| Experimental medication ketamine relieves
depression in just hours; points to targets for new medications
A new study has revealed more about how the medication ketamine, when
used experimentally for depression, relieves symptoms of the disorder in
hours instead of the weeks or months it takes for current
antidepressants to work. While ketamine itself probably won’t come into
use as an antidepressant because of its side effects, the new finding
moves scientists considerably closer to understanding how to develop
faster-acting antidepressant medications — among the priorities of the
National Institute of Mental Health (NIMH), part of the National
Institutes of Health.
Ketamine blocks a receptor called NMDA on brain cells, an earlier
NIMH study in humans had shown, but the new study in mice shows that
this is an intermediate step. It turns out that blocking NMDA increases
the activity of another receptor, AMPA, and that this boost in AMPA is
crucial for ketamine’s rapid antidepressant actions. The study was
reported online in Biological Psychiatry on July 23, by NIMH
researchers Husseini K. Manji, MD, Guang Chen, MD, PhD, Carlos Zarate,
MD, and colleagues.
“Our research is showing us how to develop medications that get at
the biological roots of depression. This new finding is a major step
toward learning how to improve treatment for the millions of Americans
with this debilitating disorder; toward eliminating the weeks of
suffering and uncertainty they have to endure while they wait for their
medications to work,” said NIH Director Elias Zerhouni, M.D.
Almost 15 million American adults have a depressive disorder. During
the long wait to begin feeling the effects of conventional medications,
patients may worsen, raising the risk of suicide for some. Depressive
disorders also affect children and adolescents.
By aiming new medications at more direct molecular targets, such as
NMDA or AMPA, scientists may be able to bypass some of the steps through
which current antidepressants indirectly exert their effects — a
roundabout route that accounts for the long time it takes for patients
to begin feeling better with the conventional medications.
While ketamine appears to achieve this, it is an unlikely candidate
to become a new treatment for depression, because of the side effects it
can cause in humans, including hallucinations. It is approved as an
anesthetic by the Food and Drug Administration at much higher doses than
those given in the study, but its use is limited because it may cause
hallucinations during recovery from anesthesia.
Both NMDA and AMPA are receptors for the neurotransmitter glutamate,
one of the chemical messengers that enable brain cells to communicate
with each other. The glutamate system has been implicated in depression
recently, leading to efforts to unravel its molecular machinery in
search of abnormalities and of better targets for antidepressant
medications.
This focus on the glutamate system is a departure from the thinking
that led to currently available antidepressants, which are thought to
relieve depression through a lengthy trickle-down process of biochemical
reactions that affect the circuitry underlying depression.
The fact that NMDA and AMPA receptors are part of the glutamate
system and that targeting them directly led to such rapid, sustained
relief of depression-like behaviors in this study — and that a single
dose of ketamine did the same in humans in the earlier study — suggests
that they are probably the key targets for antidepressant medications.
“In any other illness of depression’s magnitude, patients aren’t
expected to just accept that their treatments won’t start helping them
for weeks or months. The value of our research on compounds like
ketamine is that it tells us where to look for more precise targets for
new kinds of medications that can close the gap,” said NIMH Director
Thomas R. Insel, MD. “We’re making tremendous progress.”
To conduct the new study, researchers induced depression-like
behaviors in mice; for example, the mice gave up after being forced to
engage in hopeless tasks, such as prolonged swimming. A dose of ketamine
reversed the depression-like behaviors for at least two weeks.
When the researchers gave the mice a substance that blocks the AMPA
receptor beforehand, ketamine was not able to reverse the
depression-like behaviors. The boost in AMPA thus appears to be a
necessary ingredient for ketamine’s antidepressant effects.
In a related experiment, the scientists used two different compounds
instead of ketamine to try to block just one part of the NMDA receptor,
an even more precise target. These other compounds also reduced
depressive behaviors, suggesting that it may be feasible to develop
other fast-acting antidepressants without ketamine’s side effects.
“Today’s antidepressant medications eventually end up doing the same
thing, but they go about it the long way around, with a lot of
biochemical steps that take time. Now we’ve shown what the key targets
are and that we can get at them rapidly,” said Zarate. “Ketamine
probably can’t become the medication of choice, but this research is
leading to some very real possibilities for a whole new generation of
antidepressant medications.”
More information about depression and about current medications is
available from NIMH at
http://www.nimh.nih.gov/healthinformation/depressionmenu.cfm and
http://www.nimh.nih.gov/publicat/medicate.cfm#ptdep7.
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research on mind,
brain, and behavior. More information is available at the NIMH website:
http://www.nimh.nih.gov/.
The National Institutes of Health (NIH) — The Nation's Medical
Research Agency — includes 27 Institutes and Centers and is a
component of the U.S. Department of Health and Human Services. It is the
primary federal agency for conducting and supporting basic, clinical and
translational medical research, and it investigates the causes,
treatments, and cures for both common and rare diseases. For more
information about NIH and its programs, visit
www.nih.gov.
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