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Esketamine for depression

Studies whose primary subject is both Esketamine and Depression, with an evidence synthesis read across the most-cited and most recent of them.

State of the evidence

Synthesized

Synthesized from 25 studies in the library · AI-generated, grounded in the abstracts below

Found by searching the library for Esketamine, S-ketamine, spravato, esketamine nasal spray, Depression, major depressive disorder, then ranked by relevance.

Esketamine, given as a nasal spray (usually 56-84 mg) alongside an oral antidepressant, generally reduces depression severity faster and more than an oral antidepressant alone in treatment-resistant depression, with short-term advantages appearing within hours to days and continued treatment reducing relapse. However, results are not fully consistent: some trials missed their primary endpoint, benefits in suicidality-specific outcomes are weaker than for depressive symptoms, and long-term durability, safety, and misuse risk remain uncertain. Evidence is strongest for treatment-resistant depression and weaker for bipolar depression, suicide-risk populations, and non-TRD groups.

Evidence by study

Direction is which way each study's own result points, not our rating of the study.

What the directions mean
Supports:
the study found the intervention worked, or its hypothesis held.
Opposes:
it found the opposite, no benefit or a harm.
No effect:
no significant difference either way.
Mixed:
effects in both directions within the same study.
Unclear:
the abstract does not report a direction.
Study Design Sample size Direction Finding
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 2019 phase 3 RCT 227 Supports Esketamine nasal spray plus a newly initiated antidepressant produced a significantly greater reduction in depression severity at day 28 than antidepressant plus placebo.
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression 2019 phase 3 randomized withdrawal study 297 Supports Continuing esketamine plus an oral antidepressant reduced relapse risk by 51% in stable remitters and 70% in stable responders versus switching to placebo.
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression 2017 phase 2 RCT 67 Supports Intranasal esketamine produced a rapid, dose-related antidepressant effect, with response appearing to persist beyond 2 months at lower dosing frequency.
Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation 2021 review Supports Ketamine and esketamine are described as effective rapid-onset treatments for treatment-resistant depression, with safety, tolerability, and implementation guidance remaining key considerations.
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study 2018 RCT 68 Mixed Esketamine plus standard care improved depressive symptoms at 4 and 24 hours versus placebo but not at day 25, and did not reduce clinician-rated suicide risk.
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) 2019 phase 3 RCT 346 No effect Esketamine 84 mg plus an oral antidepressant did not significantly reduce depression scores versus placebo plus antidepressant at 4 weeks, though the 56 mg dose showed a nominal difference.
Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study 2015 RCT 30 Supports Both 0.20 mg/kg and 0.40 mg/kg intravenous esketamine produced rapid, significant antidepressant effects versus placebo, with dose-dependent adverse events.
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) 2020 phase 3 RCT 227 Supports Esketamine plus standard of care reduced depressive symptoms more than placebo plus standard of care at 24 hours, but the between-group difference in severity of suicidality was not significant.
Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis 2020 systematic review and meta-analysis 1877 Mixed Racemic ketamine showed greater response and remission rates and lower dropouts than esketamine, though both were effective.
Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent 2020 phase 3 RCT 226 Mixed Esketamine plus standard care improved depressive symptoms at 24 hours versus placebo but did not significantly reduce severity of suicidal ideation.
Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression 2020 phase 3 open-label long-term study 802 Supports Long-term esketamine plus a new oral antidepressant had a manageable safety profile and sustained improvements in depression symptoms.
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression 2023 phase 3b RCT 676 Supports Esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI for remission at week 8.
Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. 2019 RCT non-inferiority 63 Supports Esketamine 0.25 mg/kg was non-inferior to ketamine 0.5 mg/kg for remission 24 hours after a single intravenous infusion, with similar mild side effects.
Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study 2023 open-label long-term extension study 1148 Supports Improvement in depression ratings generally persisted among participants remaining on maintenance esketamine, with no new safety signal over up to 4.5 years.
The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. 2020 systematic review and meta-analysis 197 Supports Single-dose intravenous ketamine and intranasal esketamine were associated with reductions in suicidal thoughts at 2, 4, and 24 hours.
Esketamine for treatment of depression in Huntington's disease: A case report 2026 case study 1 Mixed Nasal esketamine was followed by rapid mood improvement (BDI 29 to 5 after three days), but depression worsened again by three months (BDI 20).
EFFECTS OF KETAMINE AND ESKETAMINE ON SUICIDAL IDEATION WITHIN THE FIRST 24 HOURS IN ADULTS WITH DEPRESSIVE DISORDERS: VARIABILITY IN CLINICAL FINDINGS AND INTERPRETATIVE CHALLENGES - A NARRATIVE REVIEW 2026 narrative review Mixed Intranasal esketamine added to standard care improved depressive symptoms at 24 hours, but clinician-rated suicidality did not differ significantly in either ASPIRE trial.
Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder with Comorbid Treatment-Resistant Depression: A Six-Month Case Report 2026 case study 1 Supports Over six months of intranasal esketamine, MADRS fell from 38 to 17 and Y-BOCS from 33 to 14, though the authors state the observation cannot distinguish a direct anti-obsessional effect from nonspecific factors.
507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review 2026 case study 1 Mixed About three years of intranasal esketamine maintenance was temporally associated with subsequent ketamine use disorder escalating to 2-3 g/day, with depression initially improving (CGI-S 7 to 4) and later worsening; the authors state causality cannot be inferred from a single case.
Metabolic Burden and Response to Repeated Intranasal Esketamine in Treatment-Resistant Depression: A Longitudinal Multidomain Biomarker Study 2026 longitudinal biomarker study Opposes Higher metabolic burden was associated with poorer response to repeated intranasal esketamine.
Beyond symptom reduction: Intranasal esketamine is associated with improved quality of life in treatment-resistant depression. 2026 observational Supports Intranasal esketamine was associated with improved quality of life in treatment-resistant depression.
Esketamine Use and Attempted Suicide or Intentional Self-Harm Among Individuals with Treatment-Resistant Depression: A Retrospective Cohort Study. 2026 retrospective cohort study 23140 No effect Current esketamine exposure was not associated with a statistically distinguishable difference in recorded nonfatal, medically attended suicide attempt or intentional self-harm (HR 1.017, 95% CI 0.670-1.544).
374. Intranasal esketamine in treatment-resistant bipolar depression maintained on long-acting aripiprazole 2026 case series 4 Supports Four patients with bipolar depression achieved complete remission of depressive symptoms after add-on intranasal esketamine at 84 mg, though existing data are limited.
575. A scoping review: ketamine or esketamine when used to assist psychotherapy or in combination with psychotherapy for the management of depression 2026 systematic review Unclear The authors argue that evidence for ketamine-assisted psychotherapy in depression is sparse and cannot be separated from ketamine's pharmacological antidepressant effects, and that only limited data support ketamine combined with psychotherapy.
Ketamine and esketamine for treatment-resistant depression: A systematic review of published studies 2026 systematic review Supports Both ketamine and esketamine reduce depressive symptoms relatively quickly via glutamatergic pathways, with clinical response rates in treatment-resistant depression ranging from 45% to 67% and mostly mild, transient adverse effects.

