Non-Stimulant ADHD Medication (Guanfacine) as an Adjunct to ADHD Stimulant Medications

A Research Review

Psychiatry Research 2016 236:136-141.  DOI: 10.1016/j.psychres.2015.12.017  “Supplementary guanfacine hydrochloride as a treatment of attention deficit hyperactivity disorder in adults: A double blind, placebo-controlled study.” Butterfield ME, Saal J, Young B, Young JI.

Guanfacine hydrochloride is a selective alpha-2A partial agonist that is FDA approved for the treatment of ADHD in children and adolescents (see recent reviews by Faraone et al, 2013; Hirota et al, 2014 and Ruggiero et al 2014).  It can be given alone or in combination with psychostimulant medication as its mechanism of action is complementary to these agents.   Despite growing scientific evidence of its effectiveness for this age group, very little is known about the potential benefits of guanfacine for the treatment of ADHD in adults.

In view of concerns about the importance of finding suitable non-stimulant ADHD medications for this population, the authors carried out a randomized placebo controlled trial of extended release guanfacine (GXR) as supplemental treatment for subjects with a suboptimal response to stimulant-only medication treatment. 

Subjects were recruited from local advertisements and from the clinic practice of the authors in suburban Detroit.  Entry criteria included a current diagnosis of ADHD, current treatment with a stimulant medication, and suboptimal response to this medication as evidenced by a score of > 28 on the Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) or of > 4 on the Clinical Global Impression – Severity (CGI-S) Scale.  Exclusion criteria included having another severe Axis I psychiatric disorder, along with subjects with a history of autism, chemical dependence or psychosis.  Subjects with hypertension or any medical condition that might be exacerbated by the study medication.  A total of 26 subjects in the age range of 19 – 62 years were recruited for the study, of which roughly 50% were women, and 85% were Caucasian.  Subjects were randomly assigned to receive either placebo or incremental doses of GXR ranging from 1 to 6 mg daily on a weekly basis over a 10-week study period. 

The primary outcome measures were the ADHD Rating Scale and the Clinical Global Impression – Severity.  Secondary outcome measures included the Arizona Sexual Experience Questionnaire, the Fatigue Symptom Inventory, the Pittsburgh Sleep Quality Index, the Hamilton Anxiety Inventory and the Hamilton Depression Rating Scale.  Baseline and weekly measures of cardiovascular status were collected throughout the study. 

Contrary to the study authors’ expectations, although subjects in both the placebo and the treatment arms of the study showed significant improvements in both primary and secondary outcome measures, the two groups did not differ from one another.  For instance, the mean ADHD-RS score of the placebo group decreased by 10.92 (from 35.23 to 24.31) and that of the GXR treated group decreased by 11.85 (from 35.92 to 24.08).  The CGI-S score in the placebo group decreased by 1.00 and that of the GXR group by 0.85.  There were no differences between the two groups on measures of tolerability, hemodynamics, sleep, anxiety or depression.  Moreover, no treatment x time x group effects were noted. 

The authors comment that several explanations can account for these findings including a strong placebo effect, a generalized study effect (i.e. participating in a clinical trial itself may be beneficial in and of itself), a “regression to the mean” effect for the placebo group, and a potential bias induced by participating in a clinical trial.   Of note, there were no between group differences seen in fatigue, sleep problems, sexual functioning or in hemodynamic measures – a finding that supports the tolerability and safety of GXR in adult patients. 

While this is a “negative study,” it is helpful in clarifying that GXR can be used safely in combination with stimulant medications, that it does not worsen other psychiatric symptoms (e.g. anxiety, depression) and that it may be a helpful adjunctive treatment for adults with ADHD whose stimulant medication is not sufficiently helpful in reducing their symptoms.  Further research with a larger sample size and with measures taken to minimize the placebo effect are certainly warranted.  In the meantime, clinicians who are considering using GXR can be reassured that it is well tolerated in this population.


Faraone SV, McBurnett K, Sallee FR, Steeber J, López FA (2013). Guanfacine extended release: a novel treatment for attention-deficit/hyperactivity disorder in children and adolescents. Clinical Therapeutics Nov;35(11):1778-93. doi: 10.1016/j.clinthera.2013.09.005

Hirota T, Schwartz S, Correll CU (2014). Alpha-2 Agonists for Attention-Deficit/Hyperactivity Disorder in youth: A Systematic Review and Meta-Analysis of Monotherapy and Add-On Trials to Stimulant Therapy. J. Amer.. Acad. Child Adolesc. Psychiatry 53(2):153–173.

Ruggiero S, Clavenna A, Reale L, Capuano A, Rossi F, Bonati M (2014). Guanfacine for attention deficit and hyperactivity disorder in pediatrics: A systematic review and meta-analysis.  European Neuropsychopharmacology 24: 1578-1590.