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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 24 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 shows rapid antidepressant effects in treatment-resistant depression, with several placebo-controlled trials reporting significantly greater symptom reduction than comparator (roughly 3-5 points on the MADRS) within days to 4 weeks, and maintenance trials showing substantially lower relapse risk when esketamine is continued. Results are not fully consistent: one large phase 3 trial missed its primary endpoint, and benefits on suicidality are short-lived and inconsistent. Evidence is mostly short-term and in narrowly selected trial populations, with long-term data largely open-label.

Evidence by study

Direction is which way each study's own result points, not our rating of the study. All 25 matching studies were reviewed; the 24 that directly address the question are shown here.

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 RCT 227 Supports Esketamine nasal spray plus a new antidepressant reduced MADRS scores significantly more than antidepressant plus placebo at day 28 (LS mean difference -4.0).
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression 2019 RCT (randomized withdrawal) 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 RCT (phase 2, delayed-start) 67 Supports Intranasal esketamine produced a rapid, dose-related antidepressant effect, with response appearing to persist over 2 months at reduced 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 Expert synthesis concludes ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, while flagging safety, tolerability, and implementation uncertainties.
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 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 RCT 346 No effect Esketamine 84 mg plus antidepressant did not significantly reduce MADRS scores versus placebo plus antidepressant at 4 weeks, though the 56 mg comparison 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 and 0.40 mg/kg IV esketamine produced rapid, significant MADRS improvement versus placebo by day 2, 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 RCT 227 Supports Esketamine plus standard of care reduced MADRS scores more than placebo plus standard of care at 24 hours (LS mean difference -3.9), with no significant between-group difference in suicidality severity.
Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis 2020 systematic review and meta-analysis 1877 Mixed Pooled trials showed racemic ketamine had greater response and remission rates and fewer dropouts than esketamine.
Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent 2020 RCT 226 Supports Esketamine plus standard care improved MADRS scores more than placebo at 24 hours (LS mean difference -3.8) but did not significantly reduce severity of suicidal ideation.
Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression 2020 open-label long-term study 802 Supports Long-term esketamine plus a new oral antidepressant had a manageable safety profile with sustained symptom improvements, though only about a quarter of those entering maintenance completed it.
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression 2023 RCT (open-label, rater-blind) 676 Supports Esketamine plus SSRI/SNRI produced higher remission rates at week 8 than extended-release quetiapine plus SSRI/SNRI.
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 24-hour remission, 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 1148 Supports Depression improvements generally persisted among participants remaining on maintenance esketamine for up to 4.5 years, with no new safety signal.
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 IV ketamine and intranasal esketamine were associated with reductions in suicidal thoughts at 2, 4, and 24 hours.
Quality of Life in Patients with Treatment-Resistant Depression Treated with Intranasal Esketamine as Add-On Therapy to an SSRI—A Prospective, Comparative Study in Real-World Clinical Practice 2026 observational cohort 60 Supports Both groups improved in quality of life and symptom severity, with larger absolute changes in the esketamine add-on group; authors caution the association is not evidence of an isolated causal effect.
Real-world clinical outcomes under intravenous and subcutaneous esketamine protocols for treatment-resistant depression: a multicenter, retrospective study 2026 retrospective chart review 72 Mixed Response after six sessions favored IV over subcutaneous esketamine but was not statistically significant, and no difference was seen at protocol endpoints; dissociation was more frequent with IV.
Baseline Response Criterion and Changes in Emotional Bias as Markers of Esketamine Response in Treatment-Resistant Depression 2026 observational cohort 106 Supports Esketamine responders showed early increases in emotion discrimination sensitivity and less negative categorization of neutral faces by week 4 than non-responders, and a lower baseline response criterion was associated with responder status.
Intranasal Esketamine for Treatment-Resistant Depression: A Practical Clinical Guide to Patient Selection, Dosing, Combination Strategies and Adverse-Event Management 2026 review Mixed Argues that approval trials excluded many real-world patients and leave prescribing questions unresolved, and states the evidence does not show 84 mg is more effective than 56 mg.
Multiband ALFF in patients with major depressive disorder treated with esketamine and sertraline: A preliminary study 2026 single-arm pre-post observational 40 Supports Two weeks of esketamine plus sertraline was associated with symptom improvement and frequency-specific changes in resting-state brain activity, though no region-clinical correlation survived correction.
Esketamine and Acceptance and Commitment Therapy (ACT) for Treatment-Resistant Depression: An Intervention-Development Framework and Treatment Manual 2026 theoretical Unclear Proposes an ACT-based therapy manual to accompany esketamine, arguing its psychedelic-like effects and monitoring period create therapeutic opportunities, but states the intervention is untested.
Peripheral Biomarkers of Response to Ketamine and Esketamine Treatment in Unipolar Depressive Disorder—A Scoping Review 2026 systematic review (scoping) Unclear Across 46 studies, candidate peripheral biomarkers of ketamine/esketamine response (BDNF, inflammatory markers, kynurenine metabolites) showed inconsistent results and none is ready for clinical use.
Feasibility and tolerability of virtual reality during esketamine treatment: A pilot study. 2026 pilot feasibility study 26 Mixed Patients commonly reported audiovisual discomfort during treatment and most were open to VR; in five patients using VR during an esketamine session, glasses wearers had difficulty and nausea, and altered-state scores were reduced.
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).

