What are the non-stimulant medications for Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant Medications for ADHD

The FDA-approved non-stimulant medications for ADHD include atomoxetine (Strattera), extended-release guanfacine (Intuniv), and extended-release clonidine (Kapvay), with atomoxetine being the first-line non-stimulant choice and the only agent approved across the entire lifespan from children to adults. 1, 2, 3

FDA-Approved Non-Stimulant Medications

Atomoxetine (Strattera)

• Atomoxetine is a selective norepinephrine reuptake inhibitor approved for ADHD treatment in children aged 6 years and older, adolescents, and adults. 1, 2, 3
• The medication has an effect size of approximately 0.7, which is slightly weaker than stimulants (effect size ~1.0) but demonstrates consistent efficacy in reducing core ADHD symptoms. 1
• Dosing: Start at 40 mg/day in adults, then titrate to a target dose of 80-100 mg/day (maximum 100 mg/day or 1.4 mg/kg/day, whichever is lower). 2, 3
• For children and adolescents weighing ≤70 kg, the target dose is 1.2 mg/kg/day; for those >70 kg, target 80 mg/day. 4
• Full therapeutic effects require 6-12 weeks, unlike stimulants which have rapid onset. 1, 2
• The medication provides continuous 24-hour symptom coverage without peaks and valleys. 2

Extended-Release Guanfacine (Intuniv)

• Guanfacine is an alpha-2 adrenergic agonist approved for ADHD treatment in children and adolescents aged 6-17 years. 1
• The medication has an effect size of approximately 0.7. 1
• Dosing: Weight-based at approximately 0.1 mg/kg once daily, available in 1,2,3, and 4 mg tablets. 2
• Administer in the evening due to sedation risk. 2
• FDA-approved both as monotherapy and as adjunctive therapy to stimulant medications. 1

Extended-Release Clonidine (Kapvay)

• Clonidine is an alpha-2 adrenergic agonist approved for ADHD treatment in children and adolescents aged 6-17 years. 1
• The medication has an effect size of approximately 0.7. 1
• FDA-approved both as monotherapy and as adjunctive therapy to stimulant medications. 1
• Evening administration is generally preferable due to somnolence as a common adverse effect. 1

Viloxazine (Qelbree)

• Viloxazine is a newer FDA-approved non-stimulant option for adults with ADHD. 2
• Dosing: Starting dose of 200 mg once daily with a maximum dose of 600 mg once daily. 2

Key Clinical Advantages of Non-Stimulants

When to Prioritize Non-Stimulants Over Stimulants

• Non-controlled substance status eliminates abuse potential and diversion risk, making them particularly indicated for patients with comorbid substance use disorders. 1, 2
• Comorbid tic disorders or Tourette's syndrome: Non-stimulants (especially atomoxetine and guanfacine) are preferred as first-line treatment. 1
• Comorbid anxiety disorders: Non-stimulants have lower risk of exacerbating anxiety symptoms compared to stimulants. 1, 2
• Sleep disturbances: Clonidine and guanfacine may be considered when sleep problems are prominent. 1
• Comorbid disruptive behavior disorders: Non-stimulants may be considered as first-line options. 1
• Fewer effects on appetite and growth with long-term use compared to stimulants. 1, 2

Critical Safety Monitoring

Atomoxetine-Specific Warnings

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during the first few weeks of treatment and during dose adjustments. 2, 3
• Severe liver damage can occur: Watch for itching, right upper belly pain, dark urine, yellow skin/eyes, or unexplained flu-like symptoms. 3
• Cardiovascular monitoring: Assess blood pressure and heart rate at baseline and with dose increases. 2, 3
• Common adverse effects include somnolence, fatigue, irritability, insomnia, nightmares, initial gastrointestinal symptoms (especially if dose increased too rapidly), and decreased appetite. 1

Alpha-2 Agonist-Specific Warnings (Guanfacine/Clonidine)

• Adverse effects include somnolence, dry mouth, dizziness, irritability, headache, bradycardia, hypotension, and abdominal pain. 1
• Critical: Rebound hypertension can occur after abrupt discontinuation—these medications must be tapered off rather than suddenly stopped. 1
• Adverse effects are considered more frequent and pronounced with alpha-2 agonists compared to atomoxetine. 1

Clinical Algorithm for Non-Stimulant Selection

First-Line Non-Stimulant Choice

Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma, pheochromocytoma, or concurrent MAOI use). 2, 3

When to Switch to Guanfacine

• Atomoxetine is ineffective after 12 weeks at therapeutic dose. 2
• Intolerable side effects from atomoxetine occur. 2
• Comorbid tics, anxiety, or sleep disturbances are present. 1, 2

Third-Line Consideration

• Consider bupropion (off-label) if both atomoxetine and guanfacine have failed, or if comorbid depression requires treatment. 2, 5
• Note that bupropion is not FDA-approved for ADHD. 2

Adjunctive Therapy with Stimulants

Only extended-release guanfacine and extended-release clonidine have FDA approval for adjunctive therapy with stimulant medications. 1

• This combination can increase treatment effects and/or decrease adverse effects of stimulants, particularly sleep disturbances and cardiovascular effects (elevated blood pressure and heart rate). 1
• Some limited evidence supports using atomoxetine in combination with stimulants on an off-label basis. 1

Monitoring Parameters

Baseline Assessment

• Blood pressure, heart rate, weight, and suicidality assessment. 2

Follow-Up Monitoring (2-4 weeks)

• Vital signs, side effects, and early response assessment. 2

Therapeutic Assessment

• For atomoxetine: 6-12 weeks required for full therapeutic assessment. 2
• For guanfacine: 2-4 weeks for therapeutic assessment. 2
• Evaluate ADHD symptom scales, functional impairment, and quality of life. 2

Ongoing Monitoring

• Quarterly vital signs, annual growth parameters if applicable, and continuous suicidality monitoring. 2

Special Population Considerations

Preschool-Aged Children (4-5 years)

No non-stimulant medication has received sufficient rigorous study in the preschool-aged population to be recommended for treatment of ADHD in children 4 through 5 years of age. 1

Adolescents with Substance Use

Before beginning medication treatment of adolescents with newly diagnosed ADHD, assess for symptoms of substance use; if active substance use is identified, refer to a subspecialist for consultative support. 1