Review of: Iwanami A et al, J Clin Psychiatry 2020;81(3):19m12979

Study type: Randomized, double-blind, placebo-controlled trial

Stimulants are rapid, safe, and effective first-line treatments for many adults with ADHD. However, there are inevitably patients for whom stimulants are not indicated or tolerated—those with arrhythmias or stimulant use disorders, for example. Currently our only FDA-approved non-stimulant for adults with ADHD is atomoxetine (Strattera). The alpha-2A agonists—guanfacine ER (Intuniv) and clonidine ER (Kapvay)—are FDA approved for ADHD in children and adolescents but so far have lacked controlled trials in adult ADHD.

This 12-week, randomized, double-blind, placebo-controlled study of guanfacine ER was funded by Takeda, the manufacturer of Intuniv. It took place in 2016–2017 across several sites in Japan. Researchers randomly assigned 201 adults (average age 32, 65% male) with ADHD to either guanfacine ER or placebo. Half had combined ADHD, half had inattentive type, and very few (2%) had the hyperactive type. The dose of guanfacine ER was titrated over 5 weeks toward a target of 4–6 mg/day (average 5 mg/day), followed by a 5-week maintenance period and then a 2-week forced taper. The primary endpoint was overall symptom reduction by the Japanese-validated ADHD-RS-IV, a clinician-administered rating scale.

On average, participants who received guanfacine ER saw their ADHD scores drop from 31 (out of 54) to 20 points at the end of the treatment phase, compared to a drop from 31 to 24 for those receiving placebo. Improvements were similar for inattentive and hyperactive symptoms. This was statistically significant and corresponded to an effect size of 0.5 for guanfacine ER (similar to atomoxetine’s effect size in adults but smaller than the 0.7–0.9 effect size of stimulants). There were no significant reductions in either hyperactive symptoms or overall quality of life, although these were secondary endpoints.

A noteworthy 20% of patients receiving guanfacine ER discontinued treatment, with side effects including sedation, hypotension, and dizziness. It also caused a slight reduction in heart rate and prolongation of QTc relative to placebo, and in 2% of patients those EKG changes were still detectable 2 weeks after the medicine was stopped.

TCPR’s Take
Guanfacine ER appears to be a third-line drug for ADHD. It works, but is less effective than stimulants and not as well studied as atomoxetine. For healthy patients who cannot tolerate stimulants or have other reasons to avoid them, you might consider a trial of guanfacine—if atomoxetine is not helpful. Cost is not prohibitive with guanfacine ER, which went generic in 2015. Tolerability is the main drawback, and its cardiac effects may pose a problem in patients who are older or frailer than the ones enrolled in this study.

Listen to our 10/26/20 podcast, “How to Use Guanfacine and Clonidine.” Search for “Carlat” on your podcast store.