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Clinical Drug Investigation
Published in: Clinical Drug Investigation 1/2016

Open Access 01-01-2016 | Review Article

Guanfacine Extended Release: A New Pharmacological Treatment Option in Europe

Authors: Michael Huss, Wai Chen, Andrea G. Ludolph

Published in: Clinical Drug Investigation | Issue 1/2016

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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.
Literature
1.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, Fifth Edition (DSM-5). Arlington: American Psychiatric Publishing; 2013.
2.
3.
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):52–8.PubMedCrossRef
4.
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;164:942–8.PubMedCrossRef
5.
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;29:1093–104.PubMedCrossRef
6.
Lambek R, Tannock R, Dalsgaard S, Trillingsgaard A, Damm D, Thomsen PH. Executive dysfunction in school-age children with ADHD. J Atten Disord. 2011;15:646–55.PubMedCrossRef
7.
Kasper LJ, Alderson RM, Hudec KL. Moderators of working memory deficits in children with attention-deficit/hyperactivity disorder (ADHD): a meta-analytic review. Clin Psychol Rev. 2012;32:605–17.PubMedCrossRef
8.
9.
Asherson P, Manor I, Huss M. Attention-deficit/hyperactivity disorder in adults: update on clinical presentation and care. Neuropsychiatry. 2014;4:109–28.CrossRef
10.
MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56:1073–86.CrossRef
11.
Jensen CM, Steinhausen HC. Comorbid mental disorders in children and adolescents with attention-deficit/hyperactivity disorder in a large nationwide study. Atten Defic Hyperact Disord. 2015;7:27–38.PubMedCrossRef
12.
Hodgson K, Hutchinson AD, Denson L. Nonpharmacological treatments for ADHD: a meta-analytic review. J Atten Disord. 2014;18:275–82.PubMedCrossRef
13.
Taylor E, Dopfner M, Sergeant J, Asherson P, Banaschewski T, Buitelaar J, et al. European clinical guidelines for hyperkinetic disorder—first upgrade. Eur Child Adolesc Psychiatry. 2004;13(Suppl 1):i7–30.PubMed
14.
15.
Faraone SV, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis. Eur Child Adolesc Psychiatry. 2010;19:353–64.PubMedCrossRef
16.
Faraone SV. Using meta-analysis to compare the efficacy of medications for attention-deficit/hyperactivity disorder in youths. Pharm Ther. 2009;34:678–94.
17.
Arnold LE. Methylphenidate vs. amphetamine: comparative review. J Atten Disord. 2000;3:200–11.CrossRef
18.
Spencer T, Biederman J, Wilens T, Harding M, O’Donnell D, Griffin S. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry. 1996;35:409–32.PubMedCrossRef
19.
Cortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, et al. Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry. 2013;54:227–46.PubMedCrossRef
20.
Gajria K, Lu M, Sikirica V, Greven P, Zhong Y, Qin P, et al. Adherence, persistence, and medication discontinuation in patients with attention-deficit/hyperactivity disorder—a systematic literature review. Neuropsychiatr Dis Treat. 2014;10:1543–69.PubMedPubMedCentral
21.
Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128:1007–22.PubMedCrossRef
22.
Matza LS, Secnik K, Rentz AM, Mannix S, Sallee FR, Gilbert D, et al. Assessment of health state utilities for attention-deficit/hyperactivity disorder in children using parent proxy report. Qual Life Res. 2005;14:735–47.PubMed
23.
Schwartz S, Correll CU. Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. J Am Acad Child Adolesc Psychiatry. 2014;53:174–87.PubMedCrossRef
24.
Bushe CJ, Savill NC. Systematic review of atomoxetine data in childhood and adolescent attention-deficit hyperactivity disorder 2009–2011: focus on clinical efficacy and safety. J Psychopharmacol. 2014;28:204–11.PubMedCrossRef
25.
Martinez-Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs. 2013;27:15–30.PubMedCrossRef
26.
27.
28.
29.
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.PubMedCrossRef
30.
Greven CU, Bralten J, Mennes M, O’Dwyer L, van Hulzen KJ, Rommelse N, et al. Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings. JAMA Psychiatry. 2015;72:490–9.PubMedCrossRef
31.
Cortese S, Kelly C, Chabernaud C, Proal E, Di Martino A, Milham MP, et al. Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry. 2012;169:1038–55.PubMedCrossRef
32.
Kessler D, Angstadt M, Welsh RC, Sripada C. Modality-spanning deficits in attention-deficit/hyperactivity disorder in functional networks, gray matter, and white matter. J Neurosci. 2014;34:16555–66.PubMedPubMedCentralCrossRef
33.
Cortese S. The neurobiology and genetics of attention-deficit/hyperactivity disorder (ADHD): what every clinician should know. Eur J Paediatr Neurol. 2012;16:422–33.PubMedCrossRef
34.
Cocchi L, Bramati IE, Zalesky A, Furukawa E, Fontenelle LF, Moll J, et al. Altered functional brain connectivity in a non-clinical sample of young adults with attention-deficit/hyperactivity disorder. J Neurosci. 2012;32:17753–61.PubMedCrossRef
35.
Sripada C, Kessler D, Fang Y, Welsh RC, Prem KK, Angstadt M. Disrupted network architecture of the resting brain in attention-deficit/hyperactivity disorder. Hum Brain Mapp. 2014;35:4693–705.PubMedCrossRef
36.
Shaw P, Eckstrand K, Sharp W, Blumenthal J, Lerch JP, Greenstein D, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci USA. 2007;104:19649–54.PubMedPubMedCentralCrossRef
37.
Castellanos FX, Lee PP, Sharp W, Jeffries NO, Greenstein DK, Clasen LS, et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA. 2002;288:1740–8.PubMedCrossRef
38.
39.
Mackie S, Shaw P, Lenroot R, Pierson R, Greenstein DK, Nugent TF III, et al. Cerebellar development and clinical outcome in attention deficit hyperactivity disorder. Am J Psychiatry. 2007;164:647–55.PubMedCrossRef
40.
Plessen KJ, Bansal R, Zhu H, Whiteman R, Amat J, Quackenbush GA, et al. Hippocampus and amygdala morphology in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2006;63:795–807.PubMedPubMedCentralCrossRef
41.
Qiu A, Crocetti D, Adler M, Mahone EM, Denckla MB, Miller MI, et al. Basal ganglia volume and shape in children with attention deficit hyperactivity disorder. Am J Psychiatry. 2009;166:74–82.PubMedPubMedCentralCrossRef
42.
Xia S, Li X, Kimball AE, Kelly MS, Lesser I, Branch C. Thalamic shape and connectivity abnormalities in children with attention-deficit/hyperactivity disorder. Psychiatry Res. 2012;204:161–7.PubMedPubMedCentralCrossRef
43.
van Ewijk H, Heslenfeld DJ, Zwiers MP, Buitelaar JK, Oosterlaan J. Diffusion tensor imaging in attention deficit/hyperactivity disorder: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2012;36:1093–106.PubMedCrossRef
44.
