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Esketamine
6 reviewed claim records · 17 linked source receipts Inspect source receipts
Maturity: source checked
Headline claim
Among 297 adults who had improved on esketamine, those who continued it relapsed less than those switched to placebo: risk of relapse was 51% lower in people in stable remission and 70% lower in people with stable response.
Adults with treatment-resistant depression in stable remission or response after 16 weeks of esketamine · Outcome: Time to relapseConfidence applies to this claim and context.
AttentionNot assessedNo current independent attention assessment
EvidenceNo mapped studiesNo reviewed experiment families currently mapped
ConfidenceNot assessedFor: Among 297 adults who had improved on esketamine, those who continued it relapsed less than those switched to placebo: risk of relapse was 51% lower in people in stable remission and 70% lower in people with stable response.. No current reviewed confidence assessment for this claim.
The GapAttention not measured
Attention describes reviewed public attention, evidence shows study types, and confidence applies only to the stated claim. There is no overall score.
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Why we checked it
Attention is far lower than for ketamine. English Wikipedia's Esketamine article had 7,886 views in September 2026, against 78,829 for Ketamine. Research output is steady: PubMed added 40 esketamine records in the 30 days to Oct 11 2026; many concern anesthesia uses studied outside the US.
Here's where it actually stands
Esketamine is one of the two mirror-image forms that make up ketamine. Janssen, part of Johnson & Johnson, sells it as Spravato, a nasal spray. The FDA approved it in 2019 for treatment-resistant depression, meaning depression that has not improved after other antidepressants. In 2020 it was approved for depressive symptoms in adults with acute suicidal thoughts or behavior. Since 2025 it can be used alone, not only with a pill antidepressant. It is given only in certified health care settings, and patients are monitored for at least two hours afterward under a restricted program. Its boxed warning covers sedation, dissociation, slowed breathing, misuse, and suicidal thoughts. Blood pressure can rise after each use, so the label requires it to be checked before and after. Ketamine itself is not FDA-approved for depression.
What we know
Among 297 adults who had improved on esketamine, those who continued it relapsed less than those switched to placebo: risk of relapse was 51% lower in people in stable remission and 70% lower in people with stable response.
What we don't know
For adults with treatment-resistant depression, is esketamine nasal spray more effective, or safer, than IV ketamine?
Claims
Among 297 adults who had improved on esketamine, those who continued it relapsed less than those switched to placebo: risk of relapse was 51% lower in people in stable remission and 70% lower in people with stable response. · headlineAdults with treatment-resistant depression in stable remission or response after 16 weeks of esketamine · Outcome: Time to relapseConfidence: Not assessed · source checked
Would change this claim: If SAVE (NCT07120477) shows fewer suicide attempts with esketamine, we would add a suicide-outcome claim; if not, we would keep the label wording that prevention is not shown.
Source: Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. · PMID 31166571 · JAMA Psychiatry · Abstract, Results: relapse 26.7% vs 45.3% (remitters), HR 0.49 (0.29-0.84); 25.8% vs 57.6% (responders), HR 0.30 (0.16-0.55) · Verify ↗Source: A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant Depression · NCT NCT02493868 · Janssen Research & Development, LLC · Abstract, Results: relapse 26.7% vs 45.3% (remitters), HR 0.49 (0.29-0.84); 25.8% vs 57.6% (responders), HR 0.30 (0.16-0.55) · Verify ↗In 226 adults hospitalized with depression and active suicidal ideation with intent, esketamine plus standard care lowered depression scores more than placebo plus standard care at 24 hours (difference 3.8 points). A clinician-rated measure of suicidality improved in both groups and did not differ significantly between them. A second trial of the same design (ASPIRE II, 227 adults) found the same pattern.Adults with MDD, active suicidal ideation with intent, needing hospitalization · Outcome: MADRS change at 24 hoursConfidence: Not assessed · source checkedSource: Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I). · PMID 32412700 · J Clin Psychiatry · Registrations NCT03039192 (ASPIRE I) and NCT03097133 (ASPIRE II). 32412700 Results: LS mean difference -3.8 (SE 1.39; 95% CI -6.56 to -1.09); CGI-SS-r between-group difference not significant (key secondary). 32861217 (ASPIRE II) Results: 227 analyzed; -3.9 (95% CI -6.60 to -1.11); CGI-SS-r between-group difference not statistically significant · Verify ↗Source: Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). · PMID 32861217 · Int J Neuropsychopharmacol · Registrations NCT03039192 (ASPIRE I) and NCT03097133 (ASPIRE II). 32412700 Results: LS mean difference -3.8 (SE 1.39; 95% CI -6.56 to -1.09); CGI-SS-r between-group difference not significant (key secondary). 32861217 (ASPIRE II) Results: 227 analyzed; -3.9 (95% CI -6.60 to -1.11); CGI-SS-r between-group difference not statistically significant · Verify ↗
