Gregory Mattingly, MD: What FDA’s Approval of Esketamine as Monotherapy Means for Treatment-Resistant Depression

Johnson & Johnson announced on January 21, 2025, that the US Food and Drug Administration approved esketamine (SPRAVATO) CIII nasal spray as the first monotherapy for adults with treatment-resistant depression.

The submission of the supplemental New Drug Application (sNDA) included a phase 4 randomized, double-blind, multicenter, placebo-controlled study showing that esketamine brought rapid and superior improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 weeks compared with placebo. At week 4, 22.5% of patients on esketamine achieved remission, indicated by a MADRS total score ≤ 12, compared with 7.6% on placebo.

The study did not identify any new safety concerns with esketamine, staying consistent with existing evidence in clinical and real-world settings.

HCPLive spoke with lead investigator Gregory Mattingly, MD, president of the Midwest Research Group and founding partner of St. Charles Psychiatric Associates, on what this FDA approval means for the treatment landscape of treatment-resistant depression.

“This marks a landmark indication by the FDA and that this is the first medicine that we'll be able to use intermittently as needed for patients,” Mattingly said. “No longer do they have to take a daily antidepressant. They can come and take SPRAVATO as needed…up until now, everything we've taken, you [had] to take it once a day. This will be the first treatment that is not tied to a daily antidepressant.”

Mattingly said if he would describe this approval with any word, it would be “freedom.”

“It allows patients the freedom to take medicine as needed when needed for their depression,” he said.

Many people with treatment-resistant depression do not respond to antidepressants, making them reluctant to keep taking them with little benefit and still adverse events, such as weight gain.

Esketamine works differently than antidepressants, hitting different chemicals. This drug has a rapid action, working within hours or 1 – 2 days.

“It's the first of what we call a new class of rapid-acting antidepressants,” Mattingly said.

Now with esketamine as a monotherapy option, patients have a choice whether to stay on antidepressants or switch to a treatment option that does not require antidepressants. Other medicines that also work through the glutamate cascade are currently being studied.

“We now see a host of medicines in development that target different steps along that glutamate pathway,” Mattingly said.

References

Derman, C. FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression. HCPLive. January 21, 2025. https://www.hcplive.com/view/fda-approves-esketamine-first-monotherapy-treatment-resistant-depression. Accessed January 22, 2025.