Ketamine May Give 'Almost Instantaneous' Relief for Severe Depression

BETHESDA, Md., Aug. 7 -- Symptoms of depression can be made to disappear in less than two hours with a common anesthetic, not the weeks or months required for onset of relief with traditional antidepressants, according to results of a pilot study.

"We have broken the sound barrier in depression treatment," said Carlos A. Zarate, Jr., M.D., chief of the mood disorders section the National Institute of Mental Health, who reported on the effects of ketamine, a common anesthetic, in the August 8 issue of the Archives of General Psychiatry.

Dr. Zarate and colleagues said a single injection of ketamine, which targets the N-methlyl-D-aspartate (NMDA) receptor, can eliminate depression symptoms within 110 minutes.

After a two-week drug-free run-in, patients were given IV ketamine hydrocholoride (0.5 mg/kg) or placebo on two test days a week apart. Twelve of the participants were women and the mean age of participants was 46.7 (range 16 to 60).

The endpoint of the trial was changes in score on the 21-item Hamilton Depression Rating Scale. The effect size for the drug difference was large (d=1.46 [95% CI 0.91-2.01]) after 24 hours and moderate to large (d=0.68 [95% CI 0.13-1.23]) after one week, they wrote.

At 110 minutes, patients given ketamine had an average Hamilton Depression Rating Scale score of 15, down from more than 25 at baseline which was significant (P<0.05) and at day one the average score was less than 15 which was highly significant (P<0.001). There were no significant chances from baseline among patients who received placebo injections.

"We are not replacing depression with a manic phase," Dr. Zarate said. "The effect is simply the elimination of depression. The patients, essentially, return to normal."

Of 17 patients who received ketamine injections 71% met response criteria and 29% met remission criteria the day following ketamine infusion, Dr. Zarate and colleagues wrote. Thirty-five percent of subject maintained that response for a week.

Interestingly, ketamine is a popular street drug, which is sold under a number of names including kit kat, jet and super C. Dr. Zarate, who acknowledged that common side effects included perceptual disturbances, confusion, increased blood pressure, euphoria, dizziness, and increased libido.

But the effects never lasted longer than 110 minutes, while the beneficial effect of a single dose was generally durable for seven days.

Ketamine is approved for human use, but is most commonly used as a veterinary anesthetic.

Despite his obvious enthusiasm for treatment, Dr. Zarate cautioned that the results are preliminary and are not yet ready for "the general clinician." Nonetheless, he said that the results of the 18-patient trial provide a proof-of-principle that rapid-almost instantaneous-treatment of clinical depression is possible.

And while the speed of the drug's effect was impressive, "how to maintain that effect and how to achieve it consistently is not so clear," he said.

Moreover, since the trial was limited to patients with treatment resistant major depression, it is not clear whether an N-methlyl-D-aspartate will work as well or as quickly in patients with less severe depression.

Additionally, the authors note that "limitations in preserving study blindness may have biased patient reporting by diminishing placebo effects, thereby potentially confounding results."

Dr. Zarate said his team plans additional studies with the aim of "developing strategies for maintaining the rapid response," which may mean adding one or more drugs that can "piggyback" the ketamine effect to maintain a durable response.