What non-stimulant medications are recommended for a patient with Attention Deficit Hyperactivity Disorder (ADHD)?

Non-Stimulant ADHD Medications

For patients with ADHD requiring non-stimulant treatment, atomoxetine is the first-line choice, followed by extended-release guanfacine and extended-release clonidine as second-line options. 1, 2, 3

First-Line: Atomoxetine (Strattera)

Atomoxetine should be initiated at 40 mg/day in adults, then titrated to a target dose of 80-100 mg/day, with full therapeutic effects expected in 6-12 weeks. 2, 4

Efficacy Profile

• Atomoxetine achieves a 28-30% reduction in ADHD symptom scores versus 18-20% with placebo, with an effect size of approximately 0.7 compared to stimulants' effect size of 1.0 1, 2, 5, 6
• The medication is a selective norepinephrine reuptake inhibitor that provides continuous 24-hour symptom coverage without peaks and valleys 2, 7, 8
• It is the only non-stimulant FDA-approved across the entire lifespan from children (age 6+) to adults 3, 4

Critical Safety Warning

• The FDA has issued a Black Box Warning for atomoxetine requiring close monitoring for suicidal ideation, especially during the first few weeks of treatment and during dose adjustments 2, 4
• Baseline suicidality assessment is mandatory before initiation 2, 3

Specific Clinical Advantages

• Non-controlled substance status eliminates abuse potential and diversion risk, making it particularly indicated for patients with comorbid substance use disorders 2, 3, 5, 6
• Lower risk of exacerbating anxiety symptoms compared to stimulants 2, 3
• Does not worsen tics in patients with comorbid tic disorders or Tourette's syndrome 2
• Can be administered once daily or split into two doses to reduce adverse effects 2

Common Adverse Effects

• Dry mouth, insomnia, nausea, decreased appetite, constipation, dizziness, sweating, dysuria, sexual problems, and palpitations 5, 6, 7
• Modest increases in heart rate and blood pressure that are generally well tolerated 5, 6
• Somnolence, fatigue, irritability, nightmares, and initial gastrointestinal symptoms 3

Monitoring Protocol

• Baseline: Blood pressure, heart rate, weight, and suicidality assessment 2, 3
• Follow-up at 2-4 weeks: Vital signs, side effects, and early response 2, 3
• Therapeutic assessment at 6-12 weeks: ADHD symptom scales, functional impairment, and quality of life 2, 3
• Ongoing: Quarterly vital signs, annual growth parameters if applicable, and continuous suicidality monitoring 2

Second-Line: Guanfacine Extended-Release (Intuniv)

If atomoxetine is ineffective or intolerable after an adequate 6-12 week trial, guanfacine extended-release should be initiated at 1 mg once daily in the evening, with a target range of 0.05-0.12 mg/kg/day or 1-7 mg/day maximum. 2, 9, 3

Efficacy Profile

• Guanfacine extended-release has an effect size of approximately 0.7 compared to placebo 1, 9
• Therapeutic effects require 2-4 weeks before clinical benefits are observed, unlike stimulants which work immediately 2, 9
• Provides "around-the-clock" symptom control lasting approximately 24 hours with once-daily dosing 9

Specific Clinical Indications

• Particularly indicated for patients with comorbid tic disorders, anxiety disorders, or sleep disturbances 2, 9
• May reduce tics, though evidence remains inconclusive 2
• Evening administration addresses sleep problems while providing continuous ADHD symptom control 9

Critical Safety Warning

• The FDA has warned against abrupt discontinuation of guanfacine—it must be tapered by 1 mg every 3-7 days to avoid rebound hypertension 2, 9
• Monitor for hypotension, bradycardia, and cardiac conduction abnormalities, particularly during dose adjustments 9

Common Adverse Effects

• Somnolence/sedation (most frequent), headache (20.5%), fatigue (15.2%), dry mouth, dizziness, irritability, constipation (5-16%), and abdominal pain 9, 3
• Modest decreases in blood pressure (1-4 mmHg) and heart rate (1-2 bpm) 9
• Evening administration is strongly preferred to minimize daytime somnolence 2, 9

Monitoring Protocol

• Baseline: Blood pressure, heart rate, weight, and cardiac history (including family history of sudden death, Wolff-Parkinson-White syndrome, hypertrophic cardiomyopathy, long QT syndrome) 9
• During dose adjustments: Blood pressure and heart rate at each titration 9
• Ongoing: Periodic vital signs monitoring 9

Third-Line: Clonidine Extended-Release

Clonidine extended-release is FDA-approved for ADHD in children and adolescents aged 6-17 years, with similar efficacy to guanfacine (effect size ~0.7) but requires twice-daily dosing and causes more sedation. 1, 3, 10

• Starting dose is 0.1 mg at bedtime, with careful uptitration to doses up to 0.4 mg/day 9
• Has lower alpha-2A receptor specificity compared to guanfacine, resulting in more sedation 9
• Must be tapered rather than suddenly discontinued to avoid rebound hypertension 3

FDA-Approved Adjunctive Therapy

Both extended-release guanfacine and extended-release clonidine are FDA-approved specifically as adjunctive therapy to stimulants, allowing for lower stimulant dosages while maintaining efficacy and mitigating stimulant-related adverse effects. 9, 3

• This combination is particularly appropriate for adolescents with substance abuse risk, as it allows for lower stimulant exposure 9
• Can help reduce stimulant-related sleep disturbances and cardiovascular effects 9
• Monitor for opposing cardiovascular effects when combining (stimulants increase heart rate/blood pressure, alpha-2 agonists decrease both) 9

Clinical Algorithm for Non-Stimulant Selection

1. Start with atomoxetine unless specific contraindications exist (severe cardiovascular disease, narrow-angle glaucoma, pheochromocytoma, concurrent MAOI use) 3
2. Switch to guanfacine extended-release if atomoxetine is ineffective after 6-12 weeks at optimal dosing or if comorbid tics, anxiety, or sleep disturbances are present 2, 3
3. Consider clonidine extended-release if both atomoxetine and guanfacine fail or are intolerable 3, 10
4. Consider adjunctive alpha-2 agonist with stimulant if monotherapy with any agent provides inadequate symptom control 9, 3

Important Caveats

• None of the non-stimulants have FDA approval for use in preschool-aged children (under 6 years) 1, 3
• Non-stimulants have smaller effect sizes (0.7) compared to stimulants (1.0), making stimulants generally more effective for core ADHD symptoms 1
• Pharmacogenetic tools are NOT recommended due to insufficient evidence of clinical utility, inconsistent findings, and costs of thousands of dollars typically not covered by insurance 1
• Behavioral therapy and psychosocial interventions should be integrated with pharmacotherapy as part of a comprehensive treatment program 4