For the first time, the U.S. Food and Drug Administration (FDA) has approved the use of a ketamine-like drug as a stand-alone therapy for adults with treatment-resistant depression (TRD). The drug is approved only for use in a clinical setting under the supervision of a health care provider.
TRD is a severe type of major depressive disorder in which patients’ symptoms are not relieved by standard antidepressants — specifically, patients with TRD have not responded to at least two courses of antidepressant treatments in the past. The condition is believed to affect around one-third of adults with major depressive disorder, so there is a considerable need for new, effective treatments for TRD.
Esketamine, a molecular relative of regular ketamine, was approved as a TRD treatment in 2019, but until now, it had to be taken alongside a second, traditional antidepressant. Now, the new FDA approval means that patients will be able use the ketamine-derived nasal spray, which is marketed under the brand name Spravato, without having to be on another type of antidepressant, according to a statement from the drug’s manufacturer, Janssen Pharmaceuticals, that was published online Jan. 21.
But what is esketamine? And what will the new FDA approval mean in practice?
Related: How does ketamine work as an antidepressant? It’s complicated.
What is esketamine?
Esketamine is like a “sibling” of the anesthetic ketamine in that it’s made from the same building blocks as the latter drug but it’s arranged in a subtly different way. Ketamine contains molecules with two distinct molecular “orientations,” meaning their atoms are aligned in a particular way. Esketamine, on the other hand, contains molecules with just one of these two orientations.
This chemical difference means esketamine can be inhaled through the nose, while ketamine must be injected. Esketamine is also more potent, so it can be used at lower doses. (Ketamine, although most often used as an anesthetic, can be provided off-label for depression.)
How does esketamine treat depression?
It’s unclear exactly how esketamine exerts its antidepressant effects, but the drug is thought to influence the transmission of a chemical messenger called glutamate in the brain, which plays important roles in mood regulation. Traditional antidepressants generally target other chemicals in the brain, such as serotonin and norepinephrine. Esketamine also works differently than so-called classic psychedelics, like psilocybin and LSD, which affect serotonin signaling.
Off the back of clinical trials of the drug, the FDA approved esketamine under the brand name Spravato in 2019. It was initially cleared as an “add-on” treatment for patients with TDR who were already taking another oral antidepressant.
So far, more than 80,000 people in the U.S. have already been treated with Spravato, according to the manufacturer’s website. And now, as a result of the latest FDA approval, Spravato can also be taken as a stand-alone treatment, potentially opening the door for more people to use it.
What has led to the new FDA approval?
The new FDA approval came after a clinical trial found that 22.5% of patients who took Spravato alone for four weeks entered remission — in other words, they effectively no longer had depressive symptoms — compared with 7.6% of patients who took a placebo instead. There were also “no new safety concerns” associated with taking the drug in isolation, compared with taking it with another antidepressant.
Who could benefit from the new approval of esketamine?
“Esketamine has been a transformative treatment for depression symptoms that have not responded to other treatments,” Dr. John Krystal, a professor of neuroscience at Yale University, told Live Science in an email.
The new FDA approval will target two main groups, Krystal said. First, it could help patients who previously didn’t respond to two antidepressant treatments and who are not currently being treated with one.
“Some of these people may have episodes of antidepressant medication spaced by several years,” Krystal said, and they wouldn’t have been able to use esketamine during those gaps. “Their poor experiences with prior treatments may have been an obstacle to seeking needed help for their depression.” Because of the new approval, these patients will now be able to start esketamine treatment without having to also begin taking another type of antidepressant, Krystal clarified.
A second group of people that could benefit includes patients who have tried at least two antidepressants but who wish to stop taking their current treatment when they start esketamine.
“The most common reason that they [these patients] would want to discontinue the ineffective antidepressant is side effects,” Krystal said. “Antidepressants may have side effects, including headache, weight gain, sedation, and sexual side effects — the new FDA ruling makes it possible for these people to be treated with esketamine without needing to continue their prior antidepressant.”
Does esketamine have any side effects?
Taking esketamine is not completely without risk. In fact, the FDA has approved its use through a restricted program known as the Spravato Risk Evaluation and Mitigation Strategy (REMS) program, which allows patients to take the drug only under the supervision of a health care provider in a clinic and not on their own at home.
That’s because patients may experience sedative and dissociative effects while taking Spravato. Dissociation is when people feel detached from their body or physical surroundings which can include issues with perception. In clinical trials, 41% of patients who took Spravato combined with an oral antidepressant experienced dissociation.
Ketamine and its derivatives also come with a risk of addiction, so there are concerns that unsupervised patients could misuse or abuse esketamine.
Through the REMS program, patients using Spravato also must be monitored for at least two hours after treatment. Treatments are recommended to occur twice a week for the first four weeks and then once a week for the following three weeks. They can be scheduled once a week or every other week thereafter.
This article is for informational purposes only and is not meant to offer medical advice.
