For a patient with attention‑deficit/hyperactivity disorder who cannot use or does not tolerate stimulant therapy, what non‑stimulant medications are available and what are their dosing, titration, monitoring requirements, and contraindications?

Non-Stimulant ADHD Medications: Evidence-Based Guide

For patients with ADHD who cannot tolerate or do not respond to stimulants, atomoxetine is the first-line non-stimulant option, followed by extended-release guanfacine or extended-release clonidine, with viloxazine extended-release as an emerging alternative. 1

Available FDA-Approved Non-Stimulant Medications

The three established non-stimulant classes demonstrate moderate efficacy with effect sizes around 0.7, compared to stimulants at 1.0:

1. Atomoxetine (Strattera) – Selective Norepinephrine Reuptake Inhibitor

Dosing & Titration:

• Pediatric patients ≤70 kg: Start 0.5 mg/kg/day, increase after minimum 3 days to target of 1.2 mg/kg/day, maximum 1.4 mg/kg/day or 100 mg (whichever is lower) 2
• Pediatric patients >70 kg and adults: Start 40 mg/day, increase after minimum 3 days to 80 mg/day, may increase to maximum 100 mg/day 2
• Severe renal impairment (eGFR <30): Reduce dose by 50% 3

Timeline to Effect:

• Median response time: 3.7 weeks 1
• Full therapeutic effect: 6-12 weeks 1, 2
• Probability of improvement may continue increasing up to 52 weeks 4

Monitoring Requirements:

• Baseline: Blood pressure, pulse, liver function tests, screen for suicidal ideation 2
• Weekly (first 4-6 weeks): Suicidal ideation screening, blood pressure, pulse 4
• Monthly thereafter: Blood pressure, pulse, functional assessment 4

Key Adverse Effects:

• Initial somnolence and gastrointestinal symptoms (especially with rapid titration) 1
• Decreased appetite 1
• FDA Black Box Warning: Increased risk of suicidal thoughts (requires intensive monitoring) 4, 3
• Rare: Hepatotoxicity 1

Contraindications:

• Concurrent MAOI use or within 14 days of MAOI discontinuation 3
• Narrow-angle glaucoma 2

Clinical Advantages:

• 24-hour symptom coverage with once-daily dosing 4
• No abuse potential (non-controlled substance) 4, 5
• Useful when substance misuse risk exists 4

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2. Extended-Release Guanfacine (Intuniv) – Alpha-2 Adrenergic Agonist

Dosing & Titration:

• Starting dose: 1 mg once daily (evening preferred due to sedation) 4
• Titration: Increase by 1 mg weekly 4
• Target range: 0.05-0.12 mg/kg/day 4
• Maximum dose: 4 mg/day (children), 7 mg/day (adults) 4
• Rule of thumb: 0.1 mg/kg as starting calculation 4

Timeline to Effect:

• Clinical improvement typically emerges within 2-4 weeks 4
• Allow 2-4 weeks for full treatment effects 4

Monitoring Requirements:

• Baseline: Blood pressure, pulse, cardiac history 4
• Weekly during titration: Blood pressure, pulse (guanfacine typically lowers both) 4
• Monthly during maintenance: Blood pressure, pulse 4

Key Adverse Effects:

• Somnolence/fatigue (most common—administer in evening) 1, 4
• Dry mouth 1
• Hypotension, bradycardia 4

Contraindications:

• Severe bradycardia or heart block 4
• Severe hypotension 4

Clinical Advantages:

• Particularly useful for comorbid sleep disturbances, anxiety, or tics 4
• Evening dosing leverages sedative properties to improve sleep onset 4
• Lowers blood pressure and heart rate (beneficial in patients with cardiovascular concerns) 4

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3. Extended-Release Clonidine (Kapvay) – Alpha-2 Adrenergic Agonist

Dosing & Titration:

• Starting dose: 0.1 mg once daily at bedtime 6
• Titration: Increase by 0.1 mg weekly 4
• Target range: Similar to guanfacine (0.05-0.12 mg/kg/day) 4
• Maximum dose: 0.4 mg/day 6

Timeline to Effect:

• 2-4 weeks for full therapeutic effect 4

Monitoring Requirements:

• Identical to guanfacine: baseline and regular blood pressure and pulse monitoring 4

Key Adverse Effects:

• Somnolence, dry mouth 1
• Hypotension, bradycardia 4

Contraindications:

• Similar to guanfacine: severe bradycardia, heart block, hypotension 4

Clinical Advantages:

