Spravato (esketamine) works by blocking a specific type of receptor in the brain called the NMDA receptor, which triggers a rapid surge of glutamate, the brain’s primary excitatory chemical messenger. This burst of glutamate sets off a chain reaction that helps the brain form new connections between neurons, often within hours rather than the weeks required by traditional antidepressants. It’s a fundamentally different approach from SSRIs, which work by keeping serotonin available longer in the gaps between neurons.
The Glutamate Surge
The core mechanism starts when esketamine blocks NMDA receptors on a specific type of brain cell that normally puts the brakes on neural activity. When these inhibitory cells can’t fire properly, the result is a sudden increase in glutamate release throughout key brain regions. That flood of glutamate then activates a different set of receptors called AMPA receptors on neighboring neurons, and this is where the antidepressant cascade really begins.
AMPA receptor activation triggers the release of a protein called BDNF (brain-derived neurotrophic factor), which acts as a growth signal for neurons. BDNF then switches on a cellular pathway that promotes the building of new proteins needed for synaptic connections. Research in animal models shows that esketamine restores impaired signaling along this pathway in the frontal lobe and hippocampus, two regions strongly linked to mood regulation and memory. In depressed brains, this signaling chain is often weakened or disrupted, and esketamine appears to reactivate it.
Rebuilding Lost Brain Connections
Depression physically changes the brain. Chronic stress and prolonged depressive episodes cause neurons in the prefrontal cortex to lose dendritic spines, the tiny protrusions where one neuron connects to another. Fewer spines means weaker communication between brain cells, which shows up as the cognitive fog, emotional flatness, and difficulty with decision-making that characterize treatment-resistant depression.
Esketamine reverses this process remarkably fast. Research from the National Institutes of Health found that ketamine (esketamine’s closely related parent compound) enhances the formation of new dendritic spines in the prefrontal cortex within 2 to 4 hours of administration. That timing matches the window when patients first notice mood improvement. This early spine formation is transient on its own, but it sets the stage for longer-lasting changes: by 12 hours after treatment, overall spine density increases and remains elevated. The process depends on dopamine signaling and a specific enzyme called Protein Kinase A inside the neuron, which helps stabilize these new connections.
Think of it as the brain regaining the ability to rewire itself in response to positive experiences. The initial glutamate surge opens a window of heightened plasticity, and the structural changes that follow help sustain the antidepressant effect over time.
Which Brain Regions Are Affected
Spravato doesn’t act uniformly across the entire brain. Its effects are concentrated in regions central to mood processing, and the changes differ by subregion. The anterior cingulate cortex (ACC), a strip of tissue deep in the front of the brain involved in emotional regulation and motivation, is one of the primary targets. In people with treatment-resistant depression, communication patterns between the ACC and other brain areas are often disrupted.
Imaging studies show that esketamine reshapes how the ACC connects to other regions. Specifically, it changes the communication between the ACC and the insula (a region that processes bodily awareness and emotional intensity), and these connectivity changes correlate with improvements in depression scores. Different subregions of the ACC also show altered connections to the hippocampus, the posterior cingulate cortex, and areas involved in pain and social processing. These shifts suggest that esketamine doesn’t just boost mood in a general sense. It recalibrates the networks that govern how you experience emotions, process rewards, and evaluate your own internal state.
Why It Works So Much Faster Than SSRIs
Traditional antidepressants like SSRIs and SNRIs work by gradually increasing the availability of serotonin or norepinephrine in the brain. This process requires the brain to slowly adapt its receptor sensitivity over several weeks, which is why most people don’t feel meaningful relief for 4 to 6 weeks. Some never respond at all.
Spravato bypasses that slow adaptation entirely. By acting directly on glutamate, the brain’s most abundant neurotransmitter, it produces changes in neural connectivity within hours. As Johns Hopkins Medicine describes it, esketamine “immediately impacts brain cells, offering relief from depressive symptoms within hours.” This speed is particularly important for people in crisis or those who have already failed multiple antidepressant trials.
What Causes the Dissociative Side Effects
The same glutamate surge that drives Spravato’s antidepressant effect also produces its most notable side effect: dissociation, a temporary feeling of detachment from your body, surroundings, or sense of reality. This happens because NMDA receptor blockade disrupts normal sensory processing and self-awareness circuits in the brain, particularly at higher doses.
An important finding from clinical development is that dissociation is not required for the antidepressant effect to work. Janssen’s clinical trials specifically tested this question and found that patients who experienced little or no dissociation still achieved antidepressant responses. The two effects travel through overlapping but separable pathways. There also appears to be a ceiling: increasing the dose beyond a certain plasma concentration intensifies dissociative and psychotic-like side effects without improving the antidepressant benefit.
This is one reason Spravato is administered in a healthcare setting. Patients are monitored for at least 2 hours after each dose to ensure dissociative effects have resolved before they leave.
Treatment Schedule and Long-Term Protection
The dosing schedule is designed to match the biology of how these brain changes develop and stabilize. During the first four weeks (the induction phase), treatments are given twice weekly to build up synaptic changes. After that, frequency drops to once weekly, and during long-term maintenance, sessions can be spaced to every two weeks depending on how well symptoms stay controlled.
Continuing treatment matters. A major relapse-prevention trial followed 297 adults with treatment-resistant depression who had improved on Spravato. Among those who had achieved stable remission, 26.7% relapsed when they continued Spravato alongside an oral antidepressant, compared to 45.3% who relapsed when switched to an oral antidepressant plus placebo. That translates to a 51% reduction in relapse risk. For patients who had achieved stable response (improved but not fully remitted), the protection was even stronger: continuing Spravato reduced relapse risk by 70%.
These numbers suggest that while Spravato can rapidly rebuild neural connections, maintaining those connections requires ongoing treatment for many patients. The brain changes it produces are real and measurable, but for people with treatment-resistant depression, the underlying vulnerability remains, and periodic reinforcement helps keep the new wiring intact.