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

Non-Stimulant Medications for ADHD

The three FDA-approved non-stimulant medications for ADHD are atomoxetine, guanfacine extended-release, and clonidine extended-release, with atomoxetine recommended as the first-line non-stimulant option and viloxazine (Qelbree) as a newer alternative. 1

Primary Non-Stimulant Options

Atomoxetine (First-Line Non-Stimulant)

Atomoxetine is a selective norepinephrine reuptake inhibitor that provides continuous 24-hour symptom coverage without abuse potential. 1, 2

Dosing Strategy

• Adults: Start at 40 mg/day, titrate to target dose of 80-100 mg/day (maximum 100 mg/day or 1.4 mg/kg/day, whichever is lower) 1, 2
• Children/adolescents ≤70 kg: Start at 0.5 mg/kg/day, titrate to target of 1.2 mg/kg/day (maximum 1.4 mg/kg/day) 2
• Children/adolescents >70 kg: Start at 40 mg/day, titrate to target of 80-100 mg/day 2
• Can be administered once daily (morning or evening) or split into two divided doses to minimize side effects 3, 2

Efficacy Profile

• Demonstrates 28-30% reduction in ADHD symptom scores versus 18-20% with placebo 1
• Critical caveat: Full therapeutic effects require 6-12 weeks, significantly longer than stimulants 3, 1, 2
• Effect sizes are medium range and smaller than stimulants 3

Key Advantages

• Non-controlled substance status eliminates abuse/diversion risk 1, 4
• Provides "around-the-clock" effects without peaks and valleys 3, 1, 2
• Lower risk of appetite suppression and growth effects compared to stimulants 3
• Fewer cardiovascular effects than stimulants 3

Safety Monitoring Requirements

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during first few weeks 1, 2
• Assess blood pressure and heart rate at baseline and with dose increases 1, 2
• Common adverse effects: decreased appetite, nausea, vomiting, headache, somnolence, abdominal pain 2, 5
• Adults may experience dry mouth, insomnia, constipation, urinary retention, sexual dysfunction (≈2%), dizziness 1, 4

Guanfacine Extended-Release (Second-Line Non-Stimulant)

Guanfacine is an alpha-2A adrenergic agonist that enhances prefrontal cortex function through noradrenergic neurotransmission. 3

Dosing Strategy

• Weight-based dosing: approximately 0.1 mg/kg once daily 1
• Available in 1,2,3, and 4 mg tablets 3, 1
• Administer in the evening due to sedation risk 3, 1

Specific Indications

• Guanfacine is approximately 10 times less potent than clonidine with higher specificity to alpha-2A receptors, resulting in less sedation 3
• Approved in the US as monotherapy or adjunctive to stimulants 3
• In Europe, only approved when stimulants are unsuitable, not tolerated, or ineffective 3

Adverse Effects

• Somnolence, fatigue, irritability, insomnia, nightmares 3, 1
• Hypotension, bradycardia, syncope 3
• Warnings for cardiac conduction abnormalities 3

Clonidine Extended-Release (Alternative Alpha-2 Agonist)

Clonidine shares the same mechanism as guanfacine but is approximately 10 times more potent. 3

Dosing Strategy

• Available in 0.1 and 0.2 mg tablets 3
• Start with 0.1 mg at bedtime, can increase to twice-daily administration 3
• Maximum dose: 0.4 mg/day 3
• Also available as transdermal patch (0.1,0.2,0.3 mg) 3

Key Differences from Guanfacine

• Metabolized via CYP2D6 (versus CYP3A4 for guanfacine) 3
• Excreted renally and hepatically in equal shares 3
• Not approved for ADHD in Europe 3
• More sedating than guanfacine due to lower alpha-2A receptor specificity 3

Viloxazine (Qelbree) - Newer Option

Viloxazine is a newer FDA-approved non-stimulant for adults with ADHD. 1

Dosing

• Starting dose: 200 mg once daily 1
• Maximum dose: 600 mg once daily 1

Clinical Decision Algorithm for Non-Stimulant Selection

Step 1: First-Line Non-Stimulant Choice

Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma) 1, 2

Atomoxetine is Particularly Indicated for:

• Substance use disorders (where stimulants pose unacceptable diversion/abuse risk) 3, 1
• Tic disorders or Tourette's syndrome (atomoxetine does not worsen tics) 3
• Comorbid anxiety disorders (lower risk of exacerbating anxiety versus stimulants) 3, 1
• Autism spectrum disorder with ADHD 3, 2
• Patients requiring continuous 24-hour coverage 3, 1
• Patients who cannot tolerate stimulant side effects 3

Step 2: Switch to Guanfacine If:

• Atomoxetine ineffective after 12 weeks at therapeutic dose 1
• Intolerable side effects from atomoxetine 1
• Comorbid sleep disturbances (guanfacine/clonidine specifically beneficial) 3, 2
• Comorbid tics (guanfacine may reduce tics, though evidence is inconclusive) 3
• Comorbid anxiety 1

Step 3: Consider Bupropion (Off-Label) If:

• Both atomoxetine and guanfacine have failed 1
• Comorbid depression requires treatment 1
• Important caveat: Bupropion is NOT FDA-approved for ADHD 1

Step 4: Adjunctive Therapy Option

In the US, guanfacine and clonidine are approved as adjunctive therapy to stimulants to either increase treatment effects or decrease stimulant adverse effects (particularly sleep disturbances, elevated blood pressure/heart rate) 3

Monitoring Protocol

Baseline Assessment

• Blood pressure and heart rate 1, 2
• Weight 1
• Suicidality assessment (critical for atomoxetine) 1, 2

Follow-Up Monitoring (2-4 weeks)

• Vital signs 1
• Side effects evaluation 1
• Early response assessment 1

Therapeutic Assessment Timeframe

• Atomoxetine: 6-12 weeks (delayed onset requires patience) 3, 1, 2
• Guanfacine: 2-4 weeks 1
• Assess ADHD symptom scales, functional impairment, quality of life 1

Ongoing Monitoring

• Quarterly vital signs 1
• Annual growth parameters if applicable 1
• Continuous suicidality monitoring for atomoxetine 1

Critical Clinical Pearls

Non-stimulants have medium-range effect sizes that are smaller than stimulants but offer important advantages in specific clinical scenarios. 3

The delayed onset of atomoxetine (6-12 weeks) is the most common pitfall—patients and families must be counseled about this to prevent premature discontinuation. 3, 1, 2

Alpha-2 agonists (guanfacine/clonidine) should be administered in the evening due to sedation, though no significant difference in efficacy was found between morning versus evening administration in studies. 3

Atomoxetine shows fewer effects on appetite and growth compared to stimulants, making it advantageous for long-term treatment in children. 3, 2

Despite being developed as an antidepressant, atomoxetine does NOT demonstrate efficacy for treating comorbid depression. 3