Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who do not respond well to psychostimulant monotherapy may benefit from adding guanfacine extended-release (Intuniv, Shire), a post hoc analysis of a randomized controlled trial shows.

Among a group of children and adolescents who had a suboptimal but at least partial response to a psychostimulant, adding guanfacine extended-release produced greater response and symptomatic remission rates than continued psychostimulant monotherapy, the researchers, led by Andrew J. Cutler, MD, of the Florida Clinical Research Center in Bradenton, note.

The study was published online August 18 in the Journal of the American Academy of Child and Adolescent Psychiatry.

A Realistic Goal

Several prior studies defined response as at least a 40% reduction in symptoms on the ADHD Rating Scale IV (ADHD-RS-IV), but the new analysis also used the more rigorous definition of at least a 50% reduction in symptom scores.

The 9-week, double-blind, placebo-controlled study included 461 children and adolescents aged 6 to 17 years with a suboptimal response to psychostimulant monotherapy who added either guanfacine extended-release once daily in the morning (GXR AM) or in the evening (GXR PM), or matching placebo.

With response defined as at least a 40% reduction in ADHD-RS-IV total scores, 69.8% of those who added GXR in the morning and 70.3% of those who added GXR in the evening achieved response, compared with 57.9% of those who added placebo to psychostimulant monotherapy, the researchers report.

With response defined as at least a 50% reduction in ADHD-RS-IV total scores, response rates were 63.1% with GXR AM, 64.9% with GXR PM, and 43.4% with placebo.

Results were similar for symptomatic remission (ADHD-RS-IV total scores ≤ 18: 61.1% and 62.2%, vs 46.1%) and syndromal remission (symptomatic remission plus Clinical Global Impressions of Severity of Illness score ≤ 2), they note.

No new or unexpected treatment-emergent adverse effects (TEAEs) were noted with the addition of GXR to psychostimulant monotherapy. The most common TEAEs in children receiving GXR were headache (21.2%) and somnolence (13.6%).

Although psychostimulants are widely used to manage ADHD symptoms, for 25% to 30% of children and adolescents, their symptoms are not adequately managed by psychostimulant monotherapy, the investigators note.

"Current evidence suggests that symptomatic remission may be a realistic goal in ADHD treatment, and the results of the present analysis support the feasibility of this treatment goal using GXR as an add-on when psychostimulant response is suboptimal," the authors conclude.

Confirmatory Findings

"This is an important confirmatory finding but also of incremental value because it used a more stringent definition of response," Stephen V. Faraone, PhD, distinguished professor of psychiatry and of neuroscience and physiology, SUNY Upstate Medical University, in Syracuse, New York, who was not involved in the study, told Medscape Medical News.

Dean Elbe, PharmD, BCPP, clinical pharmacy specialist in child and adolescent mental health at BC Children's Hospital in Vancouver, British Columbia, Canada, told Medscape Medical News that stimulants have a "very high effect size, but even so, with some kids, you eventually hit the wall with the dose and they still have symptoms."

"Guanfacine, when used by itself, has a moderate to large effect size, and when you add it to stimulants, it still has a moderate effect size, so it looks like there is some value to using the combo," added Dr. Elbe, who was not involved in the study.

He noted that these reanalysis data look at response and remission rates, "which we don't really have in a lot of the other RCTs with guanfacine. I find physicians like the response and remission data, as it gives them a better sense of how likely it is that my patient is going to get better. And they did use a fairly stringent definition."

Shire Development LLC provided funding for the study. Several authors have disclosed relationships with the company and other pharmaceutical companies. The original article contains a complete list of relevant financial relationships.

J Am Acad Child Adolesc Psychiatry. Published online August 18, 2014. Abstract