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Esketamine research: what the evidence shows

(S-ketamine) The S-enantiomer of ketamine, approved as a nasal spray for treatment-resistant depression and studied in its own large trial literature.

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, then ranked by relevance.

Across randomized trials, esketamine nasal spray added to an oral antidepressant generally produces a rapid, statistically significant reduction in depressive symptoms in treatment-resistant depression, with effects emerging within hours to days and short-term differences of roughly 3-4 MADRS points versus antidepressant plus placebo; however, results are not fully consistent, as one large trial missed its primary endpoint. Maintenance esketamine substantially lowers relapse risk (about 49-70% relative reduction), and it appears non-inferior to racemic ketamine and superior to quetiapine augmentation for remission. The main caveats are that benefits on suicidality-specific outcomes are less clear, long-term open-label completion is low, and evidence on cognition, biomarkers, and misuse risk remains limited or inconsistent.

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 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 nasal spray.
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression 2019 RCT 297 Supports Continuing esketamine plus an oral antidepressant reduced relapse risk by 51% in stable remitters and 70% in stable responders compared with switching to placebo plus antidepressant.
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression 2017 RCT 67 Supports Intranasal esketamine produced a rapid, dose-related antidepressant effect, with response appearing to persist for more than 2 months at a 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 An international expert group concludes that ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, while noting remaining safety, tolerability, and implementation concerns.
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 Intranasal esketamine plus standard care produced significantly greater improvement in 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 an oral antidepressant did not significantly reduce depression scores versus placebo plus antidepressant at 4 weeks, although 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 and significant antidepressant effects compared with placebo.
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 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 meta-analysis 1877 Mixed Racemic ketamine showed greater response and remission rates and lower dropouts than esketamine across pooled randomized trials.
Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent 2020 RCT 226 Mixed Esketamine plus standard care led to greater improvement in depressive symptoms at 24 hours than placebo plus standard care, 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 nasal spray plus a new oral antidepressant had a manageable safety profile and sustained improvements in depression symptoms, though only about a quarter of those entering the maintenance phase completed it.
Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study 2019 RCT 32 Supports Esketamine 0.5 mg/kg provided faster recovery and orientation recovery than 1 mg/kg racemic ketamine, with a lower incidence of adverse events.
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression 2023 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 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.
Reduction of dopamine D2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys 2016 experimental study Mixed Esketamine, but not R-ketamine, reduced dopamine D2/3 receptor binding availability in the striatum, suggesting dopamine release that may relate to psychotomimetic effects.
The Era of Rapid-Acting Antidepressants: Clinical Insights Into Ketamine, Esketamine, and Scopolamine 2026 systematic review Supports The review reports that intranasal esketamine plus oral antidepressants reduced MADRS scores over four weeks and lowered relapse risk (HR 0.49), with the most consistent evidence for maintenance intranasal esketamine.
Peripheral Biomarkers of Response to Ketamine and Esketamine Treatment in Unipolar Depressive Disorder—A Scoping Review 2026 systematic review Unclear Across 46 studies, the most frequently examined peripheral biomarkers of ketamine or esketamine response were BDNF, inflammatory markers, and kynurenine metabolites, but results were inconsistent and no biomarker is yet ready for clinical use.
Feasibility and tolerability of virtual reality during esketamine treatment: A pilot study