A Review of the Rationale and Clinical Utilization of α 2 -Adrenoceptor Agonists for the Treatment of Attention-Deficit/Hyperactivity and Related Disorders

Abstract

Objective:

Interest in the potential role for the α₂-adrenoceptor agonists clonidine and guanfacine as treatments for attention-deficit/hyperactivity disorder (ADHD) has driven additional clinical studies as well as development of new formulations of these agents. This article reviews the published data that supported United States Food and Drug Administration approval and subsequent clinical use of α₂-adrenoceptor agonists in the treatment of ADHD, and identifies promising directions for future research.

Methods:

Electronic searches were performed in PubMed through October 2012 using the base terms ADHD or attention deficit hyperactivity disorder and alpha agonists, as well as the following limits: humans, clinical trial, meta-analysis, practice guideline, randomized controlled trial, review, English. The electronic searches were complemented with reference lists from the articles retrieved by informal search of the literature, producing a qualitative review of published, pertinent drug-class preclinical and clinical data. Articles were selected for greater exposition based on hierarchy of evidence (e.g., randomized controlled trials), relevance, and quality of individual studies, as well as generalizability to clinical practice.

Results:

Results of clinical studies of immediate-release and extended-release formulations of α₂-adrenoceptor agonists and basic science investigations of cognitive effects of these drugs are discussed. Studies of both clonidine and guanfacine extended-release formulations as monotherapy and adjunctive therapy with psychostimulants for the treatment of ADHD are also reviewed.

Conclusions:

Large, randomized, placebo-controlled clinical trials support the efficacy and safety of α₂-adrenoceptor agonists as monotherapy and adjunctive therapy with psychostimulants for the symptomatic treatment of ADHD. Future research could reveal whether there are cognitive benefits associated with this drug class and thus further define the role of α₂-adrenoceptor agonists in the treatment of ADHD.

Introduction

A ttention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neuropsychiatric disorder, affecting an estimated 7.2% of children and adolescents between the ages of 4 and 17 years in the United States alone (Faraone et al. 2003; Centers for Disease Control and Prevention 2010). In addition to the academic impairments seen in children with ADHD, challenges include dysfunction with family and peer relationships, higher rates of injuries, and lower self-esteem compared with children without ADHD (Reiff and Stein 2003; American Psychiatric Association 2000; Hoza 2007; Manos et al. 2007). In clinical settings, ADHD is often comorbid with other externalizing behavior disorders, mood disorders, learning disabilities, and tic disorders (Biederman et al. 1991).

Psychostimulants are the most widely prescribed pharmacologic treatment for ADHD (Wilens and Spencer 2000). Whereas psychostimulants are viewed as first-line treatment (Pliszka 2007), for a significant number of patients, ADHD symptoms can remain inadequately controlled despite a reasonable dose of psychostimulant (Wilens and Spencer 2000). Moreover, psychostimulant effectiveness may be limited or complicated by side effects and tolerability issues (Spencer et al. 1996; Barbaresi et al. 2006). For these patients, the availability of two α2-adrenoceptor agonists (clonidine and guanfacine) for the treatment of ADHD offers hope for better ADHD control.

This review will discuss α2-adrenoceptor agonist mechanism of action, pharmacokinetics (comparing pharmacokinetics of immediate-release clonidine [CLON-IR] and guanfacine [GUAN-IR] to extended-release formulations [CLON-XR and GXR, respectively]), and data supporting efficacy and safety of α2-adrenoceptor agonists in the treatment of ADHD as monotherapy and adjunctively with psychostimulants.

Methods

A systematic electronic search of literature published through October 2012 was conducted using the PubMed database and the following base search terms: ADHD or attention deficit hyperactivity disorder and alpha agonists. Search results were limited by several filters: humans, clinical trial, meta-analysis, practice guideline, randomized controlled trial, review, English. This search returned 126 articles. Articles were selected for greater exposition based on hierarchy of evidence (e.g., randomized controlled trials), relevance, and quality of individual studies, as well as generalizability to clinical practice. The search results were complemented with reference lists from the retrieved articles, producing a qualitative review of published, pertinent drug-class preclinical and clinical data.

Results

Mechanism of action

The α2-adrenoceptor agonists were originally developed and clinically utilized as centrally active antihypertensive agents, which exert their antihypertensive activity by decreasing sympathetic tone in the central nervous system and reducing vascular resistance (Sorkin and Heel 1986). Although the mechanism through which α2-adrenoceptor agonists bring about improvement in individuals with ADHD is unknown, there is preclinical evidence to suggest that clonidine and guanfacine both act directly in the prefrontal cortex (PFC) via postsynaptic α2-adrenoceptors (Arnsten and Dudley 2005; Arnsten et al. 2007; Newcorn et al. 2011b) and indirectly by modulating locus coeruleus (LC) input to the PFC (Sara 2009). In nonhuman primates, guanfacine increased working memory in a dose-dependent manner (Arnsten et al. 1988), and reduced distractibility (Arnsten and Contant 1992). Action of α2-adrenoceptor agonists at autoreceptors located in the LC on norepinephrine (NE)-containing neuron cell bodies modulate tonic and phasic LC firing, and thus modulate NE input to the PFC (Berridge and Waterhouse 2003; Aston-Jones and Cohen 2005). Ascending NE afferent projections from the LC to the PFC are thought to modulate attention and working memory by enhancing functional connectivity between the PFC and other brain regions (Robbins and Arnsten 2009; Sara 2009). Results of a positron emission tomography study with intravenous clonidine in 13 healthy adult male volunteers (Coull et al. 1999) are consistent with the LC-PFC serving a gating function between frontoparietal cortical circuits that mediate attentional states while remaining sensitive to environmental context (i.e., cognitive load). In this model, optimal levels of tonic LC-NE discharge facilitated an enhanced “signal-to-noise” ratio, and increased phasic discharge of LC neurons tended to promote focused attention in the processing of salient information (Sara 2009). However, whether or not the purported mechanism of action derived from animal models translates to human studies remains an open question. Studies in healthy normal adults have failed to find a positive effect of α2-adrenoceptor agonists on cognition for either clonidine (Coull et al. 2001) or guanfacine (Coull et al. 2001; Muller et al. 2005). In children and adolescents with ADHD in a controlled classroom trial, Kollins et al. (2011b) observed no differences in a choice reaction timed task performance between GXR and placebo at doses that significantly improved ADHD symptoms. In contrast, Scahill et al. (2001) in a controlled trial of GUAN-IR in children and adolescents (7–15 years of age) with ADHD and tics demonstrated improvement in teacher-rated ADHD symptoms and positive continuous performance outcome measures (Table 1). This information will be more fully discussed under clinical studies.

