High Dopamine Transporter Levels Not Correlated With ADHD

Results from a brain-imaging study conducted at the U.S. Department of Energy’s Brookhaven National Laboratory in collaboration with Mount Sinai School of Medicine in New York indicate that levels of a brain protein proposed as a diagnostic marker for attention-deficit hyperactivity disorder (ADHD) are not positively correlated with the disease. In fact, the study found lower levels of these “dopamine transporter” proteins in certain brain regions of ADHD patients compared with controls. The study, which will be published in an upcoming issue of the journal Neuroimage and is now available online, also found that for any given level of dopamine transporters in the brain, ADHD patients experienced much higher levels of inattention compared with control subjects.

“These results suggest that dopamine transporter levels alone cannot account for the severity of symptoms of inattention in ADHD,” said Nora Volkow, Director of the National Institute on Drug Abuse and the lead author of the study. Added Gene-Jack Wang, who led Brookhaven’s role in the research, “It is clear from these results that clinical measures of dopamine transporters should not be used as a basis for a diagnosis of ADHD.”

ADHD is the most frequently recognized psychiatric disorder in children, with some 3 million children younger than 18 currently receiving treatment in the U.S. Yet the mechanism underlying this disorder and its treatment are still poorly understood. One prominent theory of ADHD is that there is a dysfunction in brain circuits that depend on the neurotransmitter dopamine to modulate attention, motivation, and interest. If, for example, ADHD subjects have elevated levels of dopamine transporters – proteins on dopamine-producing cells that take up excess dopamine – they could end up with depleted dopamine levels and reduced motivation/attention.

Four independent studies have reported that ADHD subjects have higher than normal levels of dopamine transporters in a brain region called the striatum. But the magnitude of the increase has varied widely, ranging from 70 percent to 5 percent elevations in transporter levels. Two other studies found no elevation of transporter levels, though one found a decrease in dopamine transporter levels in a different brain region.

“Because these discrepancies could reflect differences in medication or drug-abuse histories among subjects, we designed the current study to investigate dopamine transporter levels in ADHD subjects and control subjects while excluding these potentially confounding factors,” Wang said.

The researchers measured dopamine transporter levels in 20 adult ADHD subjects who had never received medication, never abused drugs (except nicotine), and had no past or present history of mental or neurological disease or other medical conditions that could affect cerebral function. They also asked subjects to respond to a questionnaire to gauge levels of inattention. The scientists ran the same tests in 25 healthy control subjects with the same exclusion criteria.

To measure dopamine transporter levels, each subject was given an injection of a radiotracer (a radioactively labeled chemical) designed to bind to dopamine transporters while lying in a positron emission tomography (PET) scanner. The PET camera picks up the radioactive signal from the tracer to precisely measure the level of dopamine transporters.

The PET scans revealed that ADHD subjects had significantly fewer dopamine transporters than control subjects in the nucleus accumbens, an area of the ventral striatum that is one of the main reward centers in the brain. In a dorsal striatum region known as the putamen, which plays an important role in habits and is also involved with attention, dopamine transporter levels did not differ between the two groups.

In both groups, levels of dopamine transporters in the putamen were positively associated with scores of inattention on the self-report questionnaire: the higher the level of transporters, the higher the score of inattention. This finding makes it clear that dopamine transporters play an important role in modulating attention in all people. Yet, for a given level of dopamine transporters, scores of inattention were, on average, five times greater for ADHD subjects than for controls in this study.

“These findings suggest that an additional variable in conjunction with dopamine transporters would be required to account for the severity of the symptoms of inattention in ADHD,” Volkow said. “We speculate that this other variable may be lower levels of dopamine release in ADHD subjects.”

If ADHD subjects release less dopamine to start with, they may end up with lower levels of dopamine transporters as a result of down regulation – that is, the body’s attempt to compensate for lower dopamine levels by reducing the number of reuptake proteins. This would explain the positive correlation between transporter levels and inattention: as the number of reuptake proteins rises, the amount of dopamine would decline, leading to a higher level of inattention. This would also explain why control subjects, with higher dopamine release levels, had lower scores of inattention than did subjects with ADHD with similar levels of dopamine transporters.

Jeffrey Newcorn, a child and adolescent psychiatrist and lead collaborator from Mount Sinai, emphasized that ADHD is not a simple, one-type-fits-all disorder. There are very likely variations in dopamine transporter levels among and even within ADHD subgroups.

“The significant differences across studies and investigators clearly highlight the need to look for factors affecting these inconsistencies to improve our ability to diagnose and treat ADHD,” he said. “Although levels of dopamine transporters alone do not determine whether an individual has ADHD, the association of inattention ratings and transporter levels in both ADHD and normal subjects is consistent with the use of treatments such as stimulant medications, which block activity of the transporter, in ADHD.”

