What non-stimulant medication options are available for a patient with Attention Deficit Hyperactivity Disorder (ADHD) who cannot tolerate or has a contraindication to stimulants?

Non-Stimulant ADHD Medication Options

Atomoxetine is the first-line non-stimulant medication for ADHD when stimulants are contraindicated or not tolerated, followed by extended-release guanfacine or clonidine as second-line alternatives. 1, 2, 3

First-Line Non-Stimulant: Atomoxetine

Atomoxetine (Strattera) is the only FDA-approved non-stimulant specifically indicated for ADHD across the lifespan and should be your primary choice when stimulants fail or cannot be used. 1, 4, 5

Dosing Protocol

• Children and adolescents ≤70 kg: Start at 0.5 mg/kg/day, increase after minimum 3 days to target dose of 1.2 mg/kg/day (maximum 1.4 mg/kg or 100 mg, whichever is less). 1
• Children and adolescents >70 kg and adults: Start at 40 mg/day, increase after minimum 3 days to target of 80 mg/day. After 2-4 additional weeks, may increase to maximum 100 mg/day if response inadequate. 1
• Administer as single morning dose OR divided doses (morning and late afternoon/early evening). 1

Critical Timeline Expectations

• Requires 2-4 weeks minimum before observing clinical benefits, unlike stimulants which work immediately—counsel patients accordingly to prevent premature discontinuation. 2, 5
• Full therapeutic effect may take 6-12 weeks. 6

Black Box Warning: Suicidality

The FDA mandates close monitoring for suicidal ideation, particularly in children and adolescents during the first few months of treatment or at dose changes. 1, 6

• Pooled trials showed 0.4% risk of suicidal ideation in atomoxetine-treated patients versus 0% in placebo. 1
• Monitor systematically at each visit, especially if comorbid depression exists. 6

Common Adverse Effects

• Somnolence and fatigue are the most common side effects—avoid atomoxetine as first-line if fatigue is a primary complaint. 6
• Other effects include decreased appetite, nausea, dry mouth, constipation. 7, 4

Drug Interactions

• SSRIs can elevate atomoxetine levels through CYP2D6 inhibition—dose adjustment required when combining. 6
• CYP1A2 inhibitors (e.g., oral contraceptives) also require dose reduction and monitoring. 2

Second-Line Non-Stimulants: Alpha-2 Adrenergic Agonists

Guanfacine Extended-Release (Intuniv)

Guanfacine ER is FDA-approved for ADHD monotherapy and adjunctive therapy with stimulants, making it particularly valuable when stimulants provide partial response or specific comorbidities exist. 2, 3

Mechanism and Advantages

• Alpha-2A adrenergic receptor agonist with higher specificity than clonidine, resulting in less sedation. 2, 8
• Provides "around-the-clock" symptom control with once-daily dosing. 2
• Non-controlled substance status makes it preferable in populations at risk for diversion or substance abuse. 2

Dosing Guidelines

• Start at 1 mg once daily, titrate by 1 mg weekly based on response. 2
• Target range: 0.05-0.12 mg/kg/day or 1-7 mg/day maximum. 2
• Evening administration strongly preferred to minimize daytime somnolence/fatigue. 2

Timeline and Efficacy

• Requires 2-4 weeks before clinical benefits observed. 2
• Effect size approximately 0.7 compared to placebo (medium range, smaller than stimulants). 2

Cardiovascular Monitoring Requirements

• Obtain baseline blood pressure and heart rate before initiation. 2
• Monitor at each dose adjustment and periodically during maintenance. 2
• Expect modest decreases: 1-4 mmHg BP, 1-2 bpm heart rate. 2

Critical Safety Warning

Guanfacine must NEVER be abruptly discontinued—taper by 1 mg every 3-7 days to avoid rebound hypertension. 2

Specific Clinical Scenarios Favoring Guanfacine

• ADHD with comorbid tics—treats both conditions without worsening tics. 2
• ADHD with sleep disturbances—evening dosing addresses insomnia while providing symptom control. 2
• ADHD with oppositional/disruptive behaviors—evidence supports efficacy for behavioral symptoms. 2
• ADHD with anxiety or agitation—calming effects beneficial. 6
• Substance abuse history—non-controlled status reduces diversion risk. 2