Table 1.

Clinical Trials Evaluating GUAN-IR and GXR as Monotherapy and Adjunctive Therapy in ADHD

Study design	Phase	n	Dosage	Efficacy	Safety
GXR as monotherapy in ADHD
Randomized, 8-week, double-blind, placebo-controlled study in children and adolescents (ages 6–17 years) (Biederman et al. 2008b)	III	345	Fixed dose 2, 3, or 4 mg/day	Significant reduction in ADHD-RS-IV total score for entire study population but not for 13–17 age subgroup. Effect size varied by dose from 0.64 (2 mg/day) to 0.86 (4 mg/day)	80% of patients receiving GXR and 67% receiving placebo reported TEAEs Common TEAEs were somnolence, sedation, fatigue No treatment-related serious AEs
Randomized, 9-week, double-blind, placebo-controlled study in children and adolescents (ages 6–17 years) with ADHD (Sallee et al. 2009b)	III	324	Fixed dose 1, 2, 3, 4 mg/day	Significant reduction in ADHD-RS-IV total score for entire study population but not for 13–17 age subgroup. Effect size varied by dose from 0.43 (2 mg/day) to 0.62 (4 mg/day)
GXR as adjunctive therapy in ADHD
Randomized, 9-week, placebo-controlled dose-optimization study in children and adolescents (ages 6–17 years) with suboptimal, but partial, response to extended-release psychostimulant alone (Wilens et al. 2012). Suboptimal response was defined as ADHD-RS-IV total score of ≥24 and a CGI-S score of at least “mildly” ill (i.e., a score of ≥3).	IV	461	GXR (1-4 mg/day) in am or pm titrated to optimization holding psychostimulant stable Weight-adjusted optimal GXR dose 0.09 mg/kg	Both am and pm dosed GXR significantly reduced ADHD-RS-IV total score when added to stimulant:Both child and adolescent subgroups showed GXR benefitAdjunctive GXR effect sizes of 0.377 (GXR am+stimulant) and 0.447 (GXR pm+psychostimulant)^a	TEAEs were more common in the GXR+stimulant groups (77%) compared with placebo+stimulant (63.4%). Rate of discontinuation for TEAEs was <4% in GXR groups. Decreased heart rate and blood pressure in GXR+stimulant vs placebo+stimulant
GUAN-IR as monotherapy in ADHD
Randomized, 8-week, placebo-controlled, flexible-dose study of GUAN-IR in children and adolescents (ages 6–15 years) with ADHD and tic symptoms (Scahill et al. 2001)	II	37	GUAN-IR 1.5-3 mg/day given as three divided doses. Modal dose 2.5 mg/day	Significant 37% decrease in ADHD-RS total score rated by teacher, compared with an 8% drop in the placebo group. scoresEffect size 0.90: hyperactivity/impulsivity subscales	One subject on GUAN-IR withdrew because of sedation; 6 others complained of mild sedationNo differences in frequency of side effects between groupsNo differences in cardiovascular effects between groups

In adjunctive therapy studies, the effect size of GXR observed is in addition to an unknown effect size of psychostimulant alone.

ADHD, attention-deficit/hyperactivity disorder; ADHD-RS-IV, ADHD Rating Scale IV; AE, adverse event; CGI, Clinical Global Impressions; CGI-I, CGI-Improvement; CGI-S, CGI-Severity of Illness; CPRS-R:L, Conners' Parent Rating Scale-Revised: Long Form; GUAN-IR, immediate-release guanfacine; GXR, guanfacine extended-release; PGA, Parent Global Assessment, TEAEs, treatment-emergent adverse events.

Three subtypes of the α2-adrenoceptor have been identified in humans: α2A, α2B, and α2C (MacDonald et al. 1997; Newcorn et al. 2003; Arnsten et al. 2007). Both α2A- and α2C-adrenoceptor subtypes are widely distributed in the brain, including the PFC, with the majority of physiologic and pharmacologic functions attributed to the α2A-subtype (Newcorn et al. 2003; Gyires et al. 2009). Both facilitation of working memory and hypotensive responses have been linked to actions at neuronal α2A-adrenoceptors in animal studies (MacMillan et al. 1996; Wang et al. 2007; Levy 2008). The α2C-adrenoceptor subtype is reported to play a role in cortical arousal and may antagonize the sedative effect of α2-adrenoceptor agonists in the mouse (Puolivali et al. 2002), although the significance for humans is unclear. As reviewed by Arnsten et al. (2007), the α2B-adrenoceptor subtype is the least prevalent, mostly concentrated in the thalamus, and is associated with sedative effects. Both guanfacine and clonidine have been shown to have affinity for the α2A-adrenoceptor, and guanfacine's effects on cognition are absent in animals lacking the ADR-2A gene (Sorkin and Heel 1986; Uhlen and Wikberg 1991; Franowicz et al. 2002). In addition, blockade of α2A-adrenoceptors by injection of yohimbine can reverse the cognitive effects of this drug class (Li and Mei 1994).

Pharmacokinetics

A major limitation of the immediate-release formulations of α₂-adrenergic agonists stems from their pharmacokinetic profiles. Rapid absorption of these agents leads to high-peak plasma concentrations that are associated with the side effects of sedation, dry mouth, and hypotension (Keranen et al. 1978). To mitigate these peak effects, smaller doses given more frequently were often employed to prevent peaks and troughs, although potentially at the risk of reducing compliance.

