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| Study Reveals
Differences In Patients' Response To Ritalin
Findings May Explain Variation In Doses Needed
To Treat Attention / Hyperactivity Disorder |
UPTON, NY - A new brain-imaging
study offers insight into why individual patients
respond differently to standard doses of Ritalin,
a drug used to treat millions of children with Attention
Deficit Hyperactivity Disorder (ADHD) each year.
The study, conducted at the U.S. Department of Energy's
Brookhaven National Laboratory, appears in the March
1, 2002 issue of the journal Synapse.
"Methylphenidate [Ritalin]
is very effective for the treatment of ADHD," said
Brookhaven psychiatrist Nora Volkow, lead author
on the study, "but the doses required to achieve
clinical responses vary significantly from patient
to patient. This new study suggests that this variation
may be due, in part, to individual variation in
the release of dopamine, a neurotransmitter associated
with feelings of reward and pleasure."
Volkow's group at Brookhaven
had previously shown that Ritalin exerts its attention-increasing
effects by increasing the amount of dopamine in
brain cell synapses, the space between cells (see:
"New Brookhaven Lab Study Shows How Ritalin Works").
It does this by blocking dopamine transporters,
proteins that normally transport dopamine from the
synapse back into dopamine cells, recycling it for
future use. More dopamine in the synapse yields
a stronger reward signal, and more enjoyment of
and motivation to perform certain tasks.
Volkow hypothesized that
variation in response to Ritalin might be due to
differences in the drug's ability to block the transporters
in individual patients. To test this hypothesis,
the Brookhaven scientists used a technique called
positron emission tomography (PET) to measure dopamine
transporter blockage and extracellular dopamine
in ten healthy adult volunteers before and 60 minutes
after being given a standard dose of Ritalin (60
milligrams).
Transporter blockage and
dopamine levels were measured on different days.
Transporter blockage was measured by injecting each
volunteer with a radioactive label that binds to
available, or free, dopamine transporters. The strength
of the radioactive signal picked up by the PET camera
indicates how many transporters are blocked by Ritalin
(the lower the binding of the radiotracer, the higher
the blockage by Ritalin).
Dopamine levels were measured
by injecting volunteers with a different radioactive
label, one that competes with dopamine in the brain
for binding to receptors. In this case, the lower
the signal from the radioactive label, the higher
the level of dopamine in the synapse.
The findings: The fixed dose
of Ritalin significantly blocked dopamine transporters
and significantly increased extracellular dopamine,
as expected. However, while the magnitude of the
blockade of the dopamine transporters by Ritalin
was similar across subjects, the magnitude of the
increases in dopamine differed markedly between
subjects. As a result, the correlation between Ritalin-induced
dopamine transporter blockade and the increase in
dopamine levels was not significant. In fact, there
were subjects in whom Ritalin blocked significant
numbers of dopamine transporters, but did not increase
extracellular dopamine. So the level of transporter
blockade could not explain the variability in Ritalin-induced
changes in dopamine.
"We interpret this lack of
a correlation as an indication that the dopamine
increases were due not just to dopamine transporter
blockade by Ritalin but to individual variability
in the amount of dopamine released by the dopamine
cells," Volkow said. "This means that, for an equivalent
level of transporter blockage, Ritalin will induce
smaller dopamine changes in a patient with low dopamine
cell activity than in one with high dopamine cell
activity."
"This may explain why some
patients do not respond to Ritalin," Volkow said.
Even if the drug effectively blocks dopamine transporters,
it may not significantly increase extracellular
dopamine if dopamine production is low. This
study, one more step in understanding how Ritalin
works, may help doctors find other ways to treat
patients who do not respond to the drug.
This work was funded by the
U.S. Department of Energy, which supports basic
research in a variety of scientific fields, and
the National Institute on Drug Abuse, a division
of the National Institutes of Health. The U.S. Department
of Energy's Brookhaven National Laboratory conducts
research in the physical, biomedical, and environmental
sciences, as well as in energy technologies. Brookhaven
also builds and operates major facilities available
to university, industrial, and government scientists.
The Laboratory is managed by Brookhaven Science
Associates, a limited liability company founded
by Stony Brook University and Battelle, a nonprofit
applied science and technology organization.
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