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.
OBJECTIVE
To evaluate the efficacy and safety of guanfacine extended release (XR, Intuniv; Shire Development Inc., Wayne, PA, USA) in the treatment of oppositional symptoms in children aged 6-12 years with a diagnosis of attention-deficit hyperactivity disorder (ADHD) and the presence of oppositional symptoms.


METHODS
In this randomized, double-blind, placebo-controlled, multicentre, flexible-dose, dose-optimization study, children aged 6-12 years were randomized to receive guanfacine XR (1-4 mg/day) or placebo for 9 weeks. Screening and washout periods were followed by a 5-week dose-optimization period, a 3-week dose-maintenance period and a 1-week tapering period. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L) score. Change in ADHD Rating Scale IV (ADHD-RS-IV) total score was a secondary efficacy measure. Safety assessments included adverse events (AEs), vital signs, ECG readings and laboratory studies.


RESULTS
A total of 217 children were enrolled: 138 were randomized to receive guanfacine XR and 79 to receive placebo. Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were 10.9 in the guanfacine XR group compared with 6.8 in the placebo group (p < 0.001; effect size = 0.59). A significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint was also seen in the guanfacine-treated group compared with the placebo group (23.8 vs 11.5, respectively; p < 0.001; effect size = 0.92). A post hoc correlation analysis between percentage reduction from baseline to endpoint in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores indicated that the decreases in oppositional symptoms and ADHD symptoms were highly correlated (r = 0.74). The most commonly reported, treatment-emergent AEs (TEAEs) in the guanfacine XR group were somnolence (50.7%), headache (22.1%), sedation (13.2%), upper abdominal pain (11.8%) and fatigue (11.0%) and most were mild or moderate in severity. TEAEs of sedation, somnolence or hypersomnia were experienced by 62.5% of subjects in the guanfacine XR group. These events were most common during the dose-titration period but most (63.5%) resolved prior to the taper period. TEAEs of fatigue, lethargy and asthenia were reported in 11.0%, 3.7% and 0.0% of subjects in the guanfacine XR group, respectively. Most subjects receiving guanfacine XR demonstrated modest changes in blood pressure, pulse rate and ECG readings that were not considered clinically significant.


CONCLUSIONS
In this population of children aged 6-12 years with ADHD and the presence of oppositional symptoms, significant reductions in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores were observed with guanfacine XR treatment compared with placebo. Treatment with guanfacine XR at optimized doses was associated with mostly mild or moderate TEAEs. The findings of this study support the efficacy of guanfacine XR in the treatment of children with ADHD and the presence of oppositional symptoms.


BACKGROUND
NCT00367835.
Connor
Daniel F
DF
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut 06030-1410,USA. DCONNOR@uchc.edu
Findling
Robert L
RL
Kollins
Scott H
SH
Sallee
Floyd
F
López
Frank A
FA
Lyne
Andrew
A
Tremblay
Gerald
G
D058647:Adrenergic alpha-2 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000188:drug therapy*; D002648:Child; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016316:Guanfacine / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans
D058647:Adrenergic alpha-2 Receptor Agonists; D003692:Delayed-Action Preparations; D016316:Guanfacine
Pediatrics. 2004 Jul;114(1):e1-8
15231966
J Child Neurol. 2008 Sep;23(9):981-90
18474932
Biol Psychiatry. 2005 Jun 1;57(11):1336-46
15950006
J Am Acad Child Adolesc Psychiatry. 1999 Dec;38(12):1551-9
10596256
J Am Acad Child Adolesc Psychiatry. 2005 Mar;44(3):240-8
15725968
Psychopharmacology (Berl). 2007 Jan;190(1):31-41
17093981
J Am Acad Child Adolesc Psychiatry. 2008 Feb;47(2):180-188
18182963
Psychiatr Clin North Am. 2004 Mar;27(1):83-96, ix
15062632
J Nerv Ment Dis. 2007 Jul;195(7):601-5
17632251
J Am Acad Child Adolesc Psychiatry. 2006 Jul;45(7):808-16
16832317
J Neurosci. 1988 Nov;8(11):4287-98
2903226
J Am Acad Child Adolesc Psychiatry. 2009 Feb;48(2):155-65
19106767
Pediatrics. 1993 Aug;92(2):212-8
8337019
Eur Arch Psychiatry Clin Neurosci. 2006 Sep;256 Suppl 1:i42-6
16977551
Arq Neuropsiquiatr. 2004 Jun;62(2B):399-402
15273834
Biol Psychiatry. 2006 Nov 15;60(10):1111-20
16806100
Biol Psychiatry. 2005 Jun 1;57(11):1215-20
15949990
J Child Psychol Psychiatry. 2002 Mar;43(3):375-85
11944879
Pediatrics. 2004 Nov;114(5):e541-7
15520087
Neuropsychopharmacology. 2006 Nov;31(11):2376-83
16855530
MMWR Morb Mortal Wkly Rep. 2005 Sep 2;54(34):842-7
16138075
J Am Acad Child Adolesc Psychiatry. 1996 Sep;35(9):1193-204
8824063
J Am Acad Child Adolesc Psychiatry. 2002 Mar;41(3):253-61
11886019
Behav Neurosci. 1997 Oct;111(5):883-91
9383511
Pediatrics. 2008 Jan;121(1):e73-84
18166547
Pediatr Clin North Am. 1998 Oct;45(5):1099-22, viii
9884677
Lancet. 2005 Jul 16-22;366(9481):237-48
16023516
J Am Acad Child Adolesc Psychiatry. 1999 May;38(5):578-86
10230190
J Am Acad Child Adolesc Psychiatry. 2007 Jan;46(1):126-141
17195736
J Atten Disord. 2008 Sep;12(2):126-34
17934178
Pediatrics. 2008 Feb;121(2):e314-20
18245404
Psychol Bull. 1997 Jan;121(1):65-94
9000892
Clin Pediatr (Phila). 2000 Jan;39(1):15-25
10660814
Biol Psychiatry. 2005 Jun 1;57(11):1377-84
15950011
Am J Psychiatry. 2002 Nov;159(11):1896-901
12411225
Eur J Pharmacol. 1991 Sep 17;202(2):235-43
1666366
Pediatr Clin North Am. 2003 Oct;50(5):1019-48
14558680
J Child Neurol. 2007 May;22(5):538-42
17690058
Behav Brain Funct. 2005 Apr 22;1(1):2
15916700
J Am Acad Child Adolesc Psychiatry. 1996 Oct;35(10):1314-21
8885585
J Clin Psychiatry. 2002 Dec;63(12):1140-7
12523874
J Child Adolesc Psychopharmacol. 2007 Aug;17(4):393-406
17822336
Clin Ther. 2006 Mar;28(3):402-18
16750455
J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):503-511
16601402
J Neurosci. 2002 Oct 1;22(19):8771-7
12351753
Synapse. 2002 Dec 1;46(3):140-9
12325041