Hong SB, Zalesky A, Fornito A, Park S, Yang YH, Park MH, et al. Connectomic disturbances in attention-deficit/hyperactivity disorder: a whole-brain tractography analysis. Biol Psychiatry. 2014;76:656–63.PubMedCrossRef
45.
Hart H, Radua J, Mataix-Cols D, Rubia K. Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD). Neurosci Biobehav Rev. 2012;36:2248–56.PubMedCrossRef
46.
Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry. 2013;70:185–98.PubMedCrossRef
47.
48.
Fair DA, Posner J, Nagel BJ, Bathula D, Dias TG, Mills KL, et al. Atypical default network connectivity in youth with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2010;68:1084–91.PubMedPubMedCentralCrossRef
49.
McCarthy H, Skokauskas N, Mulligan A, Donohoe G, Mullins D, Kelly J, et al. Attention network hypoconnectivity with default and affective network hyperconnectivity in adults diagnosed with attention-deficit/hyperactivity disorder in childhood. JAMA Psychiatry. 2013;70:1329–37.PubMedCrossRef
50.
Castellanos FX, Margulies DS, Kelly C, Uddin LQ, Ghaffari M, Kirsch A, et al. Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 2008;63:332–7.PubMedPubMedCentralCrossRef
51.
Fredriksson A, Archer T. Neurobehavioural deficits associated with apoptotic neurodegeneration and vulnerability for ADHD. Neurotox Res. 2004;6:435–56.PubMedCrossRef
52.
Lou HC, Rosa P, Pryds O, Karrebaek H, Lunding J, Cumming P, et al. ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Dev Med Child Neurol. 2004;46:179–83.PubMedCrossRef
53.
Purper-Ouakil D, Ramoz N, Lepagnol-Bestel AM, Gorwood P, Simonneau M. Neurobiology of attention deficit/hyperactivity disorder. Pediatr Res. 2011;69:69R–76R.PubMedCrossRef
54.
van der Kooij MA, Glennon JC. Animal models concerning the role of dopamine in attention-deficit hyperactivity disorder. Neurosci Biobehav Rev. 2007;31:597–618.PubMedCrossRef
55.
Sterley TL, Howells FM, Russell VA. Evidence for reduced tonic levels of GABA in the hippocampus of an animal model of ADHD, the spontaneously hypertensive rat. Brain Res. 2013;1541:52–60.PubMedCrossRef
56.
Ma CL, Arnsten AF, Li BM. Locomotor hyperactivity induced by blockade of prefrontal cortical alpha2-adrenoceptors in monkeys. Biol Psychiatry. 2005;57:192–5.PubMedCrossRef
57.
Ludolph AG, Kassubek J, Schmeck K, Glaser C, Wunderlich A, Buck AK, et al. Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults: a 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study. Neuroimage. 2008;41:718–27.PubMedCrossRef
58.
Volkow ND, Wang GJ, Newcorn J, Telang F, Solanto MV, Fowler JS, et al. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007;64:932–40.PubMedCrossRef
59.
Dearry A, Gingrich JA, Falardeau P, Fremeau RT Jr, Bates MD, Caron MG. Molecular cloning and expression of the gene for a human D1 dopamine receptor. Nature. 1990;347:72–6.PubMedCrossRef
60.
Grandy DK, Marchionni MA, Makam H, Stofko RE, Alfano M, Frothingham L, et al. Cloning of the cDNA and gene for a human D2 dopamine receptor. Proc Natl Acad Sci USA. 1989;86:9762–6.PubMedPubMedCentralCrossRef
61.
Lomasney JW, Lorenz W, Allen LF, King K, Regan JW, Yang-Feng TL, et al. Expansion of the alpha 2-adrenergic receptor family: cloning and characterization of a human alpha 2-adrenergic receptor subtype, the gene for which is located on chromosome 2. Proc Natl Acad Sci USA. 1990;87:5094–8.PubMedPubMedCentralCrossRef
62.
Weinberg DH, Trivedi P, Tan CP, Mitra S, Perkins-Barrow A, Borkowski D, et al. Cloning, expression and characterization of human alpha adrenergic receptors alpha 1a, alpha 1b and alpha 1c. Biochem Biophys Res Commun. 1994;201:1296–304.PubMedCrossRef
63.
Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko C, et al. Molecular characterization of the human beta 3-adrenergic receptor. Science. 1989;245:1118–21.PubMedCrossRef
64.
Kobilka BK, Matsui H, Kobilka TS, Yang-Feng TL, Francke U, Caron MG, et al. Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor. Science. 1987;238:650–6.PubMedCrossRef
65.
Regan JW, Kobilka TS, Yang-Feng TL, Caron MG, Lefkowitz RJ, Kobilka BK. Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype. Proc Natl Acad Sci USA. 1988;85:6301–5.PubMedPubMedCentralCrossRef
66.
Scheinin M, Lomasney JW, Hayden-Hixson DM, Schambra UB, Caron MG, Lefkowitz RJ, et al. Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Res Mol Brain Res. 1994;21:133–49.PubMedCrossRef
67.
Talley EM, Rosin DL, Lee A, Guyenet PG, Lynch KR. Distribution of alpha 2A-adrenergic receptor-like immunoreactivity in the rat central nervous system. J Comp Neurol. 1996;372:111–34.PubMedCrossRef
68.
Aoki C, Venkatesan C, Go CG, Forman R, Kurose H. Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons. Cereb Cortex. 1998;8:269–77.PubMedCrossRef
69.
Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007;129:397–410.PubMedCrossRef
70.
Smiley JF, Levey AI, Ciliax BJ, Goldman-Rakic PS. D1 dopamine receptor immunoreactivity in human and monkey cerebral cortex: predominant and extrasynaptic localization in dendritic spines. Proc Natl Acad Sci USA. 1994;91:5720–4.PubMedPubMedCentralCrossRef
71.
Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007;10:376–84.PubMedCrossRef
72.
Arnsten AF. The emerging neurobiology of attention deficit hyperactivity disorder: the key role of the prefrontal association cortex. J Pediatr. 2009;154:I-S43.PubMedPubMedCentral
73.
74.
Ramos BP, Stark D, Verduzco L, van Dyck CH, Arnsten AF. Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem. 2006;13:770–6.PubMedPubMedCentralCrossRef
75.
Jakala P, Riekkinen M, Sirvio J, Koivisto E, Kejonen K, Vanhanen M, et al. Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology. 1999;20:460–70.PubMedCrossRef
76.
Brunner D, Buhot MC, Hen R, Hofer M. Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. Behav Neurosci. 1999;113:587–601.PubMedCrossRef
77.
Smoller JW, Biederman J, Arbeitman L, Doyle AE, Fagerness J, Perlis RH, et al. Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD. Biol Psychiatry. 2006;59:460–7.PubMedCrossRef
78.
Carrey NJ, MacMaster FP, Gaudet L, Schmidt MH. Striatal creatine and glutamate/glutamine in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2007;17:11–7.PubMedCrossRef
79.
Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283:70–4.PubMedCrossRef
80.
Gambrill AC, Barria A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci USA. 2011;108:5855–60.PubMedPubMedCentralCrossRef
81.
Miller EM, Pomerleau F, Huettl P, Gerhardt GA, Glaser PE. Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Psychopharmacology. 2014;231:3019–29.PubMedCrossRef
82.
MacMaster FP, Carrey N, Sparkes S, Kusumakar V. Proton spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder. Biol Psychiatry. 2003;53:184–7.PubMedCrossRef
83.
Carrey N, MacMaster FP, Fogel J, Sparkes S, Waschbusch D, Sullivan S, et al. Metabolite changes resulting from treatment in children with ADHD: a 1H-MRS study. Clin Neuropharmacol. 2003;26:218–21.PubMedCrossRef
84.
Wiguna T, Guerrero AP, Wibisono S, Sastroasmoro S. Effect of 12-week administration of 20-mg long-acting methylphenidate on Glu/Cr, NAA/Cr, Cho/Cr, and mI/Cr ratios in the prefrontal cortices of school-age children in Indonesia: a study using 1H magnetic resonance spectroscopy (MRS). Clin Neuropharmacol. 2012;35:81–5.PubMedCrossRef
85.
Bollmann S, Ghisleni C, Poil SS, Martin E, Ball J, Eich-Hochli D, et al. Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder. Transl Psychiatry. 2015;5:e589.PubMedPubMedCentralCrossRef
86.
Dai H, Kaneko K, Kato H, Fujii S, Jing Y, Xu A, et al. Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors. Neurosci Res. 2007;57:306–13.PubMedCrossRef
87.
He C, Luo F, Chen X, Chen F, Li C, Ren S, et al. Superficial layer-specific histaminergic modulation of medial entorhinal cortex required for spatial learning. Cereb Cortex. 2015 (Epub ahead of print).
88.
Williams RH, Chee MJ, Kroeger D, Ferrari LL, Maratos-Flier E, Scammell TE, et al. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J Neurosci. 2014;34:6023–9.PubMedPubMedCentralCrossRef
89.
Fox GB, Pan JB, Esbenshade TA, Bennani YL, Black LA, Faghih R, et al. Effects of histamine H(3) receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup. Behav Brain Res. 2002;131:151–61.PubMedCrossRef
90.
da Silva WC, Bonini JS, Bevilaqua LR, Izquierdo I, Cammarota M. Histamine enhances inhibitory avoidance memory consolidation through a H2 receptor-dependent mechanism. Neurobiol Learn Mem. 2006;86:100–6.PubMedCrossRef
91.
Liu LL, Yang J, Lei GF, Wang GJ, Wang YW, Sun RP. Atomoxetine increases histamine release and improves learning deficits in an animal model of attention-deficit hyperactivity disorder: the spontaneously hypertensive rat. Basic Clin Pharmacol Toxicol. 2008;102:527–32.PubMedCrossRef
92.
Horner WE, Johnson DE, Schmidt AW, Rollema H. Methylphenidate and atomoxetine increase histamine release in rat prefrontal cortex. Eur J Pharmacol. 2007;558:96–7.PubMedCrossRef
93.
Froehlich TE, Anixt JS, Loe IM, Chirdkiatgumchai V, Kuan L, Gilman RC. Update on environmental risk factors for attention-deficit/hyperactivity disorder. Curr Psychiatry Rep. 2011;13:333–44.PubMedPubMedCentralCrossRef
94.
Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet. 2009;126:51–90.PubMedCrossRef
95.
Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Roser C, Nguyen TT, et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm. 2008;115:1573–85.PubMedCrossRef
96.
Nikolas M, Klump KL, Burt SA. Youth appraisals of inter-parental conflict and genetic and environmental contributions to attention-deficit hyperactivity disorder: examination of GxE effects in a twin sample. J Abnorm Child Psychol. 2012;40:543–54.PubMedPubMedCentralCrossRef
97.
Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012;85:45–58.PubMedPubMedCentral
98.
Arnsten AF, Scahill L, Findling RL. Alpha2-Adrenergic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: emerging concepts from new data. J Child Adolesc Psychopharmacol. 2007;17:393–406.PubMedCrossRef
99.
Uhlen S, Porter AC, Neubig RR. The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors. J Pharmacol Exp Ther. 1994;271:1558–65.PubMed
100.
Ernsberger P, Meeley MP, Mann JJ, Reis DJ. Clonidine binds to imidazole binding sites as well as alpha 2-adrenoceptors in the ventrolateral medulla. Eur J Pharmacol. 1987;134:1–13.PubMedCrossRef
101.
Uhlen S, Wikberg JE. Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound. Eur J Pharmacol. 1991;202:235–43.PubMedCrossRef
102.
Uhlen S, Muceniece R, Rangel N, Tiger G, Wikberg JE. Comparison of the binding activities of some drugs on alpha 2A, alpha 2B and alpha 2C-adrenoceptors and non-adrenergic imidazoline sites in the guinea pig. Pharmacol Toxicol. 1995;76:353–64.PubMedCrossRef
103.
Uhlen S, Xia Y, Chhajlani V, Felder CC, Wikberg JE. [3H]-MK 912 binding delineates two alpha 2-adrenoceptor subtypes in rat CNS one of which is identical with the cloned pA2d alpha 2-adrenoceptor. Br J Pharmacol. 1992;106:986–95.PubMedPubMedCentralCrossRef
104.
Sallee FR. The role of alpha2-adrenergic agonists in attention-deficit/hyperactivity disorder. Postgrad Med. 2010;122:78–87.PubMedCrossRef
105.
106.
Kawaura K, Karasawa J, Chaki S, Hikichi H. Stimulation of postsynapse adrenergic alpha2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder. Behav Brain Res. 2014;270:349–56.PubMedCrossRef
107.
Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF. Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci. 2002;22:8771–7.PubMed
108.
Rama P, Linnankoski I, Tanila H, Pertovaara A, Carlson S. Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys. Pharmacol Biochem Behav. 1996;55:415–22.PubMedCrossRef
109.
Avery RA, Franowicz JS, Studholme C, van Dyck CH, Arnsten AF. The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task. Neuropsychopharmacology. 2000;23:240–9.PubMedCrossRef
110.
Decamp E, Clark K, Schneider JS. Effects of the alpha-2 adrenoceptor agonist guanfacine on attention and working memory in aged non-human primates. Eur J Neurosci. 2011;34:1018–22.PubMedPubMedCentralCrossRef
111.
Wang M, Tang ZX, Li BM. Enhanced visuomotor associative learning following stimulation of alpha 2A-adrenoceptors in the ventral prefrontal cortex in monkeys. Brain Res. 2004;1024:176–82.PubMedCrossRef
112.
Jin XC, Ma CL, Li BM. The alpha(2A)-adrenoceptor agonist guanfacine improves spatial learning but not fear conditioning in rats. Sheng Li Xue Bao. 2007;59:739–44.PubMed
113.
