An update on attention deficit disorder

(This article was first printed in the May 2004 issue of the Harvard Mental Health Letter. For more information or to order, please go to http://health.harvard.edu/mental.)

It is the most commonly diagnosed childhood psychiatric disorder. Its symptoms — distractibility, impulsiveness, and hyperactivity — are being detected more often and increasingly in younger children. Researchers are finding evidence about its biological basis, developing medications, and devising ways for parents and teachers to help. But attention deficit hyperactivity disorder (ADHD) is still a center of controversy — about the legitimacy of the diagnosis itself and the risks and benefits of the drugs used to treat it.

Here we review some advances in the understanding and treatment of ADHD.

Brain function

The brains of people with ADHD show some minor differences, especially in the frontal lobes of the cerebral cortex, which govern impulse control, organization, and planning. One study showed that after correction for weight, IQ, and other factors, their brains were 3%–4% smaller than average. Other research indicates that they have less gray matter than average in the frontal cortex, along with relatively high levels of the excitatory neurotransmitter glutamate and low levels of the inhibitory transmitter gamma-aminobutyric acid. But these statistical differences do not take them out of the normal range; ADHD cannot be diagnosed with a brain scan.

Genetics

Heredity clearly contributes to the risk for ADHD. Twin and adoption studies suggest that it accounts for 60%–70% of the individual variation in susceptibility. The chance that the brother, sister, child, or parent of a person with ADHD will have the disorder may be as high as 30%. In one study, parents of preschool children with ADHD were 25 times more likely than average to have the disorder themselves.

Now a search is on for specific genes. Scientists studying families in which several members had attention deficit disorder announced that they had found a region on chromosome 16 containing a gene or genes that raise the risk for the disorder. Other researchers have found genes for autism in the same region. There is also preliminary evidence for common genes underlying a predisposition to ADHD and reading disabilities.

Another approach is to look at genes involved in the release, reabsorption, and breakdown of the neurotransmitter dopamine, which is thought to be abnormal in the brains of people with ADHD. There is increasing evidence that people with ADHD are more likely to carry certain variant forms of the genes for dopamine receptors, transporters, and metabolism.

Stimulants and addiction risk

The stimulant drugs dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) are still the standard treatments. These drugs amplify dopamine signals by promoting the release of the neurotransmitter and preventing its reabsorption. Because they resemble cocaine in their mechanism of action, the question is repeatedly raised whether medical use can be addictive in itself or raise the risk of addiction to other drugs and alcohol in adolescents and adults.

Results of animal studies are conflicting. In older research, rats treated with methylphenidate as young (in amounts equivalent to human therapeutic doses) were less likely than average to become addicted to cocaine as adults. But a more recent study has found an increased response to cocaine in adolescent rats exposed to methylphenidate. And in still another study, adult rats who had been given methylphenidate as young were less responsive to natural rewards (such as sex) and more sensitive to stress.

The significance of these findings is not clear. Rat brains differ from the human brain in many ways. And in these experiments methylphenidate was not taken orally but injected, which usually means a faster passage into the brain. The speed at which a drug enters the brain is highly correlated with addictive potential.

So far, stimulant treatment of ADHD has not been found to raise the risk of addiction in human beings. In a 2003 review covering nearly 1,200 children treated with stimulants, researchers found an average rate of adult drug and alcohol abuse. Children with ADHD who did not take stimulants had twice the average rate of substance abuse. But some prior characteristics — social class, for example — might have raised the risk both for going untreated and for later drug problems. It may always be difficult to tell because today it is not considered ethical to give children with ADHD a placebo for research purposes.

Stimulant formulas

In the form of ordinary (“immediate release”) pills, the effects of dextroamphetamine and methylphenidate last no more than a few hours, and must be taken several times a day. It’s easy to miss a dose, and taking the drug at school in the middle of the day can involve serious inconvenience or embarrassment. Another problem is that symptoms may subside when the drug is passing into the brain and return as the effect wears off before the next dose.

