FDA Approves Esketamine for Depressive, Suicidal Symptoms

This week, the US Food and Drug Administration (FDA) approved the supplemental New Drug Application (sNDA) for esketamine nasal spray (SPRAVATO) or the treatment of depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior.

The approval, granted to Janssen Pharmaceutical Companies, makes esketamine the first and only marketed therapy to capability in reducing depressive symptoms within 24 hours of administration.

The sNDA approval is based on a pair of identical phase 3 clinical trials assessing esketamine plus comprehensive standard of care. The standard of care included initial patient hospitalization, newly initiated or optimized oral antidepressant therapy, and twice-weekly treatment visits for 4 weeks.

In that time period, patients received esketamine 84 mg or placebo nasal spray.

Investigators observed a significant reduction of depressive symptoms within 24 hours—with a smaller portion of patients reporting treatment response as soon as within 4 hours.

A combination of esketamine and standard of care resulted in a 15.9- and 16-point decrease in each trial group on the Montgomery-Asberg Depression Rating Scale (MADRS)—versus redutions of 12.0 and 12.2 points in the placebo-plus-therapy arm.

Both patient treatment arms continued improvement between 4 hours and 25 days; 41% and 43% of the trials’ esketamine patients achieved clinical depression remission, versus 34% and 27% of placebo patients.

Esketamine’s effectiveness has not been shown to prevent suicide or reducing suicidal ideation and/or behavior in treated patients, and its use does not preclude the need for clinically-warranted hospitalization—even among improved patients.

SPRAVATO includes a Boxed Warning regarding a Risk Evaluation and Mitigation Strategy (REMS) for the risk of suicidal thoughts and behaviors.

Esketmine clinical investigator Gerard Sanacora, PhD, MD, Director of the Yale Depression Research Program and Co-Director of the Yale New Haven Hospital Interventional Psychiatry Service, called it “astonishing” that patients with suicidal ideation were previously excluded from most trials assessing antidepressant treatment efficacy.

“There is an immense need for high quality evidence showing effective and rapid antidepressant action in this population," Sanacora said in a statement. "The clinical trials supporting this new indication provide compelling evidence that esketamine may offer clinicians a new way to provide support to patients quickly in the midst of an urgent depressive episode and help set them on the path to remission."

In an interview with HCPLive®, Dan Iosifescu, MD, Associate Professor of Psychiatry at NYU School of Medicine and Director of Clinical Research at Nathan Kline Institute, explained both ketamine and esketamine carry “caveats” of unique cognitive effects shortly after administration, as well as increases in blood pressure and heart rate.

That said, the immediate benefits of esketamine for eligible patients makes it a valuable addition to psychiatric care.

“For the majority of patients who benefit from it, it will be essentially buying them time for other treatments—be them pharmacotherapies, device-based treatments, or psychotherapies—to be effective, because those are starting to work much slower than ketamine does,” Iosifescu explained.