What non-stimulant medications, such as atomoxetine (a selective norepinephrine reuptake inhibitor), guanfacine, or clonidine (alpha-2 adrenergic agonists), are recommended for a patient with Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant Medications for ADHD

Atomoxetine should be your first-line non-stimulant choice for ADHD, with guanfacine extended-release and clonidine extended-release as second-line options or adjunctive therapy to stimulants. 1, 2, 3, 4

First-Line Non-Stimulant: Atomoxetine

Atomoxetine is the only FDA-approved non-stimulant with the strongest evidence base among non-stimulant options. 1, 3, 5

Mechanism and Efficacy

• Atomoxetine is a selective norepinephrine reuptake inhibitor that works by enhancing noradrenergic function in the prefrontal cortex. 5, 6
• It achieves effect sizes of approximately 0.7 compared to placebo, which is slightly weaker than stimulants (effect size ~1.0) but comparable to other non-stimulants. 1, 4
• Atomoxetine provides continuous 24-hour symptom coverage with once-daily dosing, unlike stimulants that have limited duration and potential rebound symptoms. 3, 4

Dosing Protocol

• Start at 0.5 mg/kg/day (or 40 mg/day in adults) for the first 3 days, then increase to target dose of 1.2 mg/kg/day (or 80-100 mg/day in adults). 1, 4, 5
• Maximum dose is 1.4 mg/kg/day or 100 mg/day, whichever is lower. 4, 5
• Can be administered once daily in the morning or split into two divided doses (morning and late afternoon/early evening) to reduce side effects. 3, 7
• Critical timing expectation: Full therapeutic effects require 6-12 weeks, unlike stimulants which work immediately. 3, 4, 8

Safety Profile and Monitoring

• FDA Black Box Warning: Monitor closely for suicidal ideation, especially during the first few weeks and during dose adjustments. 4, 5, 7
• Common adverse effects include decreased appetite, nausea, vomiting, abdominal pain, somnolence, and initial weight loss (though growth normalizes long-term). 1, 5, 7
• Rare but serious: hepatotoxicity—monitor for right upper quadrant pain, dark urine, jaundice, or unexplained flu-like symptoms. 5, 7
• Cardiovascular effects are minimal but monitor blood pressure and heart rate at baseline and periodically. 3, 4, 7
• Baseline assessment must include: suicidality screening, personal and family cardiac history, blood pressure, heart rate, and weight. 4

Specific Clinical Advantages

• Atomoxetine is particularly beneficial for patients with:
  • Comorbid anxiety disorders (lower risk of exacerbating anxiety compared to stimulants) 3, 4
  • Comorbid tic disorders or Tourette's syndrome (does not worsen tics) 3, 7
  • Substance use disorder risk (non-controlled substance with negligible abuse potential) 3, 4, 7
  • Autism spectrum disorder comorbidity 3
• Atomoxetine has fewer and less pronounced adverse effects compared to guanfacine and clonidine. 3

Second-Line Non-Stimulants: Alpha-2 Agonists

Guanfacine Extended-Release

Guanfacine ER is the preferred alpha-2 agonist due to higher alpha-2A receptor specificity, resulting in less sedation than clonidine. 2

Mechanism and Efficacy

• Guanfacine is an alpha-2A adrenergic receptor agonist that enhances noradrenergic neurotransmission in the prefrontal cortex, strengthening regulatory control of attention and working memory. 2
• Effect size is approximately 0.7 compared to placebo, similar to atomoxetine. 1, 2
• Therapeutic effects require 2-4 weeks to emerge, unlike stimulants which work immediately. 2, 4

Dosing Protocol

• Start at 1 mg once daily in the evening, titrate by 1 mg weekly based on response and tolerability. 2, 4
• Target range: 0.05-0.12 mg/kg/day or 1-7 mg/day maximum. 1, 2, 4
• Evening administration is strongly preferred to minimize daytime somnolence and fatigue. 2, 4