These problems have increased the popularity of longer-acting stimulant products that are taken only once a day. The most commonly prescribed medication for ADHD today is Concerta, the brand name for a version of methylphenidate consisting of coated beads that dissolve at different rates, providing a steady response that lasts for up to 12 hours. Adderall XR (extended release), a combination of dextroamphetamine and its inactive left-handed variant levamphetamine, is also designed to last for 12 hours.

Metadate CD (controlled delivery) and Ritalin LA (long acting), taken once a day, work like a standard dose of methylphenidate taken twice a day. They are capsules that can be opened and sprinkled on food for young children who have difficulty swallowing pills. These formulas are not quite as long lasting as Concerta and may be useful for children who need drug treatment only during the school day.

A right-handed form of methylphenidate (excluding the inactive left-handed form of the molecule) is available under the brand name Focalin, and a longer-acting version is being developed. This allows the use of a lower dose, and although there is no proof, it might have fewer side effects.

All these products are variations on the same theme, but some patients may respond well to one and not to another. It’s a matter of trial and error; there’s no way to tell in advance which drug will work or whether stimulants will be effective at all. In one study, few characteristics of children with ADHD or their families accurately predicted a good response to stimulants. The only clear finding was that the symptoms of a child with a depressed parent were less likely to improve.

Other choices

A growing number of alternative medications are available for parents who are reluctant to let children take stimulants, for the 20%–30% of children who do not respond to stimulants, and for adults who may be at risk for drug abuse.

Atomoxetine (Strattera) is the first drug approved by the FDA for attentio n deficit disorder in adults. It acts on receptors and transporters for norepinephrine, a neurotransmitter closely related to dopamine. It’s about as effective as stimulants and not addictive, but the therapeutic response, which is almost immediate with stimulants, may take several weeks to appear.

Atomoxetine is taken once a day, and the side effects are minor, chiefly moderate appetite loss, headache, stomachache, and nausea. Other drugs, including selective serotonin reuptake inhibitors, may increase the blood level of atomoxetine and intensify its effect by competing for the attention of liver enzymes that metabolize it. A clinical trial directly comparing atomoxetine and methylphenidate is now in progress (2004).

Antidepressants are occasionally used in the treatment of ADHD. The tricyclic antidepressants imipramine (Tofranil) and desipramine (Norpramin and others) have been available for decades and are found effective in some studies, but the side effects limit their use. One study found that in adults with both depression and attention deficit disorder, the antidepressant venlafaxine (Effexor), which prevents the reabsorption of both norepinephrine and serotonin, was as effective as a stimulant combined with a tricyclic antidepressant. In another study, the norepinephrine and dopamine reuptake inhibitor bupropion (Wellbutrin) was more effective than a placebo in adolescents and children with ADHD. In preliminary research, it was also found to be useful for adults with both bipolar disorder and attention deficit disorder.

Clonidine is a drug used mainly to treat high blood pressure that also has modest effects on attention deficit disorder. Its main side effects are fatigue and drowsiness. Guanfacine, a similar drug, is longer acting and may have fewer side effects.

Modafinil (Provigil) is used in the treatment of narcolepsy, a disorder that involves sudden attacks of daytime sleepiness. In one controlled study, it has been found more effective than a placebo but not as effective as stimulants in patients with ADHD. Its most common side effects are nausea and appetite loss.

A few small studies suggest that galantamine (Reminyl) and donepezil (Aricept) may have some value in ADHD. These drugs interfere with the breakdown of the neurotransmitter acetylcholine; today they are used chiefly in the treatment of Alzheimer’s disease.

Psychosocial treatments

Results of the Multimodal Treatment Study, a large clinical trial sponsored by the National Institute of Mental Health and completed several years ago, were discouraging for advocates of alternatives to drugs. In that study, adding education, behavioral management, and parent training did not improve on the effects of stimulants. But clinicians and researchers have not given up. Medications don’t work for everyone, and a high dropout rate in drug treatment may reflect dissatisfaction that could be reduced by offering further help. Besides, these children often have many problems in addition to attention deficit disorder. In one estimate, 65% suffer from other psychiatric disorders, including conduct disorder, anxiety, depression, and (often unrecognized) bipolar disorder.

