Medications

There are an increasing number of medications available to treat ADHD.

Psychostimulants: Methylphenidate (Ritalin) and Similar Drugs

Psychostimulants, to date, are the primary drugs used to treat ADHD. Methylphenidate (Ritalin, Metadate, Concerta) is the most commonly used psychostimulant for ADHD. Its positive benefits for improving ADHD symptoms appear to be due to its actions in increasing dopamine, a neurotransmitter important for motor control. This drug is effective in both children and adults. A similar drug dexmethylphenidate (Focalin) has been approved. It is similar to in methylphenidate in effectiveness and side effects. At the time of this report, the FDA was also considering approving a new skin patch for ADHD. The patch, Daytrana, delivers a 9-hour dose of methylphenidate. It is designed for children who cannot take pills.

Regimen. The older form of Ritalin is short acting, and needs to be taken several times a day, including during school hours. As it wears off, a rebound effect can occur and ADHD symptoms intensify. Longer-acting forms (Concerta, Ritalin LA, Ritalin SR, Metadate) are now available.

Concerta is now the most commonly prescribed drug for ADHD and uses a special pump action that releases the medication gradually into the body and can be effective for 12 hours. Ritalin LA and Metadate also only need to be taken once during the entire school day. (Ritalin SR can still can wear off by early afternoon.) A patch form of methylphenidate (MethylPatch) is awaiting approval. A 4-week trial in 2002 reported that it was very effective in improving attention and improving behavior.

A 2003 study of Concerta indicated that depending on the ADHD subtype, children may require different doses. In the study, children with the inattentive type responded to lower doses than those with the combined type.

Side Effects. All stimulants have a number of side effects:

• The most common side effects of any stimulant are nervousness and sleeplessness, although some parents have reported improved sleep patterns in their children after taking stimulants.
• Children may lose weight.
• Tics or jerky, disordered movements occur in about 9% of children. Some studies indicate they are not caused by standard doses of Ritalin. In any case, low doses are often effective in controlling impulsivity without causing tics, even in some children who also have mild to moderate Tourette's syndrome.
• Other side effects include irritability, withdrawal, stomach pain, headache, depression, hallucinations, hair loss, and lack of spontaneity.

Of note, taking Ritalin with a high-fat breakfast may delay its effects.

Symptoms of Overdose. Symptoms of overdose include changes in heart rhythm and rate, hypertension, confusion, breathing difficulties, sweating, vomiting, and muscle twitches. If they occur, parents should call the doctor immediately. Even among young people who abuse Ritalin, however, less than 1% experience severe side effects (rapid heart rate, hypertension) and outcomes are generally good. (Side effects may very severe, however, if Ritalin is overused and taken with other drugs.)

Long-Term Complications. Many people have taken Ritalin for years without experiencing adverse effects or loss of effectiveness. Few long-term complications have been reported, but the following warrant some caution or additional research:

• Early research had suggested that growth may be retarded during long-term treatment. Recent studies, however, have found little evidence for any significant growth suppression in boys or girls. In addition, a 2003 study found no significant effect on onset of puberty in girls.
• A 2001 study on animals suggested that there may be some long-term effects from methylphenidate that may change brain cell structure or function. Heavy abuse of other stimulants (cocaine, amphetamines) has been associated with worsening in motor skills and attention. However, more research is needed to determine if such changes occur with long-term use of Ritalin. In fact some evidence suggests that Ritalin may help increase white matter (the primary substance that makes up the core of the brain's hemispheres).

Concerns for Abuse. Studies on both animals and humans suggest that that Ritalin lacks the properties that create addiction, particularly in doses used for treating ADHD. Although methylphenidates have properties similar to amphetamines, their drug levels rise very slowly in the brain at the oral doses given for ADHD. This slow rise prevents a so-called "high" and subsequent addiction to the drug.

A major analysis in 2003, in fact, indicated that methylphenidate treatment may even protect young people with ADHD from abusing alcohol or other drugs. In such cases, methylphenidates may reduce the need to self-medicate ADHD symptoms using nicotine, alcohol, or illegal drugs. (Ritalin does not protect against substance abuse in young people with ADHD and conduct disorder, however.)

