Thursday, April 24, 2025
processing....
Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous, multifactorial disorder that can involve aspects of temperament (ie, impulsivity), motivation (ie, reward), behavior (ie, hyperactivity), and cognition (ie, inattention, working memory).[1-3] Although the precise etiology of ADHD remains unknown, most effective therapies for these diverse dimensions of the disorder facilitate catecholaminergic transmission,[4,5] especially in the prefrontal cortex (PFC).[6] Stimulants, the current mainstay of ADHD therapy, exhibit substantial efficacy but this does not occur uniformly across all aspects of the disorder. Furthermore, 25% to 35% of patients do not receive a therapeutic benefit from stimulants because of inadequate symptom relief, intolerable side effects, or nonadherence.[7] In this context, alpha 2 adrenergic agonists (ie, guanfacine and clonidine) are considered to be alternatives to stimulants based on their ability to modulate noradrenergic tone in the PFC. This modulation is a consequence of both enhanced noradrenergic input from the locus coeruleus and direct postsynaptic stimulation of alpha 2A receptors. The latter are located on dendritic spines of cortical pyramidal cells, thereby directly promoting functional connectivity of prefrontal cortical networks and resulting in enhanced regulation of attention and behavior.[8] The specific and selective action of this class of drugs to modulate noradrenergic tone in the PFC is viewed as an essential component of their utility in specific domains of ADHD, influencing aspects of behavior, cognition, and impulsivity in a complementary manner to stimulants to optimize outcome, reduce impairment, and improve functionality.
Work with alpha 2 adrenergic agonists in ADHD began in the 1980s with the first studies of clonidine conducted by Hunt and colleagues.[9,10] These early studies, though small, suggested that clonidine improved overall impulsivity, hyperactivity, frustration tolerance, and compliance, with some potential to be therapeutically equivalent in efficacy to methylphenidate.[10,11] A subsequent meta-analysis of all clonidine studies (N = 11) conducted between 1980 and 1999 concluded, however, that the agent exhibited a modest effect size and recommended that alpha 2 adrenergic agonists be considered a second-line choice for the treatment of ADHD.[12,13] From this point until relatively recently,[14] the role of alpha 2 agonists in the pharmacotherapy of ADHD has been adjunctive in 1 of 3 capacities: as stimulant extenders, as soporifics, or as stimulant enhancers.
Alpha 2 agonists were first used as stimulant treatment extenders in the context of immediate release methylphenidate or amphetamine, when the goal was to limit both the number of stimulant doses given per day and extend the duration of therapeutic action in combination with a stimulant. The actual data on each of these goals are rather limited, with some indication that combination treatment produced equivalent efficacy with a reduced milligram-per-kilogram dose of the respective stimulant when given as monotherapy.[15,16] With the advent of long duration (8-12 hour) and once-daily stimulant formulations, this adjunctive use of alpha 2 agonists has become limited, although combination therapies remain the predominant prescribing pattern for alpha 2 agonists in cases of complex and comorbid ADHD.[16-18]
The second therapeutic strategy for alpha 2 agonists relied on their pronounced sedative side effects, with the rationale that children and adolescents with ADHD are prone to a variety of sleep disturbances and sleep disorders, such as a delay in sleep onset, resistance to going to bed, wakefulness, restlessness, difficult morning awakenings, and reduced total sleep time.[19] Furthermore, stimulant treatment itself can lead to secondary insomnia, particularly in the context of long-duration ( 8-12 hour) stimulant formulations.[20] Alpha-2 adrenergic agonists generally and clonidine particularly, because of its prominent alpha-2B receptor activity, are frequently used adjunctively as soporifics. This use was supported by a systematic 1996 chart review of 62 patients with ADHD-associated sleep disturbances that suggested that clonidine may be effective for ameliorating sleep disturbances associated with ADHD or caused by its treatment.[21]
Today the use of alpha 2 adrenergic agonists as soporifics has expanded outside the limited initial context; these agents now comprise the second most prescribed drug class for pediatric sleep disorders, without evidence of long-term efficacy or safety.[22] Stojanovski and colleagues[23] examined a large database of 18.6 million visits for sleep-related difficulty in children between1993 and 2004. The highest percentage of visits was by children ages 6 to 12 years. Pediatricians saw 35% of patients, psychiatrists saw 24%, and general/family practice physicians saw 13% of the patients. A total of 81% of visits among children with sleep difficulties resulted in a prescription for a medication, and 26% of the time that prescription was for clonidine. More recent controlled trial data with clonidine[24] and an optimized release formulation of guanfacine (GXR)[14] have shed new light on the duration of sedative effects. Daviss and colleagues[24] evaluated 63 children treated with clonidine alone (N = 31) or with clonidine in combination with methylphenidate (N = 32) for ADHD in a 16-week multicenter, double-blind trial in which doses were flexibly titrated up to 0.6 mg/day for clonidine and 60 mg/day for methylphenidate. They concluded that clonidine alone or in combination with methylphenidate was safe, and although the frequency of sedation was high initially, tolerance to this side effect developed quickly such that it was not viewed as clinically relevant. Severity of sedation to clonidine in this controlled setting was greatest during the titration period (4 weeks).
