Alpha-2 Adrenergic Agonists in Children with Inattention, Hyperactivity and Impulsiveness

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1 REVIEW ARTICLE CNS Drugs 2009; 23 Suppl.1: /09/ /$49.95/0 ª 2009 Adis Data Information BV. All rights reserved. Alpha-2 Adrenergic Agonists in Children with Inattention, Hyperactivity and Impulsiveness Lawrence Scahill Child Study Center, Yale University School of Medicine and Yale School of Nursing, New Haven, Connecticut, USA Abstract Although originally developed for the treatment of hypertension, a 2 - agonists have been used to treat Tourette s syndrome, attention-deficit hyperactivity disorder (ADHD), developmental disorders and substance abuse for nearly three decades. Based on studies of clonidine, a 2 -agonists were presumed to reduce arousal by decreasing the firing of noradrenaline neurons in locus ceruleus. Accumulated preclinical evidence indicates that guanfacine has features in common with clonidine, in addition to other pharmacological effects. Clonidine binds to the three subtypes of a 2 -receptors, A, B and C, whereas guanfacine binds more selectively to a 2A -receptors, which appears to enhance prefrontal function. Several reports on the use of the a 2 -agonists show improvements in children with ADHD and improvements in hyperactivity, impulsiveness and inattention in children with tic disorders and pervasive developmental disorders. Both clonidine and guanfacine are associated with sedation, fatigue and somnolence. Reductions in heart rate and blood pressure are modest and rarely lead to discontinuation of treatment across these trials. The a 2 -agonist clonidine has been used in the treatment of Tourette s syndrome, attentiondeficit hyperactivity disorder (ADHD), pervasive developmental disorders (PDD) and substance abuse since the late 1970s. [1-3] Interest in the use of guanfacine, also an a 2 -agonist, for these conditions has emerged during the past 15 years. Although commonly used in practice, neither clonidine nor guanfacine is approved for these indications by the US FDA. The presumed therapeutic action of a 2 - agonists in ADHD involved turning down the noradrenaline (NA) system in the brain, resulting in decreased arousal. [4] Accumulated evidence during the past 15 years suggests that a 2 -agonists may also stimulate a 2 -receptors in the prefrontal cortex (PFC). This action may improve inattention and the control of impulsive behaviour, which are key characteristics in children with ADHD and some children with tic and pervasive developmental disorders. [5,6] Preclinical data suggest that clonidine and guanfacine may differ in their affinity for a 2 -receptors in PFC, which may have relevance to clinical outcomes. [5,7] This article examines the clinical differences between clonidine and guanfacine, the potential implications of these differences, and the evidence supporting the use of clonidine and guanfacine in

2 44 Scahill children with ADHD, tic and developmental disorders. 1. Mechanism of Action in Attention- Deficit Hyperactivity Disorder There is a longstanding belief that the hyperactivity, impulsiveness and inattention in children with ADHD are due to overarousal. Fundamental to the regulation of arousal are specialized neurons in the locus ceruleus (LC). This brainstem structure has reciprocal connections with the PFC via long axons. When these neurons fire, NA is released in the PFC. According to this notion of overarousal, ADHD may be the result of poor regulation of noradrenergic output from the LC. [4,8] The prototype a 2 -agonist, clonidine, acts presynaptically on autoreceptors of LC neurons to decrease cell firing and NA release. This action leads to improved regulation of NA systems, decreased arousal and a reduction in hyperactivity and impulsiveness. [4,8] There is considerable preclinical evidence to support this proposal, but the emerging model is more complex. [5,9] In addition to the indirect effect on PFC function through improved regulation of NA, there has been increased interest in the capacity of the a 2 -agonists to enhance PFC function directly. According to this theory, PFC dysfunction adversely affects attention, emotional regulation and impulse control, [5] leading to distractibility, impulsiveness and hyperactivity. [4,10] The a 2 - agonist guanfacine has been shown to stimulate postsynaptic a 2A -receptors in the PFC and to improve attention, concentration and working memory. [11] This action may, in turn, improve regulation of subcortical activity, resulting in a reduction in hyperactivity and impulsiveness. [6] Further evidence supporting this revised theory, see Arnsten in this supplement. [12] Compared with clonidine, guanfacine is less sedating and not as potent in lowering blood pressure. [7,13] These distinctions are probably due to differences in receptor affinities. Clonidine is a potent agonist at imidazoline receptors in the medulla. The greater sedative effect of clonidine may also have to do with its higher affinity for a 2C -receptors, located on LC