Esketamine (Spravato): What the Evidence Shows

Esketamine, sold as Spravato, is the first genuinely new type of antidepressant to reach European clinics in decades. It is also the first psychedelic-adjacent medicine most patients meet through ordinary psychiatric care rather than a trial. This review sets out what the evidence supports, where it holds up well, and where marketing runs ahead of the data. It is written for patients and families, not as clinical guidance; to check routes in your country, start with our eligibility check.

TL;DR Esketamine nasal spray (Spravato) is approved across the EU for treatment-resistant depression, added to an SSRI or SNRI, after at least two antidepressants have failed — plus a second, narrower indication: acute short-term treatment of a depressive episode that constitutes a psychiatric emergency. The evidence for the main indication is solid: short-term benefit (TRANSFORM-2), relapse prevention (SUSTAIN-1), and a win over quetiapine on remission (ESCAPE-TRD). The "for suicidal thoughts" story is more complicated: esketamine has not been shown to prevent suicide or reduce suicidal ideation, and in the ASPIRE trials it did not beat placebo on the suicidality measure. It is given under supervision, raises blood pressure, causes dissociation, and carries misuse risk.

What it is

Esketamine is the S-enantiomer of ketamine: one of the two mirror-image molecules that make up ordinary "racemic" ketamine, the anaesthetic used in hospitals worldwide. Isolating that enantiomer let a manufacturer develop it as a distinct, patentable nasal-spray medicine. This matters for reading the evidence: esketamine (Spravato) and racemic ketamine are related but not interchangeable. Esketamine has been through the full regulatory trial programme and carries a marketing authorisation; racemic ketamine, given intravenously, is used off-label and rests on a separate, largely academic evidence base (our companion ketamine evidence review).

Mechanistically, esketamine acts on the brain's NMDA glutamate receptors rather than the serotonin and noradrenaline systems conventional antidepressants target, which is why it can work quickly in people for whom standard drugs have not (EMA overview).

Regulatory status in the EU: Spravato received an EU-wide marketing authorisation on 18 December 2019, held by Janssen-Cilag International (EMA EPAR). Its main authorised indication is precise: "in combination with an SSRI or SNRI, indicated for adults with treatment-resistant Major Depressive Disorder, who have not responded to at least two different treatments with antidepressants in the current moderate to severe depressive episode." Since 2021 the SmPC lists a second indication: co-administered with oral antidepressant therapy, acute short-term treatment for the rapid reduction of depressive symptoms in a moderate-to-severe episode that, according to clinical judgement, constitutes a psychiatric emergency (Spravato SmPC, section 4.1). It is a prescription-only medicine, started by a psychiatrist, and self-administered by the patient under direct supervision in a clinic. The 28–84 mg nasal spray is taken under staff observation, never dispensed for use at home. Treatment starts with sessions twice a week for the first month, then weekly, and later weekly or every two weeks depending on response (Spravato SmPC).

What the evidence shows

The honest way to read the esketamine literature is to separate what is approved and well-supported from what is promising and what remains unsettled.

Established: treatment-resistant depression (approved indication)

This is the indication esketamine is licensed for, and the evidence base is real. Across a development programme of roughly 1,800 patients, the EMA concluded that esketamine added to an SSRI or SNRI improves symptoms of treatment-resistant depression both short- and long-term (EMA overview).

The pivotal short-term trial, TRANSFORM-2 (Popova et al., American Journal of Psychiatry, 2019), randomised treatment-resistant patients to esketamine plus a newly started antidepressant versus placebo spray plus antidepressant. The esketamine group improved more on the MADRS depression scale by day 28, with a treatment difference of about 4 points — statistically significant; whether a roughly 4-point difference is clinically meaningful is debated in the literature (Popova et al. 2019). Two other short-term studies pointed the same way, though less clearly; the EMA judged the three together convincing (EMA overview).

The relapse-prevention question was addressed by SUSTAIN-1 (Daly et al., JAMA Psychiatry, 2019), a randomised-withdrawal maintenance study. Among patients who had reached stable remission, those kept on esketamine relapsed far less often than those switched to placebo spray: 26.7% versus 45.3%, a hazard ratio of 0.49, meaning roughly half the relapse risk (Daly et al. 2019). This is the evidence behind the long maintenance schedules patients are put on.