In 227 adults with treatment-resistant depression, esketamine plus a new oral antidepressant lowered depression scores more than the antidepressant plus placebo at day 28 (difference 4.0 points on the MADRS depression scale). 7% vs 0.9% stopped because of side effects.Adults with treatment-resistant depression (39 centers) · Outcome: MADRS change at day 28Confidence: Not assessed · source checkedSource: Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. · PMID 31109201 · Am J Psychiatry · Abstract, Results: LS mean difference -4.0 (95% CI -7.31 to -0.64); discontinuation for AEs 7% vs 0.9% · Verify ↗Source: A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression · NCT NCT02418585 · Janssen Research & Development, LLC · Abstract, Results: LS mean difference -4.0 (95% CI -7.31 to -0.64); discontinuation for AEs 7% vs 0.9% · Verify ↗
In a trial of adults with treatment-resistant depression (336 on esketamine, 340 on quetiapine), more people reached remission at week 8 with esketamine than with extended-release quetiapine, each added to an SSRI or SNRI (27.1% vs 17.6%). Raters were blinded, but patients were not.Adults with treatment-resistant depression (Europe) · Outcome: Remission at week 8Confidence: Not assessed · source checkedSource: Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. · PMID 37792613 · N Engl J Med · Abstract, Results: 91/336 (27.1%) vs 60/340 (17.6%), P=0.003; no relapse through week 32 after remission 21.7% vs 14.1% · Verify ↗Source: A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive Disorder · NCT NCT04338321 · Janssen-Cilag International NV · Abstract, Results: 91/336 (27.1%) vs 60/340 (17.6%), P=0.003; no relapse through week 32 after remission 21.7% vs 14.1% · Verify ↗
Two other phase 3 trials narrowly missed their main goal. In 346 adults with treatment-resistant depression, esketamine plus a new antidepressant did not significantly beat antidepressant plus placebo at day 28 for the dose tested first (difference 3.2 points; TRANSFORM-1). In adults aged 65 and older (TRANSFORM-3), the difference (3.6 points) also fell short of significance; it was larger in people aged 65 to 74 than in those 75 and older.Adults with treatment-resistant depression (TRANSFORM-1); adults aged 65 and older (TRANSFORM-3) · Outcome: MADRS change at day 28Confidence: Not assessed · source checkedSource: Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). · PMID 31290965 · Int J Neuropsychopharmacol · Registrations NCT02417064 (TRANSFORM-1) and NCT02422186 (TRANSFORM-3), not cited as separate sources because each abstract lists only its own. 31290965 Results: LS mean difference -3.2 (-6.88, 0.45), P=.088 (N=346); 31734084 Results: -3.6 (-7.20, 0.07), p=0.059; age 65-74 -4.9; 75 and older -0.4 · Verify ↗Source: Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3. · PMID 31734084 · Am J Geriatr Psychiatry · Registrations NCT02417064 (TRANSFORM-1) and NCT02422186 (TRANSFORM-3), not cited as separate sources because each abstract lists only its own. 31290965 Results: LS mean difference -3.2 (-6.88, 0.45), P=.088 (N=346); 31734084 Results: -3.6 (-7.20, 0.07), p=0.059; age 65-74 -4.9; 75 and older -0.4 · Verify ↗
Used alone, esketamine lowered depression scores more than placebo at day 28 in 378 adults with treatment-resistant depression (differences of 5.1 and 6.8 points for the two doses tested). Common side effects were nausea, dissociation, dizziness and headache.Adults with treatment-resistant depression, off oral antidepressants (51 US centers) · Outcome: MADRS change at day 28Confidence: Not assessed · source checkedSource: Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. · PMID 40601310 · JAMA Psychiatry · Abstract, Results: LS mean difference -5.1 (95% CI -7.91 to -2.33) and -6.8 (-9.48 to -4.07); nausea 24.8%, dissociation 24.3%, dizziness 21.7%, headache 19.0% · Verify ↗Source: A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant Depression · NCT NCT04599855 · Janssen Research & Development, LLC · Abstract, Results: LS mean difference -5.1 (95% CI -7.91 to -2.33) and -6.8 (-9.48 to -4.07); nausea 24.8%, dissociation 24.3%, dizziness 21.7%, headache 19.0% · Verify ↗
Mapped studies / experiment families
One experiment counts once, even with several registrations or publications. Counts above describe the headline claim.
