For years, doctors prescribing esketamine, the nasal spray sold under the brand name Spravato, had to pair it with a daily oral antidepressant. That requirement recently changed. Regulators cleared the drug for use on its own, a shift that matters most for patients who cannot tolerate standard antidepressants at all, not just the ones who have already failed a few of them.
A Narrow Approval With a Wide Impact
Spravato first reached the market in 2019, approved specifically as an add-on for adults with treatment-resistant depression who were already taking a separate antidepressant. The drug is a derivative of ketamine and works differently than most standard medications, acting on glutamate, the brain's most abundant excitatory neurotransmitter, rather than the serotonin pathways targeted by SSRIs.
The newer approval lets clinicians prescribe esketamine as a standalone treatment for major depressive disorder, without requiring a second daily medication. Clinical trial data cited in the FDA approval showed measurable improvement in depression scores compared to placebo within 24 hours, with effects holding through the 28 day study window. For patients who have struggled with side effects from oral antidepressants, or who simply want fewer daily pills, that flexibility is a meaningful change in how treatment plans get built.
Why the REMS Program Still Applies
Despite the expanded approval, esketamine remains tightly controlled. It is only available through a restricted distribution program, known as a Risk Evaluation and Mitigation Strategy, because of risks tied to sedation, dissociation, and potential misuse. Patients cannot fill a Spravato prescription at a pharmacy and take it home. It has to be self-administered under direct supervision in a certified healthcare setting, with monitoring for at least two hours afterward to watch for elevated blood pressure or lingering sedation.
That structure is part of why esketamine has stayed a clinic-based treatment rather than a take-home prescription, even as its approved use has broadened. Psychiatrists say the monitoring requirement, while inconvenient for some patients, is also what has kept the drug's safety record consistent since it first launched.
Who Is Actually a Candidate
Treatment-resistant depression is generally defined as major depressive disorder that has not improved after at least two different antidepressants, taken at adequate doses for a long enough stretch. Researchers estimate that roughly 30 percent of people with major depression fall into that category at some point, a population that runs into the millions nationally.
Clinics that focus on mood disorders have expanded their esketamine programs as awareness has grown. Village TMS's Spravato program in Manhattan is one example of a practice built specifically around evaluating candidates for the therapy, screening for the antidepressant history and clinical criteria that typically determine eligibility before a patient starts treatment.
How Esketam
ine Compares to Other Ketamine-Based Options
Esketamine is not the only ketamine-derived option available for depression that has not responded to standard care. Generic IV and intramuscular ketamine are used off-label at many clinics, a route some patients prefer for reasons ranging from dosing flexibility to cost, though it carries a different regulatory status and a different insurance picture entirely. Patients weighing the two are usually encouraged to understand how Spravato stacks up against IV ketamine infusions before choosing a path, since the two options differ in FDA status, administration, and typical course length.
That distinction matters practically as much as clinically. Because esketamine carries FDA approval for a specific indication, it tends to have a clearer path through insurance review than off-label ketamine, which most insurers still treat as investigational for mental health use.
What This Means Going Forward
The expanded approval does not turn esketamine into a first-line treatment, and psychiatrists are not treating it that way. It remains a tool reserved for depression that has resisted standard care, deployed after other options have been tried and found lacking. What has changed is the flexibility around how it is prescribed, which gives psychiatrists one more way to tailor treatment to a patient who has already been through a difficult and often discouraging search for something that works.
What Patients Should Ask Before Starting
Psychiatrists who prescribe esketamine generally recommend a handful of questions before a patient commits to a course of treatment. How many antidepressant trials have actually failed, and were they given at an adequate dose for long enough to count? What does insurance cover, and does the plan require prior authorization or documentation of past treatment attempts? What does a typical course look like in terms of frequency, since dosing usually starts more often per week and tapers as symptoms improve? And what happens if the first few sessions do not produce a noticeable change, since response can take a few weeks to become clear even when the treatment eventually works.
Those questions matter because esketamine is not risk-free and is not guaranteed to work for every patient who tries it. Clinical trial data shows a meaningful share of patients respond. Still, response rates are not universal, and the REMS monitoring requirement means the treatment asks for a real-time commitment: repeated in-person visits, each with a supervised dosing period and a recovery window before a patient can drive home.
Conclusion
For people who have already spent years cycling through antidepressants without relief, though, that time commitment tends to look different than it would to someone just starting treatment. A structured, monitored option with a clearer regulatory path through insurance is, for many, worth the extra logistics.
For a condition that affects millions of Americans and rarely responds to a one-size-fits-all approach, the flexibility of a standalone option is a small but real expansion of what is on the table.
This article is for general informational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always consult a qualified health provider with questions about a medical condition.