Clonidine Extended-Release (Kapvay)

Clonidine ER is FDA-approved for ADHD but causes more sedation than guanfacine due to lower alpha-2A receptor specificity. 2, 8

• Start at 0.1 mg at bedtime, carefully uptitrate with twice-daily administration. 2
• Maximum doses up to 0.4 mg/day. 2
• Requires twice-daily dosing, reducing adherence compared to guanfacine's once-daily regimen. 2
• Same cardiovascular monitoring and tapering requirements as guanfacine. 2

Third-Line Non-Stimulants: Bupropion

Bupropion is explicitly positioned as second-line for ADHD, to be considered only after stimulant failure or when active substance abuse disorder contraindicates stimulants. 6, 8

Evidence and Positioning

• Superior to placebo with more favorable side-effect profile than tricyclic antidepressants. 8
• Effect sizes smaller than stimulants and atomoxetine. 6
• Not FDA-approved for ADHD—off-label use only. 5

Dosing

• Start bupropion SR at 100-150 mg daily or XL at 150 mg daily. 6
• Titrate to maintenance: 100-150 mg twice daily (SR) or 150-300 mg daily (XL). 6
• Maximum 450 mg/day. 6

Specific Scenarios

• Comorbid depression with ADHD—addresses both conditions. 6
• Weight concerns—only antidepressant promoting weight loss. 6
• Smoking cessation needed concurrently. 6

Important Caveats

• Avoid in patients with prominent hyperactivity or anxiety—activating properties can worsen these symptoms. 6
• Increased seizure risk, particularly at higher doses or when combined with stimulants. 6
• Common side effects: headache, insomnia, anxiety, agitation. 6

Fourth-Line: Tricyclic Antidepressants

TCAs (desipramine, imipramine) are effective but limited by side effects and cardiac risks—reserve for refractory cases only. 7, 8, 4

• Superior to placebo but produce sedation, dry mouth, constipation. 8
• Greater lethal potential in overdose—avoid in patients with suicidal ideation. 6
• Require baseline ECG and cardiac monitoring. 7
• Explicitly second-line agents at best. 6

Emerging Option: Viloxazine Extended-Release

Viloxazine ER is a newly FDA-approved selective norepinephrine reuptake inhibitor with favorable efficacy and tolerability in clinical trials. 6, 3

• Classified as serotonin-norepinephrine modulating agent. 6
• Demonstrated efficacy in both children and adults. 6
• Limited long-term data currently available. 3

Treatment Algorithm

1. First attempt: Atomoxetine (if no contraindications, acceptable timeline of 2-4 weeks for effect)
2. Second attempt: Guanfacine ER (particularly if tics, sleep issues, or behavioral problems present)
3. Third attempt: Clonidine ER (if guanfacine not tolerated or twice-daily dosing acceptable)
4. Fourth attempt: Bupropion (especially if comorbid depression or substance abuse history)
5. Last resort: TCAs (only for truly refractory cases with appropriate cardiac monitoring)

Combination Strategies

Both guanfacine ER and clonidine ER are FDA-approved for adjunctive use with stimulants when monotherapy provides inadequate response. 2, 3

• Allows lower stimulant doses while maintaining efficacy. 2
• Can mitigate stimulant-related adverse effects (sleep disturbances, tics). 2
• Never combine guanfacine and clonidine together—increases sedation and cardiovascular effects without evidence of superior efficacy. 2

Common Pitfalls to Avoid

• Do not expect immediate results from non-stimulants—all require weeks for therapeutic effect, unlike stimulants. 2, 5
• Do not abruptly discontinue alpha-2 agonists—mandatory tapering to prevent rebound hypertension. 2
• Do not assume atomoxetine will work for both ADHD and depression—no single antidepressant proven for dual purpose. 6
• Do not use atomoxetine first-line when fatigue is chief complaint—directly contradicts adverse effect profile. 6
• Do not overlook cardiovascular monitoring with alpha-2 agonists—baseline and ongoing assessment mandatory. 2