http://www.technologyreview.com/Biotech/19156/

Tuesday, August 07, 2007
Why Ketamine Helps Fight Depression

Studying the club drug could bring about faster-acting and
more-effective treatments.

By Emily Singer

Last year, neuroscientists at the National Institute of Mental Health
(NIMH) made headlines with a surprising result. They found that a single
dose of ketamine--an anesthetic and club drug known as special K--could
relieve depression in some patients in a matter of hours, rather than in
the six or more weeks it typically takes for existing antidepressants to
kick in. What's more, the drug was successful in a group that is usually
extremely difficult to treat: patients who had failed to find relief
after trying multiple antidepressant medications.

Because of its hallucinogenic side effects, ketamine is unlikely to
become a widely used antidepressant. But now researchers think they have
discovered how ketamine exerts its fast-acting effect. Several
pharmaceutical companies are already developing compounds that target
this mechanism, one of which will be tested at the NIMH within the next
few months.

"In studying ketamine's effects, we may be heading down a path that
leads us to treatments that might help the large numbers of depressed
people who remain symptomatic despite available antidepressant
treatments," says John Krystal, a neuroscientist at Yale University who
also studies ketamine.

Ketamine is an anesthetic approved by the Food and Drug Administration.
It is also widely abused because it produces hallucinations and can
trigger an out-of-body experience at higher doses. By understanding the
mechanism underlying ketamine's antidepressant qualities, scientists
hope to be able to develop novel compounds that mimic the beneficial
effects without the accompanying hallucinations.

In the brain, ketamine blocks a receptor known as the NMDA receptor,
which plays a key role in brain signaling. But according to a new study
by Husseini Manji, Carlos Zarate, and their colleagues at NIMH, that's
just one part of the drug's biochemical influence. Blocking this
receptor actually boosts the activity of another receptor, known as the
AMPA receptor. This boost appears to be crucial for the drug's
antidepressant effects: when the researchers blocked the AMPA receptors
before administering ketamine to mice, the drug no longer stopped
depressive behavior in an animal model of the disease. The findings were
published last month in the journal Biological Psychiatry.

The findings add to a growing body of evidence showing that compounds
that trigger AMPA receptors eliminate depressive behavior in animal
models of the disorder. While no such compounds have been tested yet in
clinical trials for depression, several companies are developing
molecules that target AMPA receptors for disorders including
schizophrenia, Alzheimer's disease, and attention deficit/hyperactivity
disorder (ADHD) and trials for Alzheimer's and ADHD are underway. Zarate
and his colleagues are now planning a clinical trial of one such
compound for depression.

While scientists don't yet know exactly how ketamine works so quickly
against depression or why it seems to be effective in a broader group of
patients than currently available antidepressants are, they hypothesize
that it boosts production of an important growth factor in the brain
known as brain-derived neurotrophic factor. Popular antidepressants,
such as Prozac, also boost this growth factor, but only after a complex
series of chemical reactions. AMPA activation may circumvent this
process, acting much more quickly.

Directly targeting AMPA receptors may also bypass the drug's psychotic
side effects, says Jeff Witkin, a neuroscientist at Lilly Research Labs,
in Indianapolis. That's because the hallucinatory component of
ketamine's effects is driven specifically by NMDA receptors, rather than
by AMPA receptors.

"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," said NIMH director Thomas R. Insel in a statement
released by NIMH. "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."