Points of agreement

  • Esketamine nasal spray plus an oral antidepressant reduces depressive symptoms more than an oral antidepressant alone in treatment-resistant depression in most trials.
  • Antidepressant effects can appear rapidly, within hours to days of dosing.
  • Continued esketamine treatment is associated with reduced relapse risk and sustained symptom improvement over months to years.
  • Common adverse effects are dissociation, dizziness, nausea, headache, and transient blood pressure increases, generally mild and resolving the same day.
  • Benefits for depressive symptoms are clearer than benefits for suicidality-specific outcomes.

Conflicts

  • One phase 3 trial (TRANSFORM-1) did not achieve statistical significance on its primary endpoint, while other trials and meta-analyses reported significant benefit.
  • Meta-analytic comparison found racemic ketamine had greater response and remission rates than esketamine, whereas a direct non-inferiority trial found esketamine non-inferior to ketamine at 24 hours.
  • Suicidality outcomes are inconsistent: some analyses show reductions in suicidal thoughts, while large trials and a claims cohort found no significant difference in clinician-rated or medically attended suicidality.
  • Long-term benefit is reported in extension studies, but individual case reports describe relapse and, in one case, escalation to ketamine use disorder.

Gaps

  • Durability of benefit beyond the treatment period and after discontinuation is not well established.
  • Blinding integrity is difficult to maintain because of esketamine's dissociative effects.
  • Long-term safety data, including cognitive effects and abuse potential, remain limited.
  • Evidence in bipolar depression, Huntington's disease, OCD comorbidity, and other non-TRD populations is sparse and mostly case-based.
  • Optimal dose, dosing frequency, and duration of maintenance treatment are not clearly defined.
  • Comparative effectiveness versus racemic ketamine and versus other augmentation strategies needs more direct trials.
Browse these studies in the library

