Spravato (esketamine) explained: how it works in the brain

By Nefretiri Abat, PMHNP-BC, JD — Founder, Exxceed Wellness

If you have lived with depression long enough to fail two or three medications, you already know the math. You wait six to eight weeks for an SSRI to do something. It doesn’t. You taper, switch, wait again. Spravato is the first depression treatment that breaks that timeline — and the reason it works so quickly has almost nothing to do with serotonin.

Most patients arrive at our Hayward office with the same story. They have done the diligent thing — Lexapro, Zoloft, Wellbutrin, maybe Cymbalta or Effexor on top of one of those. Sometimes Trintellix. Sometimes lithium augmentation. They have read enough to know the language. What they want to know on the first visit is simple: why didn’t any of that work, and why is this one supposed to be different?

The honest answer requires a short detour into how the brain produces a depressive episode in the first place. It is not a serotonin shortage. That story has been quietly retired in the research literature for a decade, even though it lives on in pharmaceutical advertising.[1] What modern psychiatry now thinks is happening in treatment-resistant depression looks more like a structural problem — a kind of architectural collapse in the parts of the brain that hold mood, motivation, and cognition together.

The synapse, briefly

Picture a synapse as a handshake between two brain cells. The strength of that handshake — how reliably one neuron can talk to the next — depends on a tiny structure called a dendritic spine. In a healthy prefrontal cortex, those spines are dense, branched, and constantly being remodeled. In chronic depression, they thin out. Stress hormones, sustained inflammation, and the long fatigue of an unresolved depressive episode all push the same direction: fewer spines, weaker synapses, less signal between the regions of the brain that govern emotional regulation.[2,3]

This is the part that helps the rest of the explanation make sense. Depression, at the cellular level, is partly a deficit of synaptic connectivity. Anything that wants to treat it durably has to do something about that deficit.

Why SSRIs are slow

SSRIs raise serotonin in the synapse within hours of the first dose. Patients sometimes get hopeful when they hear this. Then they take the pill for two months and feel nothing. The reason is that increasing serotonin in the synapse is not the antidepressant action. It is upstream of the antidepressant action. The brain has to read that signal, route it through several layers of slower transcriptional changes, and eventually — over weeks — coax some new synaptic growth out of it. The synaptic growth is what relieves the depression. The serotonin bump is just the trigger that, in some people, eventually gets the brain to do that work.[3]

Two consequences fall out of this. First, the lag is not a quirk. It is built into the mechanism. Second, if your brain doesn’t translate the serotonin signal into synaptic remodeling — and a substantial minority of people don’t, for reasons that include genetics, inflammation, and the duration of the episode itself — the SSRI never works. You don’t get a partial response. You get nothing, for two months, and then a phone call where I have to tell you we’re going to try something else.

What Spravato actually does

Spravato (esketamine) is the S-enantiomer of ketamine, delivered as an intranasal spray. Pharmacologically it skips the serotonin layer entirely and goes after a different receptor: the NMDA receptor, which sits on glutamate-using neurons throughout the cortex. NMDA blockade does something counterintuitive — it triggers a brief, controlled surge of glutamate onto a different receptor called AMPA.[2,3]

That AMPA surge is the moment the cellular work begins. Within minutes to hours of dosing, the surge sets off a cascade that includes release of brain-derived neurotrophic factor — BDNF — and activation of a regulatory protein called mTORC1.[3,4] BDNF is, in plain terms, a fertilizer for synaptic spines. mTORC1 is the assembly switch that lets a neuron build new ones. Within 24 hours of a single dose, animal studies and now human imaging studies show measurable new spines, restored connectivity in the prefrontal cortex, and rebalanced communication between the prefrontal regions and the limbic regions that drive depressive emotion.[3,5]

The shorthand version: SSRIs nudge a chemistry signal and hope the brain remodels itself in response. Spravato delivers the remodeling instruction directly. That is the entire reason a patient can feel a meaningful shift within 24 hours of the first treatment, instead of two months in.

How fast is “fast”?

In the registration trials, patients with treatment-resistant depression who received esketamine plus a newly initiated oral antidepressant separated from placebo on standardized depression scores within 24 hours of the first dose. By week 4, response and remission rates were significantly higher in the esketamine arm. The most important head-to-head data came out in 2023: a New England Journal of Medicine trial directly compared esketamine plus an SSRI to quetiapine plus an SSRI in treatment-resistant depression, and esketamine produced higher remission rates at week 8 and lower relapse rates over the next eight months.[6]

In January 2025, the FDA went one step further. On January 21, 2025, Spravato was approved as monotherapy for adults with treatment-resistant depression — the first oral or intranasal monotherapy for TRD ever approved.[7,8] The supporting trial showed that esketamine alone separated from placebo on depression scores at 24 hours, with continued and progressive improvement through week 4. About 22.5% of patients on the active dose were in remission at four weeks, compared with 7.6% on placebo.[7]

None of those numbers are dazzling on their own. They look small until you remember the population. These are people who have already failed two adequate trials of standard antidepressants. The baseline expectation for that group on a third or fourth oral medication is grim. Against that, a one-in-five remission rate at four weeks, with measurable change at 24 hours, is the most movement we have seen in this corner of psychiatry in a generation.