Single-dose pharmacokinetic studies with GUAN-IR indicate that peak plasma concentrations are achieved rapidly (i.e., mean time to maximal concentration of 2.6–3.1 hours) and decline quickly following oral administration (Weiss et al. 1979; Carchman et al. 1987). The fairly rapid decline in plasma level following a single acute dose is seen despite the fairly long half-life of GUAN-IR (i.e., ∼16 hours) (Shojaei et al. 2006; Newcorn et al. 2011b). Early pharmacokinetic studies in adults have shown that the bioavailability of oral CLON-IR is high, ranging from 75% to 100%, and that 40–75% is excreted unchanged in the urine (Davies et al. 1977; Arndts 1983; Larsson et al. 2011). These early studies of CLON-IR are complicated by the use of radioimmunoassay (Arndts 1983; Cunningham et al. 1994) which exhibited cross-reactivity with at least one metabolite. Using liquid chromatography/mass spectrometry, at least five metabolites of clonidine have been identified, although the exact enzyme pathways and cytochrome P450s responsible for clonidine metabolism are poorly characterized (Buchanan et al. 2009). CLON-IR plasma concentration peaks within 3–5 hours after oral administration, and exhibits a half-life of 12–16 hours (Davies et al. 1977). Clonidine is primarily eliminated by the kidney with a low hepatic extraction ratio, as its primary metabolite (p-hydroxyclonidine) is <10% of unchanged drug in urine (Darda et al. 1978; Arndts et al. 1979; Buchanan et al. 2009).

At least one population pharmacokinetic study has been published in children and adolescents (0–15 years of age) who received CLON-IR by intravenous, rectal, and epidural administration during anesthesia, which determined that by 1 year of age, 82% of the adult clearance rate is achieved (Potts et al. 2007). Of significance is a recent finding of reduced bioavailability in children (3–10 years of age) who received CLON-IR orally (Larsson et al. 2011). CLON-IR bioavailability was found to be significantly less (55.4% vs. 75-100% in adults) and more erratic (i.e., higher coefficient of variation) in children when compared with adults (Larsson et al. 2011).

The absolute bioavailability of GUAN-IR is also high, close to 100%, with no evidence of first-pass effect (Kiechel 1980). Its volume of distribution in adults is large (6.3±1.1 L/kg) and predominately bound to plasma proteins. GUAN-IR elimination half-life is 17 hours with clearance by both renal and hepatic routes. Approximately one third of the total clearance is renal. Cytochrome P450 3A4 is the predominant enzyme involved in the oxidative metabolism of guanfacine (Intuniv 2011). Guanfacine is metabolized by oxidation of the aromatic ring, via an epoxide intermediate, to form 3-hydroxy-guanfacine. This metabolite is conjugated with glucuronic acid or sulphate, and then renally excreted (Kiechel 1980).

A rapid absorption profile is characteristic for both CLON-IR and GUAN-IR, with each formulation achieving maximal plasma concentration (C_max) relatively quickly (∼1–2 hours) (Kiechel 1980; Larsson et al. 2011), the limitations of which would subsequently be addressed by their respective extended-release formulation.

Subsequent pharmacokinetic studies of GXR demonstrated a large differences from GUAN-IR for maximal concentration (C_max), time to maximal concentration (T_max), and total systemic exposure (area under the curve [AUC]) (Swearingen et al. 2007). For GXR, increases in C_max and AUC were proportional to dose, but lower compared with GUAN-IR (e.g., the relative bioavailability of GXR compared with GUAN-IR is 57%) (PDR Network and Staff 2011). Importantly GXR also exhibits a longer T_max than GUAN-IR (Kiechel 1980; Swearingen et al. 2007; Newcorn et al. 2011a; PDR Network and Staff 2011;). In both children and adolescents, GXR T_max is 5 hours with dose-related increases in maximum concentration (C_max) (Boellner et al. 2007). However, plasma concentrations of GXR and concentration-related pharmacokinetic parameters (i.e., C_max and AUC) in children were higher than those in adolescents. This was most likely because of the higher body weights of the adolescent subjects compared with the children. There is also a food effect with GXR, with AUC increased by ∼40%, and the C_max increased by ∼75%, compared with dosing when the subject is in a fasting state (Intuniv 2011).

In a similar manner, CLON-XR exhibited a longer T_max than CLON-IR by threefold, but there was no difference in elimination rate (Kapvay 2010). Bioavailability of CLON-XR is 89% of CLON-IR, and no food effect is noted. In coadministration studies with stimulants, CLON-XR clearance was slightly higher in the presence of methylphenidate (MPH), and slightly lower in the presence of amphetamine. With regard to GXR, a recent review (Childress 2012) has detailed two studies that examined GXR pharmacokinetics in the presence of OROS MPH or lisdexamphetamine. There appears to be no effect of GXR on MPH pharmacokinetic parameters or vice-versa. The presence of lisdexamphetamine, however, increased the bioavailability (C_max) of GXR by a nominal amount (7%), not thought to be clinically significant (Childress 2012). Although time of onset of action and duration of action of these extended-release formulations are the pharmacodynamic effects of greatest interest to clinicians, to our knowledge, no articles addressing the relationships between pharmacokinetic and pharmacodynamic effects on ADHD outcomes exist in the literature; therefore, onset and offset of drug effect can only be inferred from changes in blood pressure and pulse, and relationship of these parameters to clinical improvement likewise remains inferential.

Efficacy of α₂-adrenoceptor agonists as monotherapy or adjunctive treatments to psychostimulants in the management of ADHD

Although psychostimulants are currently the mainstay of ADHD pharmacotherapy (Biederman and Faraone 2005; Pliszka et al. 2006), a sizeable minority of patients have suboptimal response and/or tolerability to psychostimulants (Elia et al. 1999; Scahill et al. 2001; Olfson 2004; Wood et al. 2007; Sallee 2010), with the actual percentage varying as a function of the study design and sample investigated. In clinical practice, both clonidine and guanfacine have been used to treat ADHD, both alone and adjunctively with psychostimulants, especially in patients unable to tolerate psychostimulants or those who present clinically with comorbid disorders such as Tourette syndrome or tic disorders, impulsive aggression, or symptoms such as insomnia (Hunt et al. 1990; Popper 1995; Scahill et al. 1999; Pohl et al. 2009; Sallee 2010). The United States Food and Drug Administration (FDA) has approved the extended-release formulations of clonidine and guanfacine as monotherapy and as adjunctive therapy to psychostimulant medications for ADHD in children and adolescents only (Kapvay 2010; Intuniv 2011). They are not indicated (i.e., FDA-approved) for the treatment of adults with ADHD or for the comorbid disorders or symptoms listed previously, such as Tourette syndrome or insomnia (Kapvay 2010; Intuniv 2011).

