A Quick Hit for Depression

As the incidence of depression has soared, the therapeutic arsenal against it has remained remarkably unchanged. Prozac and related SSRIs have been around for 30 years; less popular tricyclics and MAOIs have been on active duty for half a century.

For the one in nine Americans reportedly taking an antidepressant, most meds can take up to six weeks to have an effect, and they often make people feel worse—even suicidal—before they feel better. Side effects such as weight gain and loss of libido can render the drugs intolerable in the long term. Most troubling, at least 30 percent of people don't respond to them at all.

Into this landscape has emerged ketamine, a human and veterinary anesthetic perhaps best known as the party drug "Special K." Given intravenously in low and relatively safe doses, it acts within hours to lift mood and, most notably, quell thoughts of suicide. Though the effects of a single infusion are short-lived (typically under a week), the drug upends the conventional understanding of depression—such as where and how it originates in the brain.

It is also confounding conventional practice. An optimal dosing schedule has not been established, nor are long-term effects well studied—nor the potential for abuse. Though it isn't FDA-approved for depression, it is already available for other uses, fueling the proliferation of unregulated, independent treatment clinics where depressed patients pop in for a 40-minute infusion—often without a prescription—pay $500, and emerge in a brighter mood.

Patients and practitioners have long been eager for a new way forward. But experts worry that delivery is getting too far ahead of the data.

Deliverance

Ketamine was first approved for human use as an anesthetic in 1970 and quickly drafted into the Vietnam War as a fast-acting agent for operating on battlefield wounds. While it doesn't depress respiratory or circulatory function as other anesthetics do, it can induce hallucinations and raise blood pressure. It's an emergency room staple worldwide but used primarily for those who have respiratory problems or low blood pressure or for children needing quick sedation.

But ketamine leads a double life. It's a cheap and addictive club drug that brings on euphoria, heightened sensory perception, and dissociation, the feeling of disconnection from one's body and the surrounding world. Fatal overdose is rare, but tolerance builds quickly—and consumption of ever-higher doses begets memory loss and bladder damage.

In the brain, ketamine binds to NMDA-receptors, blocking their reuptake of the excitatory neurotransmitter glutamate. "It seems to cause a rapid increase in glutamate," says Michael Grunebaum, a professor of psychiatry at Columbia University. The glutamate burst activates another set of glutamate receptors (AMPA), which are thought to strengthen synapses in the limbic system and frontal cortex—areas involved in motivation, memory, and mood and which, in depressed people, are underactive.

From Serotonin to Glutamate

In 2000, when depression research was dominated by the serotonin-deficit hypothesis, a team at Yale decided to explore whether glutamate played any role in the disorder. They gave seven subjects subanesthetic doses of intravenous ketamine. Within just a few hours, "the patients started telling us they were better," recalls psychiatrist Dennis Charney, now dean of New York's Mount Sinai School of Medicine. "We weren't expecting that—and nobody believed it. For years, no one even attempted to replicate it."

In 2006, Charney, then at the National Institutes of Health, repeated the study with 17 subjects who had already tried an average of six antidepressants without success. Within a day, 70 percent reported full remission of symptoms—for up to a week.

This time, the field took notice. In hundreds of studies since, 60 to 70 percent of depressed patients have shown a significant improvement in mood after a single dose of ketamine, administered either intravenously or intranasally. The effects last from three to seven days.

Many of the studies use the same amount of ketamine—0.5mg/kg of body weight, infused over 40 minutes—and most stop after just one dose. Charney was among the first to test multiple doses; by administering the drug six times over 12 days, he stretched its effects to an average of 18 days after the final dose. Along with dissociation, which can be unpleasant for some, nausea and a slight increase in blood pressure are the primary side effects. They are mostly well tolerated, researchers report.

"The evidence at this point is pretty strong that ketamine has a rapid effect at reducing depression," says Columbia's Grunebaum. While it may be most promising for the many patients who fail to respond to standard antidepressants, its relatively short-lived effect makes it problematic for an illness that can fail to remit.

The greatest value of ketamine may lie in its rapid reduction of suicidality. In a 2017 study, Grunebaum and co-authors found that within 24 hours of a single intravenous infusion, suicidal ideation dropped by more than half in 44 of 80 patients with clinically notable suicidal thinking. No other known drug reduces suicidal thoughts so quickly, he observes. In fact, other antidepressants bear warnings that they may amplify suicidal thoughts—a rare, paradoxical response believed to stem from agitation, a side effect.

