Can Spravato Work on Its Own? Here’s What the Latest Research Says

If you’re struggling with depression, chances are you’ve tried more than one treatment option or maybe even several antidepressants. And if you’re exploring Spravato (known generically as esketamine), you may be wondering: does it only work when paired with another antidepressant? Or can it help on its own?

For years, a common approach with Spravato has been to combine it with an oral antidepressant. But a new 2025 study offers encouraging news: Spravato alone can significantly reduce symptoms of depression in patients who haven’t had success with other medications. At New Pathways Clinic, IV ketamine therapy is also provided as a monotherapy; in fact, the vast amount of research conducted on ketamine treats it as a monotherapy subject. 

What the Study Looked At

This peer-reviewed research, published in JAMA Psychiatry, included 378 adults diagnosed with treatment-resistant depression. That means they had already tried other medications and hadn’t found enough relief.

Rather than adding Spravato to another antidepressant, this study tested it as a monotherapy (a standalone treatment). Over four weeks, patients received either Spravato nasal spray or a placebo, twice per week.

The results were promising. 

Patients who received Spravato showed a significant improvement in their depression symptoms compared to those receiving the placebo. Some even began to feel relief within 24 hours of the first treatment.

Importantly, this trial confirms that Spravato isn’t only effective when combined with other medications; it can also work independently.

What This Means for You

This research supports what many of our patients have been asking and experiencing: that Spravato may be a viable option even if you’re no longer taking or no longer wish to take oral antidepressants.

If you’ve felt like antidepressants haven’t worked—or if you’re worn out from side effects that disrupt your day-to-day life—you’re not alone. Many people come to us after trying multiple medications over the years, only to feel stuck, numb, or discouraged. 

Spravato offers something different. It targets a different pathway in the brain: the glutamate system, which plays a major role in mood regulation, learning, and memory. That’s a big shift from traditional antidepressants, which work by adjusting serotonin or norepinephrine levels (meaning targeting only the surface-level symptoms rather than the neural networks that help make you who you are). 

Because of this unique mechanism, Spravato tends to act much faster than typical medications. Instead of waiting four to six weeks to notice a difference, many patients begin to feel relief within hours or days. That might look like a slight lifting of the fog, more energy, a more hopeful outlook, or simply a sense of feeling something again. While it’s not a magic fix, it can be a powerful step forward, especially when other options have fallen short.

Spravato does require in-clinic administration and close medical supervision. You’ll receive it in a safe, comfortable setting at New Pathways Clinic’s locations where your care team can guide you through each step of treatment.

Still Not Sure?

You don’t have to be in crisis to consider ketamine therapy. If you’ve tried a few options and still don’t feel like yourself, you’re not alone and you’re not out of options.

New Pathways offers a compassionate, professional space to explore what comes next. Whether that’s Spravato or IV ketamine, we’ll help you determine the best approach for your goals, your history, and your healing.