Common questions

What does the research agree on about esketamine for depression?
  • Esketamine nasal spray plus an oral antidepressant reduces depressive symptoms more than an oral antidepressant alone in treatment-resistant depression in most trials.
  • Antidepressant effects can appear rapidly, within hours to days of dosing.
  • Continued esketamine treatment is associated with reduced relapse risk and sustained symptom improvement over months to years.
  • Common adverse effects are dissociation, dizziness, nausea, headache, and transient blood pressure increases, generally mild and resolving the same day.
  • Benefits for depressive symptoms are clearer than benefits for suicidality-specific outcomes.
Where do studies on esketamine for depression conflict?
  • One phase 3 trial (TRANSFORM-1) did not achieve statistical significance on its primary endpoint, while other trials and meta-analyses reported significant benefit.
  • Meta-analytic comparison found racemic ketamine had greater response and remission rates than esketamine, whereas a direct non-inferiority trial found esketamine non-inferior to ketamine at 24 hours.
  • Suicidality outcomes are inconsistent: some analyses show reductions in suicidal thoughts, while large trials and a claims cohort found no significant difference in clinician-rated or medically attended suicidality.
  • Long-term benefit is reported in extension studies, but individual case reports describe relapse and, in one case, escalation to ketamine use disorder.
What is still unknown about esketamine for depression?
  • Durability of benefit beyond the treatment period and after discontinuation is not well established.
  • Blinding integrity is difficult to maintain because of esketamine's dissociative effects.
  • Long-term safety data, including cognitive effects and abuse potential, remain limited.
  • Evidence in bipolar depression, Huntington's disease, OCD comorbidity, and other non-TRD populations is sparse and mostly case-based.
  • Optimal dose, dosing frequency, and duration of maintenance treatment are not clearly defined.
  • Comparative effectiveness versus racemic ketamine and versus other augmentation strategies needs more direct trials.
How we analyze this

This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is Esketamine for depression, up to 25 in all. The most-cited set anchors the established evidence, and the recent set surfaces work that is too new to have gathered citations yet.

A study qualifies only when Esketamine for depression or a known alias appears in its title or keywords, so broad reviews that mention it only in passing are left out. Each study is read from its abstract, strongest evidence first, and the summary reports the direction of the results along with any conflicts and gaps.

The full method, including what a person does and does not review, is on the methods page.

Ask your own question in the Research Synthesis Tool

565 articles · 338 from the last two years · 1,410,076 participants across 314 studies reporting sample size

Common study designs

review 60 systematic review 37 observational cohort 38 randomized controlled trial 63 systematic review and meta-analysis 26

Research volume by year

Compare topics →

560 studies whose primary subject is esketamine for depression since 2009

Studies about esketamine for depression per year, 2009 to 2026, peaking at 160 in 2026 Bar chart: one bar per year, taller where more studies were published that year. 0 100 200 2010 2015 2020 2025
2026 is partial
Show the numbers
Studies about esketamine for depression per year, 2009 to 2026, peaking at 160 in 2026
Year Studies
2009 1
2010 0
2011 0
2012 0
2013 0
2014 0
2015 1
2016 1
2017 1
2018 4
2019 10
2020 23
2021 10
2022 36
2023 73
2024 87
2025 153
2026 160

Research

Synthesize the evidence →

Esketamine for treatment of depression in Huntington's disease: A case report

Journal of Huntington s Disease September 17, 2026 Carsten Saft, Julia Jessen, David Kiefner et al.

Depression and suicidal ideation are common in Huntington's disease (HD). We report a 60-year-old male with HD who suffered from treatment-resistant depression with intermittent suicidal thoughts for 20 years, irritability and apathy. Despite multiple trials of antidepressants, no sustained improvement was achieved. Under nasal esketamine treatment his mood improved dramatically after three...

DOI: 10.1177/18796397261489245 (opens in new tab)

EFFECTS OF KETAMINE AND ESKETAMINE ON SUICIDAL IDEATION WITHIN THE FIRST 24 HOURS IN ADULTS WITH DEPRESSIVE DISORDERS: VARIABILITY IN CLINICAL FINDINGS AND INTERPRETATIVE CHALLENGES - A NARRATIVE REVIEW

International Journal of Innovative Technologies in Social Science September 11, 2026 Marta Borkowska, Małgorzata Witaszczyk, Alicja Sołtan et al.

Background: Ketamine and esketamine have been studied as rapid-acting interventions in adults with depressive disorders and suicidal ideation, but findings vary across populations, settings, comparators, routes, and outcome measures. Aim: To examine their effects on suicidal ideation within the first 24 hours and to identify factors contributing to variability across studies. Methods: This...

DOI: 10.31435/ijitss.3(51).2026.6636 (opens in new tab)

Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder with Comorbid Treatment-Resistant Depression: A Six-Month Case Report

Psychiatry International September 10, 2026 Tommaso Barlattani, Giorgio Sernia, Chiara D’Amelio et al.

