Ketamine can temporarily relieve symptoms of depression in patients with treatment-resistant disease in as little as two hours after one intravenous dose, a finding that could lead to new drugs that become effective faster yet are tolerable over long-term use, according to an article in the August issue of the Archives of General Psychiatry.

In the randomized trial, the chosen dose of ketamine was lower than the dose range used for anesthesia.

Some participants in the current 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.

Used in very low doses, ketamine has already been important in research, but it is unlikely to become a widely used clinical treatment because of potential side effects associated with higher doses including hallucinations and euphoria. None of the patients in the current study had any serious side effects.

"The public health implications of being able to treat major depression this quickly would be enormous," said NIH Director Elias A. Zerhouni, MD. "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 randomized assigned to receive either a single intravenous dose of ketamine or a placebo. Depression improved within one day in 71 percent of those who received ketamine; 29 percent of these patients became nearly symptom-free within one day. Thirty-five percent of ketamine patients 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.

"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, MD.

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 glutamate signals. Studies indicate that dysregulation in glutamate could be among the key factors in triggering 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.