|Faster-Acting Antidepressants Closer to Becoming
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
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
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
“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
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.