Efficacy of Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder : Journal of Developmental & Behavioral Pediatrics

Secondary Logo

Journal Logo

Brief Report

Efficacy of Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder

Newcorn, Jeffrey H. MD*; Huss, Michael MD; Connor, Daniel F. MD; Hervás, Amaia MD§,‖; Werner-Kiechle, Tamara MD; Robertson, Brigitte MD**

Author Information
Journal of Developmental & Behavioral Pediatrics: September 2020 - Volume 41 - Issue 7 - p 565-570
doi: 10.1097/DBP.0000000000000822
  • Open

Abstract

Individuals with attention-deficit/hyperactivity disorder (ADHD) often have comorbid oppositional defiant disorder (ODD),1 which is characterized by anger, hostility, irritability, and refusal to comply with rules.2 Comorbid ODD is associated with greater ADHD symptom severity and significantly more parent-reported overt aggression and delinquency than ADHD alone.3,4 In addition, children with ADHD and comorbid ODD are at risk of developing conduct disorder in adolescence and antisocial behavior disorder in adulthood.3 A longitudinal study of boys with ADHD identified a developmental continuum, with ADHD predicting ODD and ODD being directly predictive of conduct disorder, anxiety, and depression.5 Although most studies have been conducted in boys, similar findings have also been reported in girls with ADHD in whom ODD, conduct disorder, and aggression are prevalent and predictive of severe adult impairments.6 Adolescents with conduct disorder are at high risk for substance use disorders and criminal behavior.7,8 From a parenting perspective, increased stress and decreased parenting effectiveness and parental agreement have been reported by the parents of children with ADHD and comorbid ODD or conduct disorder compared with the parents of children with ADHD alone.4

Effective treatment of ADHD can help to mitigate ODD symptoms when both occur.3 A meta-analysis found psychostimulants to be efficacious in the treatment of oppositional behavior, conduct problems, and aggression in children and adolescents with ADHD.9 Long-acting psychostimulants, such as lisdexamfetamine dimesylate and extended-release methylphenidate, should be taken in the morning, and they have a duration of action of 8 to 12 hours.10,11 Given the presence of oppositional symptoms throughout the whole day, additional or alternative treatment may be needed in some individuals to address behavioral problems in the evening.

Atomoxetine (ATX) and guanfacine extended release (GXR) are both non-stimulant treatment options for children and adolescents with ADHD and have been associated with small and small-to-moderate effects, respectively, on oppositional behavior.9 Although classed as a nonstimulant, ATX acts similarly to stimulants by blocking the re-uptake of noradrenaline into the presynaptic neuron.12 One ATX study found that ADHD symptoms were improved in children with ADHD and ODD, but oppositional symptoms were not significantly reduced.13 Another study indicated a potential need for higher doses of ATX to reduce ADHD symptoms in children with comorbid ODD than in those with ADHD alone.14 Although one meta-analysis reported that ATX may be more efficacious in reducing the symptoms of ADHD in individuals without comorbid ODD than with ODD, another found that the presence of oppositional symptoms did not affect the treatment of ADHD with ATX.15,16

Guanfacine extended release is a selective α2-adrenergic receptor agonist, directly stimulating postsynaptic α2A-adrenergic receptors to enhance noradrenaline neurotransmission.12 In the United States and Canada, GXR is approved for use in children and adolescents as monotherapy or adjunctive to stimulant therapy.17 In Europe, GXR is approved for the treatment of children and adolescents with ADHD when stimulants are unsuitable, not tolerated, or have been shown to be ineffective.18 Previous studies have shown GXR to be efficacious in improving ADHD symptoms, with a consistent response throughout the day regardless of the time of administration.19–21 Furthermore, GXR given as monotherapy significantly reduced oppositional symptoms in children with ADHD in a phase 3 study, assessed using the oppositional subscale of Conners Parent Rating Scale—Revised: Long Form.22

Given that ODD has been reported to affect response to ADHD treatment, we wanted to add to the limited available data about treatment efficacy in reducing symptoms of ADHD in subgroups of individuals with and without comorbid ODD. To address these aims, we conducted post hoc analyses of data from 4 phase 3 studies that included substantial proportions of participants with ODD. Here, we assessed the efficacy of GXR in reducing core ADHD symptoms in children and adolescents both with and without a diagnosis of comorbid ODD.