CLON-IR

CLON-IR is approved by the FDA for the treatment of hypertension but not for the treatment of ADHD (Catapres 2010). The typical CLON-IR dose to treat hypertension in adults is 0.2–0.6 mg/day, divided and given two times a day (Catapres 2010). This is the same approximate dose range of CLON-IR utilized in many ADHD studies (Table 2). There have been several studies of CLON-IR for the treatment of ADHD (Hunt et al. 1985,1986; Connor et al. 1999; van der Meere et al. 1999; Tourette's Syndrome Study Group 2002; Palumbo et al. 2008; Nair and Mahadevan 2009). Two small studies (n=12; n=10) (Hunt et al. 1985,1986) that evaluated the efficacy of CLON-IR in the treatment of ADHD using the Conners' Parent Behavior Rating Scale (CPRS; 48-item), the Conners' Teacher Behavior Rating Scale (CTRS; 28-item), and the Achenbach Child Behavior Checklist as measures of hyperactivity, inattention, and conduct problems, found significant improvements in parent and teacher ratings of ADHD symptoms. Additional tests of neuromaturational function via sequential finger tap and the Coding and Digit Symbol tasks from the Wechsler Intelligence Scale for Children-Revised revealed no significant benefit of clonidine treatment.

Table 2.

Clinical Trials Evaluating CLON-IR and CLON-XR as Monotherapy and Adjunctive Therapy in ADHD

Study design	Phase	n	Dosage	Efficacy	Safety
CLON-XR as monotherapy in ADHD
Randomized, 8-week, double-blind, placebo-controlled study in children and adolescents (ages 6–17 years) with ADHD (Jain et al. 2011)	III	236	Fixed dose CLON-XR 0.2 or 0.4 mg/day or placebo twice daily	Significant reduction in ADHD-RS-IV total score with CLON-XR vs placeboEffect size 0.71 for 0.2 mg/day and 0.76 for 0.4 mg/day	83% of patients receiving CLON-XR and 72% receiving placebo reported TEAEsMost common TEAEs were somnolence, and fatigue No serious AEs
CLON-IR as monotherapy and adjunctive therapy in ADHD
Randomized, 16-week, placebo-controlled flexible-dose study using a 2x2 factorial design comparing CLON-IR alone or in combination with MPH in children ages 7–12 years (Daviss et al. 2008; Palumbo et al. 2008)	II	122	CLON-IR titrated for 4 weeks followed by MPH or placebo titration for 4 weeks; 8 weeks maintenance at CLON-IR daily dose up to 0.6 mg/day given TID; modal dose 0.24 mg/day	No significant treatment effect of CLON-IR on Conners' ASQ for Teachers (primary outcome) Effect size CLON-IR plus MPH 0.73 Significant effects of CLON-IR were observed on Conners' ASQ for Parents; CGAS	Somnolence, fatigue, and nervousness were more common in subjects treated with CLON-IR but decreased in frequency over time Completion rates were significantly higher in CLON-treated subjects
CLON-XR as adjunctive therapy in ADHD
Randomized, 8-week, placebo-controlled, flexible-dose study of CLON-XR plus psychostimulant vs psychostimulant plus placebo in children and adolescents (ages 6–17 years) (Kollins et al. 2011a)	III	198	CLON-XR (0.1-0.4 mg/day) and psychostimulant, both flexibly dosed; modal dose 0.3 mg/day	Significantly greater effects of CLON-XR plus stimulant vs stimulant alone were observed on: ADHD-RS-IV total scores ADHD-RS-IV inattention and hyperactivity/impulsivity subscales CPRS-R:L Effect size (when added to stimulant)=0.3^a	45% of patients receiving CLON-XR plus stimulants and 41% receiving placebo plus stimulants reported≥1TEAEs Most common TEAEs observed in patients receiving CLON-XR plus stimulants were somnolence/sedation, headache, and fatigue
CLON-IR as adjunctive therapy in ADHD
Randomized, 6-week, placebo-controlled flexible-dose study CLON-IR in combination with psychostimulant plus PBO children and adolescents ages 6–14 years. (Hazell and Stuart 2003)	III	67	CLON-IR titrated to 0.1 mg BID	Significant treatment effect of CLON-IR on Conduct scale No significant effect on Hyperactive Index subscales of Conners' Behavior Checklist parent	Drowsiness and dizziness greater in CLON-IR group 3 subjects in CLON-IR group withdrew: none for to TEAEs

ADHD, attention-deficit/hyperactivity disorder; AE, adverse event; ASQ, Conners' Abbreviated Symptom Questionnaire; BID, twice daily; CGAS, Child Global Assessment Scale; CLON-IR, immediate-release clonidine; CLON-XR, clonidine extended-release; CPRS, Conners' Parent Rating Scale; CTRS, Conners' Teacher Rating; MPH, methylphenidate; TEAE, treatment-emergent adverse events; TID, three times daily.

In adjunctive therapy studies, the effect size of CLON-XR observed is in addition to an unknown effect size of psychostimulant alone.

Two larger-size, randomized, placebo-controlled studies have examined CLON-IR given adjunctively to MPH (Tourette's Syndrome Study Group 2002; Palumbo et al. 2008). Both studies were identical in design but differed in their study populations. The Tourette's Syndrome Study Group (2002) examined children with ADHD and comorbid chronic tic disorders (n=136). The maximum treatment benefit for both ADHD symptom reduction and tic improvement was achieved in the CLON-IR and MPH combination group.