Points of agreement

  • Multiple placebo- or active-controlled trials show esketamine produces rapid antidepressant effects in treatment-resistant depression, with MADRS differences of roughly 3-5 points.
  • Continued esketamine plus an oral antidepressant reduces relapse compared with discontinuation.
  • Antidepressant benefit appears within hours to days, faster than conventional antidepressants.
  • Common adverse events are dissociation, dizziness, nausea, and headache, generally transient and dose-related.
  • Benefits on suicidality are short-lived and not consistently significant on clinician-rated measures.

Conflicts

  • One large phase 3 trial missed its primary endpoint while other controlled trials were positive.
  • Meta-analytic pooling suggests racemic ketamine may outperform esketamine on response and remission, while a head-to-head non-inferiority trial found esketamine non-inferior to ketamine.
  • Suicidality outcomes differ: some trials show early improvement in suicidal thoughts, others find no significant reduction in clinician-rated suicide risk.

Gaps

  • Durability beyond short-term trials is supported mainly by open-label extension data without a control arm.
  • Trial populations excluded many comorbid patients (bipolar disorder, psychosis, substance use, personality disorders), limiting generalizability.
  • Optimal dose is unresolved; evidence does not establish that 84 mg outperforms 56 mg.
  • No validated peripheral biomarker predicts response.
  • Comparative effectiveness versus other augmentation strategies and racemic ketamine is based on limited head-to-head data.
  • Adjunctive psychological or VR-enhanced approaches remain untested in controlled trials.
Browse these studies in the library

Common questions

What does the research agree on about esketamine for depression?
  • Multiple placebo- or active-controlled trials show esketamine produces rapid antidepressant effects in treatment-resistant depression, with MADRS differences of roughly 3-5 points.
  • Continued esketamine plus an oral antidepressant reduces relapse compared with discontinuation.
  • Antidepressant benefit appears within hours to days, faster than conventional antidepressants.
  • Common adverse events are dissociation, dizziness, nausea, and headache, generally transient and dose-related.
  • Benefits on suicidality are short-lived and not consistently significant on clinician-rated measures.
Where do studies on esketamine for depression conflict?
  • One large phase 3 trial missed its primary endpoint while other controlled trials were positive.
  • Meta-analytic pooling suggests racemic ketamine may outperform esketamine on response and remission, while a head-to-head non-inferiority trial found esketamine non-inferior to ketamine.
  • Suicidality outcomes differ: some trials show early improvement in suicidal thoughts, others find no significant reduction in clinician-rated suicide risk.
What is still unknown about esketamine for depression?
  • Durability beyond short-term trials is supported mainly by open-label extension data without a control arm.
  • Trial populations excluded many comorbid patients (bipolar disorder, psychosis, substance use, personality disorders), limiting generalizability.
  • Optimal dose is unresolved; evidence does not establish that 84 mg outperforms 56 mg.
  • No validated peripheral biomarker predicts response.
  • Comparative effectiveness versus other augmentation strategies and racemic ketamine is based on limited head-to-head data.
  • Adjunctive psychological or VR-enhanced approaches remain untested in controlled 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

