Approved nasal spray gives hope to patients with severe depression

An antidepressant inhaled as a nasal spray is the first drug approved in 30 years that acts on a different chemical system in the brain than previous medications, and is aimed at patients whose condition is so overwhelming it puts them at risk of suicide. 

The drug, generically called esketamine, is a product of Janssen Pharmaceutical Co., a division of Johnson & Johnson, and will be sold under the brand name Spravato.

The U.S. Food and Drug Administration approved it earlier this week with the caveat that it be administered under the supervision of a health care provider. Esketamine can cause sedation and dissociation — feeling disconnected from one's thoughts and feelings. 

Because of its potential for abuse and misuse, esketamine should be monitored, FDA regulators said.

The prescription drug is for patients with a form of depression known as treatment-resistant, a devastating condition that affects about a third of those diagnosed with depression, all of whom have gone from one medication to another without success.

 “A large proportion of patients with depression fail multiple treatment attempts and after that they are termed treatment-resistant,” said Dr. Anil Malhotra, director of the division of psychiatry research at Zucker Hillside Hospital in Glen Oaks. “To date the most effective treatment for these patients has been electro-convulsive therapy.” 

The new drug rapidly reaches a critical brain chemical system via the nose, Malhotra said.

“What is most exciting about esketamine is that it has an acute effect," he said. "Patients report almost an immediate effect within hours and not longer than days." 

The medication acts on the most prominent signaling network in the brain: the glutamate system. Esketamine blocks glutamate's action on specific sites called NMDA receptors, causing severe depression to vanish. NMDA stands for N-methyl-D-aspartate, an amino acid derivative.

Esketamine is the first antidepressant to act on the glutamate system.  

Older antidepressants, such as Prozac, act on another key chemical system in the brain — serotonin — and can take as long as six to eight weeks to ease depression, studies have shown.

Prozac and drugs like it are known as selective serotonin reuptake inhibitors, which beat back depression by increasing serotonin levels in the brain. Prozac was approved by the FDA in 1988.

Esketamine, however, has a long and storied past having been first developed in its parent chemical form, ketamine, in the 1960s when it was administered as an anesthetic. The medication also went into the black market as a “party drug,” starting in the 1970s under the street name Special K, Malhotra said.

As an antidepressant, it was codeveloped by Dr. Dennis S. Charney, dean of the Icahn School of Medicine at Mount Sinai in Manhattan, and a native of Bellmore, whose first scientific paper about the medication was published in 2000.

“I started working on it when I was at Yale,” Charney told Newsday Wednesday, explaining that he and a colleague, Dr. John Krystal, the current chairman of psychiatry at Yale University, tested ketamine in a small number of people with severe depression.

“We had conducted a small study with only seven patients. When we gave them low doses, the patients got better in only a few hours. We were really surprised. Some people didn’t believe it,” Charney said.

Doctors started recognizing the discovery by the time a second study was published in 2006. That research helped launch a wave of new studies by other scientists.

Charney emphasized that as co-inventor of the drug, he holds a patent on it as does Icahn School of Medicine. He agrees with the FDA's decision to have patients monitored while being administered the nasal spray.

"I do condone that. That’s very important. Patients will feel sedated and a little dissociated. You have to check their blood pressure and pulse. So it makes sense to watch the patient," Charney said.

The drug is to be administered twice a week. 

"This is one of the most serious diseases in which suicide is a risk. So it shouldn't be an issue to come to the doctor's office twice a week." 

The nasal spray delivery method is a first of its kind. But some doctors are not ruling out hope for a pill form in the future.

“Esketamine represents the first new category of medication for depression in over 30 years, so we are all very excited by this milestone,” said Charney’s colleague, Dr. Eric Nestler, director of the Friedman Brain Institute at Mount Sinai.

Nestler noted that more research is needed to fully understand how esketamine works.

“We need to better understand esketamine’s impact on brain chemistry and long-term side effects," Nestler said. "We need to better understand how the drug works in different populations of patients. And we need to better understand how [it] exerts its rapid antidepressant effects so that orally available medications can be developed."