The U.S. Food and Drug Administration (FDA) announced last week the approval of Spravato (esketamine) nasal spray for treatment-resistant depression in adults. Spravato is approved to be used in conjunction with an oral antidepressant.

To be considered treatment-resistant, a person has to have tried at least two other antidepressant medicines without benefit. It’s estimated that more than 16 million adults in the United States have had at least one major depressive episode, according to the National Institute of Mental Health, and 1 in 3 of them haven’t responded to at least two different antidepressants.

“It is exciting that the FDA has approved esketamine for treatment-resistant depression,” says Atsushi Kamiya, MD, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins Medicine in Baltimore.

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“One thing that makes this drug different from currently available antidepressants is how long it takes to begin working,” he says. “Traditional antidepressants can take a few weeks to see an improvement in symptoms, whereas this drug can improve symptoms of depression very quickly.”

People taking Spravato can feel better in a matter of hours, not weeks. This can make a life-saving difference to someone with suicidal thoughts, says Dr. Kamiya.

"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 an FDA statement announcing the approval of Spravato.

A Different Mechanism of Action That Acts Fast

“Esketamine works in a different way than traditional antidepressants,” says Kamiya. Spravato works on the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor in the brain. The medicine is administered as a nasal spray that is absorbed by the lining of the nasal passages and into the blood stream.

Esketamine is derived from ketamine, a widely used anesthetic. In the 1980s and '90s it was known as a club drug, called Special K, that people used for its hallucinogenic effects. In the last few years, intravenous delivery of ketamine has grown increasingly popular in treating depression in clinics around the country. However, this version and method of treatment is not approved for treatment-resistant depression and generally not covered by health insurance.

“I believe esketamine will be more efficacious in treating depression than the ketamine intravenous medication. Esketamine is better at targeting the NMDA receptor than ketamine,” says Kamiya.

Spravato was studied in a robust phase 3 clinical trial program with more than 1,700 adults with treatment-resistant depression. In a short-term study, people who were on Spravato and an oral antidepressant experienced superior improvement in depression symptoms at four weeks, compared with the group taking placebo and an oral antidepressant. In a long-term study, patients in stable remission taking Spravato who continued treatment with the medicine were 51 percent less likely to relapse versus those who stayed on placebo and an oral antidepressant.

Spravato Risks: A Black Box Warning and a Restricted Distribution System

Because of the risk of serious adverse outcomes caused by Spravato administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS). It also carries a black box warning because it may cause sedation problems, affecting attention, judgment, and thinking. The warning also cautions users of the risk of abuse and suicidal thoughts.

A black box warning is the most serious safety warning issued by the FDA. Antidepressants as a class carry a black box warning already because they’re associated with an increased risk of suicidal thinking, feeling, and behavior in young people.

First Antidepressant to Receive a Breakthrough Status Designation

Janssen requested and received a Fast Track designation from the FDA for Spravato based on the belief that the drug fills an unmet need in a serious medical condition. According to Sandy Walsh, an FDA spokesperson, Spravato is the first antidepressant with a Breakthrough Therapy designation to be approved, and only the second drug to be approved for treatment-resistant depression.

Once a drug receives the Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

How Will Spravato Be Distributed?

Once your healthcare provider has determined that Spravato is appropriate for you, you will need to do some planning. Because Spravato was approved with a restricted distribution system and under a REMS, being treated with the drug is a more involved process.

Here are some things you should know:

Locate an approved center. Spravato can only be administered at a certified treatment center. People there will be trained in how the drug should be dosed and taken as well as how to watch for any potential adverse events. Janssen is working quickly to educate and certify centers that wish to administer Spravato. Sites may include clinics, community mental health centers, hospitals, or integrated health systems. Beginning in late March, people can visit www.Spravato.com for a locator tool and to sign up to receive alerts when new treatment centers are available. More locations will be added over time as new treatment centers become certified.

Spravato can only be administered at a certified treatment center. People there will be trained in how the drug should be dosed and taken as well as how to watch for any potential adverse events. Janssen is working quickly to educate and certify centers that wish to administer Spravato. Sites may include clinics, community mental health centers, hospitals, or integrated health systems. Beginning in late March, people can visit www.Spravato.com for a locator tool and to sign up to receive alerts when new treatment centers are available. More locations will be added over time as new treatment centers become certified. Expect twice a week dosing at the start of your therapy. During the first four weeks of treatment, called the induction phase, the recommended dosing frequency is twice weekly. Subsequently during the maintenance phase, the dosing frequency is reduced to once every week or every two weeks.

During the first four weeks of treatment, called the induction phase, the recommended dosing frequency is twice weekly. Subsequently during the maintenance phase, the dosing frequency is reduced to once every week or every two weeks. Allow for at least two hours at the site where you take Spravato . In accordance with the REMS, after you take Spravato you’ll need to stay at the office or clinic for at least two hours so that the healthcare provider can observe you for sedation, dissociation, and blood pressure changes, and decide when it’s safe for you to go.

. In accordance with the REMS, after you take Spravato you’ll need to stay at the office or clinic for at least two hours so that the healthcare provider can observe you for sedation, dissociation, and blood pressure changes, and decide when it’s safe for you to go. Make arrangements for transportation. After taking Spravato, people should not drive or operate heavy machinery until the next day, following a restful sleep.

What Are the Anticipated Costs of Spravato?

According to Janssen, the wholesale acquisition cost (WAC) of Spravato is $590 to $885 per treatment session, depending on whether the person was prescribed the 56 or 84 milligram dose kit.

Wholesale acquisition cost is an estimate of how much Janssen will charge wholesalers (like pharmacies) or direct purchasers (if the clinic or doctor’s office buys Spravato directly from Janssen). This price doesn’t reflect discounts or rebates that can be offered to purchasers, so it’s difficult to know the actual final cost of the drug to wholesalers or consumers.

According to a Janssen spokesperson, the company expects that treatment with Spravato will be broadly covered by insurance providers for adults with treatment-resistant depression.