In contrast to clonidine, guanfacine is selective for the alpha 2A receptor,[25] with little or no alpha 2B activity, and as a result it is thought to be less sedating than clonidine.[26] Biederman and colleagues[14] used GXR in a multicenter, fixed-dose escalation study of patients with ADHD (N = 345), ages 6 to 17 years. In this structured 8-week trial, patients randomly assigned to GXR (2, 3, or 4 mg daily) experienced sedative side effects during the first 2 weeks of dosing, but these typically resolved within 2 to 3 weeks. Again, tolerance to the sedation developed with GXR, but data do support the hypothesis that somnolence with GXR might be weight-dose related. For GXR, 24-month safety and tolerability data suggest that in a subgroup of 5% to 10% of patients somnolence may persist but is generally mild to moderate in severity and does not seem to interfere with efficacy. Given recent data regarding the temporal nature of the soporific action for both clonidine[24] and guanfacine,[14] the use of these agents as adjunctive sleep aids should be short term (less than 4 weeks) at most.
The third and most prevalent adjunctive strategy involves combining an alpha 2 adrenergic agonist with a stimulant to enhance stimulant efficacy . The use of combination treatments most typically is occasioned by the presence of comorbid ADHD. When alpha 2 adrenergic agonists are combined with stimulants, the most typical contexts are ADHD and comorbid oppositional defiant disorder, Tourette disorder, or aggressive/impulsive behavior. The rationale for combination therapy in these cases has been that the primary effects of stimulants and alpha 2 agonists are mediated by different neurotransmitter systems. A stimulant such as methylphenidate is an indirect agonist that facilitates the action of both dopamine (DA) and norepinephrine (NE) through multiple mechanisms. By contrast, alpha 2 agonists exert their effects primarily through NE activity. The mechanism of action with regard to guanfacine is even more specific and circumscribed to the postsynaptic alpha 2A receptor in the PFC. Functional neuroimaging studies[27] demonstrate that guanfacine produces selective and circumscribed activation of frontal and frontal association areas while at the same time "turning down" or inhibiting striatal activity. Avery and colleagues[28] used single photon emission computed tomography (SPECT) to scan monkeys as they were performing a spatial working memory task and showed that guanfacine increased blood flow to the dorsolateral prefrontal cortex (an area critical to the performance of the working memory task). Collateral human positron emission tomography (PET) data also confirm increased regional cerebral blood flow in frontal lobes following guanfacine administration.[29]
We now appreciate that stimulants such as methylphenidate improve working memory and regulate attention primarily through alpha 2A receptors to enhance NE tone in the PFC.[30] These effects of methylphenidate on prefrontal cortical function can be prevented by blocking either NE alpha-2 receptors or DA D1 receptors,[30] establishing that both D1 and alpha-2A receptors are essential to the optimum functioning of the PFC. In fact, excessive D1 stimulation in the PFC, brought about perhaps by inescapable stress, can impair working memory, which led Vijayraghavan and colleagues[31] to propose the "inverted U hypothesis of PFC activation." In this model, cyclic adenosine monophosphate (cAMP) levels build within the prefrontal cortical neurons causing specific ion channels, termed hyperpolarization-activated cyclic nucleotide gated (HCN) channels, to open on dendritic spines of these neurons.[8] Activation of HCN channels effectively reduces membrane resistance, cutting off synaptic inputs and disconnecting PFC network connections. As alpha 2A receptors are located in proximity to these HCN channels, their stimulation by guanfacine closes the HCN channel, inhibits further production of cAMP, and re-establishes synaptic function and the resulting network connectivity.[8] Blockade of alpha 2A receptors by yohimbine reverses this process, eroding network connectivity, and in monkeys has been demonstrated to impair working memory,[32] damage inhibition/impulse control,[33] and produce locomotor hyperactivity.[34]
Several studies support the use of an alpha 2 adrenergic agonist to enhance stimulant efficacy. For example, Palumbo and colleagues[15] conducted a randomized 16-week controlled trial to compare clonidine alone, clonidine plus methylphenidate, methylphenidate alone, or placebo in 122 children with ADHD. Effect size for combined treatment (methylphenidate plus clonidine) was 0.73 vs 0.41 for methylphenidate alone.