Is It the Ketamine?

While researchers don't yet know why ketamine works so quickly or reduces suicidal thoughts, they also puzzle over a more basic question—why any effects persist, since the drug is out of the system in a few hours. "There are many theories," Charney says; all involve glutamate setting in motion certain brain processes. "The most exciting thing about ketamine is that it opens up another mechanism in depression," says Grunebaum. With or without ketamine, he notes, studying glutamate pathways "could help us develop new antidepressants—maybe without the side effects."

It may be that ketamine itself isn't the major actor. In 2016, NIH researchers led by Carlos Zarate Jr., an early collaborator with Charney, discovered that a byproduct of ketamine metabolism—not ketamine itself—appeared to cause its antidepressant effects. The metabolite, hydroxynorketamine, doesn't block NMDA receptors, as ketamine does, but it does activate the brain's AMPA receptors. When tested on mice, hydroxynorketamine yielded the same antidepressant effects as ketamine—with none of the side effects.

"It was believed that you couldn't separate the side effects from the positive effects of the drug," says neurobiologist Todd Gould of the University of Maryland, who worked on the study. Although researchers disagree about whether hydroxynorketamine is truly responsible for ketamine's outcomes, Gould and his colleagues are working on a version for human use; safety trials are expected to begin in 2019.

Walk In, Perk Up

Others aren't waiting for the results of studies. Over the past few years, at least 85 ketamine infusion clinics have sprung up across the U.S. Typically run by psychiatrists or anesthesiologists—although they are being pitched to any enterprising medical professional as a steady income stream—they are legal but controversial.

Such "off label" use is rarely covered by insurance; patients pay out of pocket. Despite the expense, demand is high, says Bret Frey, an ER physician who runs Sierra Ketamine Clinics in Reno, Nevada. In the year since Sierra opened, the clinic has delivered nearly 700 infusions, he reports. No prescription is required. "We encourage patients to involve their primary care physician or psychiatrist whenever possible, but it's not mandatory," says Frey. On-site staff "do a thorough evaluation and consultation prior to the first infusion."

Sierra prescribes a regimen of two infusions weekly for two weeks, followed by periodic booster shots. Other clinics offer up to 10 infusions plus boosters—regimens longer than any research supports. Frey claims that the response rate at his clinic is more than 70 percent, as measured by the Quick Inventory of Depression Symptomatology scale. "The more treatments you've tried and failed, the more likely you are to respond to ketamine," he says, based on anecdotal observation.

Concern over the explosion of ketamine clinics is such that in 2017, the American Psychiatric Association released a consensus statement urging caution. The organization recommended that both patients and providers consider "the scarcity" of long-term data on large numbers of patients as "major drawbacks" before any ketamine regimen is started.

The longest formal study—on a ketamine derivative, not ketamine itself—administered the drug twice weekly by nasal spray to 705 depressed patients for a year. Although no new safety issues emerged, "safety has obviously got to be one of our primary concerns," says Husseini Manji, head of neuroscience research at Janssen Pharmaceuticals, who conducted the study. Frey says no patient has ever been admitted to the ER during treatment at Sierra. "When penicillin was developed, do you think there was a whole lot of research on it?" he asks. "No. But it started being used right away, and it saved millions of lives."

The APA statement also recommends that, given the abuse potential, patients never be prescribed ketamine to take at home. But Frey's clinic—as well as others—sends some patients home with ketamine lozenges to continue therapy on their own.

Ketamine with a Twist

Since ketamine has long been a generic drug, giving pharmaceutical firms little incentive to invest in research on it, FDA approval for depression is not on the horizon. But labs are chasing patentable derivatives, and some depression-specific analogs are moving toward FDA approval.

One such agent, esketamine, is delivered by nasal spray. More potent than ketamine, it can be taken at lower doses. Studies show it has side effects and a safety profile similar to those of its mother molecule, says Manji, whose company is developing it. The results of Phase 3 trials—the final round of research before application for approval—were submitted to the FDA in early 2018. (In February of 2019, an expert panel recommended that the FDA issue an approval; it was granted approval in early March of 2019.)

"It's out of our hands now," Manji says. If all goes according to plan, it may soon be in yours.

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