What are the differences between Straterra (atomoxetine), clonidine, and guanfacine for treating Attention Deficit Hyperactivity Disorder (ADHD)?

Strattera vs Clonidine vs Guanfacine for ADHD

All three medications—Strattera (atomoxetine), clonidine extended-release, and guanfacine extended-release—are FDA-approved nonstimulant options for ADHD that are less effective than stimulants (effect sizes ~0.7 vs 1.0 for stimulants) and should be reserved as second-line agents when stimulants fail, are not tolerated, or are contraindicated. 1

Comparative Efficacy

• Atomoxetine (Strattera), extended-release guanfacine, and extended-release clonidine all demonstrate similar moderate efficacy with effect sizes of approximately 0.7 compared to placebo, which is notably weaker than stimulants that achieve effect sizes around 1.0 1
• The evidence base supporting stimulants is considerably larger and more robust than for these nonstimulants, though all three have adequate evidence for FDA approval 1
• None of these medications are approved for preschool-aged children 1

Mechanism of Action Differences

• Atomoxetine is a selective norepinephrine reuptake inhibitor that works by blocking norepinephrine reuptake 1, 2
• Guanfacine is an alpha-2A adrenergic receptor agonist with higher specificity for alpha-2A receptors, which enhances noradrenergic neurotransmission in the prefrontal cortex and may explain its less sedative profile compared to clonidine 3
• Clonidine is also an alpha-2 adrenergic agonist but has less receptor specificity than guanfacine 3

Adverse Effect Profiles

Atomoxetine (Strattera):

• Initial somnolence and gastrointestinal symptoms, particularly if dosage is increased too rapidly 1
• Decreased appetite 1
• Increased suicidal thoughts (less common but important) 1
• Hepatitis (rare but serious) 1

Guanfacine Extended-Release:

• Somnolence/sedation and dry mouth are the primary adverse effects 1
• Headache (20.5%) and fatigue (15.2%) are common 3
• Constipation affects 5-16% of patients in a dose-dependent manner 3
• Modest decreases in blood pressure and heart rate, though typically not clinically significant 3
• Less sedating than clonidine due to higher alpha-2A receptor specificity 3

Clonidine Extended-Release:

• Somnolence and dry mouth 1
• Generally more sedating than guanfacine 3

Critical Safety Considerations

For Alpha-2 Agonists (Guanfacine and Clonidine):

• Must never be abruptly discontinued—requires tapering by 1 mg every 3-7 days to avoid rebound hypertension 3
• Warnings exist for hypotension/bradycardia, cardiac conduction abnormalities, and allergic reactions 3
• Baseline blood pressure and heart rate must be obtained before initiation, with monitoring during dose adjustments 3
• Patients with cardiac history (Wolf-Parkinson-White syndrome, unexplained fainting, family history of sudden cardiac death) require special attention 3

For Atomoxetine:

• Monitor for suicidal ideation, especially during initiation 1
• Watch for signs of hepatotoxicity 1

Onset of Action

• Atomoxetine and alpha-2 agonists require 2-4 weeks before clinical benefits are observed, unlike stimulants which work immediately 3
• This delayed onset is a critical counseling point to prevent premature discontinuation 3

Dosing Considerations

Guanfacine:

• Starting dose: 1 mg once daily, titrated by 1 mg per week 3
• Target range: 0.05-0.12 mg/kg/day or 1-7 mg/day 3
• Evening administration is generally preferable to minimize daytime somnolence and fatigue 3

Clonidine and Atomoxetine:

• Specific dosing details not provided in guidelines, but follow FDA-approved dosing schedules 1

Adjunctive Therapy

• Only extended-release guanfacine and extended-release clonidine have FDA approval and sufficient evidence for use as adjunctive therapy with stimulants 1, 3
• Atomoxetine can be combined with guanfacine for inadequate symptom control, though this is off-label 3
• Never combine clonidine and guanfacine together—this increases sedation risk and cardiovascular effects without clear evidence of superior efficacy 3

Special Clinical Scenarios

• In children with substance use disorders, guanfacine or atomoxetine may be preferred due to their non-controlled medication status 3
• When ADHD co-occurs with disruptive behavior disorders or oppositional symptoms, guanfacine may be particularly appropriate 3
• Guanfacine can potentially decrease stimulant-related adverse effects such as sleep disturbances when used adjunctively 3

Common Pitfalls to Avoid

• Do not expect immediate results—counsel families that 2-4 weeks are needed for nonstimulants to show benefit 3
• Never abruptly stop alpha-2 agonists without tapering 3
• Do not rapidly escalate atomoxetine dosing, as this increases gastrointestinal side effects 1
• Do not use these as first-line agents when stimulants are appropriate—they are second-line due to smaller effect sizes 3
• Monitor cardiovascular parameters during dose adjustments for alpha-2 agonists 3