PET, SPECT Studies Find More Evidence of Dopamine's Role in ADHD

June 24, 2003

Larry Schuster

June 24, 2003 (New Orleans) — Studies using positron emission tomography (PET) and other approaches suggest new details about the underlying biology of attention deficit-hyperactivity disorder (ADHD).

Released here at the 50th annual meeting of the Society of Nuclear Medicine, the studies offer new evidence of the role played by methylphenidate (Ritalin) in modifying behavior, and at least one laboratory test shows promise as a diagnostic to objectively diagnose ADHD.

Two of the reports were presented by Nora D. Volkow, MD, principal investigator of the studies. and director the National Institute on Drug Abuse (NIDA). The work was done earlier while she was at Brookhaven National Laboratory, and the research was supported by the Department of Energy and the NIDA.

In the first study, Dr. Volkow and colleagues demonstrated for the first time that methylphenidate increases the interest that a task elicits, and that interest may be one of the reasons why the drug improves performance in people with ADHD. The increase in the interest for the tasks seen with methylphenidate were associated with the ability of methylphenidate to increase dopamine in the brain, Dr. Volkow told Medscape. The study was performed in healthy subjects who did not have ADHD.

To determine how much dopamine is released by brain cells while the subjects were performing challenging mathematical tasks, the subjects underwent PET while performing those tasks. These scans were compared with those of a neutral task such as looking at pictures of scenery.

To measure changes in extracellular dopamine in striatum, 14 healthy subjects (12 men and two women; mean age, 35 ± 9 years) underwent PET four times using [ 11C]raclopride: (1) with methylphenidate while performing a challenging task, (2) with methylphenidate during a neutral task, (3) with placebo while performing a challenging task, (4) with placebo during a neutral task.

Neither methylphenidate when coupled with a neutral task nor placebo when coupled with a challenging task increased extracellular dopamine in the brain. In contrast, methylphenidate when coupled with the challenging task increased extracellular dopamine in caudate (6% ± 8%; P < .02) and in putamen (6% ± 9%; PM < .03). Dopamine increases were correlated with increases in the description of the stimulus as interesting, motivating, and exciting (r > 0.57; P < .05) and with decreases in tiredness (r = -0.54; P < .05).

"[Methylphenidate] enhances the interest for an academic task — a simple, simple finding, but nobody has documented it," Dr. Volkow told Medscape.

The research suggested that interest or excitement in a task or subject is also a factor in improved performance.

For example, Dr. Volkow said, using herself as an example, "If something is extremely interesting, I don't need coffee. Wouldn't we also try to get the schoolwork [to be] more interesting such that they can improve performance?"

In a press briefing, Peter Herscovitch, MD, chief of the Positron Emission Tomography Imaging Section at the National Institutes of Health (NIH) and senior staff physician at the NIH clinical center, said that the study "provides a potential mechanism for how [methylphenidate] works in the clinical environment." The researchers "conclude that [methylphenidate] increases dopamine, a neurotransmitter that's involved in reward and motivation, but only when the subjects are performing a behaviorally relevant or salient task, a challenging, mathematical task. And this was a particularly intriguing observation," Dr. Herscovitch.

In a second study, Dr. Volkow and colleagues showed that adult ADHD subjects release less dopamine in the brain than normal subjects do.

They compared the changes of dopamine release in response to methylphenidate in seven-never medicated adults with ADHD (31 ± 7 years) and seven control patients (26 ± 5 years). Each patients was scanned with PET using [ 11C]raclopride. In addition, dopamine transporter (DAT) levels were measured using [ 11C]cocaine.

The researchers found that methylphenidate-induced dopamine changes were larger in controls (23% ± 11%) than in ADHD subjects (12% ± 9%) ( P = .06). At baseline, DAT levels were significantly lower in subjects with ADHD ( P = .004). Correlation analysis between baseline measures of DAT levels and the dopamine changes induced by methylphenidate showed a trend for a negative correlation in ADHD (r = -0.66; P = .10) but not in controls (r = 0.08; P = .88). The lower the DAT levels in subjects with ADHD, the larger the DAT changes induced by methylphenidate.

"This is the first demonstration of decreased dopamine release [in ADHD patients], but there have been other studies providing evidence of an involvement of dopamine in ADHD," Dr. Volkow told Medscape. "However, in those studies it was unclear whether the changes reported would translate into changes in brain dopamine concentration."

In a third study presented at the meeting, researchers used single-photon emission computed tomography (SPECT) with I-123 altropane to image dopamine transporters as a potential diagnostic tool for ADHD. I-123 altropane binds to dopamine transporters in the basal ganglia section of the brain, which removes dopamine from the synapses between the cells.

The researchers, from Harbor-UCLA Medical Center, compared the binding in eight ADHD drug-naïve subjects with that in five age-matched control patients, aged 18 to 29 years. Classification was made using standard testing and interviews by psychologists and neurologists with special expertise in ADHD.

After image acquisition, the images were added together to permit selection of the levels best showing the basal ganglia. The images were processed using a low pass filter and attenuation correction. They drew regions of interest around the caudate and putamen as well as both together (BG) by visual inspection. For background, they drew one region over the occipital cortex (OCC).

Specific binding ratio at the time of peak uptake was calculated as: Ratio = (BG - OCC) ÷ OCC.

They found that the binding ratio of I-123 altropane to dopamine transporters was significantly higher in ADHD patients than in normal patients.

Principal investigator Fred Mishkin, MD, said that the trial is part of an ongoing study involving several centers, all sponsored by Boston Life Sciences, the maker of altropane. The UCLA group plans to continue with 30 patients.

"The results are still tentative," Dr. Mishkin said. "They need to be substantiated by further data, [but] they suggest this may be an objective way of confirming the clinical diagnosis." Right now, the diagnosis is based on expertise, which varies widely in ability to distinguish ADHD from normally active children, he said.

A new test such as this "certainly should be useful," Dr. Mishkin said. But more study is needed, he said.

In the press briefing, Dr. Herscovitch said, "The important observation was an increase in the dopamine transporter [levels] in the patients with ADHD, and similar findings were reported by other groups."

"This provides further evidence for abnormalities in the dopamine system in [ADHD]..... This observation is not necessarily conclusive, and this is an area of ongoing research. Other investigators have found somewhat different results," Dr. Herscovitch said. "Increasingly, there are observations to show that ADHD is a definite disease or abnormality of the brain with a specific underlying neurobiology."

SNM 50th Annual Meeting: Abstracts 117, presented June 22, 2003; abstracts 216 and 1544, presented June 23, 2003.

Reviewed by Gary D. Vogin, MD

Larry Schuster is a freelance writer for Medscape.

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