Ongoing research in adults with ADHD, currently being conducted at Brookhaven National Laboratory and Mount Sinai, is investigating the potential long-term impact of treatment with stimulants on the dopamine system.

Is ADHD Properly Diagnosed And Treated In Adults?

An editorial written by Professor Philip Asherson, a leading psychiatrist in adult ADHD (Attention Deficit Hyperactivity Disorder), at the Institute of Psychiatry, King’s College London strongly recommends that general adult psychiatrists should diagnose ADHD in adults appropriately with stimulant drugs. It is published in the January issue of the British Journal of Psychiatry.

Although ADHD can be effectively treated with stimulant medication, and such treatment is widespread in the young, general adult psychiatry has not yet followed suit in identifying and treating substantial numbers of affected people.

ADHD is a common disorder affecting children and adults, and is a predictor of adult mental health problems. Symptoms include high levels of inattentiveness, impulsiveness and restless over activity, and are regarded as a source of disability in children and adolescents, as well as a risk to adult psychological adjustment.

Young people are entering adult life whilst still receiving medication for ADHD, and adult psychiatrists are needed to take over treatment when symptoms persist. Moreover, some adult patients with ADHD may be misdiagnosed and ineffectively treated for other disorders, such as depression and personality disorder.

Research suggests that between 15% and 65% of children diagnosed with ADHD still have symptoms of the disorder in adulthood. However, many children with ADHD go unrecognised, and may be diagnosed in adulthood for the first time.

A survey of schoolchildren with ADHD in the London Borough of Newham found that although levels of restless activity diminished between the ages of 7 and 17, the 17-year-olds showed a level of hyperactivity similar to that found in a group of normal 7-year-olds.

When the same people were followed up at the age of 26, they were found to have disabilities associated with high levels of psychiatric disorder, which were all the more significant because of increasing demands in adult life for self-organisation and the ability to plan ahead.

Adult behaviours linked to ADHD are associated with the childhood symptoms of motor hyperactivity, attention deficit, unfocused thinking, mood changes, disorganisation and impulsiveness.

They include – at the severe end of the spectrum – feelings of restlessness, difficulty in relaxing, feeling depressed when inactive, lack of concentration on detail, depression or excitability, poor time management, difficulties sustaining relationships and a tendency to make rapid and facile decisions without full analysis of the situation.

Psychiatrists diagnosing ADHD in adults need to be aware of the fact that people with this disorder often show decreased symptoms in a novel situation like a psychiatric evaluation. It is therefore important to base mental state evaluations on a typical week and a variety of normal situations.

Mood instability is very common in adult ADHD, and can lead to diagnoses of depression or personality disorder. Many adults with ADHD also have other problems, such as antisocial personality, alcohol and drug misuse, anxiety disorders and learning difficulties. ADHD in childhood may also lead to the development of antisocial behaviour.

Some symptoms of adult ADHD are similar to those of bipolar disorder, but ADHD tends to show a persisting trait of irritability and volatility, very different from the grandiose and euphoric symptoms of mania and the depression found in bipolar disorder.

Professor Philip Asherson comments: “Adults with untreated ADHD use more healthcare resources because of smoking-related disorders, increased rates of serious accidents, and alcohol and drug misuse. Further research is needed to quantify the contribution of ADHD to psychiatric disorders in adulthood.”

Professor Asherson’s editorial is published in the British Journal of Psychiatry, January 2007.

Study Evaluates Two Medications For ADHD

University of Illinois at Chicago researchers are comparing two drugs commonly used to treat attention deficit hyperactivity disorder to determine if genetic factors predict which children will respond to either or both drugs.

Many different medications are used to treat ADHD, including stimulants and non-stimulants, says Dr. Mark Stein, principal investigator of the National Institute of Mental Health-funded study and director of the Hyperactivity, Attention, and Learning Problems Clinic at UIC.

“Unfortunately, clinicians are unable to predict in advance who will respond or not respond to a particular medication,” Stein said.

The study will be conducted in Chicago and New York. Stein and colleagues will enroll 160 children and adolescents between ages 7 and 17 in Chicago. Dr. Jeffrey Newcorn of Mt. Sinai School of Medicine heads the New York site.

Participants will undergo psychiatric evaluations, IQ and achievement tests, a blood test, an electrocardiogram and a physical exam. They will then receive several doses of atomoxetine (a non-stimulant medication), melthylphenidate (a stimulant medication), and a placebo, during a carefully monitored blinded dosing sequence to determine their optimal response to each medication.

During the 12 to 15-week study, researchers will assess the children’s ADHD symptoms, social functioning, problem-solving skills and sleep patterns to determine the efficacy and tolerability of each medication.