Safety Profile and Monitoring

• Critical warning: Guanfacine must NEVER be abruptly discontinued—taper by 1 mg every 3-7 days to avoid rebound hypertension. 2, 4
• Common adverse effects: somnolence/sedation (most frequent), fatigue, headache, dry mouth, constipation (5-16% of patients), dizziness, irritability, abdominal pain. 1, 2
• Cardiovascular effects: modest decreases in blood pressure (1-4 mmHg) and heart rate (1-2 bpm)—monitor at baseline and during dose adjustments. 2, 4
• Baseline assessment: blood pressure, heart rate, personal and family cardiac history (Wolf-Parkinson-White syndrome, sudden death, hypertrophic cardiomyopathy, long QT syndrome). 2

Specific Clinical Advantages

• Guanfacine is particularly indicated when ADHD co-occurs with:
  • Sleep disturbances (sedating properties improve sleep onset when given at bedtime) 2, 4
  • Tic disorders (may reduce tics) 2, 4
  • Disruptive behavior disorders or oppositional symptoms 2
  • Anxiety disorders 4

Clonidine Extended-Release

• Clonidine ER is also FDA-approved for ADHD with similar efficacy (effect size ~0.7) but causes more sedation than guanfacine due to lower alpha-2A receptor specificity. 1, 2
• Requires twice-daily dosing in many cases, reducing adherence compared to guanfacine's once-daily regimen. 2
• Common adverse effects: somnolence and dry mouth. 1
• Like guanfacine, clonidine must be tapered to avoid rebound hypertension. 2

FDA-Approved Adjunctive Therapy

Both guanfacine ER and clonidine ER are the ONLY medications with FDA approval and sufficient evidence for adjunctive use with stimulants. 1, 2, 4

Rationale for Combination Therapy

• Adding guanfacine or clonidine to stimulants can increase treatment effects and/or decrease stimulant-related adverse effects (particularly sleep disturbances, rebound symptoms, and cardiovascular effects). 2, 4
• Combination therapy allows for lower stimulant dosages while maintaining efficacy, potentially reducing stimulant-related side effects. 2, 4
• Particularly appropriate for adolescents with substance abuse risk, as adding a non-stimulant may minimize stimulant exposure. 2

Monitoring During Combination Therapy

• Monitor for opposing cardiovascular effects: stimulants increase blood pressure and heart rate, while alpha-2 agonists decrease both parameters. 2
• Check blood pressure and heart rate at each dose adjustment of the alpha-2 agonist. 2

Treatment Algorithm

Step 1: Initial Non-Stimulant Selection

• Start with atomoxetine for most patients requiring non-stimulant therapy. 3, 4
• Start with guanfacine ER instead if:
  • Prominent sleep disturbances are present 2, 4
  • Comorbid tic disorder is present 2, 4
  • Patient cannot wait 6-12 weeks for full atomoxetine effect and can tolerate 2-4 week onset 2, 4

Step 2: Assess Response

• For atomoxetine: Evaluate at 6-12 weeks after reaching target dose. 4
• For guanfacine: Evaluate at 2-4 weeks after reaching target dose. 2, 4
• Use standardized ADHD rating scales from parents and teachers, assess functional impairment and quality of life. 2, 4

Step 3: If Inadequate Response

• If atomoxetine fails after adequate trial (6-12 weeks at optimal dose): Switch to guanfacine ER. 4
• If guanfacine fails after adequate trial (4-6 weeks at optimal dose): Switch to atomoxetine. 2
• If monotherapy with any non-stimulant is inadequate: Consider adding to or switching to stimulant therapy (stimulants remain more effective with effect size ~1.0). 1, 4

