The Food and Drug Administration is expected to decide in the coming weeks whether to approve esketamine, which would become the first major depression treatment to hit the market in decades. The psychiatry field is buzzing with excitement — and hesitation.
Esketamine — developed by Johnson & Johnson (JNJ) and delivered as a nasal spray — would be used in combination with oral antidepressants in patients with depression that haven’t responded to other drugs. Many experts have lauded esketamine as an important option for patients in dire need of new treatments — particularly because it could work faster than existing antidepressants.
An independent advisory committee convened by the FDA earlier this month agreed with them. The panel of medical experts voted 14-to-2 that the benefits of esketamine outweigh its risks, which include blood pressure problems, the potential for misuse, and dissociation, a temporary mental state in which a person might become less aware of their surroundings.
“We’re always weighing the risk balance in treatment. On balance, [esketamine] is definitely of value,” said Dr. Wendy Marsh, a psychiatrist and the medical director of the Depression Specialty Clinic at UMass Memorial Medical Center.
But some experts aren’t convinced that there’s enough data just yet to show that esketamine is effective. And they say they want more details on how the drug should be used in the long run.
“There’s sort of a split in academia. Some are cheering for something new and others are more skeptical,” said Dr. Erick Turner, a psychiatrist at Oregon Health and Science University who serves on the FDA advisory committee that recently evaluated the drug. (Turner didn’t take part in the panel earlier this month for travel reasons.)
Johnson & Johnson submitted five Phase 3 studies on the drug: three-short term studies, one maintenance study, and a long-term safety study. Two of those turned up positive results. One was a randomized trial in adults under age 65 with treatment-resistant depression who were started on an oral antidepressant and intranasal esketamine. After a month, roughly 70 percent of patients who received the treatment responded compared to just over half in a placebo group. The researchers considered an improvement of 50 percent or more on a common depression rating scale as a successful response.
The other positive study was a maintenance-of-effect study, in which participants who responded to esketamine in one of the short-term studies were randomly assigned to either keep taking it or be switched to a placebo. The FDA generally wants to see two successful studies for approval — but historically, withdrawal studies haven’t counted toward that total.
“The threshold has been two adequate and well-controlled trials. In this case, they only got one,” said Turner. “Based on that, I would have voted no,” he added.
A spokesperson for Janssen — the subsidiary of Johnson & Johnson that developed the drug — pointed to the positive results that showed esketamine could have a significant effect on treatment-resistant depression in some patients.
“Janssen has a strong track record of bringing important medicines with novel delivery models to market that have helped to address critical healthcare needs of people around the world,” spokesperson Greg Panico said.
Julie Zito, a professor of pharmacy and psychiatry at the University of Maryland, was one of just two advisory committee members who voted “no” on the question of whether esketamine’s benefits outweighed its risks. She said that if the drug is approved, she would want to see providers, patients, and the families of patients work together to keep tabs on possible side effects and how well the drug is working.
“I have no doubt in my mind that this is a very useful treatment,” said Dr. Gerard Sanacora, a psychiatrist and the director of the Yale Depression Research Program, but that “has to be balanced with how do we use this rationally and in what step in care do we use this medicine.” Sanacora has been involved in several of the esketamine trials and has also served as a consultant to Janssen.
“This is gonna be the big question: How do we use this in the clinic?” Sanacora said. Janssen has said that esketamine would be given twice a week during the first month of treatment, then reduced to once a week or once every other week during the maintenance phase. But psychiatrists say they still have questions about long-term treatment with esketamine, including how long to keep a patient on the medication and what the risks of long-term use might be.
“I certainly would love to see ongoing studies for treatment duration and frequency,” said Marsh.
Another big concern among experts: the hype around esketamine. The drug is the chemical mirror of ketamine, a longtime anesthetic that can be abused recreationally at higher doses. In recent years, as early studies pointed to the drug’s possible antidepressant effects, there’s been a boom in the off-label use of ketamine as a treatment for depression and other mental health conditions. Dozens of clinics have opened around the country to treat patients with ketamine, which, unlike esketamine, must be administered intravenously. Patients are paying $350 to nearly $1,000 per infusion, and many get six rounds of treatment, or more.
“There’s been a lot of hype about ketamine in general. … There’s this belief out there that it’s this kind of miracle drug,” Turner said.Turner said that while there’s evidence that esketamine works, he’s worried it’ll be seen as superior to other drugs for treatment-resistant depression or as a therapy that can produce very rapid effects — two points he says studies don’t yet support. That type of hype, he said, can mean patients get their hopes up about the drug “to a degree that’s unwarranted.”
In Sanacora’s role as a researcher, he has often heard from patients who want to know why they can’t just try the drug before first seeing whether they respond to standard oral antidepressants. He’s concerned that the excitement over esketamine might lead patients to look to it as a first-line treatment before trying other antidepressants — or even as a cure.
“The danger is having it so positively portrayed,” Sanacora said. “I’ve been around enough to know this is not necessarily a condition that responds to miracle drugs.”