Previous research conducted by Stein and colleagues found that children with a variant form of a dopamine transporter gene — a variant known to be associated with ADHD — responded poorly to stimulant medication and had more side effects at lower doses. The new study will test whether patients with this genetic marker respond better to non-stimulant medication.

“At the end of the study we hope to be able to look at a child’s biological characteristics to statistically predict who is more likely to respond to a certain medication and to determine who is more likely not to respond or to have a particular side effect,” Stein said.

“The study provides an idealized standard of care in that the children will be carefully evaluated during their treatment with two different medications, with frequent monitoring that typically does not occur during the normal course of ADHD treatment,” said Stein.

At the end of the trial, participants will be referred back to their primary care provider or given a referral for ongoing treatment with information learned from the study.

Co-investigators at UIC include Drs. Edwin Cook and Elizabeth Charney.

For more information about the study, call (312) 996-2389.

For more information about the Hyperactivity, Attention, and Learning Problems Clinic at the University of Illinois at Chicago, visit http://www.psych.uic.edu/clinical/HALP.htm

University of Illinois at Chicago
601 S. Morgan St. MC 288
Chicago, IL 60607-7113
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http://www.uic.edu/index.html/

Psychologist Helps Children With ADHD Make Friends

Many children with Attention-Deficit/Hyperactivity Disorder suffer through a range of problems, from poor grades to poor relations with parents and teachers. But more than half of these children also have serious problems making friends. Too often they live lonely lives, never learning to develop the social skills they need to make friends as children or as adults.

“Children with ADHD often are peer-rejected, and their difficulties multiply as they grow to adulthood,” said Amori Yee Mikami, assistant professor of psychology and principal investigator for a new clinical study designed to help children with ADHD become better at making friends.

“Children with ADHD often grow up with depression and relationship problems, some may develop criminal behavior and substance abuse problems,” Mikami said. “There can be a spiral of failure that is partly the result of not having learned to make and keep friends as children.”

About 5 percent of school-age children are affected by ADHD. Symptoms include a short attention span, poor organization, excessive talking, disruptive and aggressive behavior, restlessness and irritability. Children with ADHD often are uncooperative and may make their own rules.

“These symptoms get in the way of making and keeping friends,” Mikami said. “The child with ADHD can become stigmatized, known as �€�the bad kid,’ and this can lead to more inappropriate behavior. It can become a vicious cycle resulting in more social isolation.”

Treatment for ADHD usually involves medication and counseling designed to help the children improve their attention spans and control impulses. But little intervention is focused on helping children with ADHD to become better at developing and maintaining good relationships with their peers.

Mikami is working to change that. Through her new “Friendship Clinic,” she is developing new methods to help parents help their children with ADHD improve social skills and develop positive behaviors. So far, the results are promising.

Parents and teachers are reporting that the children with ADHD who have participated in the intervention program are making friends more easily, are better behaved, and more willing to cooperate with peers.

“These skills are not easily taught,” Mikami said. “Making friends is a proactive process that does not come naturally to children with ADHD. We really have to work closely with the parents and children to set the stage for life-long social skills.”

Mikami’s clinic offers children with ADHD and their parents an eight-week program involving weekly 90-minute parent group training sessions, three one-hour supervised playgroups and “homework” assignments designed to put into practice the techniques learned for making friends. The parents learn new skills as a group working with a therapist, helping each other in the process.

“We teach the parents how to be friendship coaches,” Mikami said.

Parents in the program learn ways to help their children play cooperatively, how to settle social disputes, how to foster a relationship than can last. They learn to help the child pick the right playmate, they learn to structure time for positive activities and to intervene in a positive way when problems develop. Several play dates are arranged to allow Mikami and her colleagues to assess the effectiveness of the training, to see the work in practice.

“We help the parents build a relationship with their child,” Mikami said. “We do some role-playing, where the parent steps into the role of the child, to try to understand the world from the child’s point of view.”

One parent who participated in the treatment group, Stephanie Shelton, said her son Brandon and her entire family have benefited from the program.

“I came to know other people who are dealing with the same issues of having a child with ADHD,” she said. “It meant we didn’t have to deal with this alone. We had a focus group that positively helped us work through issues.”

The techniques Shelton learned, such as “active listening,” have made her personal time with her son a rich experience. “We look forward to our time together,” she said. “And his teacher said she has seen a tenfold improvement in his social skills.”

Mikami recently worked with two groups in her study: the “treatment” group, which received training, and a control group of children with ADHD who did not receive training. She is comparing the outcomes of the two groups and is finding that the treatment group children are exhibiting a marked improvement over the ADHD group that did not receive treatment.

The families in the study, from both groups, represent a range of income and education levels and both genders. So far Mikami has worked with 20 families, 10 from each group, and she is planning another phase of the study.

“The idea is to help them when they’re young, so they may have a lifetime of successful relationships, the kind of positive experiences that will carry over into everything they do,” she said.