Esketamine (Spravato): what the research shows

Also known as Spravato, S-ketamine

At a glance

Type: One mirror-image half (the S-form) of ketamine, given as a nasal spray.
How it acts: Blocks NMDA receptors in the brain's glutamate system, like ketamine.
Approved uses: Treatment-resistant depression (US 2019, Canada 2020). In the US, also depression with acute suicidal thoughts, and as a stand-alone treatment (2025).
Legal status: Prescription-only. In the US, given only in certified settings under a safety program.
How it's given: Self-administered nasal spray in a clinic, usually twice a week at first, with monitoring afterwards.
Strongest evidence: Treatment-resistant depression, from several phase 3 trials.
Biggest open question: How it compares with generic IV ketamine, and long-term outcomes of ongoing treatment.

Evidence by condition

How strong the research is for each use, on our four-level evidence scale.

Several phase 3 trials found it beat placebo alongside an antidepressant, beat quetiapine in a 676-person head-to-head trial, and reduced relapse. Two trials missed their main goal, and blinding is difficult.

Depression with active suicidal thoughts (short term) Moderate

Two phase 3 trials (226 and 230 people) found faster improvement in depression within 24 hours. Neither found a significant difference from placebo on the measure of suicidality.

What it is

Esketamine is the S-form of ketamine, one of the two mirror-image molecules that make up generic ketamine. Sold as Spravato, it’s a nasal spray and the first ketamine-based medicine formally approved for depression: in the US in March 2019⁹ and in Canada in 2020.¹⁰ For the history and science of ketamine itself, see our ketamine guide.

People use the spray themselves in a certified clinic, under supervision. They’re monitored afterwards because of short-term dissociation, sedation and blood pressure effects.⁹

How it works in the brain

Like ketamine, esketamine blocks the NMDA receptor in the brain’s glutamate system. The leading theory is that this triggers a burst of activity and growth signals that help rebuild connections between brain cells in mood-related areas. Most of the detail comes from animal research. See the ketamine guide for more.

Key studies

Treatment-resistant depression, 2019. In TRANSFORM-2, 227 adults started a new oral antidepressant plus esketamine or a placebo spray. The esketamine group improved more over four weeks.¹ In SUSTAIN-1, people who were doing well and kept taking esketamine were less likely to relapse than those switched to placebo.⁴

The trials that missed, 2019–2020. In TRANSFORM-1 (346 people), the higher dose didn’t reach statistical significance on the main measure.² In TRANSFORM-3, in adults aged 65 and over, the result narrowly missed significance. There was a benefit in people aged 65–74 but not in those 75 and over.³

Esketamine vs quetiapine, 2023. In ESCAPE-TRD, 676 people were randomised to esketamine or quetiapine (another common add-on treatment), both alongside an SSRI or SNRI. At eight weeks, 27.1% were in remission on esketamine versus 17.6% on quetiapine. More people also stayed well through 32 weeks.⁵

Esketamine on its own, 2025. In a 378-person trial, esketamine without an oral antidepressant reduced depression scores more than placebo at four weeks, with effects already visible after 24 hours.⁸ This led to US approval as a stand-alone treatment in January 2025.¹¹

Depression with active suicidal thoughts, 2020–2021. ASPIRE I (226 people) and ASPIRE II (230 people) enrolled adults hospitalised with depression and active suicidal thoughts. Esketamine plus standard care improved depression scores more than placebo plus standard care within 24 hours. In both trials, though, the difference on the suicidality measure wasn’t statistically significant.⁶⁷

Safety and risks reported in research

In the trials, the most common side effects were nausea, dissociation, dizziness, headache and vertigo, along with sleepiness and a temporary rise in blood pressure.²⁶⁸ In the monotherapy trial, about a quarter of people on esketamine had nausea or dissociation.⁸

Legal and regulatory status

Canada: Approved by Health Canada in 2020 for adults with major depression who haven’t responded to at least two antidepressants, used with an SSRI or SNRI.¹⁰
United States: Approved in 2019 for treatment-resistant depression with an oral antidepressant,⁹ in 2020 for depression with acute suicidal thoughts,¹² and in 2025 as a stand-alone treatment.¹¹ Available only in certified settings under a safety program.

History in brief

2019: TRANSFORM-2 and SUSTAIN-1 published. FDA approval in March.¹⁴⁹
2020: Health Canada approval. ASPIRE I published.¹⁰⁶
2023: ESCAPE-TRD finds esketamine beats quetiapine.⁵
2025: US approval as a stand-alone treatment.⁸¹¹

Myths vs evidence

The claim“Esketamine and ketamine clinics offer the same approved treatment.”

