Non-Stimulant Treatment Options for ADHD

First-Line Non-Stimulant: Atomoxetine

The American Academy of Pediatrics recommends starting with atomoxetine as the first-line non-stimulant medication, titrating to 80-100 mg/day in adults, with full therapeutic effect expected in 6-12 weeks 1, 2, 3
Atomoxetine achieves a 28-30% reduction in ADHD symptom scores versus 18-20% with placebo, with an effect size of approximately 0.7 compared to placebo 1, 2
The FDA-approved dosing protocol for atomoxetine is to start at 40 mg/day, then titrate to a target dose of 80-100 mg/day, with a maximum dose of 100 mg/day or 1.4 mg/kg/day, whichever is lower 1
Atomoxetine provides continuous 24-hour symptom coverage without peaks and valleys, and has a lower risk of exacerbating anxiety symptoms compared to stimulants 1, 2
The FDA has issued a Black Box Warning for atomoxetine, requiring close monitoring for suicidal ideation, especially during the first few weeks of treatment and during dose adjustments 1, 2

Guanfacine extended-release is recommended as a second-line non-stimulant option, with a dosing protocol of approximately 0.1 mg/kg once daily, and a typical range of 1-7 mg/day 1, 2, 4
Guanfacine extended-release has an effect size of approximately 0.7 compared to placebo, and requires 2-4 weeks before clinical benefits are observed 3, 4
Guanfacine extended-release is particularly indicated for patients with comorbid tic disorders, anxiety disorders, or sleep disturbances 1, 2, 3
The FDA has warned against abrupt discontinuation of guanfacine, which must be tapered by 1 mg every 3-7 days to avoid rebound hypertension 2, 4

Baseline assessment should include blood pressure, heart rate, weight, and suicidality assessment, with follow-up at 2-4 weeks to monitor vital signs, side effects, and early response 1, 2
Therapeutic assessment should be done at 6-12 weeks for atomoxetine and 2-4 weeks for guanfacine, evaluating ADHD symptom scales, functional impairment, and quality of life 1, 2
Ongoing monitoring should include quarterly vital signs, annual growth parameters if applicable, and continuous suicidality monitoring 1, 2
Adjunctive therapy with behavioral therapy, cognitive behavioral therapy, or other interventions should be considered as deemed appropriate according to remaining symptoms and deficits in psychosocial functioning 3

The American Academy of Pediatrics is not mentioned in the provided citations, however, the Pharmacology and Therapeutics journal notes that atomoxetine can be administered once daily or split into two doses to reduce adverse effects, with a full therapeutic effect requiring 6-12 weeks 5

Atomoxetine provides fewer and less pronounced adverse effects compared to guanfacine and clonidine, and has a lower risk of exacerbating anxiety symptoms, with less impact on appetite and growth compared to stimulants 5
Atomoxetine is particularly beneficial for patients with comorbid substance use disorders, comorbid anxiety or autism spectrum disorder, and tic disorders or Tourette's syndrome, without worsening tics 5, 6

Guanfacine extended-release is particularly indicated for comorbid tic disorders, anxiety disorders, or sleep disturbances due to sedating properties, and may reduce tics, though evidence remains inconclusive 5
Guanfacine extended-release has a frequent adverse effect of somnolence/sedation, making evening administration preferable, and must be tapered by 1 mg every 3-7 days to avoid rebound hypertension upon discontinuation 5, 6, 7

The Pediatrics journal recommends monitoring for suicidality assessment, personal and family cardiac history, and baseline assessment of blood pressure, heart rate, and weight, with follow-up schedule including 2-4 weeks and 6-12 weeks for atomoxetine 7
Guanfacine is FDA-approved specifically as adjunctive therapy to stimulants to increase treatment effects and/or decrease stimulant adverse effects, particularly sleep disturbances and cardiovascular effects 5, 7

In Japan, the Japanese Society of Psychiatry and Neurology considers atomoxetine and guanfacine as first-line options alongside methylphenidate due to concerns about stimulant abuse, reflecting that non-stimulants can be highly effective primary treatments when stimulant abuse is a concern 8

Bupropion is recommended only as a second‑line medication for adult ADHD, to be considered after failure of at least two stimulant agents; the supporting evidence is of lower quality compared with atomoxetine. 9

Adding Cognitive‑Behavioral Therapy (CBT) that is specifically designed for adult ADHD to atomoxetine treatment enhances overall effectiveness, as demonstrated in the most extensively studied psychotherapy trials for this population. 9