Nonstimulant Medications for the Treatment of ADHD

Journal of Child and Adolescent Psychiatric Nursing, Feb 2006 by Rains, Adrienne, Scahill, Lawrence

Introduction

Attention deficit hyperactivity disorder (ADHD) is a major public health problem affecting 5 and 10% of school age children (Scahill, Carroll, & Burke, 2004). Stimulants, which are the first-line treatment for ADHD, fail in up to 20% of children with ADHD (Ford, Greenhill, & Posner, 2003; MTA Cooperative Group, 1999). Causes of treatment failure include lack of efficacy or adverse effects such as insomnia, anorexia, or tics (Pliszka, 2003). In addition, despite their record for safety and efficacy, some families may be opposed to the use of stimulants on philosophical grounds (Perring, 1997). Thus, there is a clear role for nonstimulant alternatives in the treatment of children with ADHD. Six nonstimulant medications have demonstrated superiority to placebo in at least one randomized controlled study. These include atomoxetine, clonidine, guanfacine, desipramine, deprenyl, and bupropion. (Conners et al., 1996; Feigin et al., 1996; Kelsey et al., 2004; Michelson et al., 2002; Scahill et al., 2001; Spencer et al., 2002; Tourette's Syndrome Study Group, 2002; Weiss et al., 2005) (see Table 1). This article, the third in a four-part series addressing pharmacologic treatment of ADHD, examines four of the most commonly used nonstimulant medications for treating ADHD: clonidine, guanfacine, desipramine, and atomoxetine (see Table 2).

Clonidine and Guanfacine

Clonidine and guanfacine are alpha-2 adrenergic agonists that share some features in common, but have important differences as well. Both drugs reduce the firing of norepinephrine neurons in the locus ceruleus and exert a regulatory effect on the adrenergic system. Guanfacine also directly stimulates norepinephrine receptors in the prefrontal cortex, which is presumed to enhance prefrontal function (Newcorn, Schulz, & Halperin, 2003).

Clonidine

Clonidine comes in 0.1, 0.2, and 0.3 mg tablets as well as a transdermal patch. The oral medication acts within 30 to 60 min. Although the plasma half-life ranges from 8 to 12 hr in children, duration of the effects on behavior is usually about 4 hr (Newcorn et al., 2003). The typical daily dose is 0.2 to 0.3 mg per day in three or four divided doses. The most common adverse effects include dry mouth, drowsiness, irritability, weakness, fatigue, and mid-sleep awakening. Hypotension and bradycardia are possible, but are not typically seen in children (see Table 2). The Tourette Syndrome Study Group (2002) conducted a study in 136 children with ADHD and tic disorder. These children were randomly assigned to receive placebo, clonidine, methylphenidate, or the combination. All three active treatments were superior to placebo, with improvement on the Clinician's Global Impression (CGI) after 24 weeks of 60.6%, 75%, and 84.4%, respectively, for clonidine, methylphenidate, and methylphenidate clonidine. The combination of the two drugs was well tolerated, and clonidine's side effect of sedation was less common in the combined treatment group.

Guanfacine

The usual dose of guanfacine falls between 1 mg and 3 mg per day in three divided doses. Peak plasma concentrations occur from 1 to 4 hr after a single oral dose. The half-life of guanfacine is about 13 hr, which is longer than for clonidine. This longer half-life may be why sedation is less of a problem for guanfacine compared to clonidine (Newcorn, Schulz, & Halpern, 2003).

In a study of 34 children with ADHD and tic disorders, guanfacine was shown to be more effective than placebo in decreasing ADHD symptoms (Scahill et al., 2001). The drug was well tolerated, and 53% of those on guanfacine showed a positive response. The mean reduction in ADHD symptoms rated by teachers and parents was smaller than what is typically observed with the stimulants in children with ADHD. The most common adverse effects were sedation and mid-sleep awakening.

Desipramine

Desipramine is a tricyclic antidepressant that selectively blocks norepinephrine reuptake at the presynaptic transporter, resulting in increased availability of norepinephrine. It is this action that is presumed to account for its beneficial effects in ADHD. At daily dosing ranging from 1 to 3.5 mg/kg (Spencer et al., 2002) given in two divided doses, desipramine was superior to placebo, with 71% of the desipramine-treated subjects showing a positive response (Spencer et al). The 6-week study enrolled 42 children with ADHD and chronic tic disorder (Spencer et al.). The most common adverse effects are listed in Table 2. As with the other tricyclic antidepressants, the drug level should be checked periodically. Optimal plasma level has not been established for ADHD, but levels above 300 mg/ml are not recommended. Another concern is the potential for cardiac conduction abnormalities, particularly prolonged QT interval. For this reason, desipramine has declined in use.

Nortriptyline, another medication in the tricyclic antidepressant class, has been evaluated in a placebocontrolled descontinuation study (Prince et al., 2000). In that study, children who were assigned to gradual withdrawal (i.e., placebo substitution) showed a return of ADHD symptoms. The side effect profile is similar to that of desipramine.