The most clinically useful trial came later. ESCAPE-TRD (Reif et al., New England Journal of Medicine, 2023) compared esketamine head-to-head against extended-release quetiapine, a real-world alternative, with both added to an ongoing antidepressant. Esketamine produced more remissions at week 8 (27.1% versus 17.6%) and more patients who were both in remission at week 8 and stayed relapse-free through week 32 (21.7% versus 14.1%) (Reif et al. 2023). Beating an active comparator, not just placebo, is what moved several European payers.

Promising but unsettled: major depression with acute suicidal ideation

This is where patients are most often misled. In the United States, the FDA approved esketamine in 2020 for depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behaviour. The EU took a deliberately different route: its second indication, added in 2021, is worded as acute short-term treatment of a depressive episode that constitutes a psychiatric emergency — a hospital-context indication, not a claim about suicidality itself (Spravato SmPC, section 4.1). The SmPC is explicit that esketamine's effectiveness in preventing suicide or in reducing suicidal ideation or behaviour has not been demonstrated. If a European clinic advertises esketamine "for suicidal thoughts" as such, that framing outruns the licence.

The trials behind the US indication were ASPIRE-I and ASPIRE-II. Both showed esketamine improving depression (MADRS) faster than placebo at 24 hours, by about 4 points (ASPIRE-I, Fu et al. 2020; ASPIRE-II, Ionescu et al. 2021). But on the measure that mattered most, the clinician's rating of the severity of suicidality itself, esketamine did not separate from placebo; both groups, all receiving intensive standard care, improved similarly. So the fair reading is that esketamine adds rapid antidepressant effect on top of hospital care, not that it is a proven anti-suicidal drug in its own right. Promising, and genuinely useful in a crisis setting, but not the clean result the headline suggests — which is exactly why the EU indication speaks of a psychiatric emergency rather than of suicidality.

Early or mixed: everything else

Esketamine is sometimes discussed for bipolar depression, PTSD, OCD and other conditions. For these the evidence is early: small studies, off-label use, no EU authorisation. Anyone presenting it as an established treatment is ahead of the data. The regulated, evidence-backed use in Europe remains treatment-resistant unipolar depression.

What is being studied now

Manufacturer and academic groups run post-authorisation and real-world studies to see how esketamine performs outside the tightly controlled trial population; the EMA lists an ongoing controlled-access post-authorisation study (CONTROL-EU) among its conditions (EMA EPAR). Others examine longer-term maintenance, which patients respond best, and how esketamine compares with repeated racemic ketamine infusions. As with any registry-based or manufacturer-linked work, weigh who is funding it; verify current studies via ClinicalTrials.gov and the EU registers, and see our trials guide for how to read a study honestly.

Safety and who should not take it

Esketamine is generally manageable under supervision, which is exactly why supervision is mandatory. The most common side effects, affecting up to 3 in 10 people, are dizziness, nausea, dissociation (a sense of being disconnected from your surroundings and emotions), headache, sleepiness, vertigo, taste disturbance, reduced sense of touch and vomiting (EMA overview). In the pivotal trials dissociation was more common still, affecting roughly 4 in 10 patients, though it was transient and settled during the observation period (US prescribing information). These effects typically appear during or shortly after the session and settle as the drug clears; patients stay for a monitoring period and must not drive or use machines until the next day, after a restful sleep (Spravato SmPC).

Two risks drive the strict framework. First, esketamine raises blood pressure, so it is measured before and after each session; blood pressure should be controlled before treatment starts, and dosing is postponed if it is elevated on the day (Spravato SmPC). The label contraindicates Spravato in people with vascular weaknesses that could rupture under a pressure rise (aneurysmal vascular disease or an arteriovenous malformation), a history of bleeding in the brain, or any cardiovascular event, including a heart attack, within the previous six weeks; it is also contraindicated in anyone allergic to esketamine, ketamine or any ingredient of the spray (Spravato SmPC). Second, because esketamine can be misused, the EMA built in special-prescription controls and supervised administration to limit misuse and dependence (EMA EPAR). Caution or specialist evaluation also applies in serious respiratory or heart conditions, in people with a presence or history of psychosis, mania or bipolar disorder, or a history of drug abuse or dependence, and in conditions with raised intracranial pressure; in severe liver impairment (Child-Pugh C) use is not recommended, and the same goes for pregnancy or breastfeeding (Spravato SmPC).