dendrites that regulate LC firing. Clonidine also binds to a 2B - receptors in the thalamus that presumably contributes to the sedative effects. [14] In contrast, guanfacine is less potent at presynaptic a 2 -receptors and does not bind to a 2B -, a 2C -or imidazoline receptors. [14] Possibly because of its potency and relatively short half-life, clonidine is associated with withdrawal irritability that begins as the plasma levels decline, leading to a rapid-on, rapid-off effect at the receptor. [15] In contrast, guanfacine has a less prominent on-off effect, presumably because of slower absorption and a longer half-life. This difference is likely to be even more pronounced with the extended-release formulation of guanfacine. [16] 2. Attention-Deficit Hyperactivity Disorder, Tic Disorders and Developmental Disorders 2.1 Clonidine Several early studies showed that clonidine was effective for treatment of ADHD. In a metaanalysis of 11 trials published between 1980 and 1999 in children with ADHD accompanied by conduct disorder, developmental delays or tic disorder, Connor and colleagues noted an effect size (ES) of [17] The most common adverse events of treatment included sedation and irritability. [17] More recently, clonidine has been evaluated in children with ADHD and ADHD accompanied by tic disorders. Table I [18-24] presents findings from placebo-controlled trials conducted during the past decade. The Tourette Study Group completed a multisite trial of 136 children between the ages of 7 and 14 years. Subjects were randomized to clonidine alone, methylphenidate (MPH) alone, combined clonidine and MPH, or placebo. Outcome measures included parent and teacher measures of ADHD symptoms and ratings of tic severity. Each of the active treatments was superior to placebo on parent and teacher ratings of ADHD symptoms. Based on results presented graphically in the paper, clonidine alone or MPH alone showed a modest improvement in the range

3 Alpha-2 Adrenergic Agonists in ADHD 45 Table I. Placebo-controlled trials with a 2 -agonists in children with attention-deficit hyperactivity disorder (ADHD), tic disorders or developmental disorders published over the past decade Author/year N Study sample Design ADHD outcomes Scahill et al. [18] ADHD + tic disorders TS Study Group [19] ADHD + tic disorders Guanfacine vs placebo Clonidine, MPH combination, placebo Cummings et al. [20] TS Guanfacine vs placebo Palumbo et al. [21] ADHD Clonidine, MPH combination, placebo Handen et al. [22] PDD + ADHD symptoms Guanfacine vs placebo (crossover) Biederman et al. [23] ADHD Guanfacine XR vs placebo (parallel groups) Sallee et al. [24] ADHD Guanfacine XR vs placebo (parallel groups) Significantly active > placebo on teacher-rated ADHD Rating Scale; not on Conners Parent Rating Scale Monotherapies > placebo on Conners Teacher and Parent Rating Scales; combination showed large effect on Conners Teacher and Parent Rating Scales Active no different from placebo but only a few subjects had ADHD Monotherapies not superior to placebo on Conners Parent or Teacher Rating Scales; combination showed large effect on Conners Parent and Teacher Rating Scales Guanfacine > placebo on Conners Parent Rating Scale of hyperactivity All active doses > placebo on clinician-rated ADHD Rating Scale All active doses > placebo on clinician-rated ADHD Rating Scale MPH = methylphenidate; PDD = pervasive developmental disorder; TS= Tourette s syndrome; XR = extended-release formulation. of 15 20% on teacher ratings after adjustment for placebo. The combined treatment group showed a larger effect of about 38% placebo-adjusted improvement. [19] This trend was similar for parent ratings. Children in the MPH-alone group received approximately 26 mg/day in two divided doses. This relatively conservative dose range for MPH may partially explain the modest effect. The dose of clonidine alone was 0.25 mg/day in two or three doses, which is consistent with several other clonidine trials. [25] Thus, the modest effect of clonidine alone is likely to be a reliable reflection of what can be expected from monotherapy with clonidine on ADHD outcomes. [19] Doses of each active drug were similar in the combined treatment group. Sedation was common in the group treated with clonidine alone: 35% compared with 21% for the combined treatment group and 8% for the MPH group. On average, tics improved in all active treatment groups: 26% for clonidine, 25% for the MPH-only group and 28% for the combined group. Interestingly, across all treatment groups, including placebo, approximately 20% of the subjects reported an increase in tics. [19] In a study with the same design of 122 children with ADHD without tic disorders, Palumbo and colleagues reported that neither clonidine alone nor MPH alone was superior to placebo on the Conners Teacher Rating Scale. The placeboadjusted improvement was 1% for clonidine only, 14% for MPH only and 30% for the combination of clonidine and MPH. On the Conners Parent Rating Scale, clonidine was superior to placebo, but MPH was not. The combination was superior to placebo with a medium to large ES. [21] In this trial, the mean dose of MPH (30 mg/day in two divided doses) was also lower than the mean dose of 38 mg/day in the Multimodal Treatment of ADHD Cooperative Group trial, but higher than in the Tourette Study Group. [19,26] Nonetheless, the fact that MPH was not superior to placebo on parent or teacher ratings is somewhat surprising. The investigators presented the safety results of this trial in a separate report. [27] Adverse events were more common in subjects receiving clonidine (alone or in combination with MPH), occurring in 50 of 63 subjects compared with 29 of 59 not exposed to clonidine (p = ). Children exposed to clonidine were more likely to

