What are the alternatives for managing Attention Deficit Hyperactivity Disorder (ADHD) symptoms when stimulants are contraindicated?

When Stimulants Are Contraindicated for ADHD

When stimulants are contraindicated, atomoxetine should be the first-line pharmacological alternative, with extended-release guanfacine or extended-release clonidine as second-line options, always combined with behavioral therapy. 1, 2

Absolute Contraindications to Stimulants

Stimulants must be avoided in patients with: 1

• Previous hypersensitivity to stimulant medications
• Glaucoma
• Symptomatic cardiovascular disease
• Hyperthyroidism
• Hypertension
• History of illicit stimulant use or abuse (unless in a controlled, supervised setting)
• Concomitant MAO inhibitor use
• Active psychotic disorder

First-Line Alternative: Atomoxetine

Atomoxetine is the only FDA-approved nonstimulant medication for ADHD across all age groups and should be your primary choice when stimulants are contraindicated. 2

Key Prescribing Details:

• Starting dose (children/adolescents ≤70 kg): 0.5 mg/kg/day, increase after minimum 3 days to target of 1.2 mg/kg/day 2
• Maximum dose: 1.4 mg/kg/day or 100 mg/day, whichever is less 2
• Onset of action: 6-12 weeks for full therapeutic effect (significantly slower than stimulants) 1
• Effect size: 0.7 (compared to 1.0 for stimulants) 1
• Administration: Can be given once daily (morning) or divided twice daily to reduce GI side effects 1, 2

Specific Advantages:

• Non-controlled substance (no abuse potential) 1, 3
• Around-the-clock symptom coverage 1
• Fewer appetite/growth concerns compared to stimulants 1
• Particularly useful in comorbid conditions: substance use disorders, tic disorders, anxiety disorders 1, 3

Critical Safety Warning:

Black box warning for suicidal ideation in children/adolescents (0.4% vs 0% placebo). Monitor closely, especially early in treatment. 2

Second-Line Alternatives: Alpha-2 Agonists

When atomoxetine is not tolerated or ineffective, use extended-release guanfacine or extended-release clonidine. 1

Prescribing Hierarchy:

1. Extended-release guanfacine (preferred over clonidine due to better tolerability) 1
2. Extended-release clonidine 1

Key Details:

• Effect size: 0.7 (similar to atomoxetine) 1
• Onset: 2-4 weeks 1
• Dosing: Evening administration preferred due to somnolence 1
• Specific benefits: May help with sleep disturbances and tics 1
• FDA approval: Both approved as monotherapy AND as adjunctive therapy to stimulants 1

Common Pitfall:

Alpha-2 agonists cause more frequent somnolence and sedation compared to atomoxetine. 1 Start low and titrate slowly.

Essential Behavioral Therapy Component

Behavioral interventions are NOT optional when stimulants are contraindicated—they become even more critical. 1

Age-Specific Behavioral Approaches:

Preschool-aged children (4-5 years):

• Parent training in behavior management (PTBM) should be initiated FIRST before any medication 1
• Many young children improve with behavioral therapy alone 1
• Medication only if moderate-to-severe dysfunction persists after behavioral therapy 1

School-aged children (6-12 years):

• PTBM combined with medication provides optimal outcomes 1, 4
• Behavioral therapy addresses functional impairments that medications alone cannot 1

Adolescents (13-18 years):

• School-based training interventions focused on organizational and study skills show consistent benefits 1
• Family behavioral therapy has mixed evidence but may help some adolescents 1

Treatment Algorithm When Stimulants Are Contraindicated

Step 1: Initiate Behavioral Therapy

• Start PTBM for all ages 1
• For preschoolers, trial behavioral therapy alone for adequate duration before medication 1

Step 2: Add Atomoxetine

• First-choice nonstimulant medication 2, 3, 5
• Titrate to 1.2 mg/kg/day over 3+ days 2
• Allow 6-12 weeks for full effect 1
• Monitor for suicidal ideation, especially first 4 weeks 2

Step 3: If Atomoxetine Fails or Not Tolerated

• Switch to extended-release guanfacine (preferred) 1
• Alternative: extended-release clonidine 1
• Continue behavioral interventions throughout 1

Step 4: Consider Combination Therapy

• Atomoxetine + alpha-2 agonist can be combined if monotherapy insufficient 1
• Limited evidence but used in clinical practice 1

What NOT to Use

Insufficient evidence or not recommended: 1

• Cognitive training
• Neurofeedback
• EEG biofeedback
• Dietary modifications (except in specific documented deficiencies)
• Omega-3 fatty acids
• Mindfulness
• Cannabidiol oil
• External trigeminal nerve stimulation (eTNS)—only one small 5-week trial 1

Third-line options only (off-label, limited evidence): 3, 6

• Bupropion
• Tricyclic antidepressants (limited by cardiac side effects)
• Modafinil (investigational)

Critical Monitoring Parameters

For atomoxetine: 2

• Suicidal ideation (especially weeks 1-4)
• Blood pressure and heart rate
• Growth parameters
• Liver function (rare hepatotoxicity)

For alpha-2 agonists: 1

• Blood pressure and heart rate (can cause hypotension/bradycardia)
• Somnolence/sedation
• Do NOT abruptly discontinue (risk of rebound hypertension)

Special Population: Comorbid Substance Use Disorder

Atomoxetine is strongly preferred when substance use disorder is present or there is high risk of stimulant diversion, as it has no abuse potential. 1, 3 This is a critical clinical scenario where nonstimulants are not just alternatives but may be superior choices.