A new drug works through the same brain mechanism as
the fast-acting antidepressant ketamine: it briefly
improved treatment-resistant patients' depression
symptoms in minutes, with minimal untoward side
effects, in a clinical trial conducted by the
National Institutes of Health. The experimental
agent, called AZD6765, acts through the brain's
glutamate chemical messenger system.
Existing antidepressants available through
prescription, which work through the brainís
serotonin system, take a few weeks to work,
imperiling severely depressed patients, who can be
at high risk for suicide.
Ketamine also works in hours, but its usefulness is
limited by its potential for dissociative
side-effects, including hallucinations.
It is being studied mostly for clues to how it
"Our findings serve as a proof of concept that we
can tap into an important component of the glutamate
pathway to develop a new generation of safe,
rapid-acting practical treatments for depression,"
said Carlos Zarate, M.D., of the NIHís National
Institute of Mental Health, which conducted the
AZD6765, like ketamine, works by blocking glutamate
binding to a protein on the surface of neurons,
called the NMDA receptor.
It is a less powerful blocker of the NMDA receptor,
which may be a reason why it is better tolerated
About 32 percent of 22 treatment-resistant depressed
patients infused with ASD6765 showed a clinically
meaningful antidepressant response at 80 minutes
after infusion that lasted for about half an hour ó
with residual antidepressant effects lasting two
days for some.
By contrast, 52 percent of patients receiving
ketamine show a comparable response, with effects
still detectable at seven days.
So a single infusion of ketamine produces more
robust and sustained improvement, but most patients
continue to experience some symptoms with both
However, depression rating scores were significantly
better among patients who received AZD6765 than in
those who received placebos.
The researchers deemed this noteworthy, since, on
average, these patients had failed to improve in
seven past antidepressant trials, and nearly half
failed to respond to electroconvulsive therapy (ECT).
The patients reported only minor side effects, such
as dizziness and nausea, which were not
significantly different from those experienced with
Zarate and colleagues say their results warrant
further trials with AZD6765, testing whether
repeated infusions a few times per week or higher
doses might produce longer-lasting results.
Zarate, and colleagues, reported on their results
online Dec. 1, 2012 in the journal Biological
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