What’s the Best Way to Use Ketamine for Depression?

In March, the U.S. Food and Drug Administration (FDA) approved the first new drug for depression in decades, esketamine. The drug — which many experts are calling a groundbreaking new treatment — has the same molecular formula but different chemical structure as ketamine, also known as the illicit party drug, Special K.

Despite its reputation as a club drug, ketamine is increasingly used in medical clinics across the country for people with treatment-resistant depression (TRD), or those with clinical depression who have not been relieved of their symptoms through the use of other drugs or therapy. TRD affects one-third of the estimated 16.2 million Americans who have depression, and it carries a higher risk of suicide. Ketamine is known for acting fast and effectively, and an influential study in 2006 from the National Institute of Mental Health found that 18 people who used the drug reported a drastic shift in mood within hours.

Exactly how ketamine works as an antidepressant is unknown, but experts believe it could be that the drug increases the number of synapses, or connections, in the brain, which can be worn down by stress and depression. It’s believed that ketamine could reverse that damage, and regenerate those lost connections.

Esketamine essentially works the same way, but there are some significant differences between the two treatments. For one, esketamine, which is being developed by Janssen Pharmaceuticals and is marketed under the name Spravato, is administered, not by an intravenous (IV) infusion — typically, ketamine is provided intravenously in a clinic — but by a nasal spray. And two, unlike ketamine treatments, esketamine is approved by the FDA.

Those differences are important. With FDA approval, people can have treatments covered by their insurance, while those who use ketamine have to pay out of pocket. Administration via nasal spray instead of IV is also a less invasive process, and is meant to make the drug work faster. However, like ketamine, esketamine is only available at specialty pharmacies, clinics, and doctor’s offices, and it has to be administered on-site.

“When you give ketamine by nasal spray there are several factors that you don’t control.”

Hovering over all of this is a larger question: While esketamine is widely being heralded as an innovative and potentially lifesaving treatment, some researchers and medical professionals argue that the FDA’s approval of the drug was hasty, and question whether the nasal spray is the best way to use the drug. While an IV infusion can accurately deliver a measured dose, some evidence suggests this might not be the case with a nasal spray.

In a 2018 trial, Dr. Veronica Gálvez-Ortiz, a clinical research officer at the Sydney Neurostimulation Centre, looked at the administration of another ketamine relative — arketamine — via nasal spray. Her study found that the method had unpredictable results from one person to the next, leading to varied rates of absorption, effectiveness, and side effects.

“When you give ketamine by nasal spray, there are several factors that you don’t control,” says Gálvez-Ortiz. “For instance, the nasal anatomy affects how ketamine is absorbed, as does nasal mucosity, making it less effective or more effective depending on these factors.”

In addition to anatomy and mucus levels, the “sniffing technique” of the individual people in the study also played a big role in the effectiveness of the treatment. Though the people were given significant training for how to self-administer the drug, if the inhale isn’t done properly, part of the drug can be swallowed and therefore not absorbed in the intended way.

On the other hand, if the inhale is too strong, people using the nasal spray can reach absorption levels that are too high, causing problematic side effects including high blood pressure, psychotic-like effects, and uncoordinated motor skills that left some people in the study unable to self-administer the next dose.

“We didn’t think, in the end, that administering ketamine intranasally was practical because of all of these technical factors,” says Gálvez-Ortiz.

These results have led Gálvez-Ortiz to join the camp of researchers that are uncertain about the FDA’s approval of esketamine altogether. “There are still many questions unresolved,” she says. “There’s a lot of work left to do with ketamine.”

The decision to approve the esketamine in March was made by an independent advisory committee of 16 medical experts compiled by the FDA, which voted in favor of the drug 14–2.

Julie Zito, PhD, a professor of pharmacy and psychiatry at the University of Maryland, is one of the two committee members who voted no. “We’re called in as reviewers of the scientific evidence, and the decision for me always rests with the likelihood that the benefits will outweigh the risks,” she says. “In this case, I could not make that assertion.”

The advisory committee was given two studies on esketamine’s effectiveness, both of which were paid for and carried out by Janssen’s parent company Johnson & Johnson. The company actually ran five studies, but only two turned up positive results, which are the two studies the company gave the FDA panel for review. The first was a randomized trial of adults with treatment-resistant depression who were given an oral antidepressant as well as started on a treatment of intranasal esketamine. After 28 days, approximately 70% of people in the study who received the treatment responded — compared to just over half of the people in the placebo group.

The other successful study was a maintenance study, which took people who responded to the drug in an initial study and randomly assigned them to either keep taking the drug or switch to a placebo.

To approve a new drug, the FDA generally requires two successful studies. While Johnson & Johnson did provide two, historically, both have to be double-blind, randomized, controlled trials. Only one of the successful studies fit this standard, which gave Zito pause.

“That relaxation of this standard was because the FDA gave the drug status as an innovative breakthrough treatment,” Zito says. “And one can question whether this is an innovative breakthrough treatment.”

The trial period for the drug was short — just 28 days — which doesn’t give a clear idea of how esketamine will perform in the long term. On top of that, the measure for improvement was modest — just a three or four point increase on a 60 point scale, says Zito.

“This is a small improvement at best,” she says. “It’s statistically significant, but the idea that it’s going to prove to be clinically significant is an open question.”

This was also a question for Dr. Gregory Simon, a psychiatrist and senior investigator at the Kaiser Permanente Washington Health Research Institute who considers himself “intensely interested but uncertain” about esketamine. He’s also the principal investigator for the Mental Health Research Network, a consortium of research centers affiliated with 13 large health systems across the United States, and has done a considerable amount of work around suicide prevention.

“What I think everyone really wants to know is, will this treatment actually reduce risk of suicide attempt or suicidal behavior?” he says. “If people are in crisis, will it reduce the need for people to be hospitalized? Those are the big questions. And we have no data on those questions at all.”

The placebo-controlled study from Johnson & Johnson did show a reduction in suicidal thoughts in the group given esketamine treatment. However, three people died by suicide during the course of the study, though Johnson & Johnson says esketamine was ruled out as the cause for these deaths. There’s also the question of side effects, which include depersonalization, hallucinations, and dissociative episodes. As of yet, no one knows what the potential long-term harm of these may be. Johnson & Johnson did not respond to request for comment.

Even with the potential for serious side effects and the questions surrounding the effectiveness of the nasal spray delivery method, the approval of esketamine marks a major movement in depression treatment as it is the first new antidepressant approved since Prozac went on the U.S. market over 30 years ago. “There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition,” said Tiffany Farchione, MD, acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, in a statement.

But as groundbreaking as the FDA’s approval may be, there are still issues to iron out. “There are still many questions unresolved,” Gálvez-Ortiz says. “There’s a lot of work left to do with ketamine.”