Background: Evidence for repeated intranasal esketamine in obsessive–compulsive disorder (OCD) remains preliminary, particularly when OCD co-occurs with treatment-resistant depression (TRD). Methods: We report a 58-year-old woman treated with intranasal esketamine in routine clinical care for TRD; change in obsessive–compulsive symptoms was followed as a secondary observational outcome. Her...

DOI: 10.3390/psychiatryint7050207 (opens in new tab)

507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review

International Journal of Neuropsychopharmacology September 9, 2026 Y-H Chan, H-M Chang

Abstract Background Esketamine, the S-enantiomer of ketamine, is an NMDA receptor antagonist approved for treatment-resistant depression (TRD). Although regulated clinical trials suggest a low risk of misuse, concerns remain that esketamine exposure may facilitate transition to ketamine dependence, particularly in East Asia where illicit ketamine is widely available. Aims & Objectives To...

DOI: 10.1093/ijnp/pyag040.332 (opens in new tab)

Beyond symptom reduction: Intranasal esketamine is associated with improved quality of life in treatment-resistant depression.

J Psychiatr Res September 7, 2026

Objective: Treatment-resistant depression (TRD) is associated with severe functional impairment, poor quality of life, and increased suicide risk. This study evaluated the effectiveness of intranasal esketamine on depressive symptoms, hopelessness, suicidal ideation, and quality of life in patients with TRD, exploring whether outcomes differed according to concomitant antidepressant class (SSRI...

DOI: 10.1016/j.jpsychires.2026.09.005 (opens in new tab)

Metabolic Burden and Response to Repeated Intranasal Esketamine in Treatment-Resistant Depression: A Longitudinal Multidomain Biomarker Study

Research Square September 7, 2026 Jennifer Phillips, Ifeoluwa Olaoluwa, Areebah Ahmed et al. preprint

Abstract Metabolic, inflammatory, and neurotrophic measures may provide complementary insight into biological heterogeneity underlying treatment-resistant depression and response to ketamine-based treatments. However, biomarker studies of ketamine treatment have focused on individual markers or biological domains, most commonly inflammatory or neurotrophic, while metabolic measures remain...

DOI: 10.21203/rs.3.rs-10923483/v1 (opens in new tab)

Esketamine Use and Attempted Suicide or Intentional Self-Harm Among Individuals with Treatment-Resistant Depression: A Retrospective Cohort Study.

Drug safety September 2, 2026 You Wang, Alexandra S Storaci, G Caleb Alexander et al.

Treatment-resistant depression (TRD) is associated with elevated suicide risk, but real-world evidence on whether esketamine reduces suicide attempts and intentional self-harm remains limited. The aim was to estimate whether current esketamine exposure was associated with a higher or lower risk of recorded nonfatal, medically attended suicide attempt or intentional self-harm among adults with...

DOI: 10.1007/s40264-026-01722-1 (opens in new tab) Full text (opens in new tab)

374. Intranasal esketamine in treatment-resistant bipolar depression maintained on long-acting aripiprazole

The International Journal of Neuropsychopharmacology September 1, 2026 S Makhoul, N Abdulameer

Abstract Background Esketamine intranasal spray is FDA-approved for treatment-resistant depression (TRD), but it is not licensed for use in bipolar disorder due to the risk of antidepressants inducing manic or hypomanic episodes. To date, there is limited data on the use of intranasal esketamine in bipolar disorder, and no previous reports of using esketamine as an add-on treatment in patients...

DOI: 10.1093/ijnp/pyag040.273 (opens in new tab) Full text (opens in new tab)

575. A scoping review: ketamine or esketamine when used to assist psychotherapy or in combination with psychotherapy for the management of depression

International Journal of Neuropsychopharmacology September 1, 2026

Abstract Background Antidepressant effects of ketamine and esketamine are short lived, often lasting only weeks after multiple treatments. With that in mind, it has been considered addition of psychotherapy may enhance outcomes. One approach, knows as Ketamine Assisted Psychotherapy (KAP) focuses on "integration " of the dissociative experience induced by ketamine, and suggests this may produce...

DOI: 10.1093/ijnp/pyag040.097 (opens in new tab) Full text (opens in new tab)

Ketamine and esketamine for treatment-resistant depression: A systematic review of published studies

Medical Science August 30, 2026 Julia Rogała, Kinga Polityńska, Dominika Ruszel et al.

Treatment-resistant depression occurs in roughly one-third of individuals diagnosed with depression.Ketamine and esketamine have appeared as innovative antidepressant treatments that target the glutamatergic system and deliver promising therapeutic options for patients unresponsive to conventional monoaminergic antidepressants.This review delivers a complete analysis of the mechanisms of...

DOI: 10.54905/disssi.v30i174.e142ms3863 (opens in new tab) Full text (opens in new tab)

Clinical trials

All esketamine for depression trials →