Esketamine is a molecule derived from the anesthetic ketamine, which has itself gained steam as a novel depression treatment. The approval, which the agency announced on March 5, was widely expected after an advisory panel recommended 14 to 2 in favor in early February. But the decision is significant, the drug’s developers say, because unlike other antidepressants on the market, esketamine works through the brain’s glutamate pathways—making it the first drug with a new mechanism of action approved by the FDA to treat depression in 30 years.
“This really promises a completely new and different treatment for many patients,” says David Hough, a psychiatrist who led the clinical trials of esketamine for Janssen Pharmaceuticals, the pharmaceutical arm of Johnson and Johnson and the developer of the medication. “All the other commonly known medications—SSRIs, SNRIs, etc.—use monoaminergic pathways, which [affect] serotonin, norepinephrine, and dopamine. But this is the first one that uses glutamate pathways, which [may be] responsible for its faster onset of action and more robust treatment response.” Both esketamine and its parent molecule, ketamine, inhibit NMDA receptors in the brain, which causes a rapid increase in the neurotransmitter glutamate and the activation of another set of receptors known as AMPA. Though the mechanism of action in cases of depression is not yet fully understood, AMPA activation is thought to strengthen synapses in the frontal cortex, an area of the brain closely related to mood and motivation.
Two positive Phase 3 trials, along with three trials that didn’t garner statistically significant results, were submitted to the FDA as evidence in favor of esketamine. In one positive study, a short-term efficacy trial, more than 70 percent of 101 patients who took esketamine saw a 50 percent or more reduction in their depression symptoms, which was a statistically significant improvement over a placebo group.
The second positive study was a relapse prevention study, designed to determine whether esketamine helped maintain remission from depression in patients who responded to the drug. After showing a positive response, more than 700 patients were randomized to either continue the drug or switch to a placebo. “If the drug wasn’t doing anything, there should have been no difference in the number of relapses between the two groups,” Hough says. “But if the drug is working and maintaining [patients’] remission, then you should see a rapid increase in relapses in patients who are randomized to placebo. That’s exactly what we saw—in total, there was a 50 percent higher risk of relapsing if you withdraw the drug.”
Esketamine is delivered to patients via an intranasal spray, and will be prescribed alongside an oral antidepressant to supplement the medication's weekly or bi-weekly dosing schedule. Because its parent drug, ketamine, is used as a street drug and has a known potential for abuse, esketamine will not be prescribed for patients to take home; instead, doses will be administered in a doctor’s office, and patients will be monitored for a brief period for potential side effects (which may include dissociation, mild hallucinations, or an increase in blood pressure). Ketamine itself, which is typically infused intravenously, is not FDA-approved for depression, which means that insurance rarely covers it when it’s used off-label for that purpose. Esketamine’s official approval means that it will be covered by most insurance plans, Hough says, and will therefore likely cost significantly less out-of-pocket than intravenous ketamine. (One round of ketamine infusions may cost upward of several thousand dollars.)
Early in the approval process, esketamine was designated by the FDA as a “breakthrough therapy,” indicating a serious unmet need and compelling early evidence in favor of the drug. It was also granted priority review, Hough says, which shortened the approval process from 12 months to six and allowed Janssen “earlier and faster and more frequent access to FDA, for questions and concerns, if we want additional advice and guidance.”
In addition, the approval was seen as all but guaranteed after an FDA advisory panel—composed of academics, patient advocates, and other experts who are independent from the FDA itself—met in early February and recommended that the benefits of approving the drug outweighed the risks.
“The approval of esketamine will be a sentinel event for patients with depression,” says Walter Dunn, a psychiatrist at UCLA who served on the panel and recommended esketamine’s approval. The drug’s rapid onset—patients can start to see symptom improvement in a number of hours, as opposed to days or weeks—and its apparent ability to help maintain remission were credited as the biggest factors in his decision. “The findings of rapid onset and efficacy in treatment-resistant depression weren’t surprising, given our experience with off-label use of IV ketamine,” he adds. “What was less clear—and of significant importance—was if patients who improved on esketamine could remain depression-free long-term taking esketamine.” The relapse prevention study provides evidence for that outcome, he says.
Julie Zito, a pharmacy professor at the University of Maryland, was one of two panel members who voted no. Her concerns, she says, were related to the overall strength of the evidence—only two of five Phase 3 studies submitted to the FDA garnered positive results, though Hough argues that negative studies are a common occurrence in antidepressant research—as well as to the possible dangers of approving a drug with a known potential for abuse.
“I’m concerned about the dissociative effects. They sound very serious,” she says. “I can’t imagine that there are no consequences to having had a bad experience from dissociation—like hallucination, confusion, or lack of awareness of your surroundings. And when you’re talking about some individuals who have an impulse for suicide, then I begin to worry: What happens when the drug is not helping them?”
Six deaths occurred during the Phase 3 studies, three of which were the result of suicide. Because the deaths occurred more than a week—and in one case, nearly three weeks—after the patients’ last esketamine dose, the researchers contend that the drug would have been out of the system, and therefore likely had no effect on their decisions to kill themselves. Zito finds the deaths troubling, she says, and isn’t ready to agree that esketamine couldn’t have played a role.
She also worries about a dearth of long-term data, as well as sample sizes comprising only a few hundred patients in highly controlled clinical environments. “There were small Ns and short exposures in the trials, as well as inconsistent findings among the five trials,” she says. “At the end of the day, we know little about the overall effect in community treated populations.”
Despite what she considers weak evidence, she concedes that the challenges of living with treatment-resistant depression may make patients inclined to try esketamine anyway—especially as its potential approval, and the use of ketamine overall, has been widely publicized. “The public is not always adequately informed about benefit and risk, and promotional information [can be] a problem in that regard,” she says. “Some people who need help will take high risks because they need help—not fully understanding the benefit/risk relationship.”
Hough says that Janssen has been working with the FDA to create Risk Evaluation and Mitigation Strategies, or REMS, which are devised for drugs that have potentially serious side effects or a high risk of abuse. “We have a REMS in place, we have lots of long-term safety data, we have very precise dosing data,” he says. Despite the reservations of some of the panel members, he argues that the evidence in favor of esketamine is more robust than that of intravenous ketamine, which is already widely used. “It’s always a matter of opinion and judgment, but the overwhelming consensus [of the panel] was that we did meet the criteria,” he adds.
Esketamine, which will be sold under the brand name Spravato, is expected to be available to patients soon, says Greg Panico, a spokesperson for Janssen. "We will be working quickly after approval to educate and certify centers that wish to administer Spravato, which may include clinics, community mental health centers, hospitals, or integrated health systems, to appropriately monitor the administration of the medication and address patient needs."
Though it was only granted approval for treatment-resistant depression, esketamine is also under consideration by the FDA as a potential method to reduce suicidality in patients at imminent risk of suicide, Hough says; those Phase 3 trials are ongoing. Janssen may also soon explore esketamine’s effectiveness in other mood disorders, including bipolar disorder, but such plans have not yet been formally announced.