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Drug may quickly lift depression, study says

Ketamine, an anesthetic also used illegally as the club drug Special K, has the power to lift stubborn depression within hours, instead of the weeks it typically takes prescription antidepressants to kick in, a new federal study suggested yesterday.

Researchers and drug companies have been working for years to develop faster-acting antidepressants, but despite some promising clinical trials, none has made it to market yet. The preliminary study on ketamine, involving just 18 people, could help lead to antidepressants that work much faster than those now available, researchers say.

``The public health implications of being able to treat major depression this quickly would be enormous," Dr. Elias A. Zerhouni, director of the National Institutes of Health, said in a statement.

The weekslong gap between the moment when a depressed person starts taking antidepressants and when the drugs finally kick in is a notoriously risky one. In the initial days, patients may paradoxically feel more anxious or depressed and may experience such side effects as sleep disturbance and, rarely, an increased urge to commit suicide.

``It is this very dangerous period that lasts at least two weeks and likely closer to 4 to 6 weeks," said Dr. Matthew W. Ruble, associate training director of adult psychiatry at Cambridge Health Alliance.

Sometimes stimulants can help bridge the gap, he said, but often the best a psychiatrist can do is monitor the patient carefully and work on establishing a good therapeutic relationship while waiting for the drugs to take effect.

Ideally, antidepressants would kick in ``within hours, like you have for any other form of pain," said Dr. Thomas R. Insel, director of the National Institute of Mental Health.

Researchers cautioned that ketamine, which they gave at doses far lower than those used by club users, should not be abused and is far too experimental to be used by psychiatric patients.

``It's not ready for prime time yet," said Insel, whose agency funded the research. But if the quick antidepressant effect of ketamine is borne out in future studies, ``it would be just terrific," he said.

The study found that patients given a single intravenous infusion of ketamine began to feel their depression lift within two hours and that after a day, 71 percent reported a major improvement in mood. A control group that received an infusion containing only a placebo showed no improvement.

The patients, who suffered from treatment-resistant depression and had already tried an average of six different antidepressants, had no serious side effects. A week after the single injection, when researchers stopped observing the subjects, 35 percent were still feeling better.

``To my knowledge," Insel said in a statement, ``this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose."

Scientists cannot explain exactly why it takes existing antidepressants so long to take effect.

Other research into speeding up antidepressants has focused on a variety of other medications -- including the abortion drug mifepristone, which seems to have some antidepressant effect -- and even nondrug methods like sleep deprivation.

Researchers have known for years that keeping a depressed person awake all night can mysteriously lift persistent depression by the next day, but the effect only tends to last until the person finally goes to sleep. Federal researchers are trying to reproduce the effect of sleeplessness without keeping patients up all night, but have not cracked that problem yet.

The ketamine study, published in the Archives of General Psychiatry, adds to mounting evidence that a brain chemical called glutamate is involved in depression and can be targeted for treatment, said Dr. John H. Krystal, a professor at Yale School of Medicine.

In 2000, he and colleagues published a ketamine study involving just seven subjects that found similar dramatic antidepressant effects. He was not involved in the new paper.

Studies of brain tissue from depressed patients who have died indicate that glutamate may be one of the culprits in the disease, and brain imaging studies have also found increased glutamate levels in patients before treatment, Krystal said in an e-mail.

Current antidepressants take weeks to work, it seems, because they act near the beginning of a whole series of chemical interactions that affect mood, said Dr. Carlos A. Zarate, chief of the Mood and Anxiety Disorders Research Unit at the National Institute of Mental Health and the ketamine paper's lead author.

But by affecting glutamate, ``we're jump-starting something," Zarate said, though exactly what is not clear.

In years to come, he said, researchers may find ways to tweak ketamine so that it can be used broadly for depressed patients, or ketamine may provide clues to the biology of depression that will lead to related drugs.

For some of the research subjects, ketamine lived up to its reputation as a club drug. They experienced a short-lived sense of euphoria and psychedelic effects in the first hour or so after taking the drug, Zarate said.

Some lost their sense of time; others said they saw color distortion. Some could not put their experience into words. But any initial high was clearly separate from the lifting of depression, which tended to occur after about two hours, he said.

But Zarate emphasized that people should not experiment with the drug on themselves.

``This is a controlled substance, and by no means should people be buying street drugs," he said, because they could be contaminated, they could interact badly with other medications, or they could prove dangerous for people with certain medical conditions.

In general, he said, ``any time you anesthetize yourself, there is a risk."

Carey Goldberg can be reached at goldberg@globe.com.

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