Combined Stimulant and Guanfacine Administration in Attention-Deficit/Hyperactivity Disorder: A Controlled, Comparative Study

J Am Acad Child Adolesc Psychiatry. 2016 Aug;55(8):657-666.e1. doi: 10.1016/j.jaac.2016.05.015. Epub 2016 Jun 3.


Objective: Because models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and α2A agonism may yield enhanced clinical and cognitive responses. This study tested the hypothesis that combined effects of a dopamine and noradrenergic agonist, d-methylphenidate extended-release (DMPH) with guanfacine (GUAN), an α2A receptor agonist, would be clinically superior to either monotherapy and would have equal tolerability.

Method: An 8-week, double-blind, 3-arm, comparative trial randomized 7- to 14-year-olds with DSM-IV ADHD to GUAN (1-3 mg/day), DMPH (5-20 mg/day), or a combination (COMB) with fixed-flexible dosing. Outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Data on adverse events and safety measures were obtained.

Results: A total of 207 participants were randomized and received drug. Analyses showed significant treatment group main effects for ADHD-RS-IV ADHD total (p = .0001) and inattentive symptoms (p = .0001). COMB demonstrated small but consistently greater reductions in ADHD-RS-IV Inattentive subscale scores versus monotherapies (DMPH: p = .05; f(2) = .02; and GUAN: p = .02; f(2) = .02), and was associated with a greater positive response rate by CGI-I (p = .01). No serious cardiovascular events occurred. Sedation, somnolence, lethargy, and fatigue were greater in both guanfacine groups. All treatments were well tolerated.

Conclusion: COMB showed consistent evidence of clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and α2A agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability.

Clinical trial registration information: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1);; NCT00429273.

Keywords: ADHD; alpha2A; children; guanfacine; methylphenidate.

Publication types

  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adrenergic alpha-2 Receptor Agonists / administration & dosage
  • Adrenergic alpha-2 Receptor Agonists / adverse effects
  • Adrenergic alpha-2 Receptor Agonists / pharmacology*
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / pharmacology*
  • Child
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Guanfacine / administration & dosage
  • Guanfacine / adverse effects
  • Guanfacine / pharmacology*
  • Humans
  • Male
  • Methylphenidate / administration & dosage
  • Methylphenidate / adverse effects
  • Methylphenidate / pharmacology*
  • Outcome Assessment, Health Care*


  • Adrenergic alpha-2 Receptor Agonists
  • Central Nervous System Stimulants
  • Methylphenidate
  • Guanfacine

Associated data