Esketamine Nasal Spray for Treatment-Resistant Depression

Esketamine nasal spray is a prescription antidepressant that works through a fundamentally different brain pathway than traditional antidepressants, and it can begin reducing symptoms within hours rather than weeks. Approved under the brand name Spravato, it is the S-enantiomer of ketamine, delivered as a self-administered nasal spray under medical supervision. Its speed and novel mechanism have made it one of the most closely watched developments in psychiatry in years, but the reality of how it is used, who benefits most, and what the tradeoffs look like is more complicated than the headlines suggest.

How It Works in the Brain

Most conventional antidepressants target serotonin, norepinephrine, or dopamine. Esketamine takes a different route entirely. It blocks a receptor called NMDA, which is part of the glutamate signaling system. Glutamate is the brain’s primary excitatory chemical messenger, and NMDA receptors play a central role in how neurons communicate and adapt. Esketamine binds to these receptors with roughly two to three times the strength of its mirror-image molecule, R-ketamine, which is one reason it was developed as the active drug rather than using the full racemic mixture.¹

When esketamine blocks NMDA receptors on certain inhibitory neurons, it triggers a rapid surge of glutamate. That surge then activates a second type of receptor, AMPA, which kicks off a cascade of downstream effects related to synaptic plasticity, essentially the brain’s ability to strengthen and rewire its connections.² This chain of events is thought to be why the drug acts so fast: rather than slowly shifting the balance of neurotransmitters over weeks, it rapidly boosts signaling pathways that promote new synaptic growth.

Animal studies have shown that esketamine increases the density and maturity of dendritic spines, the tiny protrusions on neurons where connections form, particularly in the prefrontal cortex.³ It also activates a molecular pathway involving BDNF, a protein that supports neuron survival and growth, along with downstream signaling molecules that protect against the kind of oxidative damage and cell death seen in depression.⁴ Early human imaging work has now started to confirm part of this story: a study of patients with treatment-resistant depression found signs of increased dendritic complexity in a key brain region after just two weeks of esketamine treatment.⁵

Who It Is Approved For

Esketamine nasal spray currently has two approved indications in the United States. The first and most established is treatment-resistant depression, generally defined as depression that has not adequately responded to at least two different oral antidepressants at proper doses and durations. The second, added later, covers adults with major depressive disorder who have active suicidal thoughts or behavior, where the need for rapid symptom relief is urgent. In both cases, esketamine is always used alongside an oral antidepressant, not as a standalone treatment.

For the suicidality indication, clinical trials showed that esketamine plus standard care produced meaningfully greater improvement in depression scores compared to placebo plus standard care at 24 hours, with the separation between groups already visible at the 4-hour mark.⁶ In a separate analysis, the median time to remission was about 15 days with esketamine versus 23 days with placebo, and a greater share of patients reached remission by day 25.⁷

Speed of Action and What Happens After the Spray

When you spray esketamine into your nose, about half of the drug reaches the bloodstream, and blood levels peak within 20 to 40 minutes.⁸ That fast absorption is part of what makes early clinical effects possible the same day. However, that speed also means side effects tend to hit quickly and hard before fading.

Doses come in 56 mg and 84 mg. In the induction phase, you typically receive treatment twice a week for the first four weeks, then taper to once a week, and eventually to once every week or two for maintenance. A key maintenance study found that continuing esketamine plus an antidepressant cut the risk of relapse by about half among patients who had reached stable remission, compared to switching to antidepressant plus placebo. Among patients who had achieved stable response (improvement but not full remission), the risk reduction was even larger, around 70%.⁹

The Mixed Trial Results That Complicate the Story

Not every pivotal trial cleared statistical significance. In one study (TRANSFORM-1), the 84 mg dose plus a new antidepressant did not achieve a statistically significant difference over antidepressant plus placebo, though the 56 mg dose showed a nominally significant benefit.¹⁰ Another trial conducted in China and the United States also missed its primary endpoint at day 28, even though an early and clinically meaningful separation favoring esketamine appeared at 24 hours after the first dose.¹¹

These mixed results do not invalidate esketamine, but they do indicate that its advantage over a well-chosen oral antidepressant is not always dramatic, especially at the 28-day mark when oral drugs have had time to kick in. The clearest advantages tend to show up in the first hours and days, and in the relapse-prevention data. Some researchers have pointed out that the active-placebo problem is especially tricky here: patients receiving esketamine know something is happening to them (dissociation, dizziness), which could partially unblind the studies. It is a real methodological concern, though it does not fully explain the positive results either.