METHODS

Study Designs and Participants

Data were included from 4 double-blind, randomized, placebo-controlled studies of dose-optimized guanfacine extended release (GXR) monotherapy in children (6–12 years of age) and adolescents (13–17 years of age) with attention-deficit/hyperactivity disorder (ADHD): SPD503-307, SPD503-312, SPD503-316, and SPD503-314.

Study SPD503-307 was conducted in the United States and enrolled children with a baseline ADHD Rating Scale IV (ADHD-RS-IV) score ≥24, Clinical Global Impression—Severity (CGI-S) score ≥4, and Conners Parent Rating Scale—Revised: Long Form oppositional subscale ≥14 for boys and ≥12 for girls. Participants were randomized in a 2:1 ratio to receive GXR or placebo.22 Study SPD503-312 was conducted in the United States and enrolled adolescents with a baseline ADHD-RS-IV score ≥32 and CGI-S score ≥4. Participants were randomized in a 1:1 ratio to receive GXR or placebo.23 Study SPD503-316 was conducted in Europe and North America and enrolled children and adolescents with a baseline ADHD-RS-IV score ≥32 and CGI-S score ≥4. Participants were randomized in a 1:1:1 ratio to receive GXR, placebo, or atomoxetine (active reference; excluded from the present analyses).24 Study SPD503-314 was conducted in North America and enrolled children with a baseline ADHD-RS-IV score ≥28 and CGI-S score ≥4. Participants were randomized in a 1:1:1 ratio to receive GXR in the morning, GXR in the evening, or placebo.19 Participants from studies SPD503-312 and SPD503-316 were pooled, and participants from the morning and evening GXR dose groups in study SPD503-314 were pooled. An overall pooled data set from all studies could not be used for the present analysis because of differing study designs.

Other than oppositional defiant disorder (ODD), participants were excluded from all studies if they had any comorbid psychiatric diagnosis that, in the opinion of the investigator, would contraindicate GXR treatment or confound efficacy or safety assessments. Participants were categorized as either with or without a current diagnosis of comorbid ODD, based on a diagnostic interview at the screening visit, using the Kiddie Schedule for Affective Disorders and Schizophrenia—Present and Lifetime Version.25

Analyses

Efficacy was determined as the placebo-adjusted least-squares (LSs) mean change from baseline to endpoint (based on the last observation carried forward) in ADHD-RS-IV total scores. Study endpoint was defined as the last post-randomization week before tapering, for which a valid measurement was obtained. Efficacy analyses were based on the full analysis set, defined as all participants who received at least one dose of investigational product. LS mean changes, effect sizes, and p values were based on type III sum of squares from an analysis of covariance model for the change from baseline.

Data were not aggregated across studies, and data from SPD503-314 and SPD503-316 were not stratified by country. Except for those previously published for study SPD503-307,22 improvements in ODD symptoms were not included in the original study designs and so could not be assessed here. Comparisons between participants with and without ODD are descriptive only.

RESULTS

In total, 1,084 participants were included in the analyses (SPD503-312 and SPD503-316, n = 537; SPD503-314, n = 333; and SPD503-307, n = 214). Baseline demographics and clinical characteristics are summarized in Table 1. In all studies, guanfacine extended release (GXR) treatment was associated with significantly greater improvements in attention-deficit/hyperactivity disorder Rating Scale IV (ADHD-RS-IV) total score from baseline to endpoint than placebo. Safety outcomes from the 4 trials have been reported previously.19,22–24

