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Cited by 57Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorPharmaceutical studies and practices

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

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McCracken, James T., McGough, James J., Loo, Sandra K., Levitt, Jennifer, Del’Homme, Melissa, Cowen, Jennifer, Sturm, Alexandra, Whelan, Fiona +3 more·2016·Journal of the American Academy of Child & Adolescent Psychiatry
DOI 10.1016/j.jaac.2016.05.015PMC PMC4976782
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Abstract

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); http://clinicaltrials.gov/; NCT00429273.

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  • Guanfacine is often used as adjunct to stimulant medication, as the combination optimizes therapeutic actions while diminishing side effects.

    “Guanfacine is often used as adjunct to stimulant medication, as the combination optimizes the therapeutic actions while diminishing side effects (McCracken et al., 2016).”

    From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as McCracken et al., 2016

    The Discussion (page unavailable) reports modest additional ADHD symptom benefits from combining guanfacine with a stimulant, without an increased overall side-effect burden. It does not establish that the combination diminishes side effects: sedation, fatigue, and somnolence were more frequent in the guanfacine groups. The cited trial also does not establish how often guanfacine is used as an adjunct. (LLM, conf=0.90)

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Authors
McCracken, J. T., McGough, J. J., Loo, S. K., Levitt, J., Del’Homme, M., Cowen, J., Sturm, A., Whelan, F., Hellemann, G., Sugar, C., & Bilder, R. M.
Affiliations
University of California, Los Angeles (US)
Corresponding author
McCracken, James T.
ORCID
Venue
Journal of the American Academy of Child & Adolescent Psychiatry
Publisher
Elsevier BV
Published
2016-08
Volume
55
Issue
8
Pages
657-666.e1
ISSN
0890-8567 (ISSN-L)
DOI
10.1016/j.jaac.2016.05.015
PMC
PMC4976782
OpenAlex
W2416192894
Cited by
57
References
14
Citations by year
2026: 4 · 2025: 9 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 7 · 2017: 2 · 2016: 5
FWCI
5.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American Academy of Child & Adolescent Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • John Templeton Foundation
  • Purdue University
  • Sunovion
  • FORUM Pharmaceuticals
  • University of Oxford
  • H. Lundbeck A/S
  • University of California, Los Angeles
  • National Institute of Mental Health (P50MH077248)
  • David Geffen School of Medicine, University of California, Los Angeles
  • Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Keywords
attention deficit hyperactivity disorder, guanfacine, children, inattentive symptoms, treatment tolerability, adverse events
MeSH terms
Adolescent, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Child, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Methylphenidate, Guanfacine, Outcome Assessment, Health Care, Adrenergic alpha-2 Receptor Agonists

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