Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 36 (1), 1-25

Guanfacine Extended Release: A New Pharmacological Treatment Option in Europe

Affiliations
Review

Guanfacine Extended Release: A New Pharmacological Treatment Option in Europe

Michael Huss et al. Clin Drug Investig.

Abstract

Children/adolescents with attention-deficit/hyperactivity disorder (ADHD) may have a poor or inadequate response to psychostimulants or be unable to tolerate their side-effects; furthermore, stimulants may be inappropriate because of co-existing conditions. Only one non-stimulant ADHD pharmacotherapy, the noradrenaline transporter inhibitor atomoxetine, is currently approved for use in Europe. We review recent advances in understanding of the pathophysiology of ADHD with a focus on the roles of catecholamine receptors in context of the α2A-adrenergic receptor agonist guanfacine extended release (GXR), a new non-stimulant treatment option in Europe. Neuroimaging studies of children/adolescents with ADHD show impaired brain maturation, and structural and functional anomalies in brain regions and networks. Neurobiological studies in ADHD and medication response patterns support involvement of monoaminergic neurotransmitters (primarily dopamine and noradrenaline). Guanfacine is a selective α2A-adrenergic receptor agonist that has been shown to improve prefrontal cortical cognitive function, including working memory. The hypothesized mode of action of guanfacine centres on direct stimulation of post-synaptic α2A-adrenergic receptors to enhance noradrenaline neurotransmission. Preclinical data suggest that guanfacine also influences dendritic spine growth and maturation. Clinical trials have demonstrated the efficacy of GXR in ADHD, and it is approved as monotherapy or adjunctive therapy to stimulants in Canada and the USA (for children and adolescents). GXR was approved recently in Europe for the treatment of ADHD in children and adolescents for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. GXR may provide particular benefit for children/adolescents who have specific co-morbidities such as chronic tic disorders or oppositional defiant disorder (or oppositional symptoms) that have failed to respond to first-line treatment options.

Figures

Fig. 1
Fig. 1
Regulation of attention, behaviour and emotion through extensive network connections of the prefrontal cortex with other brain regions. Reproduced from Arnsten AF, Rubia K. Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J Am Acad Child Adolesc Psychiatry. 2012;51:356–67, © (2012) with permission from Elsevier
Fig. 2
Fig. 2
Attention-deficit/hyperactivity disorder (ADHD) is characterized by a delay in cortical maturation: a dorsal view and b right lateral view. View of the cortical regions where peak thickness was attained at each age (a 7–12 years, b 7–13 years) in ADHD (upper rows) and typically developing controls (lower rows). Darker colours indicate regions where a quadratic model was not appropriate (and thus a peak age could not be calculated), or the peak age was estimated to lie outside the age range covered. Both groups showed similar sequences of regions that attained peak thickness, but the ADHD group showed considerable delay in reaching this developmental marker. Reproduced with permission from Shaw et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci USA. 2007;104:19649–54. © (2007) National Academy of Sciences, USA
Fig. 3
Fig. 3
Noradrenaline and dopamine modulate the strength of network connections at dendritic spines in the prefrontal cortex to influence information processing. Methylphenidate (MPH) primarily blocks the dopamine transporter; amphetamines (AMPs) block the dopamine and noradrenaline transporters, and increase output of dopamine; atomoxetine (ATX) blocks the noradrenaline transporter. Guanfacine (G) directly stimulates postsynaptic α2A-adrenergic receptors and thereby closes hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the post-synaptic neuron and enhances noradrenaline neurotransmission. Adapted from Wang M et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007;129:397–410 © (2007) with permission from Elsevier and Arnsten AF, Rubia K. Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J Am Acad Child Adolesc Psychiatry. 2012;51:356–67, © (2012) with permission from Elsevier
Fig. 4
Fig. 4
Inverted U-shaped influence of noradrenaline (NA) and dopamine (DA) on the prefrontal cortex (PFC). Both NA and DA have an ‘inverted U-shaped’ influence on PFC physiology and cognitive performance; too little or too much of either neurotransmitter impairs PFC function. Adapted with permission from Macmillan Publishers Ltd from Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10:410–22
Fig. 5
Fig. 5
Guanfacine extended release (GXR) monotherapy administered in either the morning or evening improves attention-deficit hyperactivity disorder (ADHD) symptoms. Mean change from baseline in ADHD Rating Scale version IV (ADHD-RS-IV) total score among patients receiving GXR. p values based on type III sum of squares from an analysis of covariance model. a p < 0.05 vs. placebo based on change from baseline (Visit 2). c p < 0.001 vs. placebo based on change from baseline (Visit 2). Reproduced with permission from Newcorn et al. Randomized, double-blind trial of guanfacine extended release in children with attention-deficit/hyperactivity disorder: morning or evening administration. J Am Acad Child Adolesc Psychiatry. 2013;52:921–30. © (2013) with permission from Elsevier. LOCF last observation carried forward, LS least squares, SEM standard error of the mean

Similar articles

See all similar articles

Cited by 6 PubMed Central articles

See all "Cited by" articles

References

    1. American Psychiatric Association . Diagnostic and statistical manual of mental disorders, Fifth Edition (DSM-5) Arlington: American Psychiatric Publishing; 2013.
    1. NICE. Attention deficit hyperactivity disorder. Diagnosis and management of ADHD in children, young people and adults. National Clinical Practice Guideline Number 72. 2013. https://www.nice.org.uk/guidance/qs39. Accessed 3 Mar 2015.
    1. Huss M, Holling H, Kurth BM, Schlack R. How often are German children and adolescents diagnosed with ADHD? Prevalence based on the judgment of health care professionals: results of the German health and examination survey (KiGGS) Eur Child Adolesc Psychiatry. 2008;17(Suppl 1):52–58. doi: 10.1007/s00787-008-1006-z. - DOI - PubMed
    1. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164:942–948. doi: 10.1176/ajp.2007.164.6.942. - DOI - PubMed
    1. Ramos-Quiroga JA, Montoya A, Kutzelnigg A, Deberdt W, Sobanski E. Attention deficit hyperactivity disorder in the European adult population: prevalence, disease awareness, and treatment guidelines. Curr Med Res Opin. 2013;29:1093–1104. doi: 10.1185/03007995.2013.812961. - DOI - PubMed

Publication types

MeSH terms

Substances

Feedback