Typically, however, combined treatment trials are reported for patients with comorbid ADHD, such as Tourette disorder plus ADHD. In a study designed identically to that of Palumbo and colleagues but with a pediatric sample of patients with comorbid Tourette disorder plus ADHD , the Tourette Syndrome Study Group found that combined treatment (methylphenidate plus clonidine) was more effective than either active treatment alone for both ADHD symptoms and tics.[16]
Hazell and Stuart[35] evaluated a combined treatment (clonidine plus stimulant) in a controlled trial of children with ADHD and comorbid oppositional defiant disorder. In this 6-week study, the investigators added clonidine (0.1-0.2 mg/day (N = 38) or placebo (N = 29) to ongoing stimulant therapy in children 6 to 14 years with ADHD and comorbid oppositional defiant disorder. By parent report, clonidine plus stimulant treatment relative to stimulant alone was associated with improvements in the Conduct Scale but not the Hyperactive Index using Conners' Behavior Checklist. Of interest, clonidine-treated patients experienced less "drowsiness," "irritability," and "sad/happy" mood, suggesting a beneficial interaction that reduced typical stimulant side effects. Given the specific and circumscribed action of the alpha 2 agonists as well as their apparent synergism with stimulants to increase efficacy, the use of these agents as adjunctive treatments, particularly in highly comorbid ADHD, seems productive, although this strategy requires further controlled study to endorse its widespread use and utility.
Monotherapy trials with alpha 2 adrenergic agonists were slow to develop. The clinical consensus suggested that alpha 2 agonists were effective for the hyperactive/impulsive domain but not for inattention, and that effectiveness of these agents for ADHD was moderate at best, as estimated from small-scale trials.[36] More important, however, has been the lack of suitable formulations that would optimally achieve and sustain plasma drug concentrations so that efficacy could be maximized, while at the same time minimizing side effects (eg, hypotension and sedation). The absorption characteristics of immediate release clonidine and guanfacine are not ideal, as peak plasma concentration is achieved rapidly and declines precipitously, with considerable interindividual variation.[37] For guanfacine, these characteristics have been overcome by the development of a new optimized formulation, GXR, which achieves a broader and flatter plasma concentration profile so that therapeutic concentrations are sustained over longer periods with reduced peak-to-trough fluctuation.[38] For example, compared with guanfacine immediate release, GXR provides longer time to maximal concentration while significantly reducing peak levels.[38] This should argue for a more rapid titration to an efficacious dose and once-daily administration.
Biederman and colleagues[14] conducted a multicenter, controlled, fixed-dose escalation study in pediatric patients with ADHD (ages 6 to 17 years). This is the first published study of GXR monotherapy. A total of 345 patients were randomly assigned to receive GXR 2 mg, 3 mg, or 4 mg daily, or placebo for 8 weeks. This paper is crucial to challenging previous therapeutic perceptions because in this study GXR effectively reduced both inattentive and hyperactive/impulsive symptoms of ADHD, reflected by reductions in ADHD-Rating Scale-IV subscale scores. Furthermore, the treatment effect sizes reported on a milligram-per-kilogram basis were 0.58 for 0.05 to 0.08 mg/kg doses; 1.19 for 0.09 to 0.12 mg/kg; and 1.34 for 0.13-0.17 mg/kg. Although these results must be replicated, they suggest that GXR is highly efficacious with an effect size at higher doses approximating that of stimulants. Sedative side effects were prominent (15%-27% of patients depending on GXR dose), this sedation apparently did not affect improved attention. Emerging duration of effect data suggest a minimum of 12 hours of symptom relief,[39] lending support to GXR's utility as a once-daily ADHD therapeutic.
Long-term (24 month) open-label data from 259 child and adolescent patients (56 of whom also received a co-administered stimulant) who were treated with up to 4 mg of GXR daily support the safety and tolerability of GXR.[40] Although side effects were typically mild to moderate, no overall trends for blood pressure or pulse were detected over time or GXR dose. Sedation and fatigue, common in the shorter-term controlled trial[14] were much less frequent and less intense in the longer-term safety trial. Given these initial positive reports concerning the efficacy and safety of GXR, further exploration of its use as monotherapy in patients with ADHD is warranted. GXR will likely reform our present understanding of alpha 2 agonists in the paradigm of ADHD treatment.
Phase 3 trials of a sustained-release formulation of clonidine are currently under way in children and adolescents with ADHD (https://www.clinicaltrials.gov/). Neither clonidine nor guanfacine is approved for use in patients with ADHD, and therefore their use in this context is considered off-label.
This activity is supported by an independent educational grant from Shire.