Who Responds Best

A pooled analysis of two acute trials identified several factors linked to better outcomes. Younger patients, those who were employed, and those who had failed fewer prior antidepressants in their current episode were more likely to respond and reach remission by day 28. An early signal also helped predict who would benefit: patients whose overall severity had improved by day 8 were significantly more likely to keep improving. Among those on esketamine specifically, the absence of significant baseline anxiety was also a positive predictor.¹²

That early-improvement signal is practically useful. If you are not seeing any change by the end of the first week or two, your clinician may weigh whether to continue, adjust the dose, or try something else.

Side Effects and What to Expect on Treatment Day

Esketamine is administered in a certified healthcare setting, and you stay for at least two hours after each dose. That is not just regulatory caution. The drug routinely causes dissociation (feeling detached from yourself or your surroundings), dizziness, sedation, and temporary increases in blood pressure. These effects are real and can be unsettling, though they typically peak within about 40 minutes and resolve within an hour and a half.¹³

On the blood pressure front, roughly one in eight patients experiences an adverse event related to elevated blood pressure, compared to about one in 25 on antidepressant plus placebo.¹⁴ These increases are almost always transient and resolve during the monitoring period, but esketamine is generally not suitable for people with uncontrolled hypertension or conditions where a sudden blood pressure spike would be dangerous.

Dissociation is the side effect patients tend to find most striking. One study tracking dissociative symptoms across repeated sessions found that they spiked shortly after dosing but returned to baseline within about 40 minutes. The encouraging finding was that dissociative symptoms generally decreased with repeated treatments, even in a patient who already had preexisting dissociative symptoms before starting esketamine.¹⁵

In the United States, patients must be monitored for at least two hours after each dose, including pulse oximetry to watch for any changes in breathing. Respiratory depression is a theoretical concern given the drug’s relationship to ketamine, so this surveillance is built into the Risk Evaluation and Mitigation Strategy (REMS) program that governs every administration.¹⁶

Abuse Potential and Long-Term Safety

Because esketamine is chemically related to ketamine, which has a well-known recreational profile, questions about abuse potential were front and center from the start. The drug carries a Schedule III classification in the United States. Evidence from clinical practice, though, has been relatively reassuring. A study that tracked liking and craving across an eight-session treatment course found that patients did not develop increasing desire for the drug over time; most reported no change or a decrease in craving from the first session to the last.¹⁷

The longest follow-up data come from the SUSTAIN-3 open-label extension, which tracked patients for up to roughly four and a half years. No evidence of cognitive decline emerged in participants under 65, and there were no emerging trends related to suicidal ideation, drug abuse, or drug dependence over that period.¹⁸ That said, the same review that synthesized these findings also noted that pharmacovigilance databases have picked up scattered reports of tolerance, withdrawal-like symptoms, and off-label use. And analysis of online forums shows that some patients enjoy the dissociative effects while others find them distressing. The supervised-only administration model is specifically designed to mitigate diversion risk.¹⁹

On the urinary side, long-term ketamine abuse is known to cause bladder damage, so this concern carries over by association. A pharmacovigilance analysis comparing the two drugs found that esketamine had lower or comparable odds of renal and urinary problems relative to ketamine, and both had lower rates than might be expected given ketamine’s recreational reputation. At the supervised doses used for depression, bladder toxicity does not appear to be a meaningful clinical issue.²⁰

What About Cognition Over Time

One of the more common worries people have about any drug that alters consciousness is whether it chips away at thinking over time. For esketamine, the available data point in the opposite direction. A systematic review of cognitive outcomes found that esketamine was not associated with cognitive decline in any tested domain. The most consistent improvements were in attention and processing speed, seen in both clinical trial data and real-world observational studies. Memory remained stable in the short term and improved in studies with longer follow-up. Executive functions improved most in patients who started with baseline impairments.²¹

A separate longitudinal study found improvements in attention, memory, working memory, and inhibitory control over six months of treatment, with most gains appearing by three months and some executive function improvements continuing to emerge at six months. These cognitive gains tracked closely with improvements in depression severity, suggesting that much of the cognitive benefit comes from treating the depression itself.²²

How It Compares to IV Ketamine and ECT

Esketamine nasal spray is not the only fast-acting option for severe depression. Intravenous racemic ketamine (the full molecule, containing both the S- and R-enantiomers) has been used off-label for depression for years, and electroconvulsive therapy (ECT) remains the long-standing gold standard for treatment-resistant cases. Where esketamine fits among these alternatives is still being sorted out.