Sagvolden T. The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD). Behav Brain Funct. 2006;2:41.PubMedPubMedCentralCrossRef
114.
Arnsten AF, Cai JX, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 1988;8:4287–98.PubMed
115.
Hains AB, Yabe Y, Arnsten AF. Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Neurobiol Stress. 2015;2:1–9.PubMedPubMedCentralCrossRef
116.
Fernando AB, Economidou D, Theobald DE, Zou MF, Newman AH, Spoelder M, et al. Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists. Psychopharmacology. 2012;219:341–52.PubMedPubMedCentralCrossRef
117.
Abela AR, Chudasama Y. Noradrenergic alpha-receptor stimulation in the ventral hippocampus reduces impulsive decision-making. Psychopharmacology. 2014;231:521–31.PubMedCrossRef
118.
Freeman ZT, Rice KA, Soto PL, Pate KA, Weed MR, Ator NA, et al. Neurocognitive dysfunction and pharmacological intervention using guanfacine in a rhesus macaque model of self-injurious behavior. Transl Psychiatry. 2015;5:e567.PubMedPubMedCentralCrossRef
119.
Schulz KP, Clerkin SM, Fan J, Halperin JM, Newcorn JH. Guanfacine modulates the influence of emotional cues on prefrontal cortex activation for cognitive control. Psychopharmacology. 2013;226:261–71.PubMedPubMedCentralCrossRef
120.
Schulz KP, Clerkin SM, Newcorn JH, Halperin JM, Fan J. Guanfacine modulates the emotional biasing of amygdala-prefrontal connectivity for cognitive control. Eur Neuropsychopharmacol. 2014;24:1444–53.PubMedPubMedCentralCrossRef
121.
Bedard AC, Schulz KP, Krone B, Pedraza J, Duhoux S, Halperin JM, et al. Neural mechanisms underlying the therapeutic actions of guanfacine treatment in youth with ADHD: a pilot fMRI study. Psychiatry Res. 2015;231:353–6.
122.
Easton N, Shah YB, Marshall FH, Fone KC, Marsden CA. Guanfacine produces differential effects in frontal cortex compared with striatum: assessed by phMRI BOLD contrast. Psychopharmacology. 2006;189:369–85.PubMedCrossRef
123.
Yi F, Liu SS, Luo F, Zhang XH, Li BM. Signaling mechanism underlying alpha -adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats. Eur J Neurosci. 2013;38:2364–73.PubMedCrossRef
124.
Ji XH, Ji JZ, Zhang H, Li BM. Stimulation of alpha2-adrenoceptors suppresses excitatory synaptic transmission in the medial prefrontal cortex of rat. Neuropsychopharmacology. 2008;33:2263–71.PubMedCrossRef
125.
Calabrese B, Wilson MS, Halpain S. Development and regulation of dendritic spine synapses. Physiology (Bethesda). 2006;21:38–47.CrossRef
126.
Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H. Structure-stability-function relationships of dendritic spines. Trends Neurosci. 2003;26:360–8.PubMedCrossRef
127.
Hu J, Vidovic M, Chen MM, Lu QY, Song ZM. Activation of alpha 2A adrenoceptors alters dendritic spine development and the expression of spinophilin in cultured cortical neurones. Brain Res. 2008;1199:37–45.PubMedCrossRef
128.
Song ZM, Abou-Zeid O, Fang YY. Alpha2a adrenoceptors regulate phosphorylation of microtubule-associated protein-2 in cultured cortical neurons. Neuroscience. 2004;123:405–18.PubMedCrossRef
129.
Ren WW, Liu Y, Li BM. Stimulation of α2A-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Mol Cell Neurosci. 2012;49:205–16.PubMedCrossRef
130.
Barber ND, Reid JL. Comparison of the actions of centrally and peripherally administered clonidine and guanfacine in the rabbit: investigation of the differences. Br J Pharmacol. 1982;77:641–7.PubMedPubMedCentralCrossRef
131.
Sorkin EM, Heel RC. Guanfacine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension. Drugs. 1986;31:301–36.PubMedCrossRef
132.
van Zwieten PA, Chalmers JP. Different types of centrally acting antihypertensives and their targets in the central nervous system. Cardiovasc Drugs Ther. 1994;8:787–99.PubMedCrossRef
133.
Feldstein CA, Cohen AA, Sabaris RP, Burucua JE. Hemodynamic effects of guanfacine in essential hypertension. Clin Ther. 1984;6:325–34.PubMed
134.
Saameli K, Jerie P, Scholtysik G. Guanfacine and other centrally acting drugs in antihypertensive therapy; pharmacological and clinical aspects. Clin Exp Hypertens A. 1982;4:209–19.PubMed
135.
Kugler J, Seus R, Krauskopf R, Brecht HM, Raschig A. Differences in psychic performance with guanfacine and clonidine in normotensive subjects. Br J Clin Pharmacol. 1980;10(Suppl 1):71S–80S.PubMedPubMedCentralCrossRef
136.
Hirota T, Schwartz S, Correll CU. 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. J Am Acad Child Adolesc Psychiatry. 2014;53:153–73.PubMedCrossRef
137.
Swearingen D, Pennick M, Shojaei A, Lyne A, Fiske K. A phase I, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults. Clin Ther. 2007;29:617–25.PubMedCrossRef
138.
Boellner SW, Pennick M, Fiske K, Lyne A, Shojaei A. Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder. Pharmacotherapy. 2007;27:1253–62.PubMedCrossRef
139.
Seneca N, Gulyas B, Varrone A, Schou M, Airaksinen A, Tauscher J, et al. Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S, S)-[18F]FMeNER-D2. Psychopharmacology. 2006;188:119–27.PubMedCrossRef
140.
Carboni E, Silvagni A. Experimental investigations on dopamine transmission can provide clues on the mechanism of the therapeutic effect of amphetamine and methylphenidate in ADHD. Neural Plast. 2004;11:77–95.PubMedPubMedCentralCrossRef
141.
Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry. 1995;52:456–63.PubMedCrossRef
142.
Swanson JM, Volkow ND. Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD. Behav Brain Res. 2002;130:73–8.PubMedCrossRef
143.
Swanson JM, Volkow ND. Serum and brain concentrations of methylphenidate: implications for use and abuse. Neurosci Biobehav Rev. 2003;27:615–21.PubMedCrossRef
144.
Wilens TE, Spencer TJ. The stimulants revisited. Child Adolesc Psychiatr Clin N Am. 2000;9:573–603 (viii).PubMed
145.
Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, van Dyck CH, et al. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry. 2010;68:854–60.PubMedPubMedCentralCrossRef
146.
Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P. Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens. Proc Natl Acad Sci USA. 2009;106:2915–20.PubMedPubMedCentralCrossRef
147.
Cavaliere C, Cirillo G, Bianco MR, Adriani W, De Simone A, Leo D, et al. Methylphenidate administration determines enduring changes in neuroglial network in rats. Eur Neuropsychopharmacol. 2012;22:53–63.PubMedCrossRef
148.