Table 1. - Baseline Demographics and Clinical Characteristics (Safety Populations)
SPD503-307 SPD503-312 SPD503-316 SPD503-314
GXR (n = 136) Placebo (n = 78) GXR (n = 157) Placebo (n = 155) GXR (n = 114) Placebo (n = 111) GXR (n = 221) Placebo (n = 112)
Age, yrs
 Mean (SD) 9.4 (1.73) 9.3 (2.04) 14.5 (1.35) 14.6 (1.44) 10.9 (2.77) 11.0 (2.76) 9.2 (1.76) 8.9 (1.78)
 Median (range) 9.0 (6–12) 9.0 (6–13) 14.0 (13–17) 14.0 (13–17) 11.0 (6–17) 11.0 (6–17) 9.0 (6–12) 9.0 (6–12)
Sex, n (%)
 Male 87 (64.0) 60 (76.9) 103 (65.6) 99 (63.9) 76 (66.7) 86 (77.5) 150 (67.9) 85 (75.9)
Race, n (%)
 White 92 (67.6) 50 (64.1) 113 (72.0) 114 (73.5) 105 (93.8) 104 (95.4) 134 (60.6) 56 (50.0)
ADHD type, n (%)
 Predominantly inattentive 16 (11.8) 11 (14.1) 46 (29.3) 45 (29.0) 15 (13.2) 11 (9.9) 6 (2.7) 1 (0.9)
 Predominantly hyperactive-impulsive 3 (2.2) 4 (5.1) 5 (3.2) 4 (2.6) 6 (5.3) 5 (4.5) 5 (2.3) 1 (0.9)
 Combined 117 (86.0) 63 (80.8) 106 (67.5) 106 (68.4) 93 (81.6) 95 (85.6) 210 (95.0) 110 (98.2)
Psychiatric comorbiditiesa
 Simple phobia 2 (1.5) 0 NR NR NR NR NR NR
 Dysthymia 3 (2.2) 0 NR NR NR NR NR NR
 Other 7 (5.1) 6 (7.7) 6 (3.8) 5 (3.2) 1 (0.9) 1 (0.9) 9 (4.1) 11 (9.8)
aOther than ODD.
ADHD, attention-deficit/hyperactivity disorder; GXR, guanfacine extended release; NR, not recorded; ODD, oppositional defiant disorder.

The proportions of participants with a diagnosis of comorbid oppositional defiant disorder (ODD) were similar between GXR and placebo groups within each data set (Table 2). At baseline, all participants had an ADHD-RS-IV total score of at least 40 (range 40.9–45.7). In all populations, except for the placebo group in study SPD503-307, the participants with ODD had higher (worse) baseline ADHD-RS-IV total scores than those without ODD. No statistical comparisons were conducted to compare baseline ADHD-RS-IV total scores because the individual studies were not designed and powered for such analyses, although we note that the confidence intervals were overlapping in all cases.

Table 2. - Participants with and Without a Current Diagnosis of Comorbid ODD (Full Analysis Set)
Participants, n (%) SPD503-307 SPD503-312/SPD503-316 SPD503-314
GXR (n = 136) Placebo (n = 78) GXR (n = 271) Placebo (n = 266) GXR (n = 221) Placebo (n = 112)
With ODD 87 (64.0) 56 (71.8) 43 (15.9) 34 (12.8) 45 (20.4) 28 (25.0)
Without ODD 49 (36.0)a 22 (28.2)a 228 (84.1) 232 (87.2) 176 (79.6) 84 (75.0)
aAlthough all participants in SPD503-307 had oppositional symptoms, not all met the full DSM-IV criteria for a diagnosis of ODD.
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; GXR, guanfacine extended release; ODD, oppositional defiant disorder.

In all 3 data sets, placebo-adjusted least-square mean changes from baseline to endpoint in ADHD-RS-IV total scores were statistically significant in participants with and without ODD (all p < 0.01; Fig. 1). Although not compared statistically, treatment effect sizes were slightly larger in participants with ODD than in those without (Fig. 1). Study SPD503-307 had the highest proportions of participants with ODD symptoms (64.0% and 71.8% of the GXR and placebo groups, respectively), and participants with ODD from this study also saw the greatest overall effect size (0.962). The pooled population from studies SPD503-312 and SPD503-316 had the smallest proportion of participants with ODD (15.9% and 12.8% of the GXR and placebo groups, respectively) and also the smallest effect sizes (0.688 in participants with ODD and 0.598 in those without ODD).

F1
Figure 1.:
LS mean change in ADHD-RS-IV total scores in participants with or without a current diagnosis of comorbid ODD receiving GXR or placebo in (A) study SPD503-307, (B) studies SPD503-312/SPD503-316, and (C) study SPD503-314 (full analysis set). LS mean change, ES, and p values were based on type III sum of squares from an analysis of covariance model for the change from baseline. ADHD, attention-deficit/hyperactivity disorder; ADHD-RS-IV, ADHD Rating Scale IV; BL, baseline; EP, endpoint; ES, effect size; GXR, guanfacine extended release; LS, least-square; ODD, oppositional defiant disorder.

