|Experimental Medication Kicks Depression in
Hours Instead of Weeks
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
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
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
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.