Journal of the American Academy of Child & Adolescent Psychiatry
ReviewAlpha-2 Agonists for Attention-Deficit/Hyperactivity Disorder in Youth: A Systematic Review and Meta-Analysis of Monotherapy and Add-On Trials to Stimulant Therapy
Section snippets
Eligibility Criteria and Search Strategy
Eligibility for the study was based on the following inclusion criteria: double-blind or single-blind, randomized controlled trials (RCTs) comparing clonidine or guanfacine either in IR or XR formulation with placebo; patients diagnosed with ADHD and younger than 18 years old; and, at a minimum, change or endpoint values in the means ± standard deviations of the α-2 agonist and placebo from a rating scale based assessment of ADHD symptoms, or categorical assessments of all-cause or
Search
The computerized search yielded 599 references (Figure 1). Searching Web sites of the FDA and pharmaceutical companies revealed no additional references. After removal of 105 duplicates, 465 of the 494 unique references were excluded based on title and abstract review. Of the remaining 29 studies, 18 were excluded after full-text review for the following reasons: review articles (trials = 532, 33, 34, 35, 36), cross-over trials without data for the first pre–cross-over period (trials = 540, 41,
Discussion
Results from this comprehensive meta-analysis in youth with ADHD show robust efficacy of α-2 agonist monotherapy, and, to a lesser degree, of α-2 agonist add-on treatment to stimulants in decreasing total, hyperactivity/impulsiveness, and inattentive ADHD symptoms. Moreover, α-2 agonist monotherapy was associated with significantly lower discontinuation due to any cause or due to inefficacy, without increased risk for discontinuation due to intolerability. Used adjunctively, α-2 agonists were
References (71)
- et al.
The stimulants revisited
Child Adolesc Psychiatr Clin N Am
(2000) - et al.
Effect of stimulants on height and weight: a review of the literature
J Am Acad Child Adolesc Psychiatry
(2008) - et al.
Review of ADHD pharmacotherapies: advantages, disadvantages, and clinical pearls
J Am Acad Child Adolesc Psychiatry
(2009) - et al.
Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
(2012) - et al.
Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature
J Am Acad Child Adolesc Psychiatry
(2008) - et al.
Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders
Pharmacol Biochem Behav
(2011) - et al.
Locomotor hyperactivity induced by blockade of prefrontal cortical α-2-adrenoceptors in monkeys
Biol Psychiatry
(2005) - et al.
Association between the α-2C-adrenergic receptor gene and attention deficit hyperactivity disorder in a Korean sample
Neurosci Lett
(2008) - et al.
Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette's syndrome: preliminary clinical experience
J Am Acad Child Adolesc Psychiatry
(1995) - et al.
An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
(1995)
Comparison of clonidine response in the treatment of attention-deficit hyperactivity disorder with and without comorbid tic disorders
J Am Acad Child Adolesc Psychiatry
Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes
J Am Acad Child Adolesc Psychiatry
Clonidine extended-release tablets for pediatric patients with attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
Meta-analysis in clinical trials
Control Clin Trials
Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebo-crossover therapeutic trial
J Am Acad Child Psychiatry
Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years
Clin Ther
A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children
J Am Acad Child Adolesc Psychiatry
Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial
J Am Acad Child Adolesc Psychiatry
Do children and adolescents with ADHD respond differently to atomoxetine?
J Am Acad Child Adolesc Psychiatry
Case study: adverse response to clonidine
J Am Acad Child Adolesc Psychiatry
Severity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement
Arch Gen Psychiatry
Trends in psychopathology across the adolescent years: what changes when children become adolescents, and when adolescents become adults?
J Child Psychol Psychiatry
Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007
MMWR Morb Mortal Wkly Rep
Using meta-analysis to compare the efficacy of medications for attention-deficit/hyperactivity disorder in youths
P T
A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes
J Clin Psychiatry
ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents
Pediatrics
Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study
J Dev Behav Pediatr
Developments in pediatric psychopharmacology: focus on stimulants, antidepressants, and antipsychotics
J Clin Psychiatry
ADHD drugs and serious cardiovascular events in children and young adults
N Engl J Med
Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study
BMJ
A review of the rationale and clinical utilization of α2-adrenoreceptor agonists for the treatment of attention-deficit/hyperactivity and related disorders
J Child Adolesc Psychopharmacol
Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction
CNS Drugs
Guanfacine and guanfacine extended release: treatment for ADHD and related disorders
CNS Drug Rev
Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways
J Clin Psychiatry
A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder
Am J Psychiatry
Cited by (118)
Interventions for ADHD in childhood and adolescence: A systematic umbrella review and meta-meta-analysis
2023, Clinical Psychology ReviewTic disorders
2023, Encyclopedia of Mental Health, Third Edition: Volume 1-3An Update on Psychopharmacological Treatment of Autism Spectrum Disorder
2022, NeurotherapeuticsTrends in Antipsychotic Medication Use in Young Privately Insured Children
2021, Journal of the American Academy of Child and Adolescent Psychiatry
This article is discussed in and editorial by Dr. Michael H. Bloch on page 135.
Clinical guidance is available at the end of this article.
The authors thank Philip Hazell, BMeSc, MBChB, Ph.D., FRANZP, of Sydney Medical School; Roger Kurlan, M.D., of Atlantic Neuroscience Institute at Overlook Hospital; Michael McDermott, Ph.D., of University of Rochester Medical Center; and Shire US Inc. for providing unpublished data on their studies relevant for this meta-analysis.
Disclosure: Dr. Correll has received grant or research support from the National Institute of Mental Health, Bristol-Myers Squibb/Otsuka, the Feinstein Institute for Medical Research, Janssen/Johnson and Johnson, and the National Alliance for Research in Schizophrenia and Depression. He has served as a consultant to Actelion, Alexza Pharmaceuticals, the American Academy of Child and Adolescent Psychiatry, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Co., Genentech, the Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, the National Institute of Mental Health, Janssen/Johnson and Johnson, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda. He serves on the speakers’ bureau of Merck (nonpromotional lectures only). He owns stock in Alexza Pharmaceuticals. He has participated in continuing medical education (CME) article preparation for Medscape. He is a member of the Data Safety Monitoring Boards for Cephalon, Janssen/Johnson and Johnson, Lundbeck, Pfizer, Takeda, and Teva. Drs. Hirota and Schwartz report no biomedical financial interests or potential conflicts of interest.