Experts recommend special school report cards, coaching, classroom behavior management, and tokens to reward good behavior. A behavioral program includes weekly training sessions in which families learn how to reward good and ignore bad behavior in school and at home, how to give brief effective commands, and how to use these methods outside the home, for example, by reviewing rules before going into public places. Parents also learn problem-solving techniques and ways to communicate better with their children.

In a study published in 2001, this program was compared with problem-solving and communication training alone for adolescents with ADHD. Improvement was the same in both groups, but the more intensive program had fewer dropouts.

Adults with ADHD

As more children are diagnosed with ADHD, more parents recognize similar symptoms in themselves (see Mental Health Letter, November 2002). But a national survey found that family doctors are reluctant to diagnose the disorder in adults because they believe they have inadequate training and experience. Now there are several screening tests, including the Adult Self-Report Scale, an 18-item questionnaire developed at New York University and Harvard Medical School which takes five minutes to complete (see Resources).

Screening is only a start. Most adults who suspect they have ADHD do not. The diagnosis requires a clinical interview and, especially, evidence of attention deficit or hyperactivity in childhood. Studies show that memory is an unreliable guide. Adults who think they have attention deficit disorder are more likely to recall their childhoods as troubled. For confirmation, they need school records and other objective data.

Peddling attention deficit disorder?

Concern persists that both the diagnosis of ADHD and stimulant treatment are being overused. Many of the symptoms resemble other disorders or could have other causes. Critics continue to suggest that physicians and mental health professionals are medicalizing a problem that might be caused by inattentive parents, incompetent teachers, poorly organized schools, or intolerance of boyish high spirits. They point to national and regional variations. The vast majority of ADHD diagnoses are given in the United States, and within this country, according to a 1999 survey, the rates vary from 1.6% of school-age children in San Juan, Puerto Rico, to 9.4% in Atlanta.

Critics have also suggested that the diagnosis is being tailored to fit the treatment. They note that the United States uses 80% of the world’s prescription stimulants. They fear that pharmaceutical companies are peddling pills for profit and that the current system of managed medical care does not enable mental health professionals to undertake more expensive and labor-intensive services for troubled children. Moves have been made at state and federal levels to limit the right of teachers and other school personnel to recommend a diagnosis of ADHD or to insist on medication as a requirement for remaining in a regular classroom.

Both the number of cases diagnosed and the number of pills prescribed have certainly been rising. Because the federal government has recognized ADHD as a disability that confers eligibility for special educational services, schools are undertaking more screening and evaluation of children for the disorder. A study of Medicaid recipients in North Carolina found that between 1992 and 1998, the proportion of children age 6–14 receiving stimulants rose from 4% to nearly 10%. According to one estimate, about 1% of preschool children are now taking stimulants.

But some believe ADHD is still being diagnosed and treated too little rather than too much. According to a survey released in September 2000, physicians think that as many as half of cases are unrecognized. There’s evidence that poor and black children and those who lack private insurance or Medicaid are less likely to receive the diagnosis. In a national survey reported in 2001, nearly 90% of the parents of children diagnosed with ADHD said drugs had been recommended, but only 55% of the children were still taking them.

Prospects

The conflicting findings on the risk of addiction show a need for further research. The large regional, national, racial, and class variations in the rate of diagnosis and drug treatment suggest a need for a better understanding of the processes by which the disorder is identified and treatments are chosen.

ADHD is probably not one, but rather a group of disorders, and particular genetic types may respond to different drugs or psychosocial treatments (see “Pharmacogenomics in Psychiatry,” Mental Health Letter, January 2004). Scientists may gain more insight into the specific causes and variant forms of ADHD by experimenting with different tasks in different social environments. More sensitive brain imaging may help reveal which treatments are working for which patients. Such progress would help to accomplish the urgent task of further dispelling doubts about the reality of ADHD, while clarifying its definition and limits.