No reviewed experiment families mapped yet.
Studies & active trials
US regulatory timeline
Mar 5, 2019Spravato nasal spray approved for treatment-resistant depression, with a REMS (NDA 211243).U.S. FDA (Drugs@FDA) ↗
Jul 31, 2020New indication: depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior (S-004).U.S. FDA (Drugs@FDA) ↗
Jan 17, 2025Indication expanded to monotherapy for treatment-resistant depression (S-016).U.S. FDA (Drugs@FDA) ↗
Apr 28, 2025Bradycardia added to postmarketing adverse reactions (S-019).U.S. FDA (Drugs@FDA) ↗
Sep 17, 2026Medication Guide updated for readability and transportation after treatment (S-026); REMS workflow changes approved earlier in 2026.U.S. FDA (Drugs@FDA) ↗
Only papers and registered trials an editor reviewed for this page. Being listed is not a finding; the claims above say what they show.
Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial.PMID 40601310 · DOI 10.1001/jamapsychiatry.2025.1317Study · Published · Sep 1, 2025 · JAMA PsychiatryOpen source ↗
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.PMID 37792613 · DOI 10.1056/NEJMoa2304145Study · Published · Oct 5, 2023 · N Engl J MedOpen source ↗
Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II).PMID 32861217 · DOI 10.1093/ijnp/pyaa068Study · Published · Jan 20, 2021 · Int J NeuropsychopharmacolOpen source ↗
Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I).PMID 32412700 · DOI 10.4088/JCP.19m13191Study · Published · May 12, 2020 · J Clin PsychiatryOpen source ↗
Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).PMID 31290965 · DOI 10.1093/ijnp/pyz039Study · Published · Oct 1, 2019 · Int J NeuropsychopharmacolOpen source ↗
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.PMID 31166571 · DOI 10.1001/jamapsychiatry.2019.1189Study · Published · Sep 1, 2019 · JAMA PsychiatryOpen source ↗
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study.PMID 31109201 · DOI 10.1176/appi.ajp.2019.19020172Study · Published · Jun 1, 2019 · Am J PsychiatryOpen source ↗
Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.PMID 23982301 · DOI 10.1176/appi.ajp.2013.13030392Study · Published · Am J PsychiatryOpen source ↗
Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3.PMID 31734084 · DOI 10.1016/j.jagp.2019.10.008Study · Published · Am J Geriatr PsychiatryOpen source ↗
A Study of Esketamine Nasal Spray Versus Placebo Spray in Adult Participants With Treatment-resistant DepressionNCT NCT07716098Trial · Recruiting · Sep 25, 2026 · Janssen Research & Development, LLCOpen registry record ↗
A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder (AVENUE)NCT NCT07227454Trial · Recruiting · Sep 25, 2026 · Janssen Research & Development, LLCOpen registry record ↗
Esketamine Versus Crisis Response Planning Versus Enhanced Treatment as Usual for Suicide Prevention: A Pragmatic Randomized Trial in a Brazilian Municipality (SAVE)NCT NCT07120477Trial · Recruiting · Sep 16, 2026 · University of Sao PauloOpen registry record ↗
PCORI Comparative Effectiveness Study-Esketamine (Spravato) vs. Ketamine-Equivalence StudyNCT NCT06713616Trial · Recruiting · Sep 8, 2026 · Yale UniversityOpen registry record ↗
A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive DisorderNCT NCT04338321Trial · Completed · Janssen-Cilag International NVOpen registry record ↗
A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant DepressionNCT NCT04599855Trial · Completed · Janssen Research & Development, LLCOpen registry record ↗
A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant DepressionNCT NCT02493868Trial · Completed · Janssen Research & Development, LLCOpen registry record ↗
A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant DepressionNCT NCT02418585Trial · Completed · Janssen Research & Development, LLCOpen registry record ↗
What would change our mind
If SAVE (NCT07120477) shows fewer suicide attempts with esketamine, we would add a suicide-outcome claim; if not, we would keep the label wording that prevention is not shown.
If NCT06713616 shows IV ketamine is equivalent, we would say the two are interchangeable for short-term effect in that population.