In a study by Palumbo et al (2008), children with ADHD (n=122 enrolled, 7–12 years of age) were randomized to 1 of 4 treatment groups: placebo, CLON-IR monotherapy (≤0.6 mg/day), MPH monotherapy (≤60 mg/day), or CLON-IR and MPH combination therapy. Efficacy measures included Conners' Abbreviated Symptom Questionnaire (ASQ) for Parents and for Teachers, the Child Global Assessment Scale (CGAS), the Iowa Conners' impulsive/oppositional and oppositional/defiant subscales, and direct classroom observations of disruptive behaviors. On Conners' ASQ for Teachers (the primary efficacy measure), no significant treatment effect was observed with CLON-IR, whether administered alone or in combination with MPH. Despite this negative result, it was determined that CLON-IR was of some benefit as measured by the secondary Conners' ASQ for Parents (p=0.003) and CGAS (p=0.002) (Palumbo et al. 2008), and was well tolerated both in the presence and absence of MPH (Daviss et al. 2008).

The strength of these CLON-IR trials was their innovative aspect of examining a novel non-stimulant ADHD therapy, and further exploring for the first time, utility in combination with stimulants. Limitations generally were small sample sizes and frequent use of comorbid ADHD subgroups, particularly with tic disorders, so that generalization to typical ADHD was uncertain. Even in the largest of the CLON-IR controlled studies, treatment cells rarely exceeded 30 subjects.

CLON-XR

CLON-XR (Kapvay™, Shionogi Pharma, Inc., Atlanta, GA) is approved by the FDA for the treatment of ADHD in children and adolescents 6–17 years of age (Kapvay 2010). Approval was based on two randomized, multicenter, double-blind, placebo-controlled studies of CLON-XR for the treatment of ADHD in children and adolescents 6–17 years of age (Table 2) (Jain et al. 2011; Kollins et al. 2011a). The first (n=236 randomized) was a fixed-dose study of CLON-XR (0.2 or 0.4 mg/day in divided doses) as monotherapy (Jain et al. 2008, 2011). Significantly greater mean (standard deviation [SD]) reductions in ADHD Rating Scale IV (ADHD-RS-IV) total scores were observed at week 5 for both 0.2 mg/day (−15.6 [12.96], p<0.0001) and 0.4 mg/day (−16.5 [13.54], p<0.0001) of CLON-XR compared with placebo (−7.5 [9.41]). Also, there were significantly greater reductions in the ADHD-RS-IV inattention and hyperactivity/impulsivity subscales, CPRS-Revised: Long Form (CPRS-R:L), Clinical Global Impressions (CGI), and Parent Global Assessment (PGA) scales. A limitation of this fixed dose was the high discontinuation rate in all treatment cells, particularly that for the 0.4 mg/day assignment. Despite this fact, there was ample power to demonstrate a robust treatment effect (change from baseline of 15–16 points on ADHD-RS-IV).

The study reported by Kollins et al. (2011a) randomized 198 children and adolescents (6–17 years of age) with ADHD who had an inadequate response to psychostimulant therapy and had been on a stable regimen (short- or long-acting amphetamine or MPH treatment) during the prior 4 weeks. Psychostimulant doses were taken in the morning, and CLON-XR 0.1 mg was taken at night. If the dose was increased to ≥0.2 mg, CLON-XR was added to either the morning (0.2 mg) or the morning and night dosing regimen (0.3 mg or 0.4 mg). Unique to this trial design was the allowance for adjustment within the trial of both study drug and psychostimulant in the context of optimal titration. Significantly greater mean (SD) reductions in ADHD-RS-IV total scores were observed with CLON-XR added to a psychostimulant (−15.7 [12.3]) compared with placebo added to a psychostimulant (−11.5 [12.2]; p=0.009). In addition, there were significantly greater reductions in the ADHD-RS-IV inattention and hyperactivity/impulsivity subscales, CGI, and PGA scales. One limitation of this study was that subjects were allowed to change their stimulant dose during the trial; 18% in the placebo+stimulant group and 19% in the CLON-XR+stimulant group increased their stimulant dose. However, more subjects in the CLON-XR+stimulant group (15%) decreased their doses than in the placebo+stimulant group (9%).

GUAN-IR

GUAN-IR is FDA-approved for the treatment of essential hypertension with typical doses of 1–2 mg given once per day (Tenex 2013). There are few studies of GUAN-IR in ADHD (Table 1), and all have small sample sizes (Chappell et al. 1995; Hunt et al. 1995; Scahill et al. 2001; Taylor and Russo 2001). Hunt et al. (1995) were the first to perform an open trial in children with ADHD (n=13) and found that GUAN-IR reduced parent ratings of ADHD behaviors on the Conners' 31-item questionnaire. This lack of data for GUAN-IR in ADHD was superseded by larger trials with an extended-release formulation.

GXR

GXR (Intuniv^®, Shire Development LLC, Wayne, PA) is FDA-approved for once-daily administration for the treatment of ADHD (Boellner et al. 2007; Intuniv 2011; Shojaei et al. 2006; Swearingen et al. 2007). Two short-term (8- and 9-week) pivotal studies (Table 1) (Biederman et al. 2008b; Sallee et al. 2009b) were conducted using GXR as monotherapy. Both were multicenter, randomized, fixed-dose, placebo-controlled trials in children and adolescents 6–17 years of age. In the first (n=345) (Biederman et al. 2008b), least squares (LS) mean reductions from baseline in ADHD-RS-IV total score at end-point (the last valid assessment obtained prior to dose tapering) were significant in all randomized dose groups (2 mg/day=− 7.70; p=0.0002, 3 mg/day=−7.95; p=0.0001, and 4 mg/day=−10.39; p<0.0001). It has been suggested that the efficacy of GXR may increase with increasing weight-adjusted doses (Intuniv 2011; Newcorn et al. 2011). These study results were also analyzed by weight-adjusted doses, and significant efficacy was noted in all but the lowest weight-adjusted dose group (Biederman et al. 2008b). This might explain the fact that for the adolescent (13–17 years) subgroup, there was lacking a significant GXR treatment effect, compounded by the fact that the placebo effect was much greater for this subgroup than for children (6–12 years). Important to note is that there was a higher discontinuation rate in the highest dose group (4 mg/day), which may also have been a factor in the analysis.

