Dextroamphetamine. Dextroamphetamine (Adderall, Dexedrine, Dextrostat) can sometimes be beneficial for patients with ADHD when methylphenidate(Drug information on methylphenidate) is not helpful or is not tolerated. It has a half-life of three to six hours and has essentially the same side effects as methylphenidate; however, it may induce more depression, and its potential for abuse is better appreciated. (The available amphetamines are listed in Table 5.)
Extracellular synaptic dopamine(Drug information on dopamine) is increased because dextroamphetamine selectively binds to the dopamine transporter. In contrast to methylphenidate, dextroamphetamine also goes to the presynaptic neurons and induces the release of dopamine into the synapses; there is also norepinephrine(Drug information on norepinephrine) reuptake inhibition (Solanto et al., 2001).
Dextroamphetamine has been a popular stimulant for many decades, with a dosage range roughly half of methylphenidate. Its long-acting form (Dexedrine spansule) has been well-received with an immediate release, and then a more even and more reliable release over eight to 10 hours, in contrast to Ritalin SR. The spansule can be opened and the contents placed onto food if the patient has trouble taking pills or capsules. As with other long-acting stimulants, evening anorexia and/or insomnia may occur.
Adderall is an amphetamine consisting of mixed-salts amphetamines, 75% of the d-isomer and 25% of the l-isomer with a side-effect profile similar to dextroamphetamine. It lasts about six hours per dose. Adderall XR may provide stimulant effects up to 12 hours, with an immediate-release and also an extended-release pattern. The capsule can be opened and the beads sprinkled on food for youth who have problems swallowing tablets or capsules. There are no studies comparing these long-term agents with one another (The Medical Letter, 2001, 2000).
Other amphetamine stimulants. Methamphetamine (Desoxyn Gradumet SR) is a potent amphetamine product that is difficult to obtain and has the highest potential for addiction among the available stimulants.
Pemoline(Drug information on pemoline) (Cylert) is a well-known stimulant that is not a methylphenidate or amphetamine derivative. Magnesium pemoline can be given once a day as a regular or a chewable tablet. Although it has a reputation of taking several weeks to become effective, recent studies note its onset of action is similar to that of other stimulants. Approximately 3% of children using pemoline develop a chemical hepatitis several months after using it; once pemoline is stopped, the hepatitis disappears. However, pemoline is not currently advocated by most clinicians because of the rare occurrence of irreversible liver failure noted with its use. Patients and their families must be told of this serious adverse reaction, must provide a written informed consent in this regard and must be placed on a very strict protocol for follow-up (Greenhill et al., 2002).Non-Stimulant Medications
Alpha-2 agonists. Clonidine(Drug information on clonidine) (Catapres) is an α-2 adrenergic agonist that is central acting and presynaptic; it has a sedative effect probably due to its direct effect on the reticular system. Clonidine may be added to methylphenidate or used in place of methylphenidate to control ADHD; it is also used for Tourette syndrome, oppositional defiant disorder and posttraumatic stress disorder. Dosage ranges and some side effects are listed in Table 1. (Due to copyright concerns, this table cannot be reproduced online. Please see p48 of the print edition--Ed.) This product is available in pill and patch form. Use of the patch may blunt or avoid pill-associated problems of sedation, rebound blood pressure changes and need for daily pill use. A slow titration of this medication may reduce these side effects. Patients should have their blood pressure, pulse, liver function tests and electrocardiogram (ECG) closely monitored. It is not used in youth with attentional dysfunction only, since the sedation side effect may impair neuropsychological function. Patch-induced dermatitis may be severe and limit its use; topical steroid products and patch-site rotation often help in this regard.
Guanfacine(Drug information on guanfacine) (Tenex) is an α-2A-adrenergic agonist related to clonidine. In contrast to clonidine, guanfacine has a longer duration of action, less sedation, less hypotensive reaction, more agitation and increased headache frequency. As with clonidine, the benefit for patients with ADHD remains unclear apart from its sedative effects.