606 articles · 350 from the last two years · 1,428,186 participants across 363 studies reporting sample size

Common study designs

review 63 systematic review 43 observational cohort 38 randomized controlled trial 67 systematic review and meta-analysis 28

Research volume by year

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600 studies whose primary subject is esketamine for depression since 2009

Studies about esketamine for depression per year, 2009 to 2026, peaking at 184 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 184 in 2026
Year Studies
2009 2
2010 0
2011 0
2012 0
2013 0
2014 0
2015 1
2016 4
2017 3
2018 9
2019 10
2020 23
2021 10
2022 39
2023 73
2024 88
2025 154
2026 184

Research

Synthesize the evidence →

Ketamine and esketamine for suicidal ideation in depression: a systematic review and meta-analysis of randomized controlled trials

Middle East Current Psychiatry November 11, 2026 Kirolos Eskandar, Amr Mousa, Kerolos Shahat

Abstract: Background: Suicidal ideation is a major clinical problem in depressive disorders, while conventional antidepressants have delayed effects. Ketamine and esketamine may provide rapid relief, but their effects on suicidal ideation, durability, suicidal behavior, and safety remain uncertain. Aim: To evaluate the efficacy, durability, suicidal-behavior outcomes, acceptability, and safety...

DOI: 10.1186/s43045-026-00683-6 (opens in new tab)

A predictive nomogram based on sub-anesthetic esketamine and clinical variables for estimating the risk of postoperative depression following laparoendoscopic single-site hysterectomy

Frontiers in Medicine November 10, 2026 Kun Shao, Weili Han, Xu Cao et al.

Objective To construct a nomogram combining sub-anesthetic esketamine administration with perioperative clinical characteristics for predicting postoperative depression in patients undergoing laparoendoscopic single-site (LESS) hysterectomy. Methods Clinical records from 326 patients who underwent LESS hysterectomy were retrospectively reviewed. Participants were randomly assigned to training (...

DOI: 10.3389/fmed.2026.1943794 (opens in new tab)

Dextromethorphan-Bupropion-Esketamine Triadic Pharmacology: Molecular Targets, Enzymatic Interactions, and Risk-Benefit Assessment of a Three-Agent Combination for Treatment-Resistant Depression

International Journal of Molecular Sciences November 9, 2026 Andrea Fagiolini, Alessandro Cuomo, Giulio Corrivetti et al.

Dextromethorphan is extensively O-demethylated by cytochrome P450 2D6 (CYP2D6) to dextrorphan, and the two molecules do not share a target profile. Dextrorphan is the more potent N-methyl-D-aspartate (NMDA) channel blocker; the parent compound is the more potent serotonin transporter inhibitor; their sigma-1 affinities are comparable, so differences in sigma-1 engagement depend on exposure...

DOI: 10.3390/ijms272110036 (opens in new tab)

INTRANASAL ESKETAMINE IN TREATMENT-RESISTANT DEPRESSION: WHY DO REAL-WORLD CLINICAL PRACTICE OUTCOMES SURPASS THOSE OF CLINICAL TRIALS? A NARRATIVE REVIEW

Boletim de Conjuntura November 3, 2026 Ana Carmelita Gomes Farias, Maria Laura Vieira Martins Guimarães, Ana Carolina Ferrazi Sampaio et al.

Intranasal esketamine was approved for the treatment of treatment-resistant depression on the basis of randomized clinical trials whose effects, when pooled in meta-analyses, were of modest magnitude. In contrast, observational studies conducted in routine clinical practice have reported substantial symptom reductions and increasing remission rates over follow-up. This review aimed to...

