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In a small,
placebo-controlled clinical trial, Johns Hopkins physicians report that
the antidepressant paroxetine modestly improves decision-making and
reaction time, and suppresses inflammation in people with HIV-associated
cognitive impairment. The researchers say they believe this is the
first time that a SSRI (selective serotonin reuptake inhibitor) has been
shown to improve key measures of cognition in people with HIV in a
controlled study.
The
researchers note that many patients with HIV-associated neurocognitive
disorders may already be benefiting cognitively by taking SSRIs in the
dosages used in their study to treat depression, but the new study lends
more rigorous scientific support to the drug’s value.
The Johns
Hopkins researchers are expected to present their findings Feb. 25 at
the Conference on Retroviruses and Opportunistic Infections in Boston.
“Over a
period of 20 years and after 10 clinical trials, this is the first time
we’ve been able to clearly demonstrate benefit in a summary measure of
cognitive performance for patients with HIV-associated neurocognitive
disorders,” says lead author Ned Sacktor, M.D., professor of neurology
at the Johns Hopkins University School of Medicine.
HIV-associated
neurocognitive disorders occur when infection with the virus that
causes AIDS triggers nerve-damaging inflammation in the brain, leading
to problems with learning, memory, decision-making and motor
coordination. Up to 50 percent of people with HIV taking a cocktail of
antiretroviral drugs are estimated to suffer from cognitive impairment,
the researchers say.
In a search
for a drug to safely blunt inflammation and reverse impairment, the
investigators chose to test two drugs that looked promising based on
earlier data published in 2014 by co-author Joseph Steiner, Ph.D., an
adjunct associate professor of neurology.
Steiner had
tested Food and Drug Administration-approved drugs paroxetine and the
antifungal fluconazole, and showed that they protect neurons from death
in laboratory cultures of rat nerve cells. Both drugs also cross the
blood-brain barrier.
“There is a
huge advantage to incorporating FDA-approved drugs into a clinical trial
rather than developing whole new ones,” says senior author Justin
McArthur, M.B.B.S., M.P.H., professor and director of the Department of
Neurology. “It’s quicker, cheaper and very unlikely that there will be
any surprises or any untoward side effects because the drug has been
given to tens of thousands of people already.”
The
physicians enrolled 45 patients with HIV and cognitive impairment in a
24-week trial. Study participants couldn’t have taken an SSRI within a
month of the study’s start. Participants received either 20 milligrams
per day of paroxetine, 100 milligrams twice a day of fluconazole, the
same doses of both paroxetine and fluconazole, or placebo drugs. In this
study, both drugs were shown to be safe in combination with
antiretroviral treatment regimens.
The team
used eight neuropsychological tests to measure and evaluate psychomotor
and motor speed performance and decision-making. The NPZ8 score, as it’s
called, comes from averaging the eight test results and evaluating this
number using a statistical test that compares HIV positive patient test
scores to HIV negative scores. The numerical score represents the
standard deviation from the mean. Patients given paroxetine alone or in
combination with fluconazole improved their NPZ8 test scores by an
average of 0.15. Those not taking paroxetine showed a deterioration of
their score by -0.33 on this same measure of cognitive performance.
At the start
of the trial and after 24 weeks of drug treatment, patients were also
assessed on reaction times using the California Computerized Assessment
Package (CalCAP) test, which asks participants to complete tasks like
pressing a button when they see a number on the screen.
Patients
taking paroxetine improved test scores on a subset of the CalCAP test by
a 0.5 increase over the baseline measurement, but those not taking
paroxetine showed essentially no improvement, with only a 0.06 change in
score.
To learn if
either or none of the drug treatments reduced levels of inflammatory
proteins in the patients — a measure of inflammation — the physicians
took blood samples from the patients at the start of the study and at 24
weeks after drug treatment. They measured the level of CD163, which is
known to be higher than average in patients with HIV-associated
neurocognitive disorders and an indicator of inflammation. Before
treatment, patients with HIV had an average of 802 nanograms per
milliliter of CD163 protein in the blood, but after treatment with
paroxetine, the average level dropped to 738 nanograms per milliliter.
Patients not given paroxetine saw their CD163 levels rise by an average
of almost 400 nanograms per milliliter over the 24 weeks.
“By reducing
inflammation, we hoped to have the added benefit of improving
cognition, and our results show that to be the case,” says Sacktor.
Because the
team found no cognitive improvements with fluconazole alone, Sacktor
says his work may now focus on larger studies using paroxetine alone.
Paroxetine
treatment typically costs less than $15 a month. Some study participants
reported side effects typical of SSRIs after taking paroxetine,
including sexual dysfunction (three patients), headache (two patients),
insomnia (two patients) or vivid dreams (two patients). SSRI therapies
for depression or anxiety don’t always work for everyone, and people do
discontinue using these drugs because of unwanted side effects.
Researchers do not yet know the precise mechanism by which an SSRI may improve cognitive impairment.
Source : neurosciencenews.com
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