Non-Stimulant Medications for ADHD

FDA-Approved Non-Stimulant Medications

The American Academy of Pediatrics recommends atomoxetine, extended-release guanfacine, and extended-release clonidine as FDA-approved non-stimulant medications for ADHD treatment, with atomoxetine being the first-line non-stimulant choice and the only agent approved across the entire lifespan from children to adults 1, 2
Atomoxetine is a selective norepinephrine reuptake inhibitor approved for ADHD treatment in children aged 6 years and older, adolescents, and adults, with an effect size of approximately 0.7 1
The medication has a dosing schedule of starting at 40 mg/day in adults, then titrating to a target dose of 80-100 mg/day, and full therapeutic effects require 6-12 weeks 1, 3
Extended-release guanfacine is an alpha-2 adrenergic agonist approved for ADHD treatment in children and adolescents aged 6-17 years, with a dosing schedule of approximately 0.1 mg/kg once daily 1, 4
Extended-release clonidine is an alpha-2 adrenergic agonist approved for ADHD treatment in children and adolescents aged 6-17 years, with FDA approval for both monotherapy and adjunctive therapy to stimulant medications 1, 3, 4

Non-stimulants have a non-controlled substance status, eliminating abuse potential and diversion risk, making them particularly indicated for patients with comorbid substance use disorders 3, 2
Non-stimulants are preferred for patients with comorbid tic disorders or Tourette's syndrome, as they have a lower risk of exacerbating symptoms 3
Non-stimulants have a lower risk of exacerbating anxiety symptoms compared to stimulants, making them a suitable option for patients with comorbid anxiety disorders 3, 2

The FDA recommends monitoring patients closely for suicidal ideation, especially during the first few weeks of treatment and during dose adjustments, when using atomoxetine 2
Common adverse effects of atomoxetine include somnolence, fatigue, irritability, insomnia, nightmares, initial gastrointestinal symptoms, and decreased appetite 1, 3
Alpha-2 agonists, such as guanfacine and clonidine, have adverse effects including somnolence, dry mouth, dizziness, irritability, headache, bradycardia, hypotension, and abdominal pain, and require tapering off rather than sudden discontinuation to avoid rebound hypertension 5

Atomoxetine is the first-line non-stimulant choice unless specific contraindications exist, such as severe cardiovascular disease, narrow-angle glaucoma, pheochromocytoma, or concurrent MAOI use 2
Guanfacine can be considered as a second-line option if atomoxetine is ineffective or intolerable, or if comorbid tics, anxiety, or sleep disturbances are present 3, 2

Only extended-release guanfacine and extended-release clonidine have FDA approval for adjunctive therapy with stimulant medications, which can increase treatment effects and/or decrease adverse effects of stimulants 1, 5, 3

Baseline assessment should include blood pressure, heart rate, weight, and suicidality assessment, with follow-up monitoring at 2-4 weeks to assess vital signs, side effects, and early response 2
Therapeutic assessment requires 6-12 weeks for atomoxetine and 2-4 weeks for guanfacine, with evaluation of ADHD symptom scales, functional impairment, and quality of life 2

No non-stimulant medication has received sufficient rigorous study in the preschool-aged population to be recommended for treatment of ADHD in children 4 through 5 years of age 5
Before beginning medication treatment of adolescents with newly diagnosed ADHD, assess for symptoms of substance use, and refer to a subspecialist for consultative support if active substance use is identified 5