Chronic use of stimulants is controversial.17,18 Although stimulants may produce anorexia and weight loss, their effect on a youth’s ultimate height is less certain. Initial reports of a persistent stimulant-associated growth decrease have not been substantiated. Other studies suggest that growth deficits may represent maturational delays related to ADHD rather than to stimulant treatment.21
Stimulants may precipitate or exacerbate tic symptoms in children with ADHD. Recent work suggests that stimulants can be used safely in youth with tic disorders,22 although up to one-third may experience worsening of tic symptoms.
Despite case reports of stimulant misuse, there is little data to support stimulant abuse among treated children with ADHD.13 However, the diversion of stimulants to youth without ADHD is a concern.
Antidepressants
Antidepressants are generally considered second-line drugs for ADHD.1,16 Bupropion, an antidepressant with indirect dopamine and noradrenergic effects, has been shown effective in ADHDin controlled trials of both children and adults.23,24
Bupropion is often prescribed first for complex patients with ADHD and substance abuse or an unstable mood disorder because of its ability to reduce cigarette smoking and improve mood, lack of monitoring requirements, and few adverse effects. Dosing is typically initiated at 100 mg of the sustained-release preparation and increased weekly to a maximum of 300 mg in younger children and 400 mg in older children or adults (i.e., 200 mg bid). Adverse effects include insomnia, activation, irritability, and (rarely) seizures.
The tricyclic antidepressants (TCAs) used in ADHD—imipramine, desipramine and nortriptyline—block the reuptake of neurotransmitters including norepinephrine. TCAs are effective in controlling abnormal behaviors and improving cognitive impairments associated with ADHD, but less so than the stimulants. TCAs are particularly useful when:
- stimulants fail to control ADHD symptoms;
- oppositional behavior, anxiety, tics, or depressive symptoms coexist within ADHD or occur during its treatment.
Desipramine appears to be the most effective TCA for ADHD, followed by nortriptyline and imipramine.25,26 TCAs are dosed starting with 25 mg/d and slowly increased to a maximum of 5 mg/kg/day (2 mg/kg/day for nortriptyline). Although immediate relief can be seen, a delay of up to 6 weeks for maximal effect is common. Typical adverse effects include dry mouth, constipation, sedation, and weight gain.
Four deaths have been reported in children with ADHD treated with desipramine; however, independent evaluation of these cases failed to support a causal link. As minor increases in heart rate and ECG intervals are predictable with TCAs, ECG monitoring at baseline and at therapeutic dosages is recommended.
Although serotonin reuptake inhibitors are not generally useful for ADHD, venlafaxine appears to have mild efficacy, perhaps because of its dose-dependent noradrenergic reuptake inhibition.27
Monoamine oxidase inhibitors (MAOIs) have been shown effective in juvenile ADHD. Response to treatment is rapid, and standard antidepressant dosing is often necessary.16 A major limitation to the use of MAOIs is the potential for hypertensive crisis associated with dietetic transgressions and drug interactions.
Other treatment options
Antihypertensives The antihypertensive agents clonidine28 and guanfacine29 are used to treat the hyperactive-impulsive symptoms of ADHD in youth. Clonidine is relatively shortacting, with usual daily dosage ranges from 0.05 to 0.4 mg.28 Guanfacine is longer acting and less potent, with usual daily dosage ranges from 0.5 to 4 mg.29
Antihypertensives have been used to treat ADHD and associated tics, aggression, and sleep disturbances, particularly in younger children.16 Although sedation is more common with clonidine than guanfacine, both agents may cause depression and rebound hypertension. Cardiovascular monitoring (vital signs, ECG) remains optional.
New agents Novel compounds, along with new preparations and delivery systems of existing stimulant medications, are being investigated for managing ADHD. New agents are being tested in adults with ADHD because adults and youth respond similarly to ADHD medications, and there are ethical concerns about drug testing in children.
Atomoxetine, a noradrenergic reuptake inhibitor under development, has been shown in open and controlled studies of adults and youth30 to be effective in treating ADHD. Atomoxetine appears well tolerated, with no blood monitoring requirements.
Cholinergics and genes Selective use of cholinergic agents (e.g., donepezil) may also be helpful for the cognitive dysfunction in ADHD,24 either as monotherapy or in combination with other agents for ADHD. Multiple centers are investigating the possible link between response to pharmacologic therapy and ADHD genotype.
Combination therapy
Combinations of pharmacologic agents can be used to treat comorbid ADHD, to augment response to a single agent, for pharmacokinetic synergism, and to manage adverse effects that emerge during treatment. Examples include:
- a tricyclic antidepressant and a stimulant to heighten response to treatment;
- an antidepressant plus a stimulant for ADHD and comorbid depression;
- adjunctive use of clonidine for sleep or to manage aggressive behavior;
- use of mood stabilizers with ADHD medications for comorbid bipolar disorder.16