Of the 16 million American adults who live with depression, as many as one-quarter gain little or no benefit from available treatments, whether drugs or talk therapy. They represent perhaps the greatest unmet need in psychiatry.A newly approved treatment, called esketamine, is a nasal spray developed by Janssen Pharmaceuticals Inc., a branch of Johnson & Johnson, that will be marketed under the name Spravato. It contains an active portion of the ketamine molecule, whose antidepressant properties are not well understood yet.
“Thank goodness we now have something with a different mechanism of action than previous antidepressants,” said Dr. Erick Turner, a former F.D.A. reviewer and an associate professor of psychiatry at Oregon Health & Science University. “But I’m skeptical of the hype, because in this world it’s like Lucy holding the football for Charlie Brown: Each time we get our hopes up, the football gets pulled away.”
The generic anesthetic is already increasingly available for depression, at hundreds of clinics around the country that provide a course of intravenous treatments, and studies suggest it can help treatment-resistant people. It often causes out-of-body and hallucinogenic sensations when administered; in the 1980s and 1990s it was popular as a club drug, Special K.
The cost for these treatments typically is out of pocket, as the generic anesthetic is not approved by the F.D.A. for depression. In contrast, esketamine likely would be covered under many insurance plans, and its side effects, though similar to those of generic ketamine, are thought to be less dramatic.
The recommended course of the newly approved drug is twice a week, for four weeks, with boosters as needed, along with one of the commonly used oral antidepressants. F.D.A. approval requires that doses be taken in a doctor’s office or clinic, with patients monitored for at least two hours, and their experience entered in a registry; patients should not drive on the day of treatment.
Esketamine, like ketamine, has the potential for abuse, and both drugs can induce psychotic episodes in people who are at high risk for them. The safety monitoring will require doctors to find space for treated patients, which could present a logistical challenge, some psychiatrists said.
The wholesale cost for a course of treatment will be between $2,360 and $3,540, said Janssen, and experts said it will give the company a foothold in the $12 billion global antidepressant market, where most drugs now are generic.
The approval of esketamine marks a new approach to treating serious mood problems, experts said. Prozac and similar drugs enhance the activity of brain messengers such as serotonin; they are mildly effective, but they take weeks or months for their effects to be felt, and for many patients they provide little or no relief from depression. In contrast, the ketamine-based compounds — several others are being developed — work within hours or days, and are effective in some people who are considered “treatment resistant,” meaning they have not benefited from other antidepressants.
“These are exciting times, for sure,” said Dr. Todd Gould, an associate professor of psychiatry in the University of Maryland School of Medicine. “We have drugs that work rapidly to treat a very severe illness.” Dr. Gould was not involved in the Janssen study but has identified a metabolite, or ketamine breakdown product, that could be developed into another drug.
Experts with long experience in treating depression were encouraged by the news, but also chary. The effectiveness of the previous class of antidepressants such as Prozac and Paxil was vastly exaggerated when they came on the market. And the results of esketamine trials, which were paid for and carried out by Janssen, were mixed.
In each trial submitted, all patients were started on a new antidepressant drug, and given a course of esketamine treatment or a placebo. In one monthlong study, those on esketamine performed better statistically than those on placebo, reducing scores on a standard, 60-point depression scale by 21 points, compared to 17 points for placebo. But in two others trials, the drug did not statistically outperform placebo treatment. Historically, the F.D.A. has required that a drug succeed in two short-term trials before it is approved; the agency loosened its criteria for esketamine, opting instead to study relapse in people who did well on the drug.
In that trial, Janssen reported that only about one-quarter of subjects relapsed, compared to 45 percent of subjects who received the placebo spray. All the subjects had been given a diagnosis of treatment-resistant depression, or T.R.D., having previously failed multiple courses of drug treatment.
“We’ve had nothing new in 30 years,” said Steven Hollon, a professor of psychiatry and behavior sciences at Vanderbilt University. “So if this drug is an effective way to get a more rapid response in people who are treatment resistant, and we can use it safely, then it could be a godsend.”