Alternatives to stimulants may be used to treat attention deficit hyperactivity disorder (ADHD) in three settings:
The U.S. Food and Drug Administration (FDA) has not approved other medications for use in ADHD, so their use is considered “off-label.”
Clonidine, an alpha2-adrenergic agonist, has been used in the treatment of ADHD,97 Gilles de la Tourette’s syndrome,98 and sleep disturbances secondary to the use of stimulants in children with ADHD.99 Connor et al.100 reviewed 39 studies of the use of clonidine in ADHD. Eleven studies included sufficient information to permit a meta-analysis, with eight having some form of methodological control. Connor’s group100 concluded that clonidine can be a useful second-line medication in ADHD.
Recently, four fatalities were reported in youngsters taking a combination of methylphenidate (MPH) and clonidine,101,102 but the data are incomplete and unclear. A review by Wilens et al.103 points out that although the combination of MPH and clonidine has not been evaluated in double-blind trials, its effectiveness in clinical work and the complicating issues in the reported deaths make it a reasonable treatment option in appropriate children.
Guanfacine, another alpha2-adrenergic agonist with less sedative effect than clonidine, has also been used in the treatment of ADHD and Gilles de la Tourette’s syndrome. Unlike clonidine, guanfacine may also improve attention in ADHD.104
All tricyclic antidepressants (TCAs) inhibit reuptake of norepinephrine and, to some degree, serotonin. They are the second most frequently studied medication for treating ADHD. The TCAs most commonly used for ADHD are:
Several studies have found that TCAs are effective in ADHD.105 They are more effective for the impulsive-hyperactive symptoms than for inattention. Although immediate effectiveness may be obvious, most studies suggest a 2-week period before one should expect to see changes.
The most common side effects include fatigue and dry mouth. Their main disadvantage is the potential for serious cardiac side effects that require careful monitoring. Seven deaths have been reported in youngsters taking desipramine, which may be more cardiotoxic than other TCAs.
These medications can be given once daily, but twice-daily dosing is appropriate to reduce adverse effects. As with the stimulants, no relationship exists between effective dose and body weight. The maximum dose should be no higher than 5 mg/kg, except in the case of nortriptyline, the maximum dose of which should be 2.5 mg/kg. Cardiac and blood level monitoring should accompany dose changes.
Bupropion is a novel antidepressant with both dopaminergic and noradrenergic effects. Although bupropion appears to have some positive effects on the symptoms of ADHD, the magnitude of the effect is much less than that of the stimulants.106 Its main adverse effects are dermatologic reactions and the potential to lower seizure threshold. Dosing usually is up to 6 mg/kg per day in divided doses.
Venlafaxine is an antidepressant with noradrenergic and serotoninergic properties. Open-label trials in children and adults with ADHD suggest some efficacy in reducing symptoms but with a fair degree of adverse effects, including worsening of hyperactivity.107
The monoamine oxidase inhibitors have been used with some efficacy in adults and children with ADHD.108 However, use of these agents is severely limited in this population, whose impulsivity may preclude following a rigid diet.
Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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