Nonstimulant Medications for ADHD

Introduction to Nonstimulant Options

The American Academy of Pediatrics recommends that nonstimulant medications, such as Strattera (atomoxetine), clonidine extended-release, and guanfacine extended-release, be reserved as second-line agents for ADHD treatment due to their smaller effect sizes (~0.7 vs 1.0 for stimulants) 1

Atomoxetine, extended-release guanfacine, and extended-release clonidine 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

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 2
Clonidine is also an alpha-2 adrenergic agonist but has less receptor specificity than guanfacine, resulting in a more sedating effect 2

Atomoxetine can cause initial somnolence and gastrointestinal symptoms, particularly if dosage is increased too rapidly, as well as decreased appetite, increased suicidal thoughts, and rare but serious hepatitis 1
Guanfacine extended-release commonly causes somnolence/sedation, dry mouth, headache (20.5%), and fatigue (15.2%), with less common effects including constipation (5-16% of patients) and modest decreases in blood pressure and heart rate 1, 2

Alpha-2 agonists (guanfacine and clonidine) must never be abruptly discontinued and require tapering by 1 mg every 3-7 days to avoid rebound hypertension, with warnings for hypotension/bradycardia, cardiac conduction abnormalities, and allergic reactions 2
Baseline blood pressure and heart rate must be obtained before initiation of alpha-2 agonists, with monitoring during dose adjustments, and special attention is required for patients with cardiac history 2

Atomoxetine and alpha-2 agonists require 2-4 weeks before clinical benefits are observed, unlike stimulants which work immediately, making patient counseling on delayed onset crucial to prevent premature discontinuation 2
Guanfacine dosing starts at 1 mg once daily, titrated by 1 mg per week, with a target range of 0.05-0.12 mg/kg/day or 1-7 mg/day, and evening administration is generally preferable to minimize daytime somnolence and fatigue 2

Only extended-release guanfacine and extended-release clonidine have FDA approval and sufficient evidence for use as adjunctive therapy with stimulants, while atomoxetine can be combined with guanfacine off-label for inadequate symptom control 1, 2
In children with substance use disorders, guanfacine or atomoxetine may be preferred due to their non-controlled medication status, and guanfacine may be particularly appropriate when ADHD co-occurs with disruptive behavior disorders or oppositional symptoms 2

Expecting immediate results from nonstimulant medications and not counseling families about the 2-4 week delay in benefits, abruptly stopping alpha-2 agonists without tapering, and rapidly escalating atomoxetine dosing can lead to adverse effects or treatment failure 1, 2