For a patient with ADHD who cannot use or prefers to avoid stimulant therapy, what are the first‑line non‑stimulant medication options, their dosing schedules, monitoring requirements, and major contraindications?

Non-Stimulant ADHD Medications: First-Line Options and Clinical Management

Atomoxetine is the first-line non-stimulant medication for ADHD, started at 40 mg/day and titrated to 80–100 mg/day over 6–12 weeks, with guanfacine extended-release (1–7 mg/day) and clonidine extended-release (0.1–0.4 mg/day) serving as second-line alternatives or adjunctive agents. 1

Primary Non-Stimulant: Atomoxetine

Dosing Protocol

• Start at 40 mg once daily, then titrate to a target dose of 80–100 mg/day, with a maximum of 100 mg/day or 1.4 mg/kg/day, whichever is lower. 1
• The medication can be administered once daily or split into two doses to reduce adverse effects. 1
• Full therapeutic effect requires 6–12 weeks, substantially longer than stimulants which work immediately. 1

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. 1
• It provides continuous 24-hour symptom coverage without peaks and valleys. 1
• The medication has a lower risk of exacerbating anxiety symptoms compared to stimulants and less impact on appetite and growth. 1

Monitoring Requirements

• Baseline assessment: blood pressure, heart rate, weight, and suicidality screening. 1
• Follow-up at 2–4 weeks: monitor vital signs, side effects, and early response. 1
• Therapeutic assessment at 6–12 weeks: evaluate ADHD symptom scales, functional impairment, and quality of life. 1
• Ongoing monitoring: quarterly vital signs, annual growth parameters if applicable, and continuous suicidality monitoring. 1

Major Contraindications and Warnings

• FDA Black Box Warning: Close monitoring for suicidal ideation is required, especially during the first few weeks of treatment and during dose adjustments. 1
• Atomoxetine is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOIs. 2
• Use caution in patients with cardiovascular disease, hypertension, tachycardia, or cardiovascular abnormalities. 2

Preferred Clinical Scenarios

• Patients with comorbid substance use disorders (non-controlled medication status). 1
• Comorbid anxiety or autism spectrum disorder. 1
• Tic disorders or Tourette's syndrome (does not worsen tics). 1
• Patients who prefer to avoid stimulants or have failed stimulant therapy. 1

Second-Line Non-Stimulant: Guanfacine Extended-Release

Dosing Protocol

• Start at 1 mg once daily, titrate by 1 mg per week based on response and tolerability. 3
• Target dose range: 0.05–0.12 mg/kg/day or 1–7 mg/day. 3
• Evening administration is strongly preferred to minimize daytime somnolence and fatigue. 3

Efficacy and Onset

• Effect size of approximately 0.7 compared to placebo. 3
• Therapeutic effects require 2–4 weeks before clinical benefits are observed, unlike stimulants which work immediately. 3
• Provides "around-the-clock" symptom control with once-daily dosing. 3

Monitoring Requirements

• Baseline blood pressure and heart rate must be obtained before initiation. 3
• Monitor cardiovascular parameters at each dose adjustment and periodically during maintenance therapy. 3
• Expect modest decreases in blood pressure (1–4 mmHg) and heart rate (1–2 bpm). 3

Major Contraindications and Warnings

• Never abruptly discontinue guanfacine—taper by 1 mg every 3–7 days to avoid rebound hypertension. 3
• Contraindicated in patients with baseline bradycardia (heart rate <60 bpm) or hypotension (systolic BP <90 mmHg). 3
• Screen for personal or family history of cardiac conditions including Wolff-Parkinson-White syndrome, sudden death, hypertrophic cardiomyopathy, and long QT syndrome. 3

Common Adverse Effects

• Somnolence/sedation (most frequent, occurring in 20.5% of patients). 3
• Fatigue (15.2% of patients). 3
• Headache, dry mouth, dizziness, irritability, constipation (5–16%), and abdominal pain. 3

Preferred Clinical Scenarios

• Comorbid tic disorders (may reduce tic severity). 3
• Comorbid sleep disturbances (sedating properties improve sleep onset). 3
• Comorbid anxiety disorders. 1
• Substance use disorder populations (non-controlled medication). 3

