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

Objective: Because models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and alpha(2A) 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 alpha(2A) 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 mono therapies (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 alpha(2A) agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability.