The U.S. Food & Drug Administration Tuesday approved Johnson & Johnson’s ketamine-derived nasal spray Spravato for treatment-resistant depression. The green light means ketamine—an anesthetic abused as a party drug but promoted by some doctors without FDA approval as a necessary treatment for the most severely depressed patients—has spawned the first materially new depression treatment in decades.
Following early research by the National Institutes of Health, specialized clinics have offered intravenous ketamine treatments for depression on an off-label basis for many years. But since insurance companies would not pay for an unapproved treatment and psychiatrists are not accustomed to giving patients IV infusions in their offices, Johnson & Johnson began developing and running clinical trials on a related molecule, esketamine, that could receive a new FDA approval and be given to patients more conveniently.
Spravato is the brand name for esketamine, a molecular mirror-image of ketamine that’s three times more potent but can be given at a lower dose, as a nasal spray rather than injection. “We are going to try and make it very accessible to patients, as much as we can,” said Husseini Manji, global head of neuroscience therapeutics for Janssen Research & Development, a division of Johnson & Johnson, in an interview before the FDA approval announcement.
The drug is aimed at people with depression who have tried two antidepressant drugs and have not improved. Janssen is further testing the drug in people at a high risk for suicide.
To dissuade abuse and address safety concerns, Johnson & Johnson is requiring patients receiving Spravato to go to a certified facility and administer the nasal spray to themselves under the supervision of a healthcare professional twice a week for a month, then once a week or every other week on an ongoing basis. Patients will stay at the facility for two hours to be monitored for side effects including dissociation, sedation and increased blood pressure, and will need to be driven home afterwards, Manji says.
“We have not had a breakthrough treatment, a truly different treatment [for depression] in a long time,” says Michael Thase, professor of psychiatry and director of the Mood and Anxiety Disorders Treatment and Research Program in the Perelman School of Medicine at the University of Pennsylvania. Thase, who consulted for the company, served as a site principal investigator and treated patients as part of Janssen’s clinical trials of esketamine. Across studies, he says that for every five to ten patients treated with esketamine, one patient benefitted, while other treatments might treat 20 patients to see one of them benefit.
In 2016, 45,000 Americans died by suicide, the tenth leading cause of death in the U.S. The suicide rate increased 28% from 1999 to 2016, reaching 13.4 per 100,000 Americans. More than 16 million Americans experience depression and an estimated 30% to 40% are not helped by first-line treatments including antidepressants and psychotherapy. Existing treatment options for people with treatment-resistant depression include trying a new antidepressant, adding or changing psychotherapy, and electroconvulsive therapy.
As much as people with treatment-related depression need better options, the clinical trials on esketamine have not been uniformly positive. In a memo to the FDA advisory committee that voted to approve esketamine 14-2 with one abstaining on February 12, Tiffany R. Farchione, acting director of the FDA’s Division of Psychiatry Products, noted that the phase-3 clinical trial evidence supporting approval of esketamine came from one short-term study with a flexible dose and a randomized withdrawal study, when most approved antidepressants have at least two positive short-term trials. Another short-term study with designated doses did not demonstrate that esketamine helped patients more than a placebo.