone. At follow up, the medication-only group had caught up with the combined group in improvement in ADHD symptoms
The MTA Cooperative Group^Citation24 USA	Age: 7–9 years MTA: N = 540 (from 579 at baseline)	Multicomponent Beh; Med Mgt; Beh + Med Mgt; Community care Medication intervention as per the MTA Cooperative Group^Citation50	24-month follow up	SNAP: ADHD symptoms SNAP-ADHD symptoms (Teacher and Parent Inattention and Hyperactivity-Impulsivity Subscales); SNAP-Oppositional/Aggressive Symptoms (Teacher and Parent Oppositional Defiant Disorder subscale) SSRS-Social Skills (Teacher and Parent Social Skills subscale) SSRS-anxiety and depression (Teacher and Parent Internalizing Subscale) WIAT A negative/ineffective discipline factor	The MTA medication strategy showed persisting superiority over Beh and Community care Additional benefits of Med Mgt + Beh over Med Mgt and of Beh over Community care were not found
Volpe et al^Citation49 USA	Age 104.3 months N= 167	Intensive data-based academic intervention (IDAI) Traditional data-based academic intervention (TDAI)	27 months (15-month treatment phase with a 12-month follow up)	Teacher perceptions of math and reading performance Math achievement Reading achievement	Statistically significant improvement indicated for raw and standard scores, on reading fluency only (P < 0.01)
Jensen et al^Citation52 USA	Age: 7–9 years MTA: N = 485 (from 579 at baseline)	Multicomponent Beh; Med Mgt; Beh + Med Mgt; Community care	3-year follow up	SNAP: ADHD symptoms SNAP-ADHD symptoms (Teacher and Parent Inattention and Hyperactivity-Impulsivity Subscales); SNAP-Oppositional/Aggressive Symptoms (Teacher and Parent Oppositional Defiant Disorder subscale) SSRS-Social Skills (Teacher and Parent social skills subscale) SSRS-anxiety and depression (Teacher and Parent Internalizing Subscale) WIAT CIS (functional impairment)	The MTA medication strategy showed no superiority over Med Mgt + Beh and Beh and Community care. All of the groups showed continued symptom improvement over baseline
Molina et al^Citation53 USA	Age: 7–9 years MTA: N = 436 (from 579 at baseline) + 272 controls	Multicomponent Beh; Med Mgt; Beh + Med Mgt; Community care	8-year follow up	SNAP-ADHD symptoms (Teacher and Parent Inattention and Hyperactivity-Impulsivity Subscales); SNAP-Oppositional/Aggressive Symptoms (Teacher and Parent Oppositional Defiant Disorder subscale) SSRS-Social Skills (Teacher and Parent social skills subscale) SSRS-anxiety and depression (Teacher and Parent Internalizing Subscale) WIAT SCAPI-Delinquency CIS MASC Children’s Depression Inventory	The original randomized treatment groups did not differ significantly from the 3-year follow up results. Despite initial 14-month treatment, the MTA group were functioning less well than their non-ADHD age-matched controls, at 6–8 years following intervention

Abbreviations: ADHD, attention-deficit hyperactivity disorder; Beh, behavior therapy; CDI, Children’s Depression Inventory; CDRS-R, Children’s Depression Rating Scale-Revised; CGI-S, Clinical Global Impression-Severity; CHQ, Child Health Questionnaire; CIS, Columbia Impairment; CPRS-R: S, Conners’ Parent Rating Scales: Short form; CTRS-R: S, Conners’ Teacher Rating Scales: Short form; DISC-IV-P, Diagnostic Interview Schedule for Children-IV parent; version; HKT-SpLD, Hong Kong Test of Specific Learning Difficulties in Reading and Writing; IDAI, intensive data-based academic intervention; MASC, Multidimensional Anxiety Scale for Children; Med Mgt, medication management; PTA, Parental Attitude Toward Treatment Options of ADHD; SCAPI, Service for Children and Adolescents-Parent Interview; SD, standard deviation; SNAP, Swanson, Nolan and Pelham Scale; SSRS, Social Skills Rating System; SWAN, Strengths and Weaknesses of ADHD Rating Scale; TDAI, traditional data-based academic intervention; WIAT, Wechsler Individual Achievement Test; MTA, multimodal treatment of children with ADHD.

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