4 46 Scahill report drowsiness and fatigue than children not exposed to clonidine. They were also more likely to have a measurement of lower blood pressure and heart rate. However, these adverse events were not associated with a higher rate of early study withdrawal. [27] Trial completion rates were better for clonidine (26 of 31) than for MPH (17 of 29) and intermediate for the combination (24 of 32). [25] Taken together, these two trials suggest that monotherapy with clonidine is well tolerated in typically developing children with ADHD. The benefits are modest and appear slightly better for children with ADHD with tic disorders than children with ADHD without a tic disorder. Both trials showed additive benefit with the combination of clonidine and MPH. 2.2 Guanfacine Initial trials with guanfacine for ADHD were open-label, with daily doses ranging from 1.5 to 4.0 mg divided into three doses. [28-30] Guanfacine was superior to placebo in an 8-week randomized, controlled trial in 34 patients with ADHD and tic disorders on teacher measures of ADHD and a clinician measure of tic severity. Parent ratings of ADHD symptoms showed improvement in the guanfacine group, but were not significantly better than those of the placebo group. Most subjects in this study were male (n = 31) and most had failed to respond to prior treatment with a stimulant (n = 23). The guanfacine dose ranged from 1.5 to 3.0 mg/day with a modal dose of 1 mg in the morning, 0.5 mg in the afternoon and 1 mg at bedtime. [18] On the primary outcome measure, the teacher-rated ADHD Rating Scale IV (ADHD-RS IV), [31] the guanfacine group showed a 37% decrease compared with 8% for placebo (p 0.006). [18] The improvement on the teacher-rated ADHD-RS IV was evident on both the inattention and hyperactivity subscales. Sedation was reported by seven subjects in the guanfacine group. Of these, one withdrew early from the trial. A 10-point decrease in diastolic blood pressure was noted in six guanfacinetreated patients and two in the placebo group. Three patients in the treatment group experienced middle-of-the-night awakening versus none in the placebo group. [18] In a 4-week, randomized clinical trial of 24 children with Tourette s syndrome, Cummings and colleagues [20] examined the effects of guanfacine on tics and ADHD symptoms. Tic severity of these subjects was mild at baseline, and only four children met the criteria for ADHD. The mean guanfacine dose was lower than in previous trials, ranging from 1 to 2 mg/day. Given the small sample size and generally mild problems at baseline, it is not surprising that guanfacine was not superior to placebo on the ADHD-RS-IV. Although the ES on the clinician measure of tic severity was similar to that reported in the Scahill and colleagues study, [18] it was not superior to placebo with this sample size of 12 per group. [20] Guanfacine has also been evaluated in children with PDD accompanied by hyperactivity and impulsiveness. In an 8-week, open-label trial in 25 children between the ages 5 and 14 years with PDD who had previously failed to respond to stimulants, guanfacine showed improvement on the Aberrant Behavior Checklist (ABC) Hyperactivity subscale rated by parents and teachers. [32,33] At baseline, the mean score on the parent-rated ABC Hyperactivity subscale was At week 8, there was a 40% improvement to Teacher ratings were also positive, but the magnitude of benefit was lower than for the parent ratings. These promising results await confirmation from a placebocontrolled study. In dosages ranging from 1.0 to 3.0 mg/day in two or three divided doses, guanfacine was well tolerated in these developmentally disabled children, with no serious adverse events. Common adverse events included sedation (10 children), irritability (7), sleep disturbance (e.g. insomnia or mid-sleep awakening) (6), increased aggression or self-injury (4), decreased appetite (4), constipation (3) and perceptual disturbance (1) [report of visual distortion of size and distance]. Several adverse events occurred in the same subjects. Systolic blood pressure declined seven points on average at week 4, but returned to baseline by week 8. Diastolic blood pressure remained stable

