Anesthetic Said to Aid Depression
By NICHOLAS BAKALAR
Published: August 9, 2010
NEW YORK TIMES
A new study suggests that a 50-year-old drug commonly used as an anesthetic for humans and animals — and abused, as the drug called Special K — may deliver almost instant relief in some of the most troublesome cases of bipolar depression.
It has been known for several years that small doses of the drug, ketamine, can relieve major depression. But this study, done by researchers at the National Institute of Mental Health, is the first to demonstrate efficacy in patients with treatment-resistant bipolar depression.
Indeed, the researchers said, the effect on this group appeared to be even stronger. Although the study was small, with just 18 patients, it was conducted under the highest standards for a drug study: it was randomized, placebo-controlled and double-blinded.
In bipolar disorder, sometimes called manic-depressive illness, patients cycle between periods of elation and severe depression, and the depressive phase carries a high risk of suicide. It is commonly treated with mood stabilizers, including lithium, anticonvulsants and some antipsychotics, often in complex combinations.
Both mania and depression usually improve on these drugs. But when the depression remains, it is notoriously difficult to treat, so a fast-acting medicine with lasting effects would have obvious advantages. Ketamine probably acts by limiting the action of one type of brain receptor that moves nerve signals between neurons.
The treatment is still experimental, said Dr. Carlos A. Zarate Jr., the senior author of the study, published in the August issue of The Archives of General Psychiatry.
Because ketamine is already approved as an anesthetic, physicians could use it off label for other purposes. But Dr. Zarate, a clinical investigator with the Centers for Disease Control and Prevention, warns against it.
“I’m not encouraging it for clinical use at this time,” he said. “We need more knowledge about safety, and long-term data on efficacy and how it interacts with other antidepressants.”
The 18 patients in the study had taken lithium or the anticonvulsant valproate for at least six weeks without getting better. They were randomly assigned to receive an intravenous infusion of either ketamine or a placebo saline solution two weeks apart, with each receiving the drug on one occasion and the saline solution on the other. Neither the patients nor the experimenters were told which solution was being delivered.
Tests showed that the ketamine patients had significantly fewer depressive symptoms than those who received the placebo — beginning 40 minutes after the infusion and lasting three days. After that, the effect of the ketamine began to fade, and within two weeks those who had received the medicine had about the same symptoms of depression as those who had taken the placebo.
There were no serious side effects, although about 10 percent of both those receiving ketamine and those taking the placebo got a headache or nausea, or reported feeling woozy or lethargic after the infusions. The adverse effects associated only with ketamine included feeling strange, having a dry mouth, increased blood pressure or faster heartbeat. After about 80 minutes, there were no differences in side effects between the ketamine and placebo groups.
The scientists view these findings as highly significant, because the patients had failed an average of seven antidepressant trials, and more than half had failed to respond to electroconvulsive therapy. But they also emphasized the study’s limitations. The number of patients was small, all were late in the course of their illness, and all were also taking valproate or lithium, which may have affected the results. Finally, there was a small but insignificant placebo effect.
Dr. Dost Ongur, an assistant professor of psychiatry at Harvard, doubted that the experiment could be truly double-blinded — the vivid effects of injected ketamine can be easy to perceive, both by the patient and by the person giving the injection.
Still, he was impressed. “This is a solid piece of work that really has the potential for being a true advance,” he said. “There is real hope, there is real excitement around this, even though there is skepticism from some quarters.”
The dose of ketamine in this study was approximately 35 mg infused over a 40-minute period. This is a relatively low dose of ketamine. Based on my experience, this dose of ketamine will permit reasonable cognitive function without hallucinations during the 40-minute infusion.
Anthony Kirkpatrick, MD, PhD
A version of this article appeared in print on August 10, 2010, on page D5 of the New York edition.
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