Check this next →Receipts
A Long-term Comparison of Esketamine Nasal Spray Versus Quetiapine Extended Release, Both in Combination With a Selective Serotonin Reuptake Inhibitor/Serotonin-Norepinephrine Reuptake Inhibitor, in Participants With Treatment Resistant Major Depressive DisorderJanssen-Cilag International NV · checked Oct 11, 2026 · NCT NCT04338321; status:COMPLETED
Open source ↗A Study of Esketamine Nasal Spray, Administered as Monotherapy, in Adult Participants With Treatment-resistant DepressionJanssen Research & Development, LLC · checked Oct 11, 2026 · NCT NCT04599855; status:COMPLETED
Open source ↗A Study of Esketamine Nasal Spray Versus Placebo Spray in Adult Participants With Treatment-resistant DepressionJanssen Research & Development, LLC · checked Oct 11, 2026 · NCT NCT07716098; status:RECRUITING; primary completion 2028-12-27 (estimated)
Open source ↗A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-resistant DepressionJanssen Research & Development, LLC · checked Oct 11, 2026 · NCT NCT02493868; status:COMPLETED
Open source ↗A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder (AVENUE)Janssen Research & Development, LLC · checked Oct 11, 2026 · NCT NCT07227454; status:RECRUITING; primary completion 2031-04-09 (estimated)
Open source ↗A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant DepressionJanssen Research & Development, LLC · checked Oct 11, 2026 · NCT NCT02418585; status:COMPLETED
Open source ↗Esketamine Versus Crisis Response Planning Versus Enhanced Treatment as Usual for Suicide Prevention: A Pragmatic Randomized Trial in a Brazilian Municipality (SAVE)University of Sao Paulo · checked Oct 11, 2026 · NCT NCT07120477; status:RECRUITING; primary completion 2028-12 (estimated)
Open source ↗PCORI Comparative Effectiveness Study-Esketamine (Spravato) vs. Ketamine-Equivalence StudyYale University · checked Oct 11, 2026 · NCT NCT06713616; status:RECRUITING; primary completion 2030-12-31 (estimated)
Open source ↗Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.Am J Psychiatry · checked Oct 11, 2026 · PMID 23982301; DOI 10.1176/appi.ajp.2013.13030392
Open source ↗Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3.Am J Geriatr Psychiatry · checked Oct 11, 2026 · PMID 31734084; DOI 10.1016/j.jagp.2019.10.008
Open source ↗Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).Int J Neuropsychopharmacol · checked Oct 11, 2026 · PMID 31290965; DOI 10.1093/ijnp/pyz039
Open source ↗Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study.Am J Psychiatry · checked Oct 11, 2026 · PMID 31109201; DOI 10.1176/appi.ajp.2019.19020172
Open source ↗Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.JAMA Psychiatry · checked Oct 11, 2026 · PMID 31166571; DOI 10.1001/jamapsychiatry.2019.1189
Open source ↗Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial.JAMA Psychiatry · checked Oct 11, 2026 · PMID 40601310; DOI 10.1001/jamapsychiatry.2025.1317
Open source ↗Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II).Int J Neuropsychopharmacol · checked Oct 11, 2026 · PMID 32861217; DOI 10.1093/ijnp/pyaa068
Open source ↗Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I).J Clin Psychiatry · checked Oct 11, 2026 · PMID 32412700; DOI 10.4088/JCP.19m13191
Open source ↗Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.N Engl J Med · checked Oct 11, 2026 · PMID 37792613; DOI 10.1056/NEJMoa2304145
Open source ↗What still isn't settled?
For adults with treatment-resistant depression, is esketamine nasal spray more effective, or safer, than IV ketamine?
We found no completed randomized trial comparing them head to head for treatment-resistant depression (PubMed search 2026-10-11); each was tested against different controls.
What would answer it: Primary results of NCT06713616 (esketamine vs ketamine equivalence; 400 participants; est. primary completion 2030-12).
Shown in randomized trials: for adults with treatment-resistant depression, esketamine added to an oral antidepressant lowered depression scores more than placebo over 4 weeks in one trial; two similar trials, one in older adults, narrowly missed their main goal. People who improved and kept using it relapsed less often than those switched to placebo. In 2025 a trial also showed benefit for esketamine used alone. Its label says it has not been shown to prevent suicide or to reduce suicidal thoughts or behavior.
Does esketamine reduce suicide attempts or deaths, not only depression scores?In two trials of people with suicidal ideation, esketamine lowered depression scores, but a clinician-rated suicidality measure did not differ significantly from placebo. The label says effectiveness in preventing suicide or reducing suicidal ideation or behavior has not been demonstrated. A pragmatic suicide-prevention trial is recruiting.What would answer it: Primary results of the SAVE trial (NCT07120477; esketamine vs crisis response planning vs enhanced usual care; 478 participants; est. 2028-12).
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