Adriani W, Leo D, Greco D, Rea M, di Porzio U, Laviola G, et al. Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression. Neuropsychopharmacology. 2006;31:1946–56.PubMedCrossRef
149.
Nielsen JA, Chapin DS, Moore KE. Differential effects of d-amphetamine, beta-phenylethylamine, cocaine and methylphenidate on the rate of dopamine synthesis in terminals of nigrostriatal and mesolimbic neurons and on the efflux of dopamine metabolites into cerebroventricular perfusates of rats. Life Sci. 1983;33:1899–907.PubMedCrossRef
150.
Guix T, Hurd YL, Ungerstedt U. Amphetamine enhances extracellular concentrations of dopamine and acetylcholine in dorsolateral striatum and nucleus accumbens of freely moving rats. Neurosci Lett. 1992;138:137–40.PubMedCrossRef
151.
152.
Mantle TJ, Tipton KF, Garrett NJ. Inhibition of monoamine oxidase by amphetamine and related compounds. Biochem Pharmacol. 1976;25:2073–7.PubMedCrossRef
153.
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27:699–711.PubMedCrossRef
154.
Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, et al. Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br J Pharmacol. 2010;160:283–91.PubMedPubMedCentralCrossRef
155.
Udvardi PT, Fohr KJ, Henes C, Liebau S, Dreyhaupt J, Boeckers TM, et al. Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain—an in vivo study. Drug Des Devel Ther. 2013;7:1433–46.PubMedPubMedCentral
156.
Buitelaar J, Asherson P, Soutullo C, Colla M, Adams DH, Tanaka Y, et al. Differences in maintenance of response upon discontinuation across medication treatments in attention-deficit/hyperactivity disorder. Eur Neuropsychopharmacol. 2015.
157.
Gamo NJ, Wang M, Arnsten AF. Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry. 2010;49:1011–23.PubMedPubMedCentralCrossRef
158.
Arnsten AF, Dudley AG. Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav Brain Funct. 2005;1:2.PubMedPubMedCentralCrossRef
159.
Andrews GD, Lavin A. Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors. Neuropsychopharmacology. 2006;31:594–601.PubMedCrossRef
160.
Marquand AF, O’Daly OG, De Simoni S, Alsop DC, Maguire RP, Williams SC, et al. Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: a multi-class pattern recognition approach. Neuroimage. 2012;60:1015–24.PubMedPubMedCentralCrossRef
161.
Schulz KP, Fan J, Bedard AC, Clerkin SM, Ivanov I, Tang CY, et al. Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2012;69:952–61.PubMedCrossRef
162.
Barbaresi WJ, Katusic SK, Colligan RC, Weaver AL, Leibson CL, Jacobsen SJ. Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study. J Dev Behav Pediatr. 2006;27:1–10.PubMedCrossRef
163.
Spencer TJ, Biederman J, Harding M, O’Donnell D, Faraone SV, Wilens TE. Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays? J Am Acad Child Adolesc Psychiatry. 1996;35:1460–9.PubMedCrossRef
164.
Barkley RA, McMurray MB, Edelbrock CS, Robbins K. Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation. Pediatrics. 1990;86:184–92.PubMed
165.
Sonuga-Barke EJ, Coghill D, Wigal T, DeBacker M, Swanson J. Adverse reactions to methylphenidate treatment for attention-deficit/hyperactivity disorder: structure and associations with clinical characteristics and symptom control. J Child Adolesc Psychopharmacol. 2009;19:683–90.PubMedCrossRef
166.
Maldonado R. Comparison of the pharmacokinetics and clinical efficacy of new extended-release formulations of methylphenidate. Expert Opin Drug Metab Toxicol. 2013;9:1001–14.PubMedCrossRef
167.
Urban KR, Waterhouse BD, Gao WJ. Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons. Biol Psychiatry. 2012;72:880–8.PubMedPubMedCentralCrossRef
168.
Urban KR, Li YC, Gao WJ. Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex. Neurobiol Learn Mem. 2013;101:65–74.PubMedPubMedCentralCrossRef
169.
Wang GJ, Volkow ND, Wigal T, Kollins SH, Newcorn JH, Telang F, et al. Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder. PLoS One. 2013;8:e63023.PubMedPubMedCentralCrossRef
170.
Bukstein OG, Head J. Guanfacine ER for the treatment of adolescent attention-deficit/hyperactivity disorder. Expert Opin Pharmacother. 2012;13:2207–13.PubMedCrossRef
171.
Faraone SV, McBurnett K, Sallee FR, Steeber J, Lopez FA. Guanfacine extended release: a novel treatment for attention-deficit/hyperactivity disorder in children and adolescents. Clin Ther. 2013;35:1778–93.PubMedCrossRef
172.
Biederman J, Melmed RD, Patel A, McBurnett K, Donahue J, Lyne A. Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD. CNS Spectr. 2008;13:1047–55.PubMed
173.
Biederman J, Melmed RD, Patel A, McBurnett K, Konow J, Lyne A, et al. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008;121:e73–84.PubMedCrossRef
174.
Connor DF, Findling RL, Kollins SH, Sallee F, Lopez FA, Lyne A, et al. Effects of guanfacine extended release on oppositional symptoms in children aged 6–12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial. CNS Drugs. 2010;24:755–68.PubMed
175.
Sallee FR, Lyne A, Wigal T, McGough JJ. Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19:215–26.PubMedCrossRef
176.
Sallee FR, McGough J, Wigal T, Donahue J, Lyne A, Biederman J. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009;48:155–65.PubMedCrossRef
177.
Hervas A, Huss M, Johnson M, McNicholas F, van Stralen J, Sreckovic S, et al. Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, Phase III trial. Eur Neuropsychopharmacol. 2014;24:1861–72.PubMedCrossRef
178.
Wilens TE, Bukstein O, Brams M, Cutler AJ, Childress A, Rugino T, et al. A controlled trial of extended-release guanfacine and psychostimulants for attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:74–85.PubMedCrossRef
179.
Newcorn JH, Stein MA, Childress AC, Youcha S, White C, Enright G, 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.PubMedCrossRef
180.
Wilens TE, McBurnett K, Turnbow J, Rugino T, White C, Youcha S. Morning and evening effects of guanfacine extended release adjunctive to psychostimulants in pediatric ADHD: results from a Phase III multicenter trial. J Atten Disord. 2013 (Epub ahead of print).
181.
Sikirica V, Findling RL, Signorovitch J, Erder MH, Dammerman R, Hodgkins P, et al. Comparative efficacy of guanfacine extended release versus atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: applying matching-adjusted indirect comparison methodology. CNS Drugs. 2013;27:943–53.PubMedPubMedCentralCrossRef
182.
Ruggiero S, Clavenna A, Reale L, Capuano A, Rossi F, Bonati M. Guanfacine for attention deficit and hyperactivity disorder in pediatrics: a systematic review and meta-analysis. Eur Neuropsychopharmacol. 2014;24:1578–90.PubMedCrossRef
183.
