Scientific American Mind-June/July 2007

( This is not the fi rst time ketamine has been shown )
to be a powerful antidepressant.
hallucinations, delusions and euphoria.
Nevertheless, these psychedelic properties,
though experienced by many of the
depressed patients in the studies, appear
to be independent of the antidepressant
effect. The mind-altering effects
occur within minutes and last for
less than two hours, whereas the antidepressant
benefi ts begin as the psychedelic
effects start to subside and persist
far longer. Robert Berman of Yale University,
co-author of the 2000 report,
notes that in his study the depressed patient
who showed the most dramatic
antidepressant response with ketamine
experienced no ketamine-related psychotic
symptoms. These observations
suggest that it should be possible to design
drugs that have ketamine’s ability
to alleviate depressive symptoms without
any psychedelic side effects.
A New Understanding
Although the more recent report
about ketamine has garnered attention,
Berman’s report was largely ignored.
Berman suspects that the idea
that a drug that blocks NMDA receptors
could be an antidepressant seems
more plausible now than it did seven
years ago. That rise in acceptability is
because the hypothesis that has dominated
depression research and drug
development for the past 40 years—
that depression involves a defi ciency of
the neurotransmitter serotonin or norepinephrine—is
beginning to lose its
grip. Several lines of evidence point to
a key role of the NMDA glutamate receptor
in the action of antidepressants:
NMDA receptor blockers have antidepressant
effects in animal models of
depression; almost all antidepressants
that are given for weeks or more modify
NMDA receptor function in a time
frame consistent with their delayed
therapeutic effects; and antidepressants
alter the activity of genes that encode
the protein components of
NMDA receptors.
Notwithstanding the signifi cance
of the ketamine findings, Berman
strikes some cautionary notes. Because
of the psychedelic symptoms,
patients and investigators in the 2000
and 2006 studies could often distinguish
between ketamine and placebo.
Depression is known to be responsive
to expectation, so the obvious side effects
of ketamine might well have biased
the results in favor of a treatment
effect for this drug.
On the other hand, Berman says
that in his study he had intended to assess
the cognitive effects of ketamine,
not to examine its antidepressant properties.
Its therapeutic pluses, he says,
were a surprise. And the depressed patients
in the recent study were resistant
to treatment—they had not improved
with at least two previous courses of
antidepressant treatment. Such patients
typically have a low rate of response
to both further antidepressant
treatment and placebo, and yet, encouragingly,
71 percent showed substantial
improvement with in one day
of the ketamine infusion. Thus, although
it is not out of the ques tion that
the profound antidepressant response
to ketamine was a placebo effect, it is
unlikely.
Zarate points out that the glutamate
system’s probable role in the action
of antidepressants does not necessarily
implicate it in the causes or physiological
underpinnings of depression.
(Further Reading)
The little available data bearing on the
link between depression and the glutamate
system—one study showed that
depressed patients have elevated levels
of glutamate in one area of the brain—
are, so far, less than convincing. To
fi gure out how ketamine may alleviate
depression, Zarate and his colleagues
are using brain-imaging techniques
and searching for other promising antidepressant
drugs that block the
NMDA receptor.
But simply fi ddling with the NMDA
receptor or glutamate does not bring
immediate depression relief. Zarate’s
team found that memantine, an NMDA
receptor drug used to treat Alzheimer’s
disease, does not relieve depression.
Similarly, riluzole, which inhibits glutamate
release (and, therefore, may
cause similar effects to those of blocking
glutamate’s receptor) and is used
for amyotrophic lateral sclerosis (ALS),
or Lou Gehrig’s disease, does improve
depression but with the same time delay
as conventional antidepressants.
Zarate and his co-workers are about to
launch a study of a substance that
blocks one of the subunits (NR2B) of
the NMDA receptor. They hope that it
will retain ketamine’s antidepressant
potency without triggering perceptual
disturbances. M
WALTER BROWN is clinical professor of
psychiatry at Brown Medical School and the
Tufts University School of Medicine.
◆ Antidepressant Effects of Ketamine in Depressed Patients. Robert M. Berman, Angela
Cappiello, Amit Anand, Dan A. Oren, George R. Heninger, Dennis S. Charney and John H.
Krystal in Biological Psychiatry, Vol. 47, No. 4, pages 351–354; February 15, 2000.
◆ Small-Dose Ketamine Improves the Postoperative State of Depressed Patients. Akira
Kudoh, Yoko Takahira, Hiroshi Katagai and Tomoko Takazawa in Anesthesia and Analgesia,
Vol. 95, pages 114–118; July 2002.
◆ Subtype-Specifi c Alterations of -Aminobutyric Acid and Glutamate in Patients with
Major Depression. Gerard Sanacora et al. in Archives of General Psychiatry, Vol. 61, No.
7, pages 705–713; July 2004.
◆ A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant
Major Depression. Carlos A. Zarate et al. in Archives of General Psychiatry, Vol. 63, No.
8, pages 856–864; August 2006.
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