Aug. 21, 2018 -- Ketamine, a widely used anesthetic that’s also an illicit party drug, has taken on a new role in recent years: treating severe depression in people who have not responded to standard treatment. Researchers have called it the most exciting breakthrough in the field of depression research in the past half-century.
One form of the drug, being developed as a nasal spray called esketamine, is in the final stages of testing needed before it can go to the FDA for approval.
It has not yet been approved by the FDA in any form to treat depression, but doctors may, and do, use it “off label” to treat depression and pain. Yet many questions about its safety and effectiveness remain unanswered.
“There’s still a lot to learn before we can use ketamine on a wide scale,��� says Yale professor of psychiatry Gerard Sanacora, MD, PhD, who directs the Yale Depression Research Program in New Haven, CT. “But it seems to offer real benefits, even targeting suicidal thinking, which could be lifesaving.”
A Quick Response to Ketamine
Eight percent of American adults have depression, an often debilitating and sometimes fatal disease. People with major depression are 20 times more likely to attempt suicide. Talk therapy and antidepressant medications often help, but such treatments leave one in three people with depression searching for more help.
That’s where ketamine comes in. Among those with treatment-resistant depression, an estimated 50% respond to ketamine, says psychiatrist and researcher Carlos Zarate Jr., MD, chief of the Experimental Therapeutics and Pathophysiology Branch of the National Institute of Mental Health.
And people who do respond to ketamine respond quickly. In a review of 10 studies that Sanacora, Zarate, and others wrote last year, ketamine lessened thoughts of suicide within a day, though the effect was temporary. By contrast, commonly prescribed antidepressants generally take several weeks to begin to relieve symptoms -- when they do work.
Ketamine does not target the same brain activities as antidepressants like fluoxetine (Prozac), venlafaxine (Effexor), and sertraline (Zoloft). Rather, it blocks a receptor called N-methyl-D-aspartate, or NMDA. Why does that relieve depression for some people? Scientists can’t say for sure.
“Most of what we know comes from rodent studies,” says Sanacora. “With humans, there are probably many other factors that contribute to the response to ketamine.”
No Action from FDA -- Yet
The FDA allows doctors to prescribe approved medications “off-label,” or for purposes other than those for which they were first approved. Ketamine is one such medication. The FDA approved it as an anesthetic in 1970. Its off-label uses have not been limited to depression treatment.
“It has been used for decades, including for pain management and palliative care,” says Zarate.
Its continued use, he says, shows that its safety has been well-established, at least for short-term use.
But, he says, “research has not kept pace with its clinical use. We still know very little about its long-term effects on [the brain] or other safety measures.”
Its promise as a depression treatment -- and the ability for doctors to use it off-label -- has led more outlets to offer it to people with treatment-resistant depression. Over the last several years, clinics that offer ketamine IVs have popped up around the country, including at academic medical centers such as Yale University and the University of California San Diego.
But there’s no FDA oversight of ketamine’s use as a treatment for depression, no reliable estimate of the number of clinics offering such treatment, and no standard for treatment. And many clinics have no psychiatrist or other mental health professional on staff.
‘No Easy Answer’ to Ketamine’s Use
Last year, Sanacora and several colleagues published a statement in a leading psychiatric journal in response to the “rapidly escalating demand for clinical access to ketamine treatment and an increasing number of clinicians willing to provide it.”
The authors addressed ketamine dosing, safety, patient follow-up after treatment, and other issues that remain to be resolved.
“It’s a very complicated question, and there’s no easy answer,” Sanacora says of the off-label use of ketamine. “We realized that the biggest thing we could do to help the field is to highlight what we know, what we don’t know, and where we should be concerned.”
Many parts of ketamine treatment require more research, such as figuring out the ideal dose. Sanacora says many of the studies have been presented at medical conferences but have not yet been published in peer-reviewed journals, which would require independent researchers to examine the findings.
At the University of Minnesota, psychiatrist Kathryn Cullen, MD, studied the impact of ketamine IVs on teenagers with treatment-resistant depression. Designing the study presented many challenges because so little is known about how best to use ketamine.
“What’s the right dosing schedule? How many treatments should they get?” wondered Cullen, an associate professor and chief of child and adolescent psychiatry.
In her small study, which was published in June, 13 teens received six ketamine IVs over 2 weeks. Five of them got better, at least temporarily. But the study raised more questions than it answered, Cullen says.
“How do they do down the road? There are a lot of questions about the long-term safety and efficacy which we really can’t answer because the studies haven’t been done,” she says.
Ketamine’s Potential for Abuse
Of particular concern to parents of the participants: ketamine’s potential for abuse. Even in clinical doses, the drug sometimes produces short-lived psychedelic side effects like euphoria, hallucinations, and out-of-body experiences. Those effects have made it a popular club drug.
“On the street, the dose is much, much higher than what we use to treat,” says Cullen, “but ketamine is a drug of abuse, and parents ask me if their kids would start seeking it out. I don’t know.”
Ketamine can also cause spikes in blood pressure and heart rate. Whatever the risks, though, they may be outweighed by the benefits of quickly stopping depression, says Cullen.
“Adolescence is such a critical time for brain development,” she says. “Untreated depression can impair who they consider themselves to be as a person: how they view themselves, how they view their relationships, how they view their possibilities.”
In May, results from two recently completed clinical trials showed that esketamine nasal spray, when paired with another antidepressant, rapidly eased symptoms in patients with hard-to-treat depression. In a second study on elderly patients, esketamine showed great promise but fell just short of hitting the study’s targets.
In a study published in July, researchers, including Sanacora, reported that esketamine helped relieve depression in patients at high risk of suicide.
“In all likelihood, the FDA will be reviewing esketamine in the near future,” says Sanacora, who has received research funding from Janssen Pharmaceuticals, which makes the drug.
Focusing on Drug’s Positives
Meanwhile, Zarate has set his sights on another potential ketamine-related therapy. When you take ketamine, your body breaks it down into two dozen different byproducts, called metabolites. Zarate and his colleagues are now focusing their research on one of those metabolites, which appears to offer ketamine’s antidepressant effects without its side effects or potential for abuse.
“We will approach the FDA hopefully sometime this year and begin studies hopefully next year,” says Zarate. “If ketamine makes it to the market -- and by all means that looks very promising -- that paves the way for further ketamine-like treatments without the side effects.”
At Yale, Sanacora is studying whether ketamine may do more than relieve the symptoms of depression. He says the drug seems to temporarily change certain connections in the brain. During that period, he suggests, tough-to-treat patients may be more likely to benefit from approaches like cognitive behavioral therapy, which may help them avoid a relapse.
Sanacora also is at work on a study that will compare ketamine with electroconvulsive therapy (ECT), which he calls the gold standard for treatment-resistant depression. His research is still in the early stages.
Excitement over ketamine’s potential needs to be tempered with caution because of how much remains to be learned, says Zarate. And for at least the foreseeable future, it should be a last resort, after other treatments have failed.
“It’s important for people to first try approved medications or talk therapy, even ECT, before considering ketamine,” says Zarate. “We shouldn’t bring it too soon into the course of treatment.”