DOI: 10.56238/bocav25n84-001 (opens in new tab)

Blood pressure elevation with ketamine and esketamine in depression: a systematic review and meta-analysis of randomised trials

Open Science Framework November 2, 2026 Karim Haffar preprint

Review title: Blood pressure elevation with ketamine and esketamine in depression: a systematic review and meta-analysis of randomised trials Type and method of review: Meta analysis Stage of review at time of this submission: Review ongoing — the protocol has been finalised and the peer-reviewed search prepared; formal screening not yet started. Review question: In Adults with depression...

DOI: 10.17605/osf.io/csarj (opens in new tab)

Esketamine-Associated Lower Urinary Tract Symptoms Suggestive of Bladder Overactivity in Treatment-Resistant Depression: A Case Report

Research Square October 23, 2026 Clara De Oliveira Lapa, Mario F Juruena, Danilo Costa Pereira et al. preprint

Abstract Background Intranasal esketamine is an approved therapy for treatment-resistant depression and is recognized for its rapid and effective antidepressant effects. Although ketamine-associated cystitis has been documented in recreational users, the urinary safety profile of therapeutic esketamine remains incompletely characterized. Functional lower urinary tract disturbances suggestive of...

DOI: 10.21203/rs.3.rs-11132874/v1 (opens in new tab) Full text (opens in new tab)

Suicidality during intranasal (es)ketamine treatment: A retrospective cohort study.

Journal of Affective Disorders October 21, 2026 Yamina Ehrt-Schäfer, Georgios Schoretsanitis, Erich Seifritz et al.

Intranasal (es)ketamine has shown efficacy in therapy of treatment-resistant depression (TRD). However, its effects on suicidality have not been fully elucidated. We conducted a retrospective longitudinal cohort study of 80 patients affected by TRD, treated with intranasal (es)ketamine. Suicidality was assessed using item 10 of the clinician-rated Montgomery-Åsberg Depression Rating Scale...

DOI: 10.1016/j.jad.2026.122647 (opens in new tab) Full text (opens in new tab) Esketamine Treatment-resistant depression Suicidality

Subanesthetic-dose esketamine-assisted electroconvulsive therapy for suicidal ideation in adolescents with major depressive disorder: Interim trial results

World Journal of Psychiatry October 21, 2026 Xiao-ge Han, Qibin Chen, Su Min et al.

BACKGROUNDEvidence for adjunctive subanesthetic-dose esketamine during electroconvulsive therapy (ECT) in adolescents with major depressive disorder (MDD) is limited.Suicidal ideation is a critical early treatment target in this population.We hypothesized that adjunctive subanesthetic-dose esketamine during ECT would accelerate the reduction in suicidal ideation and improve early clinical...

DOI: 10.5498/wjp.124685 (opens in new tab)

Quality of Life in Patients with Treatment-Resistant Depression Treated with Intranasal Esketamine as Add-On Therapy to an SSRI—A Prospective, Comparative Study in Real-World Clinical Practice

Pharmaceuticals October 19, 2026 Daniel Szawarnoga, Joanna Fojcik, Michał Kamil Górski et al.

Treatment-resistant depression (TRD) remains one of the most clinically challenging forms of depressive disorders. In many patients, reduction in symptom severity does not translate into full functional recovery; therefore, assessment of treatment effectiveness should also include health-related quality of life (HRQoL). Objective: The aim of the study was to compare changes in HRQoL in patients...

DOI: 10.3390/ph19101644 (opens in new tab)

Esketamine alleviates the pain-depression dyad: insights from exploratory transcriptomic profiling and Wnt4-associated molecular alterations within the anterior cingulate cortex

Frontiers in Pharmacology October 16, 2026 Qingmei Li, Shuming Liu, Huiling Chen et al.

Objective The molecular mechanisms driving esketamine (ESK) efficacy in the pain-depression dyad (PDD) remain incompletely understood. This study investigated the effects of a sub-anesthetic ESK regimen on cortical expression profiles and exploratory signaling markers within the anterior cingulate cortex (ACC). Methods Male Sprague-Dawley rats were randomized into Sham, PDD, and PDD + ESK...

DOI: 10.3389/fphar.2026.1873924 (opens in new tab)

Clinical trials

All esketamine for depression trials →