Dependence has not been reported in children who have taken this drug for long periods in appropriate dosages. It should be noted, however, that crushing the pills and inhaling them nasally can provide a euphoric state. The primary danger for drug abuse from stimulants appears to occur in non-ADHD young people who purchase these drugs illegally. In one study, for instance, 16% of ADHD children reported pressure from their fellow students to sell or give them their medication.

Adderall

Adderall is central nervous system stimulant, or amphetamine. It combines four kinds of amphetamine salts. It is inexpensive and can be taken once or twice a day. (Adderall XR is designed to be taken once a day.) Adderall may also be effective for adults. In one major 2002 analysis of comparison studies, parents and doctors reported that Adderall was superior to standard Ritalin, but teachers found no superiority of one drug over the others. Side effects include stomach problems and mood changes, including sadness, anxiety, and irritability. A few reports of sudden unexplained death (SUD) in children taking Adderall and Adderall XR prompted Canada to stop advertising the XR version in early 2005. Most Adderall-related SUD cases have been documented in children with underlying heart problems, but some deaths were found in those without heart defects. The FDA is evaluating the data, but at the time this report was updated it had not yet reached a final conclusion concerning the drug’s safety. Patients with structural heart problems or high blood pressure should not use Adderall.

Other Central Nervous System Stimulants

Pemoline (Cylert). Pemoline is a central nervous stimulant prescribed for children who do not respond to other drugs. However, there have been 13 reports of liver failure or death in patients taking the drug. In October 2005, the FDA concluded that "the overall risk of liver toxicity from pemoline outweighs the benefits of this drug." The rate of reported liver failure in patients taking Cylert is 10 to 25 times greater than that of the general population. The FDA recommends that doctors switch patients to another drug. The drug was withdrawn in Canada in 1999.

Dextroamphetamine. Dextroamphetamine (Dexedrine) is similar to Ritalin. Although it is commonly believed that it is both less effective and less safe than Ritalin, there is no evidence of this, and one study reported a slightly better response with dextroamphetamine. Side effects are similar. The arguments against dextroamphetamine mainly rest on widespread abuse of this drug in earlier decades. Some experts believe it may be an useful alternative for people who do not respond to Ritalin.

Non-Stimulant: Atomoxetine

Atomoxetine (Strattera) was the first non-stimulant approved for ADHD in children and the first treatment approved for adult ADHD. The drug works by increasing levels of both norepinephrine and dopamine, which are generally lower than normal in ADHD. The most common side effect is decreased appetite. A few cases of atomoxetine-associated liver injury have been reported, and the FDA has warned physicians that the drug should be discontinued at the first signs of jaundice or liver problems. Long-term effects, such as any impact on growth, are still unknown. In 2005, the FDA warned that atomoxetine may cause suicidal thinking in children and adolescents, especially during the first few months of treatment. Parents should monitor children taking atomoxetine for any changes in mood or behavior, and immediately contact their doctor if changes occur.

Antidepressants

Specific antidepressants are proving to be helpful under certain conditions and some may be reasonable alternatives to psychostimulants for some people with ADHD.

Designer Antidepressants. Bupropion (Wellbutrin), reboxetine (Edronax) and venlafaxine (Effexor) are unique antidepressants, sometimes referred to as designer antidepressants. Such drugs affect one or more neurotransmitters that are not targeted by older antidepressants. These drugs may be particularly helpful for treating patients with ADHD and accompanying disorders, including depression or conduct disorder. Most studies to date have focused on bupropion and have reported good results in both children and adults.

Tricyclics. Antidepressants known as tricyclics, which include desipramine (Norpramin, Pertofrane), or imipramine (Janimine, Tofranil), have been prescribed for children who do not respond to stimulants or who have accompanying problems, such as tics, anxiety, or depression. Desipramine appears to have the best results of the tricyclics and may even help control impulsivity. Tricyclics can have distressing side effects however, including dry mouth, sleepiness, and constipation. They have mild effects on blood pressure and heart rate, but such effects do not appear to be harmful in people without existing heart disease. Reports of sudden death of a few children taking tricyclics, however, have caused alarm, although these occurrences are extremely rare and the role tricyclics may have played is not clear. Reports of delirium and increased heart rate have occurred in adolescents who take tricyclics and smoke marijuana. Careful monitoring is important.

