New types of drugs for schizophrenia, depression and other psychiatric disorders are few and far between—and a number of companies have scaled back or dropped development of this class of pharmaceuticals. One exception stands out. Ketamine, the anesthetic and illegal club drug, is now being repurposed as the first rapid-acting antidepressant drug and has been lauded as possibly the biggest advance in the treatment of depression in 50 years.

A few trials by large pharma outfits are now underway on a new, purportedly improved and, of course, more profitable variant of ketamine, which in its current generic drug form does not make pharmaceutical marketing departments salivate.

Some physicians have decided they simply can’t wait for the lengthy protocols of the drug approval process to be sorted out. They have read about experimental trials in which a low-dose, slow-infusion of ketamine seems to produce what no Prozac-like pill can achieve, lifting the black cloud in hours, not weeks.

With nothing to offer desperate, sometimes suicidal patients, physicians have decided against waiting for an expensive, ketamine lookalike to arrive and have started writing scripts for the plain, vanilla generic version that has been used for decades as an anesthetic. Ketamine, it seems, has captivated a bunch of white coats with the same grassroots energy that has propelled the medical marijuana movement.

No formal tally of off-label ketamine prescriptions has been made. But Carlos Zarate of the National Institute of Mental Health, a leader in researching ketamine for depression, receives numerous e-mails from physicians and patients. "It’s being used in many states,” Zarate says. “I know of [people in] California, New Jersey, Pennsylvania, New York, Texas Florida and around the world, Australia, Germany, the U.K.”

Physicians are allowed to prescribe drugs off-label—in other words, uses for which they have not received approval from a regulatory agency. The practice is widespread: in fact, ketamine itself is often administered for chronic pain, a use never approved by the U.S. Food and Drug Administration.

Legalities aside, not every physician thinks ketamine has met the required thresholds of safety and efficacy to become a mainstay of a walk-in clinic. “Clearly, the use of ketamine for treatment-resistant depression is not ready for prime time,” says Caleb Alexander, a physician who is a professor of epidemiology at Johns Hopkins University and co-director of the Johns Hopkins Center for Drug Safety and Effectiveness. “We have remarkably little solid scientific evidence to support its use in nonexperimental settings, that is to say, to support its use beyond research settings.”

Ketamine has a well-known side effect of inducing a trancelike state that club aesthetes dub the “K hole”—the reason it is known in clinical terminology as a “dissociative” anesthetic. Some users get sucked into the vortex spun by Special K, Vitamin K, “jet,” “special L.A. coke,” “K,” or one of the drug’s other monikers, The physician and neuroscientist John Lilly, known for his work on dolphin communication, almost drowned under the influence while immersed in his own invention, the sensory deprivation tank and had to resuscitated by his wife. Undeterred, Lilly continued binging, at one point injecting himself almost hourly for three weeks. Others haven’t been as lucky and have succumbed fatally to what Lilly’s wife called “the seduction of K.”

In the low doses administered in off-label clinics, side effects are rare or mild. “If I closed my eyes, images would present themselves like the opening credits of Dr. Who, with a tunnel of light,” says one patient.” Even so, a prospective patient must be carefully screened and turned away if there is any history of psychotic episodes.

In prescribing ketamine for depression, clinicians take it upon themselves to determine proper treatment protocols through trial and error, either by consulting colleagues or reading the methods sections of scientific papers that report the results of preliminary experimental trials not intended to evaluate the drug for clinical use. The risks are worth taking, say some psychiatrists, particularly if a patient has tried psychotherapy and one antidepressant after another with poor results—and any mention of electroconvulsive therapy produces a look of abject terror.

“I have patients who will try anything that is reasonably safe, says David Feifel, the physician who heads Adult Psychiatric Services at the University of California, San Diego, Medical Center. Feifel read the major study by Zarate in 2006 and decided to put in place one of the first clinical programs anywhere for ketamine therapy. After receiving approval from the hospital’s pharmacy and therapeutic committee, Feifel and his team began providing ketamine therapy on a routine basis in 2011. So far, 50 people with depression that did not respond to other treatments have been willing to pay out of pocket for the infusions. As many as three times that number, some from outside the U.S., have made inquiries.

Feifel shared some e-mails: “So many days I wake up and want to die, but not today,” wrote one patient after the therapy. “Thank you so much for this day of hope and contentment. It was the most beautiful day I can remember. I was a new person today and I'm looking forward to tomorrow, which is something I never say.” Another wrote: “I wanted to go out to eat last night and go for a walk today—both things I haven't wanted to do for years.”

Feifel estimates that seven out of 10 patients have improved, a substantially higher number than respond to Prozac and other conventional antidepressants and a rate comparable to reports in experimental studies. Side effects have been minimal—and the high from the drug, no problem. “If anything, the patients enjoy that,” Feifel says.

Feifel does not see himself in the role of proselytizer. Whether ketamine becomes a depression breakthrough depends on overcoming treatment effects that often last just a few weeks, even with multiple infusions. “This is in my opinion the biggest challenge, whether this is really going be a game changer for depression or a limited tool is if we can figure out how to make this a durable benefit,” he says.

Feifel always lays out multiple treatment options tailored to a particular patient, not just ketamine alone. He might, for instance, try to disabuse patients of misconceptions about the dangers of electroconvulsive therapy. The hospital is also exploring other new approaches: transcranial magnetic stimulation, a magnetic field trained on a brain area affected by depression; and treatment with scopolamine, another anesthetic that may possibly offer patients quick mood relief.

Off-label prescribing of ketamine does not usually take place at major university hospitals like U.C. San Diego Medical Center but, rather, in small clinics, some of which appear to be largely devoted to dispensing the drug. “There’s nothing else they have to offer really,” Feifel says. That one-track approach has the drawback of possibly leaving a patient who doesn’t respond to ketamine feeling even more desperate.

Read part 2 about patients with major depression who pay thousands of dollars of uncovered medical expenses for ketamine treatment at small clinics and physicians’ offices.

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