Alpha-2 agonists in the threatment of attention deficit hyperactivity disorder

Journal of Child and Adolescent Psychiatric Nursing, Oct-Dec 1999 by Scahill, Lawrence, Barloon, Linda, Farkas, Lesley

Stimulants, such as methylphenidate and d-amphetamine (dextro amphetamine), are first-line agents for treatment of attention deficit hyperactivity disorder (ADHD) (Scahill, 1997). More recently, the mixed amphetamine preparation, Adderall, also has been shown to be safe and effective for the treatment of ADHD (Swanson et al., 1998). The impressive track record of the stimulants notwithstanding, there is no convincing evidence that any one of these stimulants is more effective than another. Stimulant medications fail in as many as 20% to 30% of chiildren with ADHD, either due to lack of efficacy or because of adverse effects such as tics, mood lability, obsessive-compulsive symptoms, anorexia, and sleep disturbance (Greenhill, 1995). When stimulants are not effective, clinicians and families often seek alternative medication strategies.

The purpose of this review is to evaluate the rationale and evidence for the use of the alpha-2 agonists clonidine and guanfacine in the treatment of children with ADHD. Before considering the alpha-2 agonists, this article first examines the problem of using stimulants in children with tics and provides a brief review of nonstimulant treatments for ADHD.

Stimulants and Tics

Clinical reports during the past 25 years have observed that some children will develop tics or show a worsening of existing tics following treatment with a stimulant drug (Golden, 1974, Lipkin, Goldstein, & Adesman, 1994, Lowe, Cohen, Detlor, Kremenizer, & Shaywitz, 1982). The de novo emergence of tics such as eye blinking, head shaking, facial grimaces, and/or vocalizations has been documented in two placebo-controlled trials that excluded children with tic disorders (Barkley, McMurray, Edelbrock, & Robbins, 1992, Borcherding, Keysor, Rappoport, Elia, & Amass, 1990). These studies included a total of 127 school-age children who were tic-free at baseline. Both studies employed a crossover design in which each subject received placebo and multiple doses of stimulant. Because each child received all doses of medication, this design allows subjects to act as their own control. The Barkley et al. study used placebo and two dose levels of methlyphenidate. Borcherding et al. included two dose levels of methylphenidate and d-- amphetamine. Unambiguous tics emerged in at least 13% of subjects. Further, if a broader definition of tics is accepted, the frequency of tics de novo ran as high as 38%.

Three studies have evaluated the stimulants in children with ADHD and tic disorders. Using an on-off-on design in a group of 5 boys, Riddle and colleagues (1995) observed a significant decline in tics when methyl-phenidate was withdrawn. By contrast, two recent placebocontrolled crossover trials involving a total of 54 children with ADHD and tic disorders (51 boys and 3 girls) reported a worsening of tics in only a small percentage of subjects (up to 15%) (Castellanos et al., 1997; Gadow, Sverd, Sprafkin, Nolan, & Ezor, 1995). Gadow et al. evaluated three dose levels of methylphenidate for 2 weeks at each dose level. Castellanos et al. studied multiple dose levels of both methylphenidate and d-amphetamine for 1 week at each dose level.

Summary. Taken together, the data from clinical case reports and controlled studies suggest that 10% to 38% of children with ADHD will exhibit tics when exposed to stimulant medication. In many of these cases, the tics may be mild and transient (Borcherding et al., 1990). In some cases, the tics may become sufficiently severe to warrant discontinuation of stimulant treatment. If the child does not have a tic disorder, the stimulant-induced tics will diminish after stopping the stimulant. In children with both ADI-fD and a tic disorder, it is clear that some can tolerate stimulant treatment without a clinically significant exacerbation of tics, though others will show an increase in tics. At present, it is not possible to predict which children will demonstrate either the de novo emergence of tics or worsening of existing tics when treated with stimulant medication.

Nonstimulant Medications for Treatment of ADHD

To date, there have been only a handful of controlled studies of nonstimulant medications in children and adolescents with ADHD. Two studies (Biederman, Baldessarini, Wright, Knee, & Harmatz, 1989; Singer et al., 1995), which included 96 subjects, showed that desipramine is superior to placebo. Biederman and colleagues used relatively high doses of desipramine (mean = 4.6 mg/kg per day), whereas Singer et al. used lower doses (range = 2.0-3.0 mg/kg per day)- Despite the encouraging results of these two studies, some clinicians are reluctant to use desipramine because of concerns about prolonged cardiac conduction times and related potential for fatal arrhythmias (Riddle, Geller, & Ryan, 1993).

There have been two controlled studies of the novel antidepressant bupropion (Barrickman et al., 1995; Conners et al., 1996). In doses ranging from 50 to 200 mg/day given in divided doses, both studies provided evidence for the efficacy of bupropion with response in the range of 30% to 50% improvement on teacher and parent rating scales. Bupropion was generally well tolerated in these two studies, which included 124 subjects. In the study by Conners et al., 4 subjects withdrew because of skin rash with urticaria, and 3 subjects showed mild and potentially drug-related changes in the electroencephalogram (EEG). Adult studies in depression suggest that the frequency of seizures is approximately 0.4% with bupropion. Both EEG changes and seizure activity are presumed to return to normal after discontinuation of drug.