Spravato (esketamine) is a nasal spray that works by blocking a specific receptor in the brain called the NMDA receptor, triggering a rapid surge of the chemical messenger glutamate. This cascade of signaling is fundamentally different from traditional antidepressants, which typically take weeks to build up effect. Spravato can produce noticeable improvements in depressive symptoms within hours of the first dose.
The Brain Chemistry Behind Spravato
Traditional antidepressants like SSRIs work by increasing serotonin levels in the brain. Spravato takes a completely different route. Its active ingredient, esketamine, blocks NMDA receptors, which are gateways on brain cells that normally respond to glutamate, the brain’s most abundant excitatory chemical messenger. When these receptors are blocked, it paradoxically causes a burst of glutamate activity elsewhere in the brain.
That glutamate surge is where things get interesting. The flood of glutamate activates a separate set of receptors (called AMPA receptors), which kick off a chain reaction inside brain cells. This chain reaction switches on a key growth pathway that does two things: it stimulates the production of a protein called BDNF (brain-derived neurotrophic factor), and it triggers the building of new synaptic connections between neurons.
BDNF acts like fertilizer for brain cells. Once released, it binds to receptors on the same neuron and creates a positive feedback loop, stimulating even more growth signaling. Animal studies show this pathway activates rapidly after a dose and stays elevated for at least 72 hours. The regions most affected are the prefrontal cortex (involved in decision-making and emotional regulation), the hippocampus (critical for memory and mood), and the amygdala (which processes emotions). These are exactly the areas where chronic depression causes neurons to shrink and lose connections.
Why It Works So Much Faster Than Other Antidepressants
SSRIs, SNRIs, and other conventional antidepressants need weeks to gradually shift brain chemistry and promote neural changes. Spravato’s mechanism bypasses that slow buildup entirely. By flooding the brain with glutamate signaling all at once, it rapidly stimulates the growth of new dendritic spines, the tiny protrusions on neurons where connections form. Research shows this new spine growth occurs in the prefrontal cortex within hours.
In clinical trials, patients showed statistically significant improvements in depression scores within 24 hours of their first dose. Across Phase 3 trials, benefits emerged within hours and were maintained throughout treatment. This makes esketamine the fastest-acting antidepressant currently available.
Esketamine vs. Ketamine
Ketamine, the parent drug, is a mixture of two mirror-image molecules. Esketamine is the isolated “S” form of that molecule, and it binds to the NMDA receptor with about four times the potency of the mixed version. That higher potency means lower doses can be used, which reduces the intensity of dissociative side effects. This distinction is part of what made esketamine viable as an FDA-approved, standardized treatment rather than the off-label IV ketamine infusions some clinics offer.
What Happens During a Treatment Session
Spravato isn’t something you take at home. It’s only available through a restricted program that requires administration in a certified healthcare setting. You spray the medication into your nose yourself under supervision, but you must remain at the clinic for at least two hours afterward. During that observation window, staff monitor your blood pressure, sedation level, and any dissociative symptoms before clearing you to leave. You cannot drive for the rest of the day after a session.
The first dose is always 56 mg. Starting at the second session (day 4), your provider can increase the dose to 84 mg based on how you respond and how well you tolerate the medication. During the initial four-week induction phase, sessions happen twice per week. After that, the frequency drops. In the maintenance phase, sessions typically occur once a week or once every two weeks, depending on how well your symptoms stay controlled. Your provider adjusts the frequency over time based on your depression scores.
How Well It Works in Clinical Trials
Spravato is not a standalone treatment. It’s always prescribed alongside an oral antidepressant. In the largest long-term study (SUSTAIN-3), about half of patients achieved at least a 50% reduction in their depression scores by day 28 of treatment. Remission, meaning symptoms dropped to minimal levels, occurred in 35.6% of patients by the end of the four-week induction phase. That number continued to climb: by the one-year mark, 50.9% of patients had reached remission.
These results are notable because Spravato is specifically approved for people whose depression has already resisted treatment. To qualify, patients must have tried at least two different antidepressants at adequate doses and durations without sufficient improvement. Spravato is also approved for adults with major depressive disorder who have acute suicidal ideation or behavior, though the FDA notes its effectiveness in actually preventing suicide has not been demonstrated.
Common Side Effects
The two most characteristic side effects are dissociation and a temporary rise in blood pressure, both of which typically peak within the two-hour observation window.
Dissociation, a feeling of being detached from your body or surroundings, is one of the most frequently reported experiences. It’s generally mild to moderate and resolves before you leave the clinic. This is part of why the observation period exists.
Blood pressure increases were reported in about 12.8% of patients across Phase 2 and 3 clinical trials, compared to 3.9% in patients receiving a placebo nasal spray. Real-world data from nearly 60,000 patients tracked through the safety monitoring program showed a similar rate of 11.7%. In a long-term safety study of over 1,100 patients, blood pressure-related side effects occurred in about 20% of participants, though serious events like hypertensive emergency were rare (0.1%). The blood pressure rise is transient, typically resolving within the monitoring period, but it’s the reason clinics check your vitals before and after each dose.
Other commonly reported side effects include nausea, dizziness, a feeling of spinning, and sedation. Most of these are short-lived and confined to the hours immediately following treatment.