• Effect size approximately 0.7 1
• Can be used as monotherapy or adjunctive therapy with stimulants 1
• Useful for comorbid tics or oppositional symptoms 4

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4. Viloxazine Extended-Release (Qelbree) – Serotonin-Norepinephrine Modulating Agent

Dosing & Titration:

• Pediatric 6-11 years: Start 100 mg once daily, increase by 100 mg weekly, maximum 400 mg/day 3
• Pediatric 12-17 years: Start 200 mg once daily, increase by 200 mg after 1 week, maximum 400 mg/day 3
• Adults: Start 200 mg once daily, increase by 200 mg weekly, maximum 600 mg/day 3
• Severe renal impairment: Start 100 mg once daily, titrate by 50-100 mg weekly, maximum 200 mg/day 3

Timeline to Effect:

• Pivotal trials demonstrated favorable efficacy in children, though specific timeline not established 5, 7

Monitoring Requirements:

• Baseline: Blood pressure, pulse, screen for suicidal ideation and family history of suicide/bipolar disorder/depression 3
• During titration and periodically: Blood pressure, pulse 3
• Ongoing: Monitor for suicidal thoughts and behaviors 3

Key Adverse Effects:

• FDA Black Box Warning: Higher rates of suicidal thoughts and behaviors (0.9% pediatric, 1.6% adult vs. 0.4% and 0% placebo) 3
• Insomnia, irritability 3
• Nausea, decreased appetite 3

Contraindications:

• Concurrent MAOI use or within 14 days of MAOI discontinuation 3
• Concurrent use with sensitive CYP1A2 substrates or those with narrow therapeutic range 3

Clinical Advantages:

• Repurposed antidepressant with novel mechanism (serotonin-norepinephrine modulation) 4, 5
• No abuse potential 5
• Minimal dopamine elevation in nucleus accumbens compared to stimulants 5

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Treatment Algorithm for Non-Stimulant Selection

Step 1: First-Line Non-Stimulant

• Atomoxetine is the single FDA-approved non-stimulant for adult ADHD and has the most robust evidence base 4, 2
• Choose atomoxetine when: patient requires 24-hour coverage, substance misuse risk exists, or comorbid anxiety is present 4

Step 2: If Atomoxetine Insufficient or Not Tolerated

• Trial extended-release guanfacine OR extended-release clonidine 4
• Choose alpha-2 agonists when: comorbid sleep disturbances, tics, severe anxiety, or oppositional symptoms exist 4
• Allow 2-4 weeks for treatment effects before declaring failure 4

Step 3: Emerging Alternative

• Viloxazine extended-release for patients who have failed atomoxetine and alpha-2 agonists 4, 3, 5
• Requires intensive suicidal ideation monitoring 3

Step 4: Consider Adjunctive Therapy

• Extended-release guanfacine and clonidine are the only FDA-approved adjunctive agents to combine with stimulants 1
• Use when monotherapy with either stimulants or non-stimulants is insufficient 1

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Critical Comparative Points

Medication	Effect Size	Time to Effect	Abuse Potential	Key Advantage	Major Caution
Atomoxetine	0.7 [1]	6-12 weeks [1,2]	None [4]	24-hour coverage [4]	Suicidal ideation [3]
Guanfacine ER	0.7 [1]	2-4 weeks [4]	None [4]	Improves sleep [4]	Hypotension/bradycardia [4]
Clonidine ER	0.7 [1]	2-4 weeks [4]	None [4]	Useful for tics [4]	Hypotension/bradycardia [4]
Viloxazine ER	Not established	Not established	None [5]	Novel mechanism [5]	Suicidal ideation [3]

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Common Pitfalls to Avoid

Do not abandon atomoxetine prematurely: Most clinicians discontinue before the 6-12 week window required for full effect 4, 2

Do not underdose alpha-2 agonists: A 1 mg nightly dose of guanfacine is typically insufficient; most patients require 2-4 mg for therapeutic effect 4

Do not skip cardiovascular screening: Obtain detailed personal and family cardiac history before initiating any ADHD medication, including non-stimulants 4

Do not use pharmacogenetic testing: Current evidence does not support clinical utility of these tools, which cost thousands of dollars and are not covered by insurance 1

Do not forget behavioral therapy: Non-stimulants should be combined with evidence-based behavioral interventions for optimal functional outcomes 4

Do not assume non-stimulants are "safer": While lacking abuse potential, atomoxetine and viloxazine carry FDA black box warnings for suicidal ideation requiring intensive monitoring 3