Psychostimulants and the non-stimulant atomoxetine increase the extracellular availability of dopamine and noradrenaline at the synaptic cleft. Although methylphenidate is generally the first choice medication for children/adolescents with attention deficit/hyperactivity disorder (ADHD) in Europe, stimulants can be unsuitable for some patients. |
Guanfacine is a selective α2A-adrenergic receptor agonist that acts directly on α2A-adrenergic receptors to enhance noradrenaline neurotransmission; preliminary evidence suggests that guanfacine also influences dendritic spine plasticity in the prefrontal cortex. |
Guanfacine extended-release (GXR) is a new non-stimulant pharmacotherapy for ADHD in Europe for children and adolescents for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. The selective mode of action of 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. |
1 Introduction
2 Methods of Literature Search
3 Pathophysiology of Attention-Deficit/Hyperactivity Disorder (ADHD)
3.1 Neuroimaging
3.2 Neurochemistry
3.2.1 Dopamine and Noradrenaline
3.2.2 Other Neurotransmitters
3.3 Genetics
4 Pharmacological Treatment of ADHD
Pharmacotherapy | Mechanism of action |
---|---|
Stimulants | |
Amphetaminea
| Blocks dopamine and noradrenaline transporters and increases output of dopamine |
Methylphenidatea
| Primarily acts by blocking the dopamine transporter to increase dopamine levels |
Non-stimulants | |
Atomoxetine | Blocks the noradrenaline transporter to moderately increase dopamine and noradrenaline levels |
Clonidineb
| Directly stimulates post-synaptic α2A-adrenergic receptors; also binds to other α2-adrenergic receptor subtypes |
Guanfacinec
| Directly stimulates post-synaptic α2A-adrenergic receptors to enhance noradrenaline neurotransmission |
4.1 α2-Adrenergic Receptor Agonists
4.1.1 Guanfacine Extended Release (GXR)
4.2 Other ADHD Pharmacotherapies
5 Clinical Considerations on GXR
5.1 Clinical Data on GXR in ADHD
Study design | Primary efficacy endpoint | Key clinical findings (primary endpoint and effect size) |
---|---|---|
GXR as monotherapy | ||
A randomized, multi-centre, double-blind, parallel-group, placebo-controlled, fixed-dose escalation study conducted in the USA [173] Children/adolescents (aged 6–17 years) with ADHD (N = 345) GXR dose: 2, 3 and 4 mg/day | Change in ADHD-RS-IV total score from baseline to endpoint | Significant reduction in placebo-adjusted LS mean change from baseline in ADHD-RS-IV total scores in all GXR groups: −7.7 (p = 0.0002), −7.95 (p = 0.0001) and −10.39 (p < 0.0001) for the GXR 2, 3 and 4 mg/day groups, respectively GXR effect size: 0.64, 0.66 and 0.86 for the 2, 3 and 4 mg/day groups, respectively (post hoc analysis) |
A randomized, double-blind, parallel-group, multi-centre, placebo-controlled, dose-ranging study conducted in the USA [176] Children/adolescents (aged 6–17 years) with ADHD (N = 324) GXR dose: 1–4 mg/day | Change in ADHD-RS-IV total score from baseline to endpoint | Significant reduction in placebo-adjusted LS mean change in ADHD-RS-IV total scores in all GXR groups: −6.75 (p = 0.0041), −5.41 (p = 0.0176), −7.34 (p = 0.0016) and −7.88 (p = 0.0006) in the GXR 1a, 2, 3 and 4 mg/day groups, respectively GXR effect size: 0.53, 0.43, 0.58 and 0.62 for the GXR 1a, 2, 3 and 4 mg/day groups, respectively (post hoc analysis) |
A double-blind, randomized, multi-centre, placebo-controlled, dose-optimization study conducted in the USA [179] Children (aged 6–12 years) with ADHD (N = 340) GXR dose: 1–4 mg/day (morning or evening dosing) | Change in ADHD-RS-IV total score from baseline to Visit 10 (LOCF) | Significant reduction in LS mean change in ADHD-RS-IV total scores: −20.0, −19.8 and −20.1 for the GXR all active, GXR morning and GXR evening dosing groups, respectively (p < 0.001 for all groups vs. placebo) GXR effect size: 0.77, 0.75 and 0.78 for the GXR all active, GXR morning and GXR evening dosing groups, respectively |
A study comprising an open-label optimization phase followed by a double-blind, placebo-controlled, multi-centre, randomized withdrawal phase, conducted in the EU, USA and Canada [231] Children/adolescents (aged 6–17 years) with ADHD (N = 528) [231] GXR dose: 1–7 mg/day | Proportion of treatment failuresb [231] | Treatment failure occurred in 49 % of the GXR vs. 65 % of the placebo group (p = 0.006) [231] GXR effect sizec (at end of randomized withdrawal phase): 0.51d
|
A randomized, double-blind, multi-centre, parallel-group, placebo- and active-controlled (ATX reference arm), dose-optimization study conducted in the EU, USA and Canada [177] Children/adolescents (aged 6–17 years) with ADHD (N = 338) GXR dose: 0.05–0.12 mg/kg/day | Change in ADHD-RS-IV total score from baseline to Visit 15 | Significant reduction in placebo-adjusted LS mean change from baseline in ADHD-RS-IV total score for GXR was −8.9 (p < 0.001) GXR effect size: 0.76 (ATX effect size: 0.32) |
GXR as adjunctive therapy | ||
