Esketamine nasal spray appears both effective and fast acting for treatment-resistant depression, but questions still remain about the drug’s safety.
Researchers published the results of a phase III clinical trial of the drug this week in the American Journal of Psychiatry. The trial was designed to test the efficacy and safety of Spravato, the FDA-approved esketamine nasal spray developed by Janssen Pharmaceuticals.
The double-blind, active-controlled study included nearly 200 patients across 39 outpatient centers from 2015 to 2017.
Some patients were given esketamine nasal spray alongside a traditional oral antidepressant, while the placebo group received saline and a traditional oral antidepressant. The trial lasted for 28 days, and patients were evaluated for symptoms of depression and anxiety at baseline and throughout the course of treatment.
Those taking esketamine showed significantly more improvement than individuals taking placebo. Additionally, improvement in symptoms began to take place in as little as 24 hours after the first dose — highlighting one of the most exciting aspects of the drug, its fast-acting mechanism.
“This trial of esketamine was one of the pivotal trials in the FDA’s review of this treatment for patients with treatment resistant depression… The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpin just how important this development is for patients with difficult to treat depression,” said Dr. Michael Thase, professor of psychiatry at the University of Pennsylvania and one of the study authors, in a press statement
The study also addressed safety concerns about the drug and identified the most common side effects.
Dizziness, dissociation, dysgeusia (change or distortion in sense of taste), vertigo, and nausea were the most common side effects of the drug. Most tended to occur shortly after dosing and cleared up within 90 minutes.
Nine patients stopped the trial after experiencing adverse events including headache, panic attack, and “feeling drunk.”
However, the consensus of the study was that overall the drug was safe and tolerable.
“Most experts and clinicians feel that the marketing of intranasal esketamine will be a boon for a subset of patients who suffer greatly and for whom other currently available treatments have been insufficiently effective,” Dr. Timothy B. Sullivan, chair of psychiatry and behavioral sciences at Staten Island University Hospital in Staten Island, NY, told Healthline.
Sullivan wasn’t involved in the research.
Despite the promising results of the study, questions remain about the drug’s safety.
In an accompanying editorial in the same issue of the American Journal of Psychiatry, Dr. Alan F. Schatzberg, the Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, expresses some of those concerns.
“It’s not clear to me that we really understand what’s the optimal way of using it, how much we should give, how long we should give it for, [and] what we should do when we stop it,” Schatzberg told Healthline.
“That doesn’t mean that someone shouldn’t go ahead and use it. But I think there has to be a modicum of caution that we don’t really have all the answers,” he added.
Schatzberg’s biggest concerns include the potential for abuse and issues with withdrawal. He suggests that, like opioids, there is the potential to have adverse health events when discontinuing use.
In a statement sent to Healthline, a spokeswoman for Janssen pointed out that Spravato nasal spray is the “first new mechanism of action for an antidepressant medication in decades,” and that prior to this physicians have had limited options to help patients with treatment-resistant depression.
“These findings, which represent part of the Phase 3 clinical trial program of more than 1,700 patients, reinforce the robust efficacy and safety profile of the medicine and the significant improvement of depression symptoms that SPRAVATO™ may offer adults with TRD,” the statement read.
Esketamine is chemically nearly identical to ketamine, a powerful anesthetic. Over the years, ketamine has garnered a reputation as a powerful narcotic club drug, capable of rendering users incapacitated.
Because of the risks involved with the administration of esketamine, it is only administered under a doctor’s supervision within a clinical environment.
“This unique agent will not be generally available for some time. Although this may be disappointing to some, it is important with any such novel and complex treatment to carefully observe its effects and risks once administered to less controlled and selected populations,” said Sullivan.
The problem, it seems, with esketamine at this point in its development is the unknowns that can only be revealed through future research among more patients.
Fittingly, Schatzberg ends his editorial with a series of questions: How long should it be prescribed? How frequently? What happens when you stop taking it?
Only time, and research, will tell. As Schatzberg puts it: “We’re headed into uncharted waters.”
“I don’t think we’ve answered all the questions that we need to to be one-hundred percent comfortable, but that doesn’t mean we shouldn’t use the drug,” said Schatzberg.