For patients with treatment-resistant depression — defined as depression that hasn’t responded to at least two adequate antidepressant trials — the options have historically been limited and largely unsatisfying. Adding a second antidepressant, augmenting with lithium or atypical antipsychotics, ECT.
Spravato (esketamine) represents something genuinely new: the first antidepressant with a completely different mechanism of action than anything before it, and a rapid onset that standard antidepressants can’t match.
What Is Spravato?
Spravato is an FDA-approved nasal spray containing esketamine — the S-enantiomer of ketamine. It was approved in 2019 for treatment-resistant depression and in 2020 for major depressive disorder with acute suicidal ideation or behavior.
Unlike conventional antidepressants (which modulate serotonin, norepinephrine, or dopamine), Spravato blocks NMDA glutamate receptors. This mechanism produces rapid antidepressant effects — often within hours to days of the first treatment, versus 4–6 weeks for SSRIs.
Who Is It For?
FDA-approved indications:
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Treatment-resistant depression (TRD) — adults who haven’t responded to at least two different antidepressants
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Major depressive disorder with acute suicidality — as an adjunct to standard antidepressants in the acute setting
Typical candidates:
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Patients who have tried 2+ antidepressants without adequate response
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Patients who respond initially then stop responding (“tachyphylaxis”)
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Patients who cannot tolerate standard antidepressant side effects
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Patients needing faster response than standard antidepressants provide
How Spravato Is Used
Spravato must be administered under supervision in a certified healthcare setting (REMS program). Patients self-administer the nasal spray in the office and are monitored for 2 hours afterward due to dissociative side effects.
Dosing schedule:
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Induction (weeks 1–4): twice weekly
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Maintenance (weeks 5–8): once weekly
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Maintenance (week 9+): once weekly or every two weeks
Most patients also continue an oral antidepressant concurrently.
What to Expect
Side effects that occur during and shortly after administration:
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Dissociation (feeling detached, dreamlike) — common, transient
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Dizziness and nausea — usually mild
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Elevated blood pressure — monitored during the 2-hour observation period
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Sedation — reason for the 2-hour observation requirement
These effects typically resolve within 1–2 hours and patients can drive home after the observation period.
The Evidence
Clinical trials in treatment-resistant depression showed significant superiority over placebo, with many patients achieving remission who had failed multiple prior treatments. The rapid onset — particularly important for patients with severe or suicidal depression — represents a genuine clinical advance.