Medicines that interact: tell the prescribing team about every medicine you take. Sedatives such as benzodiazepines or opioids (and alcohol) can deepen the sedation during a session, while stimulants and MAOI antidepressants can amplify the blood-pressure rise and require closer monitoring. Clinics also ask about bladder or urinary symptoms during treatment, a precaution carried over from long-term ketamine use (Spravato SmPC).

A responsible service screens cardiovascular health, current medicines and psychiatric history before the first dose; if a provider skips that, treat it as a warning sign.

Legal status and how access works in Europe

Esketamine is the most widely accessible route in this field precisely because it is a fully authorised medicine. But access varies sharply by country, driven by reimbursement rather than legality. Germany's G-BA first rated the added benefit "not proven" in 2021, then upgraded it to "considerable added benefit" in 2023 after ESCAPE-TRD, an unusual and telling shift for a psychiatric drug (G-BA news). Others reached their own conclusions: reimbursed in Czechia since 2025, delivered through designated centres in Switzerland, financed in the hospital system in Spain and France, and open through some but not all public systems elsewhere. In the UK, NICE does not recommend esketamine on the NHS for treatment-resistant depression (guidance TA854), so access is largely limited to private clinics and clinical trials (NICE TA854).

The practical picture across twelve countries — what is reimbursed, the criteria, and who decides — is laid out in our Europe-wide reimbursement map. For country specifics, see the guides for Germany, the Netherlands, Czechia and others, and use the eligibility check to see which route may be open to you.

Frequently asked questions

Is esketamine the same as ketamine?

Not quite. Esketamine is one of the two mirror-image molecules that make up racemic ketamine. Esketamine (Spravato) is an approved nasal-spray medicine with its own trial programme; racemic ketamine is the older anaesthetic, used off-label for depression by intravenous infusion. They share a mechanism but differ in evidence base and regulatory status; see our ketamine evidence review.

What is esketamine actually approved for in Europe?

Two indications: treatment-resistant major depressive disorder, in adults who have not responded to at least two antidepressants in the current episode, taken in combination with an SSRI or SNRI; and, with an oral antidepressant, acute short-term treatment of a moderate-to-severe depressive episode that constitutes a psychiatric emergency (Spravato SmPC, section 4.1). Anything else is off-label.

Can I get esketamine for suicidal thoughts in Europe?

Not as a suicidality indication. The EU's second indication covers acute short-term treatment of a depressive episode that constitutes a psychiatric emergency — a hospital-context use — but esketamine has not been demonstrated to prevent suicide or reduce suicidal ideation or behaviour, and in the trials it did not outperform placebo on the suicidality measure itself (ASPIRE-I). If you are in crisis, contact your local emergency number or crisis line immediately.

How strong is the evidence, really?

For treatment-resistant depression, genuinely solid: short-term benefit, relapse prevention, and a win over an active comparator (quetiapine) in ESCAPE-TRD (Reif et al. 2023). Effect sizes are moderate rather than dramatic, and it is an add-on to ongoing antidepressant treatment, not a standalone cure.

Why does it have to be given in a clinic?

Because of the blood-pressure rise, the dissociation and the misuse potential, the EMA built the whole framework around supervised, monitored administration (EMA EPAR). You self-administer the spray, then stay for observation and cannot drive until the next day, after a restful sleep.

Sources

This review is for general information only and is not medical advice, a diagnosis, or a recommendation of any treatment. Approved indications, reimbursement rules and clinical evidence change; always verify current information with the EMA, your national regulator, or a licensed clinician who knows your history. If you are in crisis, contact your local emergency number or a crisis line immediately.

Reviewer's note. An accurate, well-sourced picture of where esketamine stands in Europe: a supervised add-on treatment for treatment-resistant depression with solid short-term and relapse-prevention data. The article is commendably honest about the ASPIRE suicidality results and the moderate effect sizes.

— Dr. Grischa Judanin, MD, physician and medical advisor, PsyAccess review board

Medically reviewed by Dr. Grischa Judanin, MD, on 11 August 2026.