DISCUSSION

Oppositional defiant disorder (ODD) is the most common comorbidity in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), affecting both sexes, and is associated with increased ADHD symptom severity.3,26,27 In the present post hoc analysis of ADHD treatment response in 4 randomized controlled trials, guanfacine extended release (GXR) consistently reduced core symptoms of ADHD in children and adolescents both with and without comorbid ODD. These findings support GXR as a potential alternative, or adjunctive, to stimulant therapy for individuals with ADHD and ODD.

Attention-deficit/hyperactivity disorder and ODD have some similar and overlapping behavioral features, such as difficulties in controlling impulsive behavior and emotions. Indeed, ODD has been shown to be predicted by ADHD, a relationship that seems to be driven by the symptoms of hyperactivity–impulsivity rather than inattention.5 Data from study SPD503-307, which included a higher proportion of individuals with ODD than without, showed that decreases in Conners Parent Rating Scale—Revised: Long Form oppositional subscale and ADHD Rating Scale IV total scores were highly correlated over the 9-week treatment.22 Given these overlapping features, it is not possible to conclude whether the reductions in ADHD symptoms reported here were because of improvements in oppositional symptoms or conversely, whether the reduction in ADHD symptoms led to improvement in oppositional symptoms. Although not compared statistically, treatment effect sizes were numerically larger in all data sets in the present study in participants with ODD than in those without. This may be explained by increased symptom severity, providing greater scope for a reduction in symptom scales in children with comorbid ODD than without.3

Stimulants have previously been shown to be effective in treating children and adolescents with ADHD and ODD. In a meta-analysis that included 8 randomized controlled trials, psychostimulants were found to have a moderate-to-large effect in the management of oppositional behavior, conduct problems, and aggression in youth with ADHD.9 Findings from a separate meta-analysis of 28 studies showed that stimulants had a significant effect on aggression-related behavior in children with ADHD, with moderate-to-large effect sizes.28 Despite these findings, some individuals may not respond to stimulants or may not tolerate the side-effect profile. Given its efficacy in treating both ADHD and oppositional symptoms, GXR may provide a suitable intervention in these individuals, either as an alternative to stimulants or as adjunctive therapy.17,18 Moreover, studies have shown response to GXR to be consistent regardless of the time of administration, which may be beneficial when attempting to manage symptoms throughout the day and into the evening.19,21,22

An important limitation in the present analyses is that improvements in ODD symptoms could not be assessed because they were not included in the original study designs except for study SPD503-307.22 In addition, because the original studies were not powered for these post hoc analyses, it was not considered appropriate to compare subgroups statistically, and the findings presented here are therefore largely descriptive. Also because these different studies used slightly different study designs, study populations could not be pooled into one large data set with greater statistical power than each individual study alone. Despite these drawbacks, the findings presented here provide information for physicians beyond what has already been published and support GXR as a potentially useful intervention for children and adolescents with ADHD and comorbid ODD. Future studies to disentangle the relationship among ODD, ADHD, and treatment response would help physicians provide optimal treatment for children and adolescents with these commonly comorbid features.

ACKNOWLEDGMENTS

The authors thank the participants and investigators involved in the studies. This post hoc analysis and the original studies were funded by the sponsor, Shire Development LLC, a member of the Takeda group of companies. Under the direction of the authors and funded by Shire International GmbH, a member of the Takeda group of companies, Dr. A.L. Jones of Oxford PharmaGenesis provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by Oxford PharmaGenesis.

