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Ed. Note: The following is a press
release from the National Institutes Of Health.
August 7, 2006 -- People
with treatment-resistant depression experienced symptom relief in as little
as two hours with a single intravenous dose of ketamine, a medication
usually used in higher doses as an anesthetic in humans and animals, in a
preliminary study. Current antidepressants routinely take eight weeks or
more to exert their effect in treatment-resistant patients and four to six
weeks in more responsive patients — a major drawback of these medications.
Some participants in this study, who previously had tried an average of six
medications without relief, continued to show benefits over the next seven
days after just a single dose of the experimental treatment, according to
researchers conducting the study at the National Institutes of Health’s
National Institute of Mental Health.
This is among the first studies
of humans to examine the effects of ketamine on depression, a debilitating
illness that affects 14.8 million people in any given year. Used in very low
doses, the medication is important for research, but is unlikely to become a
widely used clinical treatment for depression because of potential side
effects, including hallucinations and euphoria, at higher doses. However,
scientists say this research could point the way toward development of a new
class of faster- and -longer-acting medications. None of the patients in
this study, all of whom received a low dose, had serious side effects. Study
results were published in the August issue of the Archives of General
Psychiatry.
“The public health implications
of being able to treat major depression this quickly would be enormous,”
said NIH Director Elias A. Zerhouni, M.D. “These new findings demonstrate
the importance of developing new classes of antidepressants that are not
simply variations of existing medications.”
For this study 18
treatment-resistant, depressed patients were randomly assigned to receive
either a single intravenous dose of ketamine or a placebo (inactive
compound). Depression improved within one day in 71 percent of all those who
received ketamine, and 29 percent of these patients became nearly
symptom-free within one day. Thirty-five percent of patients who received
ketamine still showed benefits seven days later. Participants receiving a
placebo infusion showed no improvement. One week later, participants were
given the opposite treatment, unless the beneficial effects of the first
treatment were still evident. This “crossover” study design strengthens the
validity of the results.
“To my knowledge, this is the
first report of any medication or other treatment that results in such a
pronounced, rapid, prolonged response with a single dose. These were very
treatment-resistant patients,” said NIMH Director Thomas R. Insel, M.D.
Ketamine blocks a brain protein
called the N-methyl-D-aspartic acid (NMDA) receptor. Previous
studies have shown that agents that block the NMDA receptor reduce
depression-like behaviors in animals.
NMDA receptors are critical for
receiving the signals of glutamate, a brain chemical that enhances the
electrical flow among brain cells that is required for normal function.
Studies indicate that dysregulation in glutamate could be among the culprits
in depression. Using ketamine to block glutamate’s actions on the NMDA
receptor appears to improve function of another brain receptor — the AMPA
receptor — that also helps regulate brain cells' electrical flow.
Scientists think the reason
current antidepressant medications take weeks to work is that they act on
targets close to the beginning of a series of biochemical reactions that
regulate mood. The medications’ effects then have to trickle down through
the rest of the reactions, which takes time. Scientists theorize that
ketamine skips much of this route because its target, the NMDA receptor, is
closer to the end of the series of reactions in question.
“This may be a key to developing
medications that eliminate the weeks or months patients have to wait for
antidepressant treatments to kick in,” said lead researcher Carlos A. Zarate
Jr., of the NIMH Mood and Anxiety Disorders Program.
The researchers who conducted the
study now are zeroing in on other areas of the glutamate system. Specifying
which components of the system are affected by compounds such as ketamine
may help scientists understand how and why depression occurs, reveal
biological markers that may one day aid in diagnosis, and point the way to
more precise targets for new medications.
Dr. Zarate was joined in this
research by Husseini K. Manji, chief of the NIMH Mood and Anxiety Disorders
Program, and colleagues Jaskaran B. Singh, Paul J. Carlson, Nancy E.
Brutsche, Rezvan Ameli, David A. Luckenbaugh, and Dennis S. Charney.
NIMH is part of the National
Institutes of Health (NIH), the Federal Government's primary agency for
biomedical and behavioral research. NIH is a component of the U.S.
Department of Health and Human Services.
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