Antidepressants. Although not approved for ADHD by the FDA, there is ample research to indicate that TCAs are helpful for this disorder and are considered as a second-line of pharmacologic management if stimulants cannot be used (Greydanus and Sloane, 1997; Weiss and Weiss, 2002). Tricyclic antidepressants block serotonin and norepinephrine reuptake and are involved with downregulation of α-adrenergic receptors. Imipramine(Drug information on imipramine) (Tofranil) inhibits serotonin reuptake while desipramine (Norpramin) inhibits the uptake of norepinephrine. Tricyclic antidepressants may be helpful for youth with both ADHD and a mood disorder; this group of antidepressants may also be augmented by stimulants (especially methylphenidate) in selected cases of refractory depression. Desipramine may be helpful for youth with ADHD and tic disorder, while nortriptyline(Drug information on nortriptyline) may be especially useful for the combination of ADHD with oppositional behavior. Tricyclic antidepressants may be useful for youth with ADHD and other conditions, such as migraine headaches, insomnia, panic disorder, obsessive-compulsive disorder and nocturnal enuresis. The side effects of TCAs are numerous, such as those that are anticholinergic, and are well-described in the literature (Greenhill et al., 2002; Greydanus et al., in press; Greydanus et al., 2002; Greydanus and Sloane, 1997; Weiss and Weiss, 2002). As with all applications of psychopharmacology, the medicated patient must be carefully monitored, and guidelines are available to assist clinicians (Elliott, in press; Varley and Smith, in press). There is no correlation between TCA plasma level and efficacy for ADHD. In contrast to stimulants, TCAs lead to less rebound, but are associated with more tolerance problems. Rare cases of sudden death in children and adolescents on desipramine (less commonly imipramine) have been reported (Elliott, in press; Varley and Smith, in press).
Bupropion, a unicyclic antidepressant with both noradrenergic and dopaminergic effects, can be helpful in youth with attentional dysfunction, irritability, depression and/or nicotine(Drug information on nicotine) addiction (Greenhill et al., 2002; Greydanus et al., in press; Greydanus et al., 2002; Greydanus and Sloane, 1997; Weiss and Weiss, 2002). It is available in tablet and sustained-release formulations. Side effects are listed in Table 1. The risk for seizures can be reduced by prescribing the sustained-release version, not using high doses of the regular tablets, not taking doses less than eight hours apart and by slow medication titration. A different bupropion formulation (Zyban) is available for nicotine addiction, and a once-a-day bupropion formulation, Wellbutrin XL is scheduled to be available in 2003.
Others. Research has indicated atomoxetine(Drug information on atomoxetine), a nonstimulant chemical, has beneficial effects in children and adolescents with ADHD (Kratochvil et al., 2002; Michelson et al., 2001). Its mechanism of action includes the blockade of the presynaptic norepinephrine transporter in the prefrontal cortex; there is an increase in extracellular dopamine and norepinephrine levels in this cortex. This drug has minimal activity at histaminic, serotonergic, cholinergic or adrenergic (α-1 and α-2) receptor sites. Atomoxetine has not led to tics, euphoria or a withdrawal syndrome. Currently, there are only minimal studies comparing it to other established medications for ADHD and none showing superior efficacy to the less expensive stimulants (Kratochvil et al., 2002). Research is also evaluating such medications as the atypical antidepressant venlafaxine (Effexor) and the anti-narcolepsy drug modafinil(Drug information on modafinil) (Provigil). The use of polypharmacy is also under active study to improve efficacy and/or blunt medication side effects (e.g., irritability, moodiness, rebound, insomnia).
Agents and management methods that have not been shown to benefit youth with ADHD are listed in Table 6 (Baumgaertel, 1999; Chan, 2002; Greydanus et al., in press). Herbal products (e.g., ephedra) are not recommended because of their failure for purity, potential side effects and their lack of efficacy (Greydanus and Patel, 2002).