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Ketamine lifts depression via a byproduct of its metabolism (2016-05-12)
A chemical byproduct, or metabolite, created as the
body breaks down ketamine likely holds the secret to
its rapid antidepressant action, National Institutes
of Health (NIH) scientists and grantees have
discovered. This metabolite singularly reversed
depression-like behaviors in mice without triggering
any of the anesthetic, dissociative, or addictive
side effects associated with ketamine.
“This discovery fundamentally changes our
understanding of how this rapid antidepressant
mechanism works and holds promise for development of
more robust and safer treatments,” said Carlos
Zarate, M.D. of the NIH’s National Institute of
Mental Health (NIMH), a study co-author and a
pioneer of research using ketamine to treat
depression. “By using a team approach, researchers
were able to reverse-engineer ketamine’s workings
from the clinic to the lab to pinpoint what makes it
NIMH grantee Todd Gould, M.D. (link is external), of
the University of Maryland School of Medicine, in
collaboration with Zarate and other colleagues,
report on their findings May 4, 2016 in the journal
Nature. The team also included researchers at the
NIH’s National Center for Advancing Translational
Sciences (NCATS) and National Institute on Aging
(NIA), and the University of North Carolina.
“Now that we know that ketamine’s antidepressant
actions in mice are due to a metabolite, not
ketamine itself, the next steps are to confirm that
it works similarly in humans, and determine if it
can lead to improved therapeutics for patients,”
Clinical trials by Zarate and others have shown that
ketamine can lift depression in hours, or even
minutes — much faster than the most commonly used
antidepressant medications now available, which
often require weeks to take effect. Further, the
antidepressant effects of a single dose can last for
a week or longer. However, despite legitimate
medical uses, ketamine also has dissociative,
euphoric, and addictive properties, making it a
potential drug of abuse and limiting its usefulness
as a depression medication.
In hopes of finding leads to a more practical
treatment, the research team sought to pinpoint the
exact mechanism by which ketamine relieves
depression. Ketamine belongs to a class of drugs
that block cellular receptors for glutamate, the
brain’s chief excitatory chemical messenger. Until
now, the prevailing view was that ketamine produced
its antidepressant effects by blocking
N-methyl-D-aspartic acid (NMDA) glutamate receptors.
However, human trials of other NMDA-receptor
blockers failed to produce ketamine’s robust and
sustained antidepressant effects. So the team
explored the effects of ketamine on
antidepressant-responsive behaviors in mice.
Ketamine harbors two chemical forms that are mirror
images of each other, denoted (S)- and (R)-ketamine.
The investigators found that while (S)-ketamine is
more potent at blocking NMDA receptors, it is less
effective in reducing depression-like behaviors than
the (R) form.
The team then looked at the effects of the
metabolites created as the body breaks down (S)- and
(R)-ketamine. It was known that ketamine’s
antidepressant effects are greater in female mice.
NIA researchers Irving Wainer, Ph.D., and Ruin
Moaddel, Ph.D. identified a key metabolite
(2S,6S;2R,6R)-HNK (hydroxynorketamine) and showed
that it is pharmacologically active.
The team then discovered that levels of this
metabolite were three times higher in female mice,
hinting that it might be responsible for the sex
difference in the antidepressant-like effect. To
find out, the researchers chemically blocked the
metabolism of ketamine. This prevented formation of
the metabolite, which blocked the drug’s
Like ketamine, this metabolite includes two forms
that mirror each other. By testing both forms, they
found that one – (2R,6R)-HNK – had
antidepressant-like effects similar to ketamine,
lasting for at least three days in mice. Notably,
unlike ketamine, the compound does not inhibit NMDA
receptors. It instead activates, possibly
indirectly, another type of glutamate receptor,
acid (AMPA). Blocking AMPA receptors prevented the
antidepressant-like effects of (2R,6R)-HNK in mice.
The experiments confirmed that the rapid
antidepressant-like effects require activation of
AMPA receptors, not inhibition of NMDA receptors.
Ketamine also has effects in mice that mimic its
dissociative, euphoric effects in humans and
underlie its abuse and addictive potential; however,
these effects were not observed with (2R,6R)-HNK.
(2R,6R)-HNK did not cause the changes in physical
activity, sensory processing, and coordination in
mice that occur with ketamine. In an experimental
situation where mice were able to self-administer
medication, they did so with ketamine but not the
(2R,6R)-HNK metabolite, indicating that (2R, 6R)-HNK
is not addictive.
“Working in collaboration with NIH and academic
researchers, NCATS chemists played a critical role
in isolating the specific metabolite of ketamine
responsible for fighting depression,” said
Christopher P. Austin, M.D., NCATS director.
“Overall, our collective efforts exemplify how a
collaborative, team science approach can help
advance the translational process in ways that help
get more treatments to more patients more quickly.”
“Unraveling the mechanism mediating ketamine’s
antidepressant activity is an important step in the
process of drug development,” said Richard J. Hodes,
M.D., NIA director. “New approaches are critical for
the treatment of depression, especially for older
adults and for patients who do not respond to
“Pending confirmation in humans, this line of
studies exemplifies the power of mouse translational
experiments for teasing out brain mechanisms that
hold promise for future treatment breakthroughs,”
added NIMH acting director Bruce Cuthbert, Ph.D.
The researchers are now following up on their
discovery with safety and toxicity studies of the
metabolite as part of a drug development plan in
advance of a NIMH clinical trial in humans for the
treatment of depression.
For more information
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell
J, Elmer GI, Manickavasagom A, Yuan P, Pribut HJ,
Singh NS, Dossou KSS, Fang Y, Huang X-P, Mayo CL,
Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ,
Zarate CA, Gould TD.
NMDA receptor inhibition-independent antidepressant
actions of a ketamine metabolite.
Nature, May 4, 2016, doi: 10:1038/nature17998. Link...
Depression: Ketamine steps out of the darkness Link...
The U.S. National Institute of Mental Health (NIMH)
Highlight: Ketamine: A New (and Faster) Path to
Treating Depression Link...