In the second trial (n=329) (Sallee et al. 2009b), placebo-adjusted LS mean reductions in ADHD-RS-IV total scores from baseline to end-point were also significant in all randomized dose groups (1 mg/day=− 6.75 [p=0.0041], 2 mg/day=−5.41 [p=0.0176], 3 mg/day=−7.34 [p=0.0016], and 4 mg/day=−7.88 [p=0.0006]). Significant efficacy was also seen in all weight-adjusted dose groups, but as in Biederman et al. (2008b), the adolescent age subgroup did not exhibit a significant improvement in ADHD-RS-IV score from baseline to end-point. Taking these two monotherapy GXR trials together, their limitation was an insufficient adolescent sample (<25% of total) to fully analyze effects in this subgroup.

An open-label study of GXR administered adjunctively with psychostimulants in subjects with suboptimal response to psychostimulants, as well as the long-term extension study that included a subgroup of those subjects, found significant decreases in ADHD-RS-IV scores with the addition of GXR to psychostimulants (Sallee et al. 2009a; Spencer et al. 2009). The open-label investigation was followed by a larger, pivotal, randomized, double-blind, placebo-controlled, dose-optimization study of GXR administered adjunctively to psychostimulants (Table 1) (Wilens et al. 2012). This study examined children and adolescents 6–17 years of age (n=461) who had a suboptimal but partial response to psychostimulants alone. Subjects continued their stable morning psychostimulant and were randomized to receive optimized doses of GXR (1–4 mg/day) in the morning (GXR am), GXR in the evening (GXR pm), or placebo. At end-point, GXR treatment groups showed significantly greater improvement from baseline ADHD-RS-IV total scores compared with placebo (GXR am, p=0.002; GXR pm, p<0.001). Similar results were observed on ADHD-RS-IV inattention (GXR am, p=0.002; GXR pm, p<0.001) and hyperactivity/impulsivity (GXR am, p=0.002; GXR pm, p<0.001) subscales. In the GXR study arms, both younger and older age groups showed significantly greater improvement from baseline in ADHD-RS-IV total scores compared with placebo plus psychostimulant (Wilens et al. 2012). Whereas effect sizes of both the GXR am+psychostimulant (0.377) and the GXR pm+psychostimulant (0.447) groups versus psychostimulant alone were lower relative to those observed in monotherapy trials versus placebo alone, symptom improvement with adjunctive treatment was still demonstrated over psychostimulant alone. However, the study entry criterion of suboptimal response to psychostimulants was reliant on investigator judgement and retrospective assessment rather than a controlled observation period of psychostimulant treatment. Additionally, the dose of psychostimulant was fixed during the study; therefore, it is unclear if simply increasing psychostimulant dosage would have resulted in the same effect sizes as demonstrated with adjuvant GXR therapy.

α₂-Agonists in the treatment of symptoms and disorders comorbid with ADHD

The diagnosis and treatment of ADHD is often complicated by the presence of comorbid conditions such as disruptive behavior disorders (i.e., oppositional defiant disorder [ODD], conduct disorder [CD]), tic disorders, anxiety, and depressive disorders (Jensen 2009). Although several small uncontrolled studies have examined the efficacy of α₂-adrenoceptor agonists in the treatment of ADHD with comorbid symptoms and disorders, no formulation of either clonidine or guanfacine has been approved for their treatment.

Historically, studies of clonidine and guanfacine for treating ADHD in the context of comorbid tics and tic disorders were first to appear in the literature and were largely fueled by concerns that psychostimulants may exacerbate tics (Chappell et al. 1995; Singer et al. 1995; Scahill et al. 2001; Tourette's Syndrome Study Group 2002). The largest and best controlled of studies investigating the effects of α agonists on a commonly occurring comorbid condition in ADHD was that of Connor et al. (2010) in children with ADHD who also exhibited oppositional symptoms. Connor et al. (2010) conducted a placebo-controlled, double-blind, dose-optimization study to examine the efficacy of GXR in reducing oppositional symptoms as measured by the oppositional subscale of the CPRS-R:L. Subjects were 6–12 years of age, with a diagnosis of ADHD (n=217), an ADHD-RS-IV score of ≥24, and a score of ≥12 (for females) or ≥14 (for males) on the oppositional subscale of the CPRS-R:L. Of the total children enrolled, 138 were randomized to receive GXR (dose range 1–4 mg/day) and 79 were randomized to receive placebo. LS mean reductions from baseline to end-point 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). Significant differences between treatment groups were also found for ADHD-RS-IV total score from baseline to end-point with GXR reduction of 23.8 versus 11.5 in the placebo group (effect size=0.92).

Safety and tolerability

The safety of all the guanfacine and clonidine formulations is generally consistent with that which might be expected of α2-adrenoceptor agonists, and as centrally active antihypertensive agents, these drugs produce small but consistent decreases in pulse and blood pressure, both systolic and diastolic, within the dose range used for clinical effect in ADHD. Blood pressure and pulse reductions are dose dependent and across all studies, greatest effects are noted at higher doses and at maximal plasma concentrations (C_max) (Biederman et al. 2008b; Sallee et al. 2009b).

Somnolence and/or related symptoms (e.g., fatigue, sedation, and hypersomnia [SSH]) in this spectrum have been among the most commonly reported adverse events (AEs) in studies of α2-adrenoceptor agonists (Newcorn et al. 2003). In the randomized pivotal study of CLON-XR as monotherapy, the frequency of SSH AEs approached 40%, with somnolence and fatigue being the most common reasons for discontinuation (Jain et al. 2011). In the CLON-XR augmentation with stimulant trial (Kollins et al. 2011a), the frequency of SSH AEs was considerably less overall than that reported in the monotherapy study, but roughly twofold higher in CLON-XR+stimulant groups than for stimulant alone. In two short-term GXR clinical trials, the rate of SSH events was 44.2% (Rubin et al. 2010) and 32.5% (Lopez et al. 2010). In both GXR monotherapy pivotal trials (Biederman et al. 2008b; Sallee et al. 2009b), SSH events were the most common AEs and the most commonly reported AEs leading to discontinuation in subjects who received GXR in those studies. In the Wilens et al. (2012) study of GXR as augmentation therapy to psychostimulants (Table 1), headache and somnolence were the most common treatment emergent AEs (TEAEs) associated with optimized doses of GXR (1–4 mg/da) delivered in the morning (GXR am) or evening (GXR pm) on top of a stable psychostimulant regimen. As was the case for CLON-XR augmentation, no unique AEs were observed with adjunctive therapy when compared with those reported with either treatment alone.