Martin P, Satin L, Kahn RS, Robinson A, Corcoran M, Purkayastha J, et al. A thorough QT study of guanfacine. Int J Clin Pharmacol Ther. 2015;53:301–16.PubMed
184.
Fossa AA, Zhou M, Robinson A, Purkayastha J, Martin P. Use of ECG restitution (beat-to-beat QT-TQ interval analysis) to assess arrhythmogenic risk of QTc prolongation with guanfacine. Ann Noninvasive Electrocardiol. 2014;19:582–94.PubMedCrossRef
185.
Bangs ME, Tauscher-Wisniewski S, Polzer J, Zhang S, Acharya N, Desaiah D, et al. Meta-analysis of suicide-related behavior events in patients treated with atomoxetine. J Am Acad Child Adolesc Psychiatry. 2008;47:209–18.PubMedCrossRef
186.
187.
Spencer TJ, Greenbaum M, Ginsberg LD, Murphy WR. Safety and effectiveness of coadministration of guanfacine extended release and psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19:501–10.PubMedPubMedCentralCrossRef
188.
Huss M, Hervas A, Newcorn J, Harpin V, Lyne A, Robertson B, et al. Guanfacine extended release for attention-deficit/hyperactivity disorder following inadequate response to prior methylphenidate (P.7.d.013). Eur Neuropsychopharmacol. 2014;24:S727–8.CrossRef
189.
Warikoo N, Faraone SV. Background, clinical features and treatment of attention deficit hyperactivity disorder in children. Expert Opin Pharmacother. 2013;14:1885–906.PubMedCrossRef
190.
Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF. Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry. 2009;48:884–93.PubMedPubMedCentralCrossRef
191.
Cohen DJ, Detlor J, Young JG, Shaywitz BA. Clonidine ameliorates Gilles de la Tourette syndrome. Arch Gen Psychiatry. 1980;37:1350–7.PubMedCrossRef
192.
Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology. 2002;58:527–36.CrossRef
193.
Rizzo R, Gulisano M, Cali PV, Curatolo P. Tourette syndrome and comorbid ADHD: current pharmacological treatment options. Eur J Paediatr Neurol. 2013;17:421–8.PubMedCrossRef
194.
Chappell PB, Riddle MA, Scahill L, Lynch KA, Schultz R, Arnsten A, et al. Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette’s syndrome: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry. 1995;34:1140–6.PubMedCrossRef
195.
Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001;158:1067–74.PubMedCrossRef
196.
Weisman H, Qureshi IA, Leckman JF, Scahill L, Bloch MH. Systematic review: pharmacological treatment of tic disorders—efficacy of antipsychotic and alpha-2 adrenergic agonist agents. Neurosci Biobehav Rev. 2013;37:1162–71.PubMedPubMedCentralCrossRef
197.
Pringsheim T, Doja A, Gorman D, McKinlay D, Day L, Billinghurst L, et al. Canadian guidelines for the evidence-based treatment of tic disorders: pharmacotherapy. Can J Psychiatry. 2012;57:133–43.PubMed
198.
Roessner V, Plessen KJ, Rothenberger A, Ludolph AG, Rizzo R, Skov L, et al. European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment. Eur Child Adolesc Psychiatry. 2011;20:173–96.PubMedPubMedCentralCrossRef
199.
Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1995;34:50–4.PubMedCrossRef
200.
Signorovitch J, Erder MH, Xie J, Sikirica V, Lu M, Hodgkins PS, et al. Comparative effectiveness research using matching-adjusted indirect comparison: an application to treatment with guanfacine extended release or atomoxetine in children with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. Pharmacoepidemiol Drug Saf. 2012;21(Suppl 2):130–7.PubMedCrossRef
201.
Findling RL, McBurnett K, White C, Youcha S. Guanfacine extended release adjunctive to a psychostimulant in the treatment of comorbid oppositional symptoms in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2014;24:245–52.PubMedPubMedCentralCrossRef
202.
Spencer T, Biederman J, Wilens T. Growth deficits in children with attention deficit hyperactivity disorder. Pediatrics. 1998;102:501–6.PubMed
203.
Biederman J, Spencer TJ, Monuteaux MC, Faraone SV. A naturalistic 10-year prospective study of height and weight in children with attention-deficit hyperactivity disorder grown up: sex and treatment effects. J Pediatr. 2010;157(635–40):e1.PubMed
204.
Poulton A, Briody J, McCorquodale T, Melzer E, Herrmann M, Baur LA, et al. Weight loss on stimulant medication: how does it affect body composition and bone metabolism? A prospective longitudinal study. Int J Pediatr Endocrinol. 2012;2012:30.PubMedPubMedCentralCrossRef
205.
Hasnain M, Vieweg WV. Weight considerations in psychotropic drug prescribing and switching. Postgrad Med. 2013;125:117–29.PubMedCrossRef
206.
207.
Lurbe E, Cifkova R, Cruickshank JK, Dillon MJ, Ferreira I, Invitti C, et al. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens. 2009;27:1719–42.PubMedCrossRef
208.
George MG, Tong X, Wigington C, Gillespie C, Hong Y. Hypertension screening in children and adolescents—National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, and Medical Expenditure Panel Survey, United States, 2007–2010. Morb Mortal Wkly Rep. 2014;63:47–53.
209.
Martin L, Oepen J, Reinehr T, Wabitsch M, Claussnitzer G, Waldeck E, et al. Ethnicity and cardiovascular risk factors: evaluation of 40,921 normal-weight, overweight or obese children and adolescents living in Central Europe. Int J Obes (Lond). 2015;39:45–51.CrossRef
210.
Wigal SB. Efficacy and safety limitations of attention-deficit hyperactivity disorder pharmacotherapy in children and adults. CNS Drugs. 2009;23(Suppl 1):21–31.PubMedCrossRef
211.
Wood AC, Rijsdijk F, Asherson P, Kuntsi J. Inferring causation from cross-sectional data: examination of the causal relationship between hyperactivity-impulsivity and novelty seeking. Front Genet. 2011;2:6.PubMedPubMedCentralCrossRef
212.
Basar K, Sesia T, Groenewegen H, Steinbusch HW, Visser-Vandewalle V, Temel Y. Nucleus accumbens and impulsivity. Prog Neurobiol. 2010;92:533–57.PubMedCrossRef
213.
Humphreys KL, Eng T, Lee SS. Stimulant medication and substance use outcomes: a meta-analysis. JAMA Psychiatry. 2013;70:740–9.PubMedCrossRef
214.
Kim S, Bobeica I, Gamo NJ, Arnsten AF, Lee D. Effects of alpha-2A adrenergic receptor agonist on time and risk preference in primates. Psychopharmacology. 2012;219:363–75.PubMedPubMedCentralCrossRef
215.