What about the dissociation?

This is the question almost every patient asks before they say yes. They have read about ketamine clinics. They have heard the word dissociation. Some of them are afraid of it; some are intrigued by it; almost all of them assume that the strange perceptual experience must be where the antidepressant effect comes from. After all, the drug feels like something. Surely the something is the thing.

The science says no.

A 2020 review in Nature Communications brought together every published trial that had looked at the question and concluded that there is no consistent relationship between the intensity of dissociation a patient experiences and the magnitude of their antidepressant response.[9] Some patients who dissociate strongly get better. Some who barely dissociate at all get better. Some who dissociate intensely don’t respond. The variables move independently of each other, which is exactly what you would expect if dissociation and antidepressant action are happening through different mechanisms — which is what mechanistic research has been suggesting for years.[3,5]

What dissociation appears to be is a temporary perceptual side effect of how the drug interacts with thalamic and cortical NMDA receptors during the dose itself. It comes on within minutes, peaks during the monitoring period, and resolves before patients leave the office.[10] The antidepressant effect, by contrast, lives in the synaptic remodeling that begins after the dose ends and continues quietly for days. Two different processes, on two different timelines, in two different parts of the brain.

Dissociation is what the dose feels like. The treatment is what happens after.

Practically, this means that a patient who finds dissociation unpleasant is not failing the treatment, and a patient who finds it interesting is not benefiting more because of it. We can adjust dose, posture, lighting, and pre-dose anti-nausea medication to make the experience more tolerable without worrying that we are weakening the therapeutic effect.

What a Spravato visit actually looks like

This part is dictated by the FDA’s Risk Evaluation and Mitigation Strategy program, the REMS protocol that every Spravato-certified clinic operates under.[8] The drug is never dispensed for home use. You take it in our office. You self-administer the nasal spray under direct supervision. You sit, recline, or use noise-canceling headphones in a quiet treatment room. We check blood pressure at baseline, at 40 minutes, and at the two-hour mark. You stay until you are clinically stable, which for most patients means around two hours from the first spray. You do not drive home.

The induction phase is twice weekly for four weeks. Most patients who are going to respond show clear improvement by the end of that month. From there, dosing tapers — once weekly for a month, then every one or two weeks long-term, depending on what your symptoms do. There is no fixed endpoint. People who maintain remission can continue as long as the medication is helping and the safety profile remains clean.

Who Spravato is for, and who it isn’t

It is for adults with major depressive disorder who have tried two adequate trials of oral antidepressants without adequate response. It is also approved for major depression with active suicidal ideation. It is not a first-line treatment, and it is not a substitute for therapy, sleep, exercise, or whatever combination of behavioral and structural changes you and your clinician have agreed are part of the longer plan.

It is not the right drug for someone with uncontrolled hypertension, certain cardiovascular conditions, a history of intracranial bleeding, or active substance use disorder involving dissociatives. It requires the time commitment of in-office visits and a ride home, twice a week for the first month. Some insurance plans require prior authorization, and we handle that on the practice side so that the financial logistics don’t decide whether someone gets care.

What I tell patients on the first visit

If you have been told you have treatment-resistant depression, you are not failing your medications. The medications are failing the cellular problem. Every additional SSRI tried after the second one has progressively lower odds of working, and a year of waiting between attempts is a year of an episode that is itself doing damage to the same circuits the next medication will be asked to repair. The case for trying something with a different mechanism, sooner rather than later, is not radical. It is conservative.

Spravato is one of the things in that different-mechanism category. SAINT TMS is another. Some patients are candidates for both, in sequence or in combination. The decision is not which one is better in the abstract — it is which one matches your particular history, your insurance, your schedule, and your tolerance for the trade-offs each one carries. That conversation is what a consultation is for.

What I do not want patients to do is stay on a fourth or fifth oral antidepressant for another six months because no one offered them a real conversation about why the first three didn’t work. That conversation is the one we have on the first visit at Exxceed Wellness, and the explanation above is essentially the version I sketch on the back of a chart while we have it.