The past experience of clonidine used as an adjunct to stimulants has raised questions regarding the cardiovascular safety of this augmentation strategy (Popper 1995; Swanson et al. 1995; Newcorn et al. 2003). Potentially harmful interactions of clonidine and psychostimulants were hypothesized as a result of reports of untoward cardiac events such as syncope and catastrophic events, including three case reports of sudden death in children. However, an FDA report documenting these cases concluded that there was no reason to postulate a drug interaction; any cardiovascular effects exerted by clonidine and MPH were deemed independent of each other, and the causes of death in those cases were either determined to be unknown or not attributable to medication (Popper 1995). In addition, recent studies have uniformly not supported the presence of harmful interactions (Daviss et al. 2008; Jain et al. 2011; Kollins et al. 2011a). Similarly, studies of GUAN-IR and GXR have not found harmful interactions between guanfacine and psychostimulants (Scahill et al. 2006; Spencer et al. 2009; Wilens et al. 2012). Specifically in the GXR augmentation trial by Wilens et al (2012) at study end-point, small mean (SD) decreases in systolic blood pressure (SBP) (GXR am+psychostimulant,−1.5 [9.74]; GXR pm+psychostimulant,−2.9 [9.74] mm Hg), diastolic blood pressure (DBP) (GXR am+psychostimulant,−1.1 [7.47]; GXR pm+psychostimulant,−1.2 [8.52] mm Hg), and supine heart rate (HR) (GXR am+psychostimulant,−5.8 [12.30]; GXR pm+psychostimulant,−5.4 [11.77] bpm) were assessed in subjects receiving GXR+psychostimulant versus subjects receiving placebo+psychostimulant (−0.6 [8.38] mm Hg,−0.0 [7.61] mm Hg, and 2.1 [10.65] bpm, respectively). No subjects in any treatment group met outlier criteria of a QTcF interval ≥480 msec or a QTcB interval ≥500 msec.

Although syncope was not reported in either of the short-term controlled pivotal GXR monotherapy trials (Biederman et al. 2008b; Sallee et al. 2009b), it is important to counsel families that syncope can occur, as syncopal events that were deemed possibly or probably related to study medication were reported in the two long-term open-label trials (Biederman et al. 2008a; Sallee et al. 2009a). Of the pediatric subjects in the GXR clinical program, 1% reported syncope (Intuniv 2011). One case of syncope in the context of nausea, vomiting, and sinusitis, deemed unrelated to study medication, was reported in a subject receiving GXR plus a psychostimulant in the controlled trial of GXR as adjunctive therapy (Wilens et al. 2012). Neither of the two published short-term trials of CLON-XR as monotherapy or adjunctive to a psychostimulant mention any cases of syncope (Jain et al. 2011; Kollins et al. 2011a). However, physicians should use caution when prescribing GXR or CLON-XR to patients with a history of syncope or predisposing factors (e.g., hypotension, orthostatic hypotension, bradycardia, or dehydration) (Kapvay 2010; Intuniv 2011;). Patients should also be advised to avoid dehydration and becoming overheated.

Discussion

The α2-adrenoceptor agonists have proven efficacious in ADHD, as is borne out by the culmination of research over the last quarter century, with the largest controlled studies only being available in the last 5 years. Perhaps the greatest clinical utility of drugs in this class is their combined effectiveness with psychostimulants. Whereas the majority of studies of CLON-IR, CLON-XR, GUAN-IR, and GXR indicate that adjunctive therapy with psychostimulants may provide additional clinical benefit compared with use of psychostimulants alone, the magnitude of this benefit is perhaps modest. In some of these adjunctive studies, it was not known if subjects had attained the highest level of benefit possible from psychostimulant treatment (i.e., through optimal dosing) before the addition of CLON-IR or GXR (Hazell and Stuart 2003; Sallee et al. 2009a; Spencer et al. 2009; Wilens et al. 2012). In addition, with the exception of the study by Kollins et al. (2011a), changes in psychostimulant doses were not allowed during these trials, and separate groups treated with monotherapy with psychostimulants were not included for comparison. These are important points, because it is unknown whether truly optimized psychostimulant administration could have eliminated the need for adjunctive therapy and, if so, in what proportion of patients could optimized psychostimulant doses be achieved in clinical practice. It is interesting to note that in the Kollins et al. (2011a) study, 15% of the CLON-XR plus stimulant group were able to reduce their psychostimulant dose.

Effect sizes have been proposed as a means of comparing results across studies, despite differences in measures and study design (Faraone and Buitelaar 2010). A meta-analysis of studies with CLON-IR determined the overall effect size (SD) to be 0.58 (0.16) (Connor et al. 1999). Few data are available for GUAN-IR; a small study by Scahill and colleagues reported an effect size for ADHD-RS total scores of >1 in youth with ADHD and tic disorders; however, this may not be representative of all youth with ADHD and tic disorders (Scahill et al. 2001). In the studies of CLON-XR (Jain et al. 2011; Kollins et al. 2011a), effect sizes of 0.71 and 0.77 were reported for CLON-XR monotherapy (0.2 mg/day and 0.4 mg/day, respectively), and an effect size of 0.34 was reported for CLON-XR as an adjunctive therapy with psychostimulants. In the two controlled trials of GXR monotherapy for ADHD treatment, effect sizes ranged between 0.43 and 0.86 (Biederman et al. 2008b; Sallee et al. 2009b). In the study of GXR as an adjunctive therapy with psychostimulants, effect sizes were 0.38 and 0.45 for the GXR am and GXR pm groups, respectively (Wilens et al. 2012). It is important to note that, in adjunctive therapy studies in which psychostimulants were also administered in the placebo groups (e.g., psychostimulant alone), the effect size of CLON-XR or GXR observed is in addition to an unknown effect size of psychostimulant alone. Overall, these data demonstrate the comparability of effect sizes for studies with CLON-XR and GXR formulations for both monotherapy and therapy adjunctive to psychostimulants.

