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Study suggests anesthetic agent may have rapid antidepressant effects

The JAMA Network Journals

A single intravenous infusion of a drug known as ketamine, which is a general anesthetic agent, may relieve symptoms of depression within two hours and remain effective for up to one week, according to a report in the August issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

The discovery of antidepressant medications has revolutionized the treatment of depression, according to background information in the article. However, most currently available medications do not begin to relieve the symptoms of depression for several weeks. During this lag period, patients are at risk for self-harm and even suicide, especially within the first nine days of treatment. "Pharmacological strategies that have rapid onset of antidepressant effects within hours or even a few days and that are sustained would therefore have an enormous impact on public health," the authors write.

Carlos A. Zarate Jr., M.D., and colleagues at the National Institute of Mental Health, Bethesda, Md., studied the effects of ketamine in 12 women and six men (average age 46.7 years) with treatment-resistant depression, meaning that they were unsuccessfully treated with other antidepressants at least twice. After a two-week drug-free period, participants received two intravenous infusions one week apart, one with ketamine (.5 milligrams per kilogram of body weight) dissolved in saline and the other with 50 milliliters of pure saline (placebo). Patients were randomly assigned to receive either the ketamine or the placebo infusion first. They underwent tests to assess the severity of their depression one hour before the infusion as well as 40, 80, 110 and 230 minutes and one, two, three and seven days afterward.

Within 110 minutes after the infusion, patients who received ketamine rather than placebo showed significant improvement. The effect lasted through the following week. On the day after treatment, 71 percent of the 17 participants who received the ketamine (one dropped out of the study after receiving only the placebo infusion) responded to the drug and 29 percent met criteria for remission from depression, compared with none who received the placebo. Thirty-five percent of those who received ketamine had effects that lasted for at least one week. "To our knowledge, there has never been a report of any other drug or somatic treatment (i.e., sleep deprivation, thyrotropin-releasing hormone, antidepressant, dexamethasone or electroconvulsive therapy) that results in such a dramatic rapid and prolonged response within a single administration," the authors write. No serious adverse events occurred during the study.

Most currently available antidepressants work by increasing the levels of chemicals in the brain known as monoamines, including serotonin and dopamine, the authors write. Over time, this accumulation of chemicals acts to improve a patient's mood. However, ketamine directly targets a different brain pathway--the glutamatergic system, which is important to learning and memory. "This line of research holds considerable promise for developing new treatments for depression with the potential to alleviate much of the morbidity and mortality associated with the delayed onset of action of traditional antidepressants," the authors conclude. "Future studies need to be carried out in an attempt to develop strategies for maintaining the rapid antidepressant response obtained with ketamine long-term." (Arch Gen Psychiatry. 2006;63:856-864. Available pre-embargo to the media at


Editor's Note: This study was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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