What are the non-stimulant medication options for children with Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant Medications for ADHD in Children

For children with ADHD who cannot use stimulants or have not responded adequately to them, atomoxetine is the recommended first-line non-stimulant medication, with extended-release guanfacine and extended-release clonidine as alternative second-line options. 1, 2

Primary Non-Stimulant Option: Atomoxetine

Atomoxetine (Strattera) is the only FDA-approved non-stimulant with the strongest evidence base for ADHD treatment in children ages 6-18 years. 1, 2, 3

Dosing Protocol

• For children ≤70 kg: Start at 0.5 mg/kg/day, increase after minimum 3 days to target dose of 1.2 mg/kg/day (maximum 1.4 mg/kg/day or 100 mg, whichever is less) 3
• For children >70 kg: Start at 40 mg/day, increase after minimum 3 days to target of 80 mg/day (maximum 100 mg/day) 3
• Can be given as single morning dose or divided (morning and late afternoon/early evening) 3
• No tapering required for discontinuation 3

Efficacy Considerations

• Effect size approximately 0.7 compared to placebo (weaker than stimulants at 1.0) 1
• Approximately 50% of methylphenidate non-responders will respond to atomoxetine 4
• Approximately 75% of methylphenidate responders will also respond to atomoxetine 4
• Requires 4-8 weeks for full therapeutic effect, unlike stimulants which work immediately 4, 5

Safety Monitoring and Adverse Effects

• Obtain cardiac history and perform ECG if risk factors present before initiating 1
• Screen for personal/family history of bipolar disorder, mania, or hypomania before starting 3
• Common adverse effects: initial somnolence, gastrointestinal symptoms (especially with rapid titration), decreased appetite 1
• FDA black box warning for increased suicidal thoughts 1
• Rare but serious: hepatitis (extremely rare) 1
• Growth delays in first 1-2 years with normalization by 2-3 years 1, 2

Alternative Non-Stimulant Options: Alpha-2 Agonists

Extended-Release Guanfacine

Extended-release guanfacine is an alpha-2A adrenergic receptor agonist that enhances prefrontal cortex function and is FDA-approved for ADHD treatment. 6

Dosing Guidelines

• Start at 1 mg once daily, titrate by 1 mg per week based on response 6
• Target dose: 0.05-0.12 mg/kg/day or 1-7 mg/day 6
• Evening administration strongly preferred to minimize daytime somnolence 6
• Provides 24-hour symptom control with once-daily dosing 6

Efficacy and Timeline

• Effect size approximately 0.7 compared to placebo 1, 6
• Requires 2-4 weeks before clinical benefits observed 6
• Sustained improvements demonstrated over 24 months in extension trials 6

Safety Profile

• Common adverse effects: somnolence, dry mouth, dizziness, irritability, headache, bradycardia, hypotension, abdominal pain 1, 6
• Must be tapered by 1 mg every 3-7 days when discontinuing to avoid rebound hypertension—never stop abruptly 1, 6
• Monitor blood pressure and heart rate at baseline and during dose adjustments 6

Extended-Release Clonidine

Extended-release clonidine is another alpha-2 agonist option with similar efficacy to guanfacine but potentially more sedating effects. 1

• Effect size approximately 0.7 compared to placebo 1
• Adverse effects: somnolence, dry mouth, dizziness, irritability, headache, bradycardia, hypotension, abdominal pain 1
• Must be tapered when discontinuing to avoid rebound hypertension 1

Special Population: Preschool-Aged Children (4-5 Years)

No non-stimulant medication has sufficient rigorous study in preschool-aged children to be recommended for ADHD treatment in this age group. 1

• Methylphenidate is the recommended medication for preschool children with moderate-to-severe ADHD who fail behavioral therapy 1
• Non-stimulants lack adequate evidence in children under 6 years 1

Adjunctive Therapy with Stimulants

Both extended-release guanfacine and extended-release clonidine are FDA-approved for adjunctive use with stimulants when stimulant monotherapy is insufficient. 1, 6, 2

• Atomoxetine has limited off-label evidence supporting combination with stimulants 1, 2
• Can be co-administered during switching periods without excessive cardiovascular concerns, though monitoring required 4

Clinical Decision Algorithm

1. First-line non-stimulant: Atomoxetine for children ≥6 years when stimulants are contraindicated, not tolerated, or ineffective 1, 2

2. Second-line non-stimulants: Extended-release guanfacine or extended-release clonidine, particularly useful when: 1, 6, 2

   • Comorbid tic disorders present
   • Sleep disturbances need addressing
   • Concerns about substance abuse/diversion exist
   • Oppositional symptoms prominent

3. Adjunctive therapy: Add extended-release guanfacine or extended-release clonidine to stimulants if partial response 1, 6

Critical Pitfalls to Avoid

• Inadequate cardiovascular screening: Always obtain detailed cardiac history and perform ECG if risk factors present before starting any non-stimulant 1, 2
• Abrupt discontinuation of alpha-2 agonists: Must taper guanfacine and clonidine to prevent rebound hypertension 1, 6
• Premature discontinuation of atomoxetine: Requires 4-8 weeks for full effect, unlike stimulants 4, 5
• Rapid atomoxetine titration: Increases gastrointestinal adverse effects; follow weight-based titration schedule 1, 3
• Ignoring hepatic impairment: Atomoxetine requires dose reduction (50% for moderate, 25% for severe hepatic insufficiency) 3
• Missing bipolar screening: Screen for personal/family history before starting atomoxetine 3