What the evidence says Misleading

Esketamine (Spravato) is the approved nasal spray, studied in phase 3 trials. IV ketamine for depression uses generic ketamine off-label. It has strong research of its own, but a different regulatory status.⁹ See our ketamine guide.

The claim“Esketamine is proven to prevent suicide.”

What the evidence says Unproven

In two phase 3 trials of people with active suicidal thoughts, esketamine improved depression faster than placebo. But the difference on the suicidality measure itself wasn't statistically significant.⁶⁷ No trial has shown it reduces suicide deaths.

See all myths vs evidence →

Frequently asked questions

How is esketamine different from ketamine?

Ketamine is a 50/50 mix of two mirror-image molecules. Esketamine is one of them, the S-form. It's given as a nasal spray, and it's the version that went through the full approval process for depression. Generic IV ketamine for depression is used off-label.

Why is esketamine only given in a clinic?

Because it can cause dissociation, sedation and a temporary rise in blood pressure, and it has potential for misuse. In the US it's available only through certified treatment centres under a safety program (REMS), with patients monitored after each dose.

Does esketamine have to be taken with another antidepressant?

It was first approved alongside an oral antidepressant. In 2025, after a 378-person trial, the US FDA also approved it as a stand-alone treatment. Rules differ by country. Talk to a qualified health professional about your own situation.

Is esketamine available in Canada?

Yes. Health Canada approved it in 2020 for adults with major depression who haven't responded to at least two antidepressants, used alongside an SSRI or SNRI.

Clinical trials

A Study of Esketamine Nasal Spray Versus Placebo Spray in Adult Participants With Treatment-resistant DepressionRecruiting · Phase 3 · Depressive Disorder, Treatment-Resistant · Japan, Taiwan
Esketamine Versus Crisis Response Planning Versus Enhanced Treatment as Usual for Suicide Prevention: A Pragmatic Randomized Trial in a Brazilian Municipality (SAVE)Recruiting · Phase 4 · Suicide Prevention, Ketamine · Brazil
Esketamine With or Without Integration Therapy for Treatment-Resistant DepressionRecruiting · Phase 4 · Treatment-resistant Depression (TRD) · Puerto Rico
A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive DisorderRecruiting · Phase 3 · Depressive Disorder, Major · Brazil, Hungary
Ayahuasca, Esketamine and PTSDRecruiting · Phase 2 · Posttraumatic Stress Disorder (PTSD) · Brazil
Subanesthetic Esketamine in Modified ECT for Severe Depression in Adolescents: Clinical and Mechanistic StudyRecruiting · Early phase 1 · Esketamine, ECT · China
Virtual Reality-Based Mindfulness as an Adjunct to Treatment as Usual in Treatment-Resistant DepressionRecruiting · N/A · Depression - Major Depressive Disorder, Depression Disorder · Spain
The Efficacy and Safety of Short Term S-ketamine Infusion as an Adjunctive Therapy in Patients With FibromyalgiaRecruiting · N/A · Fibromyalgia, Pregabalin · China

Showing 8 of 36 active trials in our tracker.

See all trials in the tracker →

References

Popova V, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression (TRANSFORM-2). American Journal of Psychiatry. 2019;176(6):428–438. Source
Fedgchin M, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression (TRANSFORM-1). International Journal of Neuropsychopharmacology. 2019;22(10):616–630. Source
Ochs-Ross R, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression (TRANSFORM-3). American Journal of Geriatric Psychiatry. 2020;28(2):121–141. Source
Daly EJ, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in treatment-resistant depression (SUSTAIN-1). JAMA Psychiatry. 2019;76(9):893–903. Source
Reif A, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression (ESCAPE-TRD). New England Journal of Medicine. 2023;389(14):1298–1309. Source
Fu DJ, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent (ASPIRE I). Journal of Clinical Psychiatry. 2020;81(3):19m13191. Source
Ionescu DF, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent (ASPIRE II). International Journal of Neuropsychopharmacology. 2021;24(1):22–31. Source
Janik A, et al. Esketamine monotherapy in adults with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2025;82(9):877–887. Source
Janssen. U.S. FDA approval of SPRAVATO (esketamine) CIII nasal spray for adults with treatment-resistant depression. Press release, March 5, 2019. Source
Health Canada. Regulatory Decision Summary: Spravato (esketamine). 2020. Source
AJMC. Esketamine approved by FDA as first monotherapy for treatment-resistant depression. January 2025. Source
Canady VA. FDA approves esketamine treatment for MDD, suicidal ideation. Mental Health Weekly. 2020. Source