What are the non-stimulant medication options for pediatric patients with Attention Deficit Hyperactivity Disorder (ADHD) aged 6 and older?

Pediatric Non-Stimulant ADHD Medication Options

For children aged 6 and older with ADHD, the three FDA-approved non-stimulant options are atomoxetine, extended-release guanfacine, and extended-release clonidine, with atomoxetine generally preferred as first-line non-stimulant therapy due to its superior efficacy profile and fewer cardiovascular effects compared to the alpha-2 agonists. 1

Primary Non-Stimulant Options

Atomoxetine (First-Line Non-Stimulant)

Atomoxetine should be initiated at 0.5 mg/kg/day for children ≤70 kg and increased after a minimum of 3 days to a target dose of 1.2 mg/kg/day (maximum 1.4 mg/kg/day or 100 mg, whichever is less). 2

• For children >70 kg and adolescents, start at 40 mg/day and increase after 3 days to 80 mg/day, with a maximum of 100 mg/day 2
• Can be administered as a single morning dose or divided into morning and late afternoon/evening doses 2
• Therapeutic effects require 6-12 weeks to fully manifest, unlike stimulants which work immediately 1
• Atomoxetine shows fewer appetite suppression effects and less impact on growth compared to stimulants 1

Critical Safety Warnings for Atomoxetine:

• FDA black box warning for increased suicidal ideation, particularly in early-late adolescence 1
• Screen for personal or family history of bipolar disorder before initiating treatment 2
• Rare but serious risk of hepatitis requires monitoring 1
• Can be discontinued abruptly without tapering or rebound effects 2

Extended-Release Guanfacine (Alpha-2A Agonist)

Guanfacine ER should be started at 1 mg once daily in the evening, titrated by 1 mg per week to a target range of 0.05-0.12 mg/kg/day or 1-7 mg/day maximum. 3

• Evening administration is strongly preferred due to frequent somnolence and fatigue 1, 3
• Provides "around-the-clock" symptom coverage with once-daily dosing 1, 3
• Requires 2-4 weeks before clinical benefits become apparent 1, 3
• Effect sizes are moderate (approximately 0.7) compared to stimulants (approximately 1.0) 3

Critical Safety Warnings for Guanfacine:

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

Extended-Release Clonidine (Alpha-2 Agonist)

Clonidine ER is dosed similarly to guanfacine with comparable efficacy and adverse effect profile, though it may be slightly more sedating. 1

• Evening administration preferred to minimize daytime sedation 1
• Must be tapered when discontinuing to avoid rebound hypertension 1
• Adverse effects include somnolence, dry mouth, dizziness, irritability, headache, bradycardia, hypotension, and abdominal pain 1

Clinical Decision Algorithm

Choose atomoxetine as first-line non-stimulant when:

• Stimulants have failed or are contraindicated 1
• Comorbid anxiety or autism spectrum disorder is present 1
• Substance use disorder risk exists (atomoxetine is non-controlled) 1
• Patient requires consistent 24-hour coverage without rebound 1

Choose guanfacine or clonidine as first-line non-stimulant when:

• Comorbid tic disorder or Tourette's syndrome is present 1
• Comorbid disruptive behavior disorders or oppositional defiant disorder exists 1
• Sleep disturbances are prominent (can help with sleep initiation) 1
• Substance use disorder risk exists (both are non-controlled) 1

Adjunctive Therapy with Stimulants

Extended-release guanfacine and extended-release clonidine are the only FDA-approved medications for adjunctive use with stimulants when monotherapy is insufficient. 1, 3

• Combination therapy can reduce stimulant-related adverse effects including sleep disturbances, elevated blood pressure, and heart rate 1, 3
• Atomoxetine has limited evidence for combination use with stimulants on an off-label basis 1
• Monitor for opposing cardiovascular effects when combining stimulants (which increase BP/HR) with alpha-2 agonists (which decrease BP/HR) 3

Special Population: Preschool Children (Ages 4-5)

No non-stimulant medication has sufficient evidence for use in children aged 4-5 years, and none are recommended for this age group. 1

• Methylphenidate remains the only medication with adequate (though still off-label) evidence in preschoolers 1
• Non-stimulants should not be used in preschool-aged children due to lack of rigorous study 1

Common Pitfalls to Avoid

• Do not expect immediate results with non-stimulants—counsel families that atomoxetine requires 6-12 weeks and alpha-2 agonists require 2-4 weeks for full therapeutic effect 1, 3
• Never abruptly discontinue guanfacine or clonidine—this is a critical safety issue that can cause rebound hypertension 1, 3
• Do not increase atomoxetine dosing too rapidly—this increases gastrointestinal adverse effects and initial somnolence 1
• Do not overlook cardiac screening—obtain cardiac history and consider ECG if risk factors are present before starting any non-stimulant 1
• Monitor for suicidal ideation with atomoxetine, especially during the first few months of treatment and in adolescents 1

Newer Option: Viloxazine ER

Extended-release viloxazine is a recently approved non-stimulant with a unique mechanism modulating both serotonin and norepinephrine, offering once-daily dosing with common adverse effects of somnolence, decreased appetite, and headache. 4

• May be particularly beneficial for patients with comorbid depression 4
• Continued evaluation of long-term efficacy and safety is needed 4