Third-Line Non-Stimulant: Clonidine Extended-Release

Dosing Protocol

• Start at 0.1 mg once daily at bedtime. 4
• Titrate by 0.1 mg every 3–7 days based on blood pressure response and tolerability. 4
• Maximum dose: 0.4 mg/day. 4

Key Differences from Guanfacine

• Less selective for alpha-2A receptors compared to guanfacine, resulting in more pronounced sedation and cardiovascular effects. 4
• Greater risk of rebound hypertension after abrupt discontinuation than guanfacine. 4
• Requires twice-daily dosing in some cases, reducing adherence compared to guanfacine's once-daily regimen. 3

Safety Warnings

• Must be tapered by 0.1 mg every 3–7 days—never stop abruptly to avoid hypertensive crisis. 4
• Monitor blood pressure and heart rate at baseline and during dose adjustments. 4

When to Consider Clonidine Over Guanfacine

• When guanfacine is unavailable or not tolerated. 4
• Comorbid tics or Tourette syndrome (may help reduce tic severity, though evidence is mixed). 4
• Sleep disturbances requiring bedtime administration. 4

Combination Therapy with Stimulants

FDA-Approved Adjunctive Use

• Both guanfacine extended-release and clonidine extended-release are FDA-approved specifically for adjunctive therapy with stimulants. 3
• Combination therapy allows for lower stimulant dosages while maintaining efficacy and potentially reducing stimulant-related adverse effects. 3

When to Add Non-Stimulants to Stimulants

• ADHD symptoms remain inadequately controlled despite optimized stimulant monotherapy. 3
• Stimulant-related sleep disturbances require management. 3
• Adolescents with substance abuse risk may benefit from adding guanfacine to minimize stimulant exposure. 3

Monitoring During Combination Therapy

• Check blood pressure and heart rate at each dose adjustment, as stimulants raise these parameters while alpha-2 agonists lower them. 3
• Monitor for excessive somnolence, hypotension, and bradycardia. 3

Treatment Algorithm for Non-Stimulant Selection

Clinical Scenario	First Choice	Rationale
Standard ADHD without comorbidities	Atomoxetine 40→80–100 mg/day	Strongest evidence, 24-hour coverage, fewer side effects [1]
Comorbid tic disorder	Guanfacine ER 1→4–7 mg/day	May reduce tics, does not worsen tics [3]
Comorbid sleep disturbance	Guanfacine ER (evening dosing)	Sedating properties improve sleep onset [3]
Comorbid anxiety disorder	Atomoxetine or Guanfacine ER	Lower risk of anxiety exacerbation [1]
Substance use disorder history	Atomoxetine or Guanfacine ER	Non-controlled medications [1]
Partial response to stimulant	Add Guanfacine ER or Clonidine ER	FDA-approved adjunctive therapy [3]
Guanfacine failure or intolerance	Atomoxetine	Different mechanism, better tolerability [4]
Atomoxetine and Guanfacine failure	Clonidine ER	Alternative alpha-2 agonist [4]

Critical Safety Pitfalls to Avoid

• Do not abruptly discontinue guanfacine or clonidine—always taper to prevent rebound hypertension. 3, 4
• Do not expect immediate results with non-stimulants—counsel families that atomoxetine requires 6–12 weeks and guanfacine/clonidine require 2–4 weeks for full therapeutic effect. 3, 1
• Do not combine two alpha-2 agonists (clonidine + guanfacine together)—this increases sedation risk and cardiovascular effects without clear evidence of superior efficacy. 3
• Do not overlook suicidality monitoring with atomoxetine—the FDA Black Box Warning requires close monitoring, especially during initiation and dose changes. 1
• Do not initiate clonidine at full 1 mg dose—start at 0.1 mg to avoid excessive hypotension and sedation. 4

When Non-Stimulants Are Preferred as First-Line

While stimulants demonstrate larger effect sizes (approximately 1.0) compared to non-stimulants (approximately 0.7) and remain first-line therapy for most patients, non-stimulants should be strongly preferred as first-line when ADHD co-occurs with: 3, 1

• Sleep disturbances (guanfacine evening dosing addresses both conditions)
• Tic disorders (guanfacine/atomoxetine do not worsen tics)
• Substance use risk (non-controlled medications)
• Stimulant contraindications or intolerance
• Patient/family preference to avoid stimulants