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Antidepressant modestly improves HIV-related cognitive impairment
Liz Highleyman, 2016-03-31 07:50:00
The SSRI antidepressant
paroxetine (Paxil) was associated
with modest improvement in cognitive function and reduced central nervous
system inflammation in people with HIV-related neurocognitive disorder, but the
antifungal drug fluconazole showed no apparent benefit even though it reduced
oxidative stress, according to a study presented at the Conference on Retroviruses
and Opportunistic Infections (CROI 2016) last month in Boston.
While advanced HIV dementia is
no longer commonly seen among people receiving effective antiretroviral therapy
(ART), more subtle changes in cognitive function, known as HIV-related neurocognitive disorder or
HAND, is more prevalent. However,
the precise causes of neurocognitive problems – e.g. HIV in the brain, resulting
inflammation, antiretroviral toxicities – and how best to manage them is not
Ned Sacktor of Johns Hopkins University School of Medicine and
colleagues studied the safety and efficacy of paroxetine
and fluconazole, taken alone or together, for the treatment of HAND.
HAND is associated with persistent central nervous system (CNS)
inflammation, macrophage activation and oxidative stress, and adjunctive
therapies that affect these processes may play a role in its management, the researchers
noted as background.
Members of Sacktor’s team previously screened 2000 compounds for neuro-protective
effects in an in vitro model of oxidative stress in rat nerve cells
exposed to neurotoxins including the HIV tat protein. After finding that
paroxetine and fluconazole appeared protective in the laboratory, the drugs
were evaluated in this small clinical trial.
The study enrolled 45 people with HIV, on stable ART
for at least three months, who demonstrated evidence of impairment on at least two
neuropsychological tests. A subset of 24 people with better than 90% adherence
were included in an as-treated analysis.
Three-quarters of the participants were women, most
were black, the median age was approximately 50 years and they had a median 12
years of education. Most had undetectable HIV viral load, median CD4 count was
approximately 500 cells/mm3 and roughly half had hepatitis C virus
co-infection. They had not taken selective serotonin reuptake inhibitors (SSRIs) within the previous month.
Participants in this double-blind trial were randomly
assigned to receive 20mg once-daily oral paroxetine, 100mg twice-daily
fluconazole, the same doses of both drugs, or placebo for 24 weeks.
assessed changes in neuropsychological and motor performance using the ‘NPZ8’
summary measure of eight tests (including trail-making, symbol-digit, reaction
time and timed gait) and the ‘CalCAP’ computerised test of executive function.
Depression was evaluated using the Beck Depression Inventory. They measured
biomarkers of neuronal injury, oxidative stress (including ceramides), macrophage/monocyte
activation (CD163) and inflammation in blood serum and cerebrospinal fluid
Participants in the paroxetine arms – either
alone or in combination with fluconazole – showed a small but significant
improvement in their NPZ8 score, while those taking fluconazole alone or
placebo experienced a decline after adjusting for depression (mean change +0.16
vs -0.33, respectively). Participants taking paroxetine also showed a
significant improvement on the CalCAP sequential reaction time test (mean
change 0.41 vs 0.06, respectively).
People taking fluconazole, however, showed no
improvement and some evidence of worsening on neuropsychological performance
There was no significant difference in
depression symptom changes in the groups taking or not taking paroxetine.
People taking paroxetine showed a decrease in CD163,
indicating reduced inflammation and macrophage activation. Those taking
fluconazole, either alone or with paroxetine, had changes in CSF lipid markers
indicating reduced oxidative stress.
Paroxetine and fluconazole, alone or together,
were generally safe and well-tolerated, with similar overall frequency of
adverse events across the arms.
“Paroxetine treatment may be associated with cognitive
improvement, even after adjusting for depression symptomatology,” the
researchers summarised. “Paroxetine may also be associated with less systematic
macrophage activation. However, the neurocognitive improvement with paroxetine
was not associated with decreases in CSF lipid markers of oxidative stress.”
“Paroxetine is the first adjunctive agent to
demonstrate neurocognitive improvement for a summary measure of neurocognitive
performance in a double-blind, placebo controlled study for the treatment of
HAND and warrants further study,” they concluded. “Fluconazole was not
associated with neurocognitive improvement.”
“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,” Sacktor stated in a press
release issued by Johns Hopkins.