Psychopharmacology for ADHD in Adolescents: Quo Vadis?

Attention-deficit/hyperactivity disorder is a fascinating condition that has perplexed clinicians, researchers, parents and patients for a long time. Research indicated that management of ADHD in children and adolescents should emphasize a multimodal approach, with attention to proper school placement, appropriate psychological therapy and, in many situations, psychopharmacology. This review focuses on the medications that have been noted to provide benefit to adolescents with ADHD.

Stimulants

Methylphenidate (Ritalin, Concerta, Metadate, Methylin) is the most commonly prescribed stimulant with hundreds of randomized, controlled studies noting that it may provide benefit to patients with ADHD in various ways: enhance concentration, reduce hyperarousal as well as impulsivity, improve tasks (i.e., homework completion, school and/or work performance), and/or lessen antisocial and aggressive behavior. Research reveals that the methylphenidate mechanism of action involves increasing extracellular dopamine levels by selective binding of the presynaptic dopamine transporter in the central nervous system (prefrontal and striatal areas) in addition to norepinephrine transporter blockage (Solanto et al., 2001).

Table 1 (due to copyright concerns, this table cannot be reproduced online. Please see p48 of the print edition--Ed.) outlines the well-known daily dosage schedule and some of the adverse reactions for methylphenidate. This chemical crosses the blood-brain barrier after gastrointestinal absorption, with stimulant effects that begin in 30 to 45 minutes, peak in one to two hours and then wane after three to five hours.

This immediate-release (IR) methylphenidate can be taken up to three times a day if necessary. Ritalin and its generic version have been used for decades to medically manage adolescents with ADHD. If a stimulant effect is needed for longer than the duration of IR methylphenidate, Ritalin sustained-release (SR) or its generic version can be used to deliver an equivalent of 7 mg IR methylphenidate for several hours. However, this product has not been well-received because of unpredictable absorption related to limited bioavailability and erratic gastric absorption; also, it is only made in a 20 mg tablet that limits prescription as well as titration flexibility. If the tablet is broken, the sustained-release mechanism is destroyed.

Because of the popularity of IR methylphenidate as a stimulant and the negative reputation of Ritalin SR, an aggressive search has been launched over the past decade to find the optimal sustained-release stimulant product. Table 2 lists the currently available methylphenidate products.

New Products

Concerta employs an osmotic time-release OROS mechanism in which there is a tri-layer core enveloped by a membrane that is semipermeable; this allows slow release of methylphenidate using a laser-drilled opening at one end. Approximately 22% of the tablet is on the outer membrane, and this allows the first peak plasma concentration to appear in one to two hours. Concerta is manufactured as 18 mg, 36 mg and 54 mg extended-release tablets. It is nearly impossible to alter the tablet and use its methylphenidate as a drug of abuse. It cannot be chewed, divided or crushed.

Ritalin LA is available as 20 mg, 30 mg and 40 mg capsules that release two methylphenidate doses four hours apart, using immediate-release and sustained-release beads. If the adolescent has problems swallowing pills, the capsule can be opened and the beads mixed into their food.

Methylin contains immediate-release methylphenidate and is made as tablets of 5 mg, 10 mg and 20 mg strength. Methylin ER consists of 10 mg and 20 mg extended-release methylphenidate tablets, lasting up to eight hours.

Metadate ER allows a more continuous methylphenidate release for up to eight hours; it is made in 10 mg and 20 mg strengths. Metadate CD is made as 20 mg capsules in which 30% is immediate-release methylphenidate and the remaining is released over six to 10 hours. The capsule can be opened and the beads placed in food, if swallowing is a problem. This, as with any long-acting stimulant product, may cause anorexia in the evening and induce insomnia.

Focalin (dexmethylphenidate HCL) is the d-threo-enantiomer of racemic methylphenidate hydrochloride, which may have more pharmacologic activity than the l-form. It is made as 2.5 mg, 5 mg and 10 mg tablets (half the dosage of Ritalin) and is an immediate-release product that lasts four to six hours.

Noven Pharmaceuticals is developing a transdermal methylphenidate formulation called MethyPatch; a new drug application is pending at the U.S. Food and Drug Administration.

How does the clinician choose with the recent explosion of these various methylphenidate products? The most comprehensive, unbiased and often quoted study on the benefits of methylphenidate is the National Institutes of Mental Health's Multisite Multimodal Treatment Study of Children with Attention-Deficit Hyperactivity Disorder (MTA). This study, released in 1999, indicated that short-acting methylphenidate provided several times a day was more effective in improving core ADHD symptoms (i.e., inattention, hyperactivity/impulsiveness and aggression) than psychosocial/behavioral treatment alone (Jensen et al., 2001; MTA Cooperative Group, 1999).