5 Alpha-2 Adrenergic Agonists in ADHD 47 throughout the trial. There were no clinically significant changes at week 8 compared with baseline in the electrocardiogram read by a paediatric cardiologist at each site. Four children withdrew prematurely because of adverse events; two discontinued because of lack of efficacy. Using a crossover design, Handen and colleagues [22] examined the efficacy and safety of guanfacine in 11 children with developmental disabilities (PDD = 6; intellectual disability without PDD = 5), as well as prominent symptoms of ADHD. Subjects were randomly assigned to receive guanfacine for 4 weeks followed by a 1-week washout and another week of placebo or a week of placebo followed by 4 weeks of guanfacine and then the 1-week washout. The ten boys and one girl were aged from 5 to 9 years. Guanfacine was administered three times daily (morning, noon and late afternoon). The modal dosage was 3 mg/day (range 1 3 mg). The mean change on the ABC Hyperactivity subscale was significant showing 35% placebo-adjusted change; 5 of 11 children (45%) achieved 50% improvement. Drowsiness occurred in five children and limited upward dose adjustment in three. The study design called for a target dosage of 3 mg/day, which was tolerated in 8 of 11 children. The rationale for this target dose is not clear. Future trials might benefit from a more flexible dosage schedule. 2.3 Guanfacine Extended Release A new extended-release formulation of guanfacine has been developed and tested in children with ADHD. Results of two phase III trials with this new extended-release formulation have been reported. [23,24] In the first of these trials, 345 children aged 6 to 17 years with ADHD were randomized to one of four groups: placebo or guanfacine at 2, 3 or 4 mg/day for 5 weeks followed by a 3-week taper. [23] Patients randomized to active drug received 1 mg for the first week followed by an incremental dose increase of 1mg/week until the target dose was achieved. Thus, patients on the 2 mg dose were observed for 3 weeks, those on 3 mg were observed for 2 weeks and those on 4 mg were observed for 1 week and then all doses were tapered under blinded conditions. Approximately 75% of the patients were male, 70% were Caucasian and 72% had combinedtype ADHD. Compared with placebo at week 5, each dose of active medication showed statistically significant improvement on the ADHD-RS scored by a clinician following an interview with the parent (p < ). Improvements were observed on both hyperactivity and inattention subscales of the ADHD-RS-IV. [23] The most common adverse events associated with guanfacine included sedation, abdominal pain, and fatigue. [23] Most adverse events were mild to moderate, lasted a mean of 3 weeks, and resolved in all but 5 10% of cases. [22] Severe adverse events occurred in 24 of 259 (9.3%) guanfacine-treated patients in a dose-dependent manner compared with no patients in the placebo group. Study withdrawal due to adverse events occurred in 9 of 87 (10.3%) patients treated with 2 mg/day and 20 of 86 (23.3%) patients receiving 4mg/day. [23] Small dose-dependent decreases in heart rate and blood pressure were noted, but this was generally time-limited. [23] Results of the second phase III trial, which used a similar design, showed comparable findings in efficacy and safety. [24] The major limitation of both studies was their brief duration. Additional studies are needed to guide the use of this new formulation in clinical practice. Another point to consider when evaluating the results of these trials is that the ADHD-RS-IV was rated by a clinician following a caretaker interview. Historically, most trials in ADHD have used parent and teacher ratings. Rare cases of hallucinations and mania have been reported in children treated with guanfacine. [34-36] The role of the medication in these cases is not completely clear, but suggests that clinicians should monitor heart rate, blood pressure and mental status during treatment with guanfacine. 3. Conclusion Clonidine and guanfacine have been shown to be effective for the treatment of hyperactivity, impulsiveness and inattention across several

6 48 Scahill subgroups of children. After nearly three decades of experience with clonidine, its advantages and disadvantages are well known. Although commonly used in practice, guanfacine has not been well studied in children with ADHD. The new extended-release formulation of guanfacine offers an additional treatment option for children with ADHD and requires more study in children with tic disorders and developmental disorders. Acknowledgements Lawrence Scahill, MSN, PhD, has been a consultant for Bristol-Myers Squibb, Janssen Pharmaceuticals Inc., Neuropharm, Shire Pharmaceuticals Inc. and Supernus Pharmaceuticals Inc. References 1. Cohen DJ, Young JG, Nathanson JA, et al. Clonidine in Tourette s syndrome. Lancet 1979; 2 (8142): Gold MS, Redmond Jr DE, Kleber HD. Clonidine blocks acute opiate-withdrawal symptoms. Lancet 1978; 2 (8090): Riddle MA, Bernstein GA, Cook EH, et al. Anxiolytics, adrenergic agents, and naltrexone. 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