FDA Expands Approval of Ketamine-Derived Spravato for Treatment-Resistant Depression

The U.S. Food and Drug Administration (FDA) has expanded its approval of Spravato (esketamine), a ketamine-derived nasal spray, allowing its use as a standalone therapy for adults suffering from treatment-resistant depression (TRD). Previously, patients using Spravato were required to pair it with an oral antidepressant. The new approval removes that requirement, making the treatment more accessible to those who cannot tolerate oral antidepressants.  

“This really makes the therapy so much more accessible to patients,” said Dr. Haviva Malina, co-founder of the ketamine infusion clinic Keta Medical Center. “A lot of patients experience adverse effects from antidepressants or feel they don’t work as they’d like. Now, they don’t have to be on concurrent antidepressants.”  

A Revolutionary Option for TRD  

Spravato, first approved in 2019, provides hope to nearly one-third of adults with major depressive disorder who show little response to oral antidepressants. The nasal spray, administered under a healthcare provider's supervision, utilizes esketamine—a molecule derived from ketamine, which is FDA-approved as an anesthetic.  

The updated approval stems from clinical trial data demonstrating Spravato’s effectiveness as a monotherapy. In a study comparing Spravato as a standalone treatment to a placebo, 22.5% of participants achieved remission from depression symptoms within four weeks, compared to 7.6% of those taking the placebo.  

This data cleared a “high bar” to receive FDA authorization, according to Dr. Gerard Sanacora, director of the Yale Depression Research Program. However, he emphasized that managing TRD often requires more than medication alone. Close follow-ups with mental health professionals remain critical.  

“[Patients taking Spravato] may not have to be on another oral antidepressant medication, but that doesn’t mean they shouldn’t be followed closely by a mental healthcare professional,” Sanacora said.  

How Spravato Works  

Clinical trials show that patients may notice improvements in depressive symptoms as quickly as 24 hours after beginning treatment. Spravato works by targeting neural pathways in the brain differently from traditional antidepressants, which often take weeks to take effect.  

Typically, dosing involves twice-weekly administration during the first month, then reducing to once per week for another month. After the initial eight weeks, patients may receive Spravato every one to two weeks, depending on their needs.  

Dr. Malina noted that some patients feel better after just a few treatments, while others may return for maintenance doses for months or years, depending on life circumstances. “The treatment is tailored to each individual and their needs. You can come in weekly during difficult times and space treatments out during calmer periods,” Malina said.  

Safety and Monitoring  

Esketamine treatment comes with safety measures under the FDA’s Risk Evaluation and Mitigation Strategy (REMS) program, which requires patients to administer Spravato in a clinic under a healthcare provider’s supervision.  

“Esketamine’s safety profile is well studied, and we probably know more about its adverse events than those of many other antidepressants,” Dr. Sanacora explained.  

Spravato can cause psychedelic effects, including altered perception and cognition. Healthcare professionals monitor these effects during treatment and provide emotional support alongside medical supervision. “Patients enter a temporary, dream-like state during treatment, but it is transient,” said Malina. “We ensure patients are supported emotionally and medically throughout the process.”  

Ketamine and the Future of Depression Treatments  

Spravato is the only ketamine-derived drug currently approved by the FDA for psychiatric conditions. However, ketamine therapy is increasingly offered off-label in clinics for conditions such as depression, anxiety, and post-traumatic stress disorder (PTSD). These treatments may involve intravenous infusions or oral tablets.  

“In our center, we’ve seen incredible results with Spravato and ketamine in general,” Malina said. “A majority of our patients respond quickly, experience few side effects, and achieve mood and motivation improvements that traditional medications cannot match.”  

Looking ahead, researchers are actively studying new drugs targeting the same neural pathways as ketamine, aiming to replicate antidepressant benefits without the hallucinogenic side effects.  

“This is an unprecedented moment in the field of psychiatric medicine," said Sanacora. “There’s immense promise with psychedelic treatments, but challenges such as abuse potential and cognitive effects must be addressed with care. It’s an exciting and complex time for innovation in depression treatment.”  

The FDA’s expanded approval of Spravato offers renewed hope for people living with TRD, marking progress in personalized and rapidly effective mental health care.