Many youth do not like taking several methylphenidate doses during the day, especially during school hours. Therefore, numerous clinicians are starting with a sustained- or extended-release methylphenidate product when first placing a patient on stimulant medication. The problem in choosing a specific longer-acting methylphenidate product is that there are too few current scientific studies comparing these various products (The Medical Letter, 2001, 2000). Furthermore, some current studies may be biased since many were conducted under sponsorship of the very pharmaceutical companies that are making these products. Patients and parents must understand that we do not have all the answers at this time and that all these methylphenidate products have side effects. It is also important to understand that not all youth with ADHD respond positively to methylphenidate (Table 3; due to copyright concerns, this table cannot be reproduced online. Please see p49 of the print edition--Ed.)

Table 4 (due to copyright considerations, this table cannot be reproduced online. Please see p49 of the print edition--Ed.) lists side effects of methylphenidate medications that are well-reviewed in the literature (Greenhill et al., 2002; Greydanus et al., in press; Greydanus et al., 2002). Contraindications for stimulants include known sensitivity to a specific stimulant component, psychosis, symptomatic cardiovascular disorders, glaucoma, uncontrolled hypertension, hyperthyroidism, concomitant use of monoamine oxidase inhibitors and drug dependence. Various drug interactions with stimulants are described, including MAOIs, tricyclic antidepressants and some anticonvulsants (Greenhill et al., 2002; Greydanus et al., in press; Greydanus et al., 2002).

When side effects arise, it is important to note if there is any relationship to low or high levels of the stimulant. For example, headaches may occur with the methylphenidate peak or as the level recedes; analgesics may be helpful for these headaches. A stimulant-induced mild rise in heart rate and blood pressure is usually not of concern. Appetite suppression often occurs and may lead to weight loss and a nutritionally induced growth delay; constitutional delay in growth and adolescence may also be found in adolescents with ADHD, especially male patients. Although the patient may be taking stimulants for many years, it is important to note the final height is not compromised.

Tolerance is a somewhat controversial side effect that is not clearly documented by research. Families can be taught that it does not signify addiction and changing stimulants or other medications used for ADHD may be helpful. The notion of rebound remains controversial; although it is observed and commented on by clinicians and authors, it has not been clearly identified by research. It can be seen in the late morning or early afternoon if an IR stimulant is being used and in the late afternoon for a SR agent. Alternating various stimulants (IR and SR types) and/or using longer-acting medications (such as TCAs, α-2 agonists or bupropion [Wellbutrin]) may help, depending on the timing of the rebound. Early evening rebound is difficult to manage without causing sleep dysfunction. Early morning rebound may be helped by waking adolescents up 30 minutes to 45 minutes earlier to give them stimulant medication and allow them more rest until the medication peaks.

Sleep disturbances are commonly seen in youth on stimulant medications, especially if longer-acting agents are still active at bedtime. Other causes of insomnia should be corrected, such as excess caffeine intake, poor sleep habits, and concomitant anxiety or depression. Sleep disturbances can be managed by using a stimulant schedule that is not pharmacologically active at bedtime and adding an α-2 agonists or other sedative medication and an antidepressant if depression is a comorbid illness.

The presence of tics and Tourette syndrome is not a contraindication to the use of stimulant medications. Medications (e.g., pimozide [Orap], haloperidol [Haldol] or risperidone [Risperdal]) to treat the tics may be added and the stimulants continued if they are helpful. When stimulants are prescribed to youth with tics and ADHD, one-third report worsening of the tics, one-third note no change, and one-third improve (Gadow et al., 1999; Jankovic, 2001). Some medications can improve ADHD without worsening the tics; these include α-2 agonists, TCAs and atomoxetine (Strattera). The tics may worsen or stay the same on bupropion.

Although Ritalin can be abused to develop a state of euphoria, there is no evidence that providing methyl-phenidate to a youth with ADHD increases the risk for subsequent psychoactive drug disorder; some literature even suggests the risk is reduced (Wilens et al., 2003).

Depression or anxiety may develop as a side effect of being on the stimulant or because of a comorbid mood disorder or anxiety disorder. A stimulant trial may precipitate acute mania in youth with ADHD and latent bipolar disorder. A careful assessment is necessary to pinpoint the precise issue and appropriate management. Youth on high doses of stimulants may appear withdrawn and in a state of perseveration; this dazed or "drugged" appearance usually responds to medication dose reduction.

Clinicians should be sure that the stimulant is not being diverted to someone else in or outside the home.

Amphetamines

Dextroamphetamine. Dextroamphetamine (Adderall, Dexedrine, Dextrostat) can sometimes be beneficial for patients with ADHD when 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 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 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 (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 (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 (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 (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 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 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, 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 (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).

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