A double-blind, randomized, multi-centre, placebo-controlled, dose-optimization study conducted in the USA [178, 180] Children/adolescents (aged 6–17 years) with ADHD and a suboptimal response to stimulants (N = 461) GXR dose: 1–4 mg/day (morning or evening dosing) plus current long-acting, oral stimulant (amphetamine or methylphenidate) | Change in ADHD-RS-IV total score from baseline to endpoint | Significant reduction in placebo-adjusted LS mean change in ADHD-RS-IV total scores in both GXR groups: −4.5 (p = 0.002) and −5.3 (p < 0.001) GXR morning plus stimulant and GXR evening plus stimulant dosing groups GXR effect size: 0.38 and 0.45 for the GXR morning plus stimulant and GXR evening plus stimulant dosing groups, respectively |
5.2 Practical Applications of GXR in ADHD Clinical Practice
Range of prevalence of condition among patients with ADHD | Range of prevalence of ADHD among patients with condition | |
---|---|---|
Stimulants associated with a suboptimal response, contraindicated or potentially unsuitable | ||
Suboptimal response to stimulant | N/A | |
Intolerant of stimulant side-effects | N/A | |
Chronic tic disorders (including Tourette’s syndrome) | ||
Cardiovascular disorders (including hypertension and tachycardia) | No data found | 70 % in HLHS [252] |
Problems relating to emotional regulation and impulse control | ||
Emotional dysregulation | No data found | |
Oppositional defiant disorder | 30 % [243] | |
Conduct disorder | 40 % [243] | |
Addictive behaviour | ||
Eating disorders | 10 % [243] | |
Substance abuse/dependence | 54 % (children) [268] |
Study design | Key findings |
---|---|
Patients with a suboptimal response to stimulants | |
An open-label, dose-optimization study of children/adolescents (aged 6–17 years) with a suboptimal response to MPH (n = 42) or amphetamine (n = 33) [187] | Adjunctive GXR was associated with a significant improvement in ADHD-RS-IV total scores (−16.1, p < 0.0001) |
A randomized, placebo-controlled trial of children/adolescents (aged 6–17 years) with a suboptimal response to extended-release MPH or amphetamine, who received adjunctive GXR (morning dosing n = 150; evening dosing n = 152) or adjunctive placebo (n = 153) [178] | Adjunctive GXR significantly improved ADHD-RS-IV total scores (placebo-adjusted least squares mean reductions: −4.5 for GXR morning dosing [p = 0.002] and −5.3 [p < 0.001] for GXR evening dosing) |
A pre-specified analysis of data from children/adolescents (aged 6–17 years) in an RCT and the open-label phase of a randomized withdrawal trial [188] | GXR monotherapy was associated with significant improvement in ADHD-RS-IV total scores in both prior-MPH-treated and stimulant-naïve patients (difference in least squares mean vs placebo: −9.8 [p < 0.001; n = 45] and −7.6 [p < 0.001; n = 60], respectively, for the RCT and −24.3 [n = 221] and −26.7 [n = 206], respectively, for the LTE trial [descriptive statistics only]) |
Patients with chronic tic disorders (including Tourette’s syndrome) | |
An open-label study of guanfacine immediate release among children (aged 8–16 years) with ADHD and Tourette’s syndrome (n = 10) [194] | Guanfacine immediate release was associated with improvement in the A task of the Continuous Performance Test (commission errors, p < 0.02; omission errors, p < 0.01) and the severity of motor and phonic tics (both p < 0.02) |
A randomized, placebo-controlled trial of guanfacine immediate release among children (aged 7–14 years) with ADHD and tic disorders (n = 34) [195] | Guanfacine immediate release improved ADHD-RS total scores (37 vs. 8 %; p < 0.001) and Yale Global Tic Severity Scale scores (31 % vs. 0; p = 0.05) versus placebo |
Patients with oppositional defiant disorder (or oppositional symptoms) | |
A randomized, double-blind, placebo-controlled, dose-optimization study of children (aged 6–12 years) with ADHD and oppositional symptoms (GXR, n = 138 and placebo, n = 79) [174] | GXR significantly improved ADHD-RS-IV total scores and CPRS-R:L oppositional subscale scores compared with placebo (−23.8 vs. −11.5 [p < 0.001] and −10.9 vs. −6.8 [p < 0.001]). A post hoc analysis showed high correlation between improvement of oppositional and ADHD symptoms (r = 0.74) [174] |
A matching-adjusted indirect comparison of randomized, double-blind, placebo-controlled trial data to assess the efficacy of GXR (n = 58) and ATX (n = 98) in reducing oppositional symptoms among children (mean age 10 years) with ADHD and ODD or oppositional/disruptive symptoms [200] | GXR was associated with a greater reduction in mean CPRS-R:S, oppositional subscale scores compared with ATX (−5.0 vs. −2.4; p = 0.01) |
An assessment of the effect of GXR adjunctive to psychostimulant on oppositional symptoms using data from a multicentre, randomized, double-blind, placebo-controlled, dose-optimization study of children/adolescents (aged 6–17 years) with a suboptimal response to a stimulant alone [201]. Patients received GXR (1–4 mg/day) administered in the morning (n = 86) or evening (n = 93), or placebo (n = 95) | GXR adjunctive to a stimulant significantly improved CPRS–R:L oppositional subscale scores (placebo-adjusted least square mean change from baseline: GXR morning −3.6 [p = 0.001] and GXR evening −2.7 [p = 0.013]) in a predefined subgroup with oppositional symptoms. A post hoc analysis showed no significant improvement in CPRS–R:L oppositional subscale scores among children/adolescents with a diagnosis of ODD (n = 90; although the analysis may have been underpowered to detect a difference between groups) |