REFERENCES

1. Connor DF, Steeber J, McBurnett K. A review of attention-deficit/hyperactivity disorder complicated by symptoms of oppositional defiant disorder or conduct disorder. J Dev Behav Pediatr. 2010;31:427–440.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Arlington, VA: American Psychiatric Publishing; 2013.
3. Connor DF. Pharmacological management of pediatric patients with comorbid attention-deficit hyperactivity disorder oppositional defiant disorder. Paediatr Drugs. 2015;17:361–371.
4. Connor DF, Doerfler LA. ADHD with comorbid oppositional defiant disorder or conduct disorder: discrete or nondistinct disruptive behavior disorders? J Atten Disord. 2008;12:126–134.
5. Burke JD, Loeber R, Lahey BB, et al. Developmental transitions among affective and behavioral disorders in adolescent boys. J Child Psychol Psychiatry. 2005;46:1200–1210.
6. Tung I, Li JJ, Meza JI, et al. Patterns of comorbidity among girls with ADHD: a meta-analysis. Pediatrics. 2016;138:e20160430.
7. Satterfield JH, Faller KJ, Crinella FM, et al. A 30-year prospective follow-up study of hyperactive boys with conduct problems: adult criminality. J Am Acad Child Adolesc Psychiatry. 2007;46:601–610.
8. Villodas MT, Pfiffner LJ, McBurnett K. Prevention of serious conduct problems in youth with attention deficit/hyperactivity disorder. Expert Rev Neurother. 2012;12:1253–1263.
9. Pringsheim T, Hirsch L, Gardner D, et al. The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 1: psychostimulants, alpha-2 agonists, and atomoxetine. Can J Psychiatry. 2015;60:42–51.
10. Concerta XL (prolonged-release methylphenidate hydrochloride) patient information leaflet. Available at: https://www.medicines.org.uk/emc/files/pil.6872.pdf. Accessed April 15, 2019.
11. Elvanse (lisdexamfetamine dimesylate) patient information leaflet. Available at: https://www.medicines.org.uk/emc/files/pil.6828.pdf. Accessed April 15, 2019.
12. Huss M, Chen W, Ludolph AG. Guanfacine extended release: a new pharmacological treatment option in europe. Clin Drug Investig. 2016;36:1–25.
13. Kaplan S, Heiligenstein J, West S, et al. Efficacy and safety of atomoxetine in childhood attention-deficit/hyperactivity disorder with comorbid oppositional defiant disorder. J Atten Disord. 2004;8:45–52.
14. Newcorn JH, Spencer TJ, Biederman J, et al. Atomoxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry. 2005;44:240–248.
15. Biederman J, Spencer TJ, Newcorn JH, et al. Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data. Psychopharmacology (Berl). 2007;190:31–41.
16. Cheng JY, Chen RY, Ko JS, et al. Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents-meta-analysis and meta-regression analysis. Psychopharmacology (Berl). 2007;194:197–209.
17. Intuniv (guanfacine) capsules US prescribing information. Available at: http://pi.shirecontent.com/PI/PDFs/Intuniv_USA_ENG.pdf. Accessed February 14, 2019.
18. European Medicines Agency. Intuniv: EPAR—product information. 2015. Available at: https://www.ema.europa.eu/en/documents/product-information/intuniv-epar-product-information_en.pdf. Accessed November 20, 2019.
19. Newcorn JH, Stein MA, Childress AC, 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;52:921–930.
20. Stein MA, Sikirica V, Weiss MD, et al. Does guanfacine extended release impact functional impairment in children with attention-deficit/hyperactivity disorder? Results from a randomized controlled trial. CNS Drugs. 2015;29:953–962.
21. Young J, Rugino T, Dammerman R, et al. 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;24:435–441.
22. Connor DF, Findling RL, Kollins SH, 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;24:755–768.
23. Wilens TE, Robertson B, Sikirica V, et al. A randomized, placebo-controlled trial of guanfacine extended release in adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2015;54:916–925.e2.
24. Hervas A, Huss M, Johnson M, 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;24:1861–1872.
25. Kaufman J, Birmaher B, Brent D, et al. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980–988.
26. Demmer DH, Hooley M, Sheen J, et al. Sex differences in the prevalence of oppositional defiant disorder during middle childhood: a meta-analysis. J Abnorm Child Psychol. 2017;45:313–325.
27. Ottosen C, Larsen JT, Faraone SV, et al. Sex differences in comorbidity patterns of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2019;58:412–422.e413.
28. Connor DF, Glatt SJ, Lopez ID, et al. Psychopharmacology and aggression. I: a meta-analysis of stimulant effects on overt/covert aggression-related behaviors in ADHD. J Am Acad Child Adolesc Psychiatry. 2002;41:253–261.
Keywords:

attention-deficit/hyperactivity disorder; oppositional defiant disorder; guanfacine extended release

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.