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Cited by 161Attention Deficit Hyperactivity DisorderBehavioral and Psychological StudiesDevelopmental and Educational Neuropsychology

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

Hirota, Tomoya, Schwartz, Shimon, Correll, Christoph U.·2014·Journal of the American Academy of Child & Adolescent Psychiatry
DOI 10.1016/j.jaac.2013.11.009
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Abstract

Objective To meta-analyze the efficacy and safety of α-2 agonists in pediatric attention-deficit/hyperactivity disorder (ADHD).Method We searched MEDLINE, EMBASE, Cochrane Library, CINAHL, and PsycINFO until May 2013 for randomized trials comparing α-2 agonists with placebo in ADHD youth. Primary outcome was reduction in overall ADHD symptoms. Secondary outcomes included hyperactivity/impulsivity, inattentiveness, oppositional defiant disorder symptoms (ODD symptoms), all-cause discontinuation, specific-cause discontinuation, and adverse effects. Standardized mean differences (SMD), relative risk (RR), and number-needed-to-treat/number-needed-to-harm (NNT/NNH) were calculated. Data were analyzed separately in monotherapy and as add-on to psychostimulants.Results Altogether, 12 studies (N = 2,276) were included. Across 9 studies (n = 1,550), α-2 agonist monotherapy significantly reduced overall ADHD symptoms (SMD = -0.59, p < .00001), hyperactivity/impulsivity (SMD = -0.56, p < .00001), inattention (SMD = -0.57, p < .00001), and ODD symptoms (SMD = -0.44, p = .0004). Similarly, α-2 agonist add-on treatment (3 studies, n = 726) significantly reduced overall ADHD symptoms (SMD = -0.36, p < .0001), hyperactivity/impulsivity (SMD = -0.33, p < .0001), and inattention (SMD = -0.34, p < .0001), but effect sizes were lower than in monotherapy trials (p = .03-0.04). As monotherapy, α-2 agonists had lower all-cause (RR = 0.70, p = .01, NNT = 10) and inefficacy-related (RR = 0.39, p < .0001) discontinuations than did placebo; however, intolerability-related discontinuation was similar, despite significantly more common fatigue (NNH = 10), sedation (NNH = 17), and somnolence (NNH = 4) and significantly greater hypotensive (clonidine-IR), bradycardic (clonidine-IR), and QTc prolonging (guanfacine-XR) effects. Added to stimulants, α-2 agonists had all-cause and specific-cause discontinuations that were comparable to those of placebo, but somnolence (NNH = 10) was more common, and hypotensive and bradycardic effects (clonidine-XR and guanfacine-XR) were greater than with placebo.Conclusions α-2 Agonist monotherapy and, possibly to a lesser extent, co-treatment, are significantly superior to placebo for overall, hyperactivity, and inattentive ADHD symptoms. Efficacy advantages need to be balanced against fatigue, somnolence/sedation, hypotension, bradycardia, and possibly QTc prolongation.

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  • Only extended-release guanfacine and extended-release clonidine have evidence supporting their use as adjunctive therapy with stimulant medications sufficient to have achieved FDA approval.

    “Only extended-release guanfacine and extended-release clonidine have evidence supporting their use as adjunctive therapy with stimulant medications sufficient to have achieved FDA approval.127”

    From Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents (2019) · cites this paper as [127]

  • Data from randomized trials, systematic reviews, and meta-analyses show that atomoxetine and alpha-2-adrenergic agonists are more effective than placebo in reducing the core symptoms of ADHD, but as a class, they are less effective than stimulants.

    “Data from randomized trials, systematic reviews, and meta-analyses show that atomoxetine and alpha-2-adrenergic agonists are more effective than placebo in reducing the core symptoms of ADHD, but as a class, they are less effective than stimulants [49, 55, 56].”

    From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [56]

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Authors
Hirota, T., Schwartz, S., & Correll, C. U.
Affiliations
  • Vanderbilt University Medical Center (US)
  • Northwell Health (US)
  • Albert Einstein College of Medicine (US)
Corresponding author
Correll, Christoph U.
ORCID
Venue
Journal of the American Academy of Child & Adolescent Psychiatry
Publisher
Elsevier BV
Published
2014-02
Volume
53
Issue
2
Pages
153-173
ISSN
0890-8567 (ISSN-L)
DOI
10.1016/j.jaac.2013.11.009
OpenAlex
W2050973084
Cited by
161
References
73
Citations by year
2026: 7 · 2025: 8 · 2024: 11 · 2023: 12 · 2022: 16 · 2021: 8 · 2020: 13 · 2019: 12 · 2018: 11 · 2017: 13 · 2016: 16 · 2015: 22 · 2014: 11
FWCI
2.17
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of the American Academy of Child & Adolescent Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Social Sciences › Psychology › Developmental and Educational Psychology › Behavioral and Psychological Studies
  • Social Sciences › Psychology › Neuropsychology and Physiological Psychology › Developmental and Educational Neuropsychology
Keywords
alpha-2 adrenergic agonists, attention deficit hyperactivity disorder, children with ADHD, monotherapy, adjunctive therapy, stimulant medication, hyperactivity/impulsivity, inattention, oppositional defiant disorder, treatment discontinuation, adverse effects, fatigue, sedation, treatment efficacy and safety, number needed to treat, number needed to harm, children and adolescents
MeSH terms
Adolescent, Attention Deficit Disorder with Hyperactivity, Humans, Adrenergic alpha-2 Receptor Agonists

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