Perhaps more important than the metric of comparing effect sizes are comparative effectiveness studies, one of which indirectly compares GXR with atomoxetine across different studies in reducing oppositional symptoms in children with ADHD and comorbid ODD (Signorovitch et al. 2012). The conclusion of Signorovitch et al. (2012) is that GXR was associated with significantly greater reduction in Conners' Parent Rating Scale oppositional subscale symptoms than was atomoxetine. Cost effectiveness of GXR as adjunctive therapy to stimulants was also recently compared with stimulant monotherapy (Sikirica et al. 2012). Extrapolating the results to the entire drug class suggests that adjunctive therapy with α₂-adrenergic agonists may be a cost-effective treatment strategy that may meet a need among ADHD patients with suboptimal response to stimulant monotherapy.

Given the salience of PFC noradrenergic neurotransmission in psychiatric disorders (Newcorn et al. 2003), research into the neurobiologic mechanisms by which α-agonists might exert their neurocognitive and behavioral effects remains an important topic for future research. Given the cognitive actions of α₂-adrenoceptor agonists to modify attentional orientation and promote adaptation to environmental demands, there is currently ongoing research to examine the mechanisms by which these agents impact functioning of specific brain regions within circuits subserving attention and self-regulation, including emotion regulation (Schulz et al. 2013). Recent reviews (Sara 2009; Brady et al. 2011) and one open-label study of children with symptoms of traumatic stress (Connor et al. 2013) have suggested that cognitive enhancement via α₂-adrenoceptor agonists might be beneficial in conditions other than ADHD (e.g., posttraumatic stress disorder and substance use disorder). Given the importance of cognitive dysfunction across multiple psychiatric disorders, additional research in this area would be welcome.

Conclusions

Both the early studies of IR formulations of clonidine and guanfacine and the larger placebo-controlled trials of the XR formulations have supported the efficacy of these medications as treatments for ADHD. Initial questions regarding safety and tolerability have been satisfactorily resolved through extensive study with both the IR and XR formulations over the past decade.

Clinical Significance

The clinical studies reviewed here indicate that α₂-adrenoceptor agonists are effective and safe as monotherapy and as adjunctive treatments to psychostimulants in the management of ADHD in children and adolescents (Kapvay 2010; Intuniv 2011). However, certain caveats apply. The approved dose ranges for the clinical use of each of the extended-release formulations (1–4 mg/day for GXR and 0.1–0.4 mg/day CLON-XR) may, however, be insufficient to achieve efficacy in adolescent patients with ADHD. Caution should be used when prescribing GXR or CLON-XR to patients with a history of syncope or its predisposing factors (e.g., hypotension, orthostatic hypotension, bradycardia, or dehydration) (Kapvay 2010; Intuniv 2011) and patients should be advised to avoid dehydration and becoming overheated. When administering α₂-adrenoceptor agonists for the treatment of ADHD, HR and BP should be measured prior to initiation of therapy, periodically during therapy, and after dose increases (Kapvay 2010; Intuniv 2011). As is the case with other antihypertensives, sudden discontinuation of CLON-XR or GXR treatment is not recommended, although one small study in healthy young adults failed to find clinically significant increases in BP or HR with abrupt discontinuation of GXR (Kisicki et al. 2007). Discontinuation of CLON-XR or GXR should be accomplished by tapering. Because the absorption and pharmacokinetic characteristics of both GUAN-IR and CLON-IR differ from those of GXR and CLON-XR, respectively, and because switch studies are lacking in the literature, there remains no guidance for dose substitution on a milligram-for-milligram basis (Karachalios et al. 2005; Kapvay 2010; Intuniv 2011).

Footnotes

Acknowledgments

The authors thank Jennifer Steeber for her contributions to the initial manuscript draft. Under the direction of the authors, Jennifer Steeber of SCI Scientific Communications & Information (SCI), and Melissa Brunckhorst of MedErgy, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by SCI and MedErgy. Drs. Jonathan Rubin, Ryan Dammerman, and Gina D'Angelo, from Shire Development LLC, also reviewed and edited the manuscript for scientific accuracy.

Disclosures

Dr. Sallee receives funding through consultancies from Otsuka, P2D Inc, Shionogi, and Shire. He has stock ownership and is a member of the board of directors for P2D Inc. Dr. Sallee has given expert testimony on behalf of Johnson & Johnson and Sun Pharma. He has a patent awarded on behalf of the University of Cincinnati and is a founder of Satiety Solutions, LLC. Dr. Connor is a consultant for Neos Therapeutics, Rhodes Pharmaceuticals, Shire Pharmaceuticals, and Supernus. He is a speaker for Shire Pharmaceuticals. He receives educational and research grant support from Shire Pharmaceuticals. He is a consultant to a National Institute of Mental Health-funded research grant and receives additional support from the State of Connecticut. Dr. Newcorn receives research grant support from Eli Lilly, Ortho-McNeil-Janssen, and Shire. He is also a consultant and/or advisor for Alcobra, Biobehavioral Diagnostics, GencoSciences, Sunovian, and Shire.

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A Review of the Rationale and Clinical Utilization of α 2 -Adrenoceptor Agonists for the Treatment of Attention-Deficit/Hyperactivity and Related Disorders

Abstract

Objective:

Methods:

Results:

Conclusions:

Introduction

Methods

Results

Mechanism of action

Pharmacokinetics

Efficacy of α2-adrenoceptor agonists as monotherapy or adjunctive treatments to psychostimulants in the management of ADHD

CLON-IR

CLON-XR

GUAN-IR

GXR

α2-Agonists in the treatment of symptoms and disorders comorbid with ADHD

Safety and tolerability

Discussion

Conclusions

Clinical Significance

Footnotes

Acknowledgments

Disclosures

References

Efficacy of α₂-adrenoceptor agonists as monotherapy or adjunctive treatments to psychostimulants in the management of ADHD

α₂-Agonists in the treatment of symptoms and disorders comorbid with ADHD