What is the preferred first‑line non‑stimulant medication for attention‑deficit/hyperactivity disorder, including recommended dosing, titration, and monitoring?

Best Non-Stimulant Medication for ADHD

Atomoxetine is the preferred first-line non-stimulant medication for ADHD, as it is the only FDA-approved non-stimulant for both children and adults, with the most robust evidence base among non-stimulant options. 1, 2, 3

Dosing and Titration

Initial dosing:

• Children and adolescents ≤70 kg: Start at 0.5 mg/kg/day, which can be given as a single morning dose or divided into morning and late afternoon/early evening doses 2
• Children and adolescents >70 kg and adults: Start at 40 mg/day 2

Target dosing:

• Children and adolescents ≤70 kg: 1.2 mg/kg/day 2, 4
• Children and adolescents >70 kg and adults: 80 mg/day 2, 5

Maximum dosing:

• Children and adolescents ≤70 kg: 1.4 mg/kg/day 2
• Children and adolescents >70 kg and adults: 100 mg/day (or 1.4 mg/kg/day, whichever is lower) 2, 5

Titration schedule:

• Increase dose after a minimum of 3 days to the target dose 2
• Further increases to the maximum dose can be made after 2-4 weeks if needed 5
• Full therapeutic effect requires 6-12 weeks, with median time to response of 3.7 weeks 1

Key Clinical Advantages

Why atomoxetine is preferred over other non-stimulants:

• Only FDA-approved non-stimulant for adult ADHD 1
• Non-controlled substance with no abuse potential, making it ideal for patients with substance use history 1, 6
• Provides 24-hour symptom coverage with once-daily dosing 1, 3
• Can be dosed flexibly: single morning dose, split dosing (morning and evening), or evening-only dosing to minimize side effects 1
• Has evidence supporting efficacy in ADHD with comorbid anxiety and autism spectrum disorder 1

Monitoring Requirements

Baseline assessment:

• Blood pressure and pulse 1
• Height and weight (particularly in pediatric patients) 1
• Screen for bipolar disorder before initiating treatment 2
• Assess for cardiovascular disease, hypertension, or cerebrovascular disease 2

Ongoing monitoring:

• Blood pressure and pulse at each visit during titration and regularly during maintenance 1
• Height and weight at each visit in pediatric patients 1
• Suicidality screening at every visit - atomoxetine carries an FDA black box warning for increased risk of suicidal ideation in children and adolescents 2, 1
• Monitor for clinical worsening and unusual behavioral changes, especially during the first few months or at dose changes 2

Common Adverse Effects

• Gastrointestinal disorders (dyspepsia, nausea, vomiting) 4, 3
• Decreased appetite and weight loss 4, 3
• Somnolence and fatigue (most common) 1
• Dry mouth, insomnia, constipation (more common in adults) 6
• Urinary hesitancy or retention 2
• Sexual dysfunction in approximately 2% of adults 6

These adverse effects are generally mild to moderate and transient in nature 3, 4

Contraindications

• Hypersensitivity to atomoxetine 2
• Use within 2 weeks of discontinuing an MAOI 2
• Narrow-angle glaucoma 2
• Pheochromocytoma or history of pheochromocytoma 2
• Severe cardiovascular disorders that might deteriorate with increases in heart rate and blood pressure 2

Dose Adjustments Required

Hepatic impairment:

• Moderate impairment (Child-Pugh Class B): Reduce to 50% of normal dose 2
• Severe impairment (Child-Pugh Class C): Reduce to 25% of normal dose 2

CYP2D6 considerations:

• Patients taking strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) or known CYP2D6 poor metabolizers: Dose adjustment may be necessary 2, 1

Alternative Non-Stimulant Options (Second-Line)

Extended-release guanfacine:

• Starting dose: 1 mg once daily 5
• Titrate by 1 mg weekly based on response 5
• Target dose range: 0.05-0.12 mg/kg/day or 1-7 mg/day 5
• Effect size around 0.7 1
• Particularly useful when comorbid tics, sleep disturbances, or oppositional symptoms are present 1
• Never abruptly discontinue - taper by 1 mg every 3-7 days to avoid rebound hypertension 1

Extended-release clonidine:

• Similar efficacy and indications as guanfacine 1
• Effect size around 0.7 1
• Requires 2-4 weeks for full effect 1
• Never abruptly discontinue - risk of rebound hypertension 1

Viloxazine extended-release:

• Starting dose: 200 mg once daily 5
• Titrate by 200 mg increments at weekly intervals 5
• Maximum dose: 600 mg/day 5
• Limited data on efficacy for adult ADHD 5
• Not currently available in Canada 5

Efficacy Comparison

• Atomoxetine: Medium-range effect size of approximately 0.7 compared to stimulants (effect size 1.0) 1
• Alpha-2 agonists (guanfacine/clonidine): Effect sizes around 0.7 1
• Stimulants remain gold standard with 70-80% response rates and largest effect sizes 1

Critical Clinical Pitfalls to Avoid

• Do not expect rapid response - atomoxetine requires 6-12 weeks for full therapeutic effect, unlike stimulants that work within days 1, 3
• Do not underdose - ensure titration to target dose of 1.2 mg/kg/day (or 80-100 mg/day in adults) before concluding treatment failure 1
• Do not assume atomoxetine treats comorbid depression - despite its development as an antidepressant, evidence does not support efficacy for depression 1
• Do not abruptly discontinue alpha-2 agonists if switching from guanfacine or clonidine - taper gradually to prevent rebound hypertension 1
• Do not overlook suicidality monitoring - systematic screening is essential at every visit, especially in the first few months 2, 1