SSRIs. The antidepressant drugs known as selective serotonin reuptake inhibitors (SSRIs), which include fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), and paroxetine (Paxil), are sometimes recommended for treating depression in ADHD patients with both conditions. They have little effect on ADHD and in fact they may increase the risk for impulsive behavior. The effects of long-term use of SSRIs in young people are not clear. Some SSRIs such as paroxetine (Paxil) have been linked to increased risk for suicidal thoughts and behavior in children and teenagers. Fluoxetine (Prozac) is currently the only SSRI approved for treating depression in children and adolescents. [For more information, see In-Depth Report #8: Depression].

Alpha-2 Agonists (Clonidine)

Alpha-2 agonists stimulate the neurotransmitter norepinephrine, which appears to be important for concentration. They include clonidine (Catapres) and guanfacine (Tenex). They are used for Tourette's syndrome and may be beneficial when other drugs have failed for ADHD children with tics or those whose primary symptoms are severe impulsivity and aggression.

These drugs have a number of side effects. (Guanfacine may have fewer than clonidine.) Sedation is the most common. A clonidine skin patch, which gradually releases the medication, helps reduce the sedative effect. Because clonidine slows the heart down, it can have adverse effects in some children. Going off too quickly or missing doses can cause rapid heartbeats and other symptoms that may lead to severe problems.

Studies in general report that the drug is safe, including in combination with stimulants. Of concern, however, were reports of five deaths in children taking clonidine with other medications. Experts strongly recommend that no child be given this medication without a preliminary examination for heart problems, and no child with existing heart, kidney, or circulatory problems should take it.

Other Medications Investigated for ADHD

Selegiline. Selegiline (Eldepryl, Movergan, Zelepar), also known as deprenyl, metabolizes into compounds found in methamphetamine and blocks monoamine oxidase B (MAO-B), an enzyme that degrades dopamine. A well-conducted study in 2003 suggested that it may be as effective as Ritalin with fewer size effects. Selegiline can cause hypertension if combined with drugs that increase serotonin levels--such drugs include nearly every major antidepressant.

Modafinil. Modafinil (Provigil) promotes wakefulness and is used to treat patients with narcolepsy. It is being investigated for adults and children with ADHD, but studies have been mixed on its benefits.

Determining a Correct Regimen

Doctors still have a difficult time predicting which medications will produce beneficial results, so treatment is individualized and performed on a trial and error basis, which requires close observation and cooperation between all participants. In developing an effective medication plan, the following steps may be helpful:

• Before any drug is administered, a child should be given a thorough examination for any medical problems to be sure there are no medical conditions that interfere with the medication.
• Both the doctor and the parents should be very clear about the specific behaviors they hope the medication will target.
• The goal is to use the lowest possible dosage that produces improved behavior.
• If an initial regimen doesn't work, changing the dosage, adding another drug, or changing to a different medication often brings improvement. Some experts recommend trying a second psychostimulant if a first one fails. If the child still doesn't respond, antidepressants or other second-line drugs may be beneficial.
• Frequent follow-up visits should be scheduled to assess the response and to detect possible side effects.

Medications in Older Children. As children enter adolescence, the social stigma associated with ADHD often makes them reluctant to continue drug treatment. If the drug has proven to be effective, it is very important to keep the young person on the regimen during this critical period.

Medications for Adults. One report suggested that two-thirds of adults with ADHD may also be successfully treated with stimulants and psychotherapy. Certain antidepressants may also be effective treatments in adults.

Combination Therapy. A 2002 study reported that children with ADHD are increasingly being treated with a combinations of psychostimulants and certain antidepressants (such as tricyclic antidepressants and bupropion), and psychostimulants plus clonidine. Experts warn that there is little evidence that such combinations add any benefits and their long-term safety is unknown. Nevertheless, combinations may be warranted in certain severe cases, such as in children who are also suffering from an accompanying emotional disorder, such as bipolar or anxiety disorder.

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Review Date: 12/7/2005
Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.