If you’ve been living with depression that hasn’t responded to antidepressants, you’ve likely heard the word “treatment-resistant” more times than you’d like. You’ve tried the medications. You’ve waited the weeks it takes for them to potentially kick in. And for one reason or another, they haven’t given you the relief you were hoping for.
Spravato was developed specifically for people in that situation. It is an FDA-approved esketamine nasal spray that works differently from every antidepressant that came before it. Understanding how it works helps explain why some many people who haven’t found relief through other treatments find it here.
To understand Spravato, it helps to understand why traditional antidepressants work the way they do — and why they sometimes don’t.
Most antidepressants, including SSRIs and SNRIs, work by increasing levels of serotonin, norepinephrine, or dopamine. These are neurotransmitters — chemical messengers that allow brain cells to communicate with each other. The thinking behind these medications is that depression is linked to low levels of these chemicals, and that boosting them will improve mood over time.
For many people, this approach works. But for others, it doesn’t — and researchers have come to understand that depression is more complex than a simple neurotransmitter deficiency. In people with treatment-resistant depression, there is often significant structural and functional impairment in the synapses — the connections between brain cells — particularly in regions of the brain responsible for mood and emotional behavior. No amount of serotonin adjustment is going to rebuild those connections.
That’s where Spravato comes in.
Spravato targets a completely different system in the brain. Rather than acting on serotonin or dopamine pathways, it targets NMDA receptors — a type of receptor involved in regulating glutamate, the most abundant excitatory neurotransmitter in the brain.
Glutamate plays a critical role in synaptic plasticity: the brain’s ability to form, strengthen, and maintain connections between neurons. It is essential for learning, memory, and mood regulation. In people with depression, glutamate signaling is often disrupted, and the neural circuits that regulate mood and emotional processing become weakened.
When Spravato is administered, it blocks NMDA receptors on certain inhibitory neurons. This triggers a cascade of activity that enhances glutamate signaling in key brain regions — including the prefrontal cortex, hippocampus, and amygdala — areas directly involved in how we process emotions and regulate mood.
The increase in glutamate activity sets off a downstream chain of events that researchers believe is central to Spravato’s antidepressant effect. The enhanced glutamate signaling stimulates the production of brain-derived neurotrophic factor (BDNF), a protein that supports the growth and maintenance of neurons. This, in turn, activates signaling pathways that promote synaptogenesis — the formation of new connections between brain cells.
In practical terms, Spravato is thought to help rebuild the synaptic connections that depression has weakened or destroyed. As neuroplasticity increases, the brain becomes better able to cope with stress, regulate emotion, and form new, more constructive patterns of thought and behavior. The fog begins to lift — not because there’s more serotonin in the system, but because the brain’s underlying wiring is being repaired and restored.
This mechanism is fundamentally different from anything that came before it. As one Johns Hopkins psychiatrist described it, esketamine is the first mechanistically novel antidepressant in decades — not simply a refinement of existing drugs, but an entirely new approach to treating depression at its roots.
One of the most striking things about Spravato is how quickly it works. Traditional antidepressants can take four to six weeks to produce a noticeable effect, and that’s assuming they work at all. Spravato’s effects can occur within hours — and often within 24 hours of the first treatment.
The reason comes back to the mechanism. Rather than slowly adjusting neurotransmitter levels over weeks, Spravato triggers an almost immediate response at the receptor level, rapidly promoting the synaptic changes that lead to symptom relief. For someone in the depths of severe depression — especially someone experiencing suicidal thoughts — that speed is not just a convenience. It can be life-changing.
Spravato is not something you take at home. It is a controlled substance administered in a certified clinical setting, under direct supervision of a healthcare provider. At Advantage TMS, that means getting settled comfortably in our private Spravato treatment room, administering the nasal spray, and then relaxing while our team monitors you for two hours. You cannot drive yourself home after a session, so you will need to arrange a ride or rideshare transportation.
During and after the session, some patients experience temporary dissociation — a feeling of being spacey, disconnected, or sedated. Nausea and dizziness are also possible. These side effects typically peak around 40 minutes after administration and resolve within the two-hour monitoring window, though you may feel tired for the remainder of the day. Our team monitors you throughout to ensure your comfort and safety.
Our Spravato program is led by Dr. Rizzo, a board-certified psychiatrist, and Cathi Stephens, a board-certified psychiatric nurse practitioner, both of whom specialize in treating treatment-resistant depression. Beyond the clinical care, patients also have access to free group therapy twice a week led by our full-time Licensed Clinical Social Worker, and free monthly events like sound bowls, yoga, and trivia nights. We’ve been a family-owned practice for ten years, and the personal attention we give every patient reflects that.
If you’ve tried antidepressants without success and are wondering whether there’s something else that might help, Spravato may be worth exploring. Contact Advantage TMS today to schedule a free consultation and learn whether you qualify.
Raza, A. A., Ahmed, G. U., Zafar, H., Akhtar, S. O., Bin Mobin, M., & Samadi, A. (2025). Spravato for Treatment-Resistant Depression: Efficacy and Sexual Side Effect Profile. Neuropsychiatric disease and treatment, 21, 2125–2140. https://doi.org/10.2147/NDT.S548944
Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M. (2020). Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatric disease and treatment, 16, 221–234. https://doi.org/10.2147/NDT.S198774
Bathina, S., & Das, U. N. (2015). Brain-derived neurotrophic factor and its clinical implications. Archives of medical science : AMS, 11(6), 1164–1178. https://doi.org/10.5114/aoms.2015.56342
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