Step 4: Adjunctive Therapy Considerations

• If patient is already on optimized stimulant with inadequate symptom control: Add guanfacine ER or clonidine ER (FDA-approved for adjunctive use). 1, 2, 4
• If patient on stimulant develops intolerable side effects (insomnia, rebound, tics): Add guanfacine ER or clonidine ER rather than discontinuing stimulant. 2, 4

Common Pitfalls and How to Avoid Them

Pitfall 1: Expecting Immediate Results

• Atomoxetine requires 6-12 weeks for full effect; guanfacine requires 2-4 weeks. Counsel families extensively about delayed onset to prevent premature discontinuation. 2, 3, 4
• This contrasts sharply with stimulants, which work immediately after administration. 2, 4

Pitfall 2: Abrupt Discontinuation of Alpha-2 Agonists

• Never stop guanfacine or clonidine abruptly—always taper by 1 mg every 3-7 days to avoid rebound hypertension and potential hypertensive crisis. 2, 4

Pitfall 3: Inadequate Suicidality Monitoring with Atomoxetine

• The FDA Black Box Warning is serious: 4 out of 1,000 patients developed suicidal thoughts in clinical trials. 5
• Monitor closely during the first few weeks and during any dose adjustments. 4, 5
• Watch for anxiety, agitation, panic attacks, irritability, hostility, aggressiveness, impulsivity, restlessness, mania, or depression. 5

Pitfall 4: Missing Cardiac Screening

• Before starting any ADHD medication, obtain personal and family cardiac history: Wolf-Parkinson-White syndrome, unexplained fainting, sudden death in family, hypertrophic cardiomyopathy, long QT syndrome. 1, 2
• Baseline blood pressure and heart rate are mandatory. 2, 4

Pitfall 5: Overlooking Drug Interactions

• Atomoxetine: CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) significantly increase atomoxetine levels—reduce atomoxetine dose by 50% when co-administered. 7
• Guanfacine: CYP3A4 inhibitors/inducers affect guanfacine levels; CNS depressants (benzodiazepines, alcohol, phenothiazines) cause additive sedation. 2
• Never combine atomoxetine with MAOIs or within 14 days of MAOI discontinuation. 5

Pitfall 6: Using Non-Stimulants as First-Line When Stimulants Are Appropriate

• Stimulants remain first-line treatment for ADHD due to superior effect sizes (1.0 vs 0.7) and immediate onset. 1, 4
• Non-stimulants should be reserved for: stimulant failure, stimulant intolerance, comorbid substance use disorder, comorbid tic disorder, patient/family preference, or as adjunctive therapy. 1, 2, 3, 4

Pitfall 7: Combining Two Alpha-2 Agonists

• Never combine clonidine and guanfacine together—this increases sedation and cardiovascular effects without evidence of superior efficacy. 2

Contraindications

Atomoxetine Contraindications

• Current or recent (within 14 days) MAOI use 5
• Narrow-angle glaucoma 5
• Pheochromocytoma (current or history) 5
• Known hypersensitivity to atomoxetine 5

Guanfacine/Clonidine Relative Contraindications

• Baseline bradycardia (heart rate <60 bpm) or hypotension (systolic BP <90 mmHg) 2
• Known cardiac conduction abnormalities 2

Special Populations

Pregnancy and Breastfeeding

• Atomoxetine: Limited safety data; pregnancy registry available at 1-866-961-2388. 5
• Guanfacine: Limited safety data; one small study showed no congenital malformations but 20% low birth weight. 2
• Both medications: Unknown if excreted in breast milk—discuss risks/benefits with patient. 5

Hepatic Impairment

• Atomoxetine: Dose reduction required in moderate hepatic impairment (50% reduction); severe hepatic impairment (75% reduction). 7
• Monitor closely for signs of hepatotoxicity. 5, 7

Poor CYP2D6 Metabolizers

• Approximately 7% of Caucasians are poor CYP2D6 metabolizers, resulting in 10-fold higher atomoxetine exposure. 7
• These patients may require lower doses and experience more adverse effects. 7