Is Ketamine a Quick Fix for Hard-to-Treat Depression?

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Glass capsules containing ketamine

During the 1990s, the brief popularity of all-night (and in some cases multiday) raves led to a national panic over club drugs. The federal government staged elaborate crackdowns on ecstasy (known colloquially as E and in the lab as MDMA, short for 3,4-methylenedioxymethamphetamine) and an anesthetic called ketamine (or K). While ecstasy had been outlawed in 1985, trafficking ketamine was no more illegal in the '90s than selling unused penicillin. But by 1999, the government had classified ketamine under the Controlled Substances Act, and today, dealing the drug can earn you the same sentence that you would get for selling heroin or meth.

Now it turns out that both ecstasy and ketamine may have healing qualities. On Aug. 2, the esteemed Archives of General Psychiatry published the results of a randomized, controlled trial hailing ketamine as a promising treatment for depression among patients with bipolar disorder. Just two weeks ago, another study showed that MDMA is a potentially valuable therapy for posttraumatic stress disorder.

I approached the new studies with skepticism, having written in the 1990s slightly panicky articles about both ecstasy and ketamine. (A more balanced cover story about ecstasy would follow.) But stranger substances than club drugs have been used for therapeutic benefit. The new study on ketamine makes the point that many severely depressed patients need unusual treatments; standard medications simply don't work for them, particularly when they are in a depressive crisis. Antidepressants can take weeks to have any effect. "This delayed onset of antidepressant effects can result in considerable morbidity, including increased suicide risk," the study authors write.

Typical treatments for bipolar depression include lithium and antidepressants like Zyprexa and Prozac. Does the unconventional drug ketamine work better? The best answer is that it works differently. Many antidepressants relieve depression by altering levels of the neurotransmitter serotonin in the brain. Ketamine dissociates patients from negative thoughts and feelings by preventing another neurotransmitter, glutamate, from interacting with a receptor in the brain that usually processes it. Brain autopsies have suggested that glutamate activity is associated with bipolar disorder, and past studies have shown that severing the glutamate-receptor link can rapidly lift symptoms in people with major depression within two hours. So the thinking is that in bipolar patients, a fast-acting injection of ketamine can break down emotional responses and counteract depression's most immediate effects.

The new study was conducted at the government-sponsored Mood Disorders Research Unit under the supervision of Dr. Carlos Zarate Jr., of the National Institute of Mental Health. Zarate and his team focused their study on patients with severe bipolar disorder who did not improved with prior orthodox treatments.

Zarate and his team recruited only 18 patients to participate in their proof-of-concept trial, which — as in the ecstasy study two weeks ago — is the biggest drawback: it's a tiny sample. But the results were remarkable. All patients were randomly and blindly given one 0.5 mg/kg dose of ketamine and one equal dose of placebo saline through an IV drip two weeks apart. Patients taking ketamine were significantly more likely than those on the placebo to show short-term improvement in their depression symptoms. This is crucial for bipolar patients who are in depressive crisis and at high risk of suicide: if you can give them something to block short-term suicidal impulses, you may be able to settle them — and then treat them for long-term problems.

The new paper says that in most cases, ketamine "resulted in a robust and rapid (within minutes) antidepressant response." However, the authors note that the antidepressant effects did not last: two weeks after receiving ketamine, patients were no better off than before.

Physically speaking, ketamine is a safe drug. It is the rare anesthetic that has no direct effect on the heart or lungs, meaning that it could not, on its own, cause cardiac arrest. In fact, ketamine was used as a battlefield anesthetic during World War I because it's so forgiving to the central nervous system. The drug is still used in babies, very old people and others who might not be able to tolerate other anesthetics that slow breathing and heart rate. It is also widely used in veterinary medicine, which is the source of the dance-floor rumor that the drug is a horse or cat tranquilizer.

Many human patients dislike ketamine for the very reason some clubgoers seek it: at high doses, it can cause hallucinations. A prominent experimenter with ketamine was John Lilly, a neuroscientist who pioneered communication with dolphins and who was played by William Hurt in the 1980 film Altered States. In 1997, Lilly (who died in 2001) told me that a doctor had first given him ketamine in the '70s to treat his migraines. Lilly then began injecting himself and at one point was taking 50 mg of ketamine an hour, 20 hours a day, for three weeks. Fifty mg is a relatively small dose (clubgoers will typically snort that amount in a single bump) but considered over such a long period, Lilly took enough to anesthetize a whale. He became convinced that he was "a visitor from the year 3001" and that he was talking to aliens.

Will ketamine or ecstasy ever become mainstream treatments? Hard to say, but it's important to note that both drugs would be inexpensive for any psychiatric facility: neither was ever patented, and their chemical formulations are available to anyone. At least for the time being — Zarate and his colleague Dr. Husseini Manji of Johnson & Johnson have submitted a patent application on behalf of the government for the use of ketamine in treating depression. Still, that means potential therapies for depression and bipolar disorder may lie not in pricey new pharmaceutical research but in substances that we used to think of as party drugs.