Fliers EA, Buitelaar JK, Maras A, Bul K, Hohle E, Faraone SV, et al. ADHD is a risk factor for overweight and obesity in children. J Dev Behav Pediatr. 2013;34:566–74.PubMedCrossRef
216.
Cortese S, Comencini E, Vincenzi B, Speranza M, Angriman M. Attention-deficit/hyperactivity disorder and impairment in executive functions: a barrier to weight loss in individuals with obesity? BMC Psychiatry. 2013;13:286.PubMedPubMedCentralCrossRef
217.
Whalen CK, Henker B, Ishikawa SS, Jamner LD, Floro JN, Johnston JA, et al. An electronic diary study of contextual triggers and ADHD: get ready, get set, get mad. J Am Acad Child Adolesc Psychiatry. 2006;45:166–74.PubMedCrossRef
218.
Rugino TA. Effect on primary sleep disorders when children with ADHD are administered guanfacine extended release. J Atten Disord. 2014 (Epub ahead of print).
219.
Corkum P, Moldofsky H, Hogg-Johnson S, Humphries T, Tannock R. Sleep problems in children with attention-deficit/hyperactivity disorder: impact of subtype, comorbidity, and stimulant medication. J Am Acad Child Adolesc Psychiatry. 1999;38:1285–93.PubMedCrossRef
220.
Young J, Rugino T, Dammerman R, Lyne A, Newcorn JH. Efficacy of guanfacine extended release assessed during the morning, afternoon, and evening using a modified conners’ parent rating scale-revised: short form. J Child Adolesc Psychopharmacol. 2014;24:435–41.PubMedPubMedCentralCrossRef
221.
Arnsten AF. Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness. Cereb Cortex. 2007;17(Suppl 1):i6–15.PubMedCrossRef
222.
Biederman J, Petty CR, Spencer TJ, Woodworth KY, Bhide P, Zhu J, et al. Examining the nature of the comorbidity between pediatric attention deficit/hyperactivity disorder and post-traumatic stress disorder. Acta Psychiatr Scand. 2013;128:78–87.PubMedPubMedCentralCrossRef
223.
Birnbaum SG, Podell DM, Arnsten AF. Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats. Pharmacol Biochem Behav. 2000;67:397–403.PubMedCrossRef
224.
Connor DF, Grasso DJ, Slivinsky MD, Pearson GS, Banga A. An open-label study of guanfacine extended release for traumatic stress related symptoms in children and adolescents. J Child Adolesc Psychopharmacol. 2013;23:244–51.PubMedPubMedCentralCrossRef
225.
Malhotra PA, Parton AD, Greenwood R, Husain M. Noradrenergic modulation of space exploration in visual neglect. Ann Neurol. 2006;59:186–90.PubMedCrossRef
226.
Singh-Curry V, Malhotra P, Farmer SF, Husain M. Attention deficits following ADEM ameliorated by guanfacine. J Neurol Neurosurg Psychiatry. 2011;82:688–90.PubMedPubMedCentralCrossRef
227.
McAllister TW, McDonald BC, Flashman LA, Ferrell RB, Tosteson TD, Yanofsky NN, et al. Alpha-2 adrenergic challenge with guanfacine one month after mild traumatic brain injury: altered working memory and BOLD response. Int J Psychophysiol. 2011;82:107–14.PubMedPubMedCentralCrossRef
228.
Kauser H, Sahu S, Kumar S, Panjwani U. Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits. Physiol Behav. 2014;123:187–92.PubMedCrossRef
229.
Bruxel EM, Akutagava-Martins GC, Salatino-Oliveira A, Contini V, Kieling C, Hutz MH, et al. ADHD pharmacogenetics across the life cycle: new findings and perspectives. Am J Med Genet B Neuropsychiatr Genet. 2014;165:263–82.CrossRef
230.
Hodgkins P, Dittmann RW, Sorooshian S, Banaschewski T. Individual treatment response in attention-deficit/hyperactivity disorder: broadening perspectives and improving assessments. Exp Rev Neurother. 2013;13:425–33.CrossRef
231.
232.
Pliszka S. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:894–921.PubMedCrossRef
233.
Ahmann PA, Theye FW, Berg R, Linquist AJ, Van Erem AJ, Campbell LR. Placebo-controlled evaluation of amphetamine mixture-dextroamphetamine salts and amphetamine salts (Adderall): efficacy rate and side effects. Pediatrics. 2001;107:E10.PubMedCrossRef
234.
Wang Y, Zheng Y, Du Y, Song DH, Shin YJ, Cho SC, et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry. 2007;41:222–30.PubMedCrossRef
235.
Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry. 2008;165:721–30.PubMedCrossRef
236.
Greenhill LL, Swanson JM, Vitiello B, Davies M, Clevenger W, Wu M, et al. Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial. J Am Acad Child Adolesc Psychiatry. 2001;40:180–7.PubMedCrossRef
237.
Wilens T, McBurnett K, Stein M, Lerner M, Spencer T, Wolraich M. ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study. J Am Acad Child Adolesc Psychiatry. 2005;44:1015–23.PubMedCrossRef
238.
Smalley SL, McGough JJ, Moilanen IK, Loo SK, Taanila A, Ebeling H, et al. Prevalence and psychiatric comorbidity of attention-deficit/hyperactivity disorder in an adolescent Finnish population. J Am Acad Child Adolesc Psychiatry. 2007;46:1575–83.PubMedCrossRef
239.
Gau SS, Ni HC, Shang CY, Soong WT, Wu YY, Lin LY, et al. Psychiatric comorbidity among children and adolescents with and without persistent attention-deficit hyperactivity disorder. Aust N Z J Psychiatry. 2010;44:135–43.PubMedCrossRef
240.
Steinhausen HC, Novik TS, Baldursson G, Curatolo P, Lorenzo MJ, Rodrigues PR, et al. Co-existing psychiatric problems in ADHD in the ADORE cohort. Eur Child Adolesc Psychiatry. 2006;15(Suppl 1):I25–9.PubMedCrossRef
241.
Schlander M, Schwarz O, Rothenberger A, Roessner V. Tic disorders: administrative prevalence and co-occurrence with attention-deficit/hyperactivity disorder in a German community sample. Eur Psychiatry. 2011;26:370–4.PubMedCrossRef
242.
Zavadenko NN, Suvorinova NI. Disorders comorbid to attention deficit hyperactivity syndrome in children. Zh Nevrol Psikhiatr Im S S Korsakova. 2007;107:30–5.PubMed
243.
Anckarsater H, Lundstrom S, Kollberg L, Kerekes N, Palm C, Carlstrom E, et al. The child and adolescent twin study in Sweden (CATSS). Twin Res Hum Genet. 2011;14:495–508.PubMedCrossRef
244.
Amiri S, Fakhari A, Golmirzaei J, Mohammadpoorasl A, Abdi S. Tourette’s syndrome, chronic tics, and comorbid attention deficit/hyperactivity disorder in elementary students. Arch Iran Med. 2012;15:76–8.PubMed
245.
