The research behind Spravato, in plain English.
Spravato has been studied in thousands of adults with depression that hadn’t responded to other treatment. Here’s what the main studies found, what the label says about safety, and, just as important, what nobody knows yet.
A different system in the brain.
Most antidepressants act on serotonin, norepinephrine, or both. Spravato works on the brain’s glutamate signalling instead. That’s the plain reason it can help people whose earlier medications didn’t.
Head to head with a standard alternative.
ESCAPE-TRD is the largest trial to compare Spravato directly with another active treatment: quetiapine, a common add-on medication, in 676 adults with treatment-resistant depression, all also taking an oral antidepressant.1
Remission means depression scores low enough to count as minimal: a high bar. The full ESCAPE-TRD story.
Spravato: the head-to-head data.
Spravato was tested head-to-head against another real treatment, in 676 people who had already failed at least two antidepressants. Most depression drugs are only ever tested against a placebo.
More than half in remission at week 32, against about a third on the comparator. Fewer people stopped because of side effects, too — 4.5% against 10.1%. Straight lines between the timepoints the trial published. Reif A, et al. N Engl J Med 2023;389:1298–1309.
Continuing treatment protects the improvement.
In the SUSTAIN-1 relapse-prevention trial, people who had reached stable remission on Spravato were randomly assigned either to keep taking it or to switch to placebo. Those who kept taking it were 51% less likely to relapse.2
Staying on it long term holds up too. In the SUSTAIN-3 study, patients were followed for up to six and a half years: no new safety concerns appeared, and the improvement generally held for people who stayed on treatment.4
It shows that continuing helps. If Spravato is helping, you can stay on it for as long as you need the treatment. We also check in with you regularly to find the least frequent schedule that keeps you well: for some people that’s once a week, for others once a month, and everywhere in between.
The trials studied people like you. Check if you qualify.
Spravato is approved for adults whose depression hasn’t responded to at least two antidepressants. See what qualifies and what rules it out.
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Request an evaluationWhat the label says, plainly.
- Approved uses: treatment-resistant depression in adults, on its own or with an oral antidepressant (monotherapy approved January 2025); and, with an oral antidepressant, depression with suicidal thoughts or actions.
- Common effects: dissociation in 61%–84% of people and sedation in 48%–61%, mostly in the first hours; a temporary rise in blood pressure.
- Rare: loss of consciousness in 0.3%–0.4%.
- Rules it out: aneurysm or similar blood-vessel disease, a past bleed in the brain, allergy to esketamine or ketamine.
- Why it’s only given in certified offices: the risks of sedation, dissociation and misuse. About the safety program (REMS).
How it stacks up against the alternatives.
- IV ketamine: it isn’t FDA-approved for depression, and it’s usually paid for out of pocket. It also hasn’t been shown to work better: the few direct comparisons found no significant difference, and most weren’t randomized. Spravato vs ketamine.
- Oral antidepressants: most haven’t been compared head to head with Spravato. But their side effects come every day, while Spravato’s are mostly gone by the end of each visit. So the results are likely similar, with a much easier side-effect profile and far less frequent dosing.
Two open questions.
Who will respond: there’s no test that predicts it. Suicide prevention: Spravato hasn’t been shown to prevent suicide. That said, in our practice we’ve seen many patients whose thoughts of self-harm eased dramatically once they began Spravato.