A meta-analysis pooling data from six studies found that IV ketamine had a non-significantly higher odds of response and remission compared to intranasal esketamine, with some evidence of faster onset from individual studies.²³ An earlier meta-analysis reported larger effect sizes for racemic ketamine in both response and remission rates, along with lower dropout rates.²⁴ A real-world analysis of pooled data found IV ketamine produced larger reductions in depression scores and higher response rates after the initial treatment phase, although remission rates at that early time point were similar between the two.²⁵

These comparisons deserve a caveat. IV ketamine for depression is largely off-label, administered in variable doses and settings, and has far less regulatory-grade evidence behind it. Esketamine’s advantage is not necessarily that it works better molecule for molecule, but that it has a standardized protocol, a formal safety monitoring framework, and insurance pathways that IV ketamine often lacks.

Against ECT, the picture is different. A review found ECT was superior for reducing depressive symptoms overall. On suicidal ideation, the two treatments performed similarly. Where esketamine had an edge was cognition: patients treated with esketamine showed better attention, verbal memory, and executive function outcomes, whereas ECT is known to cause temporary cognitive disruption, particularly affecting memory. Esketamine also carried a lower risk of headache and muscle pain, though it produced more dissociative symptoms and visual disturbances.²⁶ A cost-utility analysis found ECT to be less expensive and to produce more quality-adjusted life-years than esketamine in virtually every scenario modeled.²⁷

The Cost Problem

Esketamine is expensive. A cost-effectiveness analysis projected that over five years, adding esketamine increased the proportion of time patients spent in remission from about 25% to 31% and yielded a modest gain in quality-adjusted life-years. But the associated increase in costs was substantial. The resulting cost-effectiveness ratio exceeded $230,000 per quality-adjusted life-year gained, well above the $100,000 to $150,000 threshold that health economists commonly use as a benchmark for good value. At the commonly referenced $150,000 threshold, the analysis estimated esketamine’s value-based price would be about $140 per dose, considerably below its actual price point at the time.²⁸

Insurance coverage varies. Many commercial plans and Medicare do cover esketamine, but the prior authorization process can be extensive, and the requirement that every dose be administered in a certified healthcare setting adds logistical costs beyond the price of the drug itself. For patients with truly treatment-resistant depression, the cost calculus may be different than for those with other options still untried.

Older Adults

The evidence for esketamine in people over 65 is less straightforward. The pivotal trial in older adults (TRANSFORM-3) did not reach statistical significance on its primary endpoint. A closer look at the data showed a clear age split: patients aged 65 to 74 showed a meaningful improvement over placebo, while those 75 and older showed essentially no difference. Similarly, patients whose depression began before age 55 benefited more than those with later-onset depression.²⁹

Real-world data from a naturalistic study of 30 older adults painted a more encouraging picture, with over half responding and about a third reaching remission. However, adverse effects were frequent: half reported dizziness, a third had dissociation, and about 30% experienced sedation. One in five ultimately discontinued treatment.³⁰ For older patients, the balance between potential benefit and a heavier side-effect burden requires especially careful discussion between patient and clinician, and the blood pressure monitoring component takes on added importance given the higher cardiovascular baseline risk in this age group.

What the REMS Program Actually Looks Like

Every dose of esketamine in the United States is governed by the REMS program, which is one of the most restrictive distribution frameworks the FDA uses. You cannot pick up esketamine at a pharmacy and take it at home. Each treatment session happens in a certified clinic or office. You self-administer the spray under direct supervision, then sit in the facility for at least two hours while a healthcare provider checks your blood pressure, watches for sedation and dissociation, and monitors your oxygen levels. You cannot drive for the rest of the day after treatment.

The REMS database now contains several years of real-world safety data. A comprehensive analysis covering roughly the first five years since approval (March 2019 through January 2024) evaluated patient monitoring forms and adverse event reports to track patterns of sedation, dissociation, blood pressure changes, and serious events across routine clinical use.³¹ This ongoing surveillance is one of the things that distinguishes esketamine from off-label ketamine clinics, where monitoring practices vary widely and post-treatment data collection is not standardized.

For many patients, the logistical demands of REMS are the biggest practical barrier. Twice-weekly clinic visits during the induction phase, each lasting two-plus hours, requires flexible work schedules or an understanding employer. Adding travel time, a designated driver, and the fact that treatment days are essentially half-days off, the commitment is substantial even before you consider the drug’s cost.