Biederman J, Faraone SV. The Massachusetts General Hospital studies of gender influences on attention-deficit/hyperactivity disorder in youth and relatives. Psychiatr Clin N Am. 2004;27:225–32.CrossRef
246.
Larson K, Russ SA, Kahn RS, Halfon N. Patterns of comorbidity, functioning, and service use for US children with ADHD, 2007. Pediatrics. 2011;127:462–70.PubMedPubMedCentralCrossRef
247.
Lebowitz ER, Motlagh MG, Katsovich L, King RA, Lombroso PJ, Grantz H, et al. Tourette syndrome in youth with and without obsessive compulsive disorder and attention deficit hyperactivity disorder. Eur Child Adolesc Psychiatry. 2012;21:451–7.PubMedPubMedCentralCrossRef
248.
Freeman RD. Tic disorders and ADHD: answers from a world-wide clinical dataset on Tourette syndrome. Eur Child Adolesc Psychiatry. 2007;16(Suppl 1):15–23.PubMedCrossRef
249.
Khalifa N, von Knorring AL. Psychopathology in a Swedish population of school children with tic disorders. J Am Acad Child Adolesc Psychiatry. 2006;45:1346–53.PubMedCrossRef
250.
Kadesjo B, Gillberg C. Tourette’s disorder: epidemiology and comorbidity in primary school children. J Am Acad Child Adolesc Psychiatry. 2000;39:548–55.PubMedCrossRef
251.
Ghanizadeh A, Mosallaei S. Psychiatric disorders and behavioral problems in children and adolescents with Tourette syndrome. Brain Dev. 2009;31:15–9.PubMedCrossRef
252.
Mahle WT, Clancy RR, Moss EM, Gerdes M, Jobes DR, Wernovsky G. Neurodevelopmental outcome and lifestyle assessment in school-aged and adolescent children with hypoplastic left heart syndrome. Pediatrics. 2000;105:1082–9.PubMedCrossRef
253.
Strine TW, Lesesne CA, Okoro CA, McGuire LC, Chapman DP, Balluz LS, et al. Emotional and behavioral difficulties and impairments in everyday functioning among children with a history of attention-deficit/hyperactivity disorder. Prev Chronic Dis. 2006;3:A52.PubMedPubMedCentral
254.
Spencer TJ, Faraone SV, Surman CB, Petty C, Clarke A, Batchelder H, et al. Toward defining deficient emotional self-regulation in children with attention-deficit/hyperactivity disorder using the Child Behavior Checklist: a controlled study. Postgrad Med. 2011;123:50–9.PubMedPubMedCentralCrossRef
255.
Sjowall D, Roth L, Lindqvist S, Thorell LB. Multiple deficits in ADHD: executive dysfunction, delay aversion, reaction time variability, and emotional deficits. J Child Psychol Psychiatry. 2013;54:619–27.PubMedPubMedCentralCrossRef
256.
Anastopoulos AD, Smith TF, Garrett ME, Morrissey-Kane E, Schatz NK, Sommer JL, et al. Self-regulation of emotion, functional impairment, and comorbidity among cildren with AD/HD. J Atten Disord. 2011;15:583–92.PubMedPubMedCentralCrossRef
257.
Stringaris A, Goodman R. Mood lability and psychopathology in youth. Psychol Med. 2009;39:1237–45.PubMedCrossRef
258.
Sobanski E, Banaschewski T, Asherson P, Buitelaar J, Chen W, Franke B, et al. Emotional lability in children and adolescents with attention deficit/hyperactivity disorder (ADHD): clinical correlates and familial prevalence. J Child Psychol Psychiatry. 2010;51:915–23.PubMedCrossRef
259.
Goez H, Back-Bennet O, Zelnik N. Differential stimulant response on attention in children with comorbid anxiety and oppositional defiant disorder. J Child Neurol. 2007;22:538–42.PubMedCrossRef
260.
Ter-Stepanian M, Grizenko N, Zappitelli M, Joober R. Clinical response to methylphenidate in children diagnosed with attention-deficit hyperactivity disorder and comorbid psychiatric disorders. Can J Psychiatry. 2010;55:305–12.PubMed
261.
Harty SC, Miller CJ, Newcorn JH, Halperin JM. Adolescents with childhood ADHD and comorbid disruptive behavior disorders: aggression, anger, and hostility. Child Psychiatry Hum Dev. 2009;40:85–97.PubMedPubMedCentralCrossRef
262.
Hurtig T, Ebeling H, Taanila A, Miettunen J, Smalley S, McGough J, et al. ADHD and comorbid disorders in relation to family environment and symptom severity. Eur Child Adolesc Psychiatry. 2007;16:362–9.PubMedCrossRef
263.
Souza I, Pinheiro MA, Denardin D, Mattos P, Rohde LA. Attention-deficit/hyperactivity disorder and comorbidity in Brazil: comparisons between two referred samples. Eur Child Adolesc Psychiatry. 2004;13:243–8.PubMedCrossRef
264.
August GJ, Realmuto GM, MacDonald AW III, Nugent SM, Crosby R. Prevalence of ADHD and comorbid disorders among elementary school children screened for disruptive behavior. J Abnorm Child Psychol. 1996;24:571–95.PubMedCrossRef
265.
Biederman J, Ball SW, Monuteaux MC, Surman CB, Johnson JL, Zeitlin S. Are girls with ADHD at risk for eating disorders? Results from a controlled, five-year prospective study. J Dev Behav Pediatr. 2007;28:302–7.PubMedCrossRef
266.
Rastam M, Taljemark J, Tajnia A, Lundstrom S, Gustafsson P, Lichtenstein P, et al. Eating problems and overlap with ADHD and autism spectrum disorders in a nationwide twin study of 9- and 12-year-old children. Sci World J. 2013;2013:315429.CrossRef
267.
Madsen AG, Dalsgaard S. Prevalence of smoking, alcohol and substance use among adolescents with attention-deficit/hyperactivity disorder in Denmark compared with the general population. Nord J Psychiatry. 2014;68:53–9.PubMedCrossRef
268.
Wu LT, Gersing K, Burchett B, Woody GE, Blazer DG. Substance use disorders and comorbid Axis I and II psychiatric disorders among young psychiatric patients: findings from a large electronic health records database. J Psychiatr Res. 2011;45:1453–62.PubMedPubMedCentralCrossRef
269.
Hovens JG, Cantwell DP, Kiriakos R. Psychiatric comorbidity in hospitalized adolescent substance abusers. J Am Acad Child Adolesc Psychiatry. 1994;33:476–83.PubMedCrossRef
Metadata
Title
Guanfacine Extended Release: A New Pharmacological Treatment Option in Europe
Authors
Michael Huss
Wai Chen
Andrea G. Ludolph
Publication date
01-01-2016
Publisher
Springer International Publishing
Published in
Clinical Drug Investigation / Issue 1/2016
Print ISSN: 1173-2563
Electronic ISSN: 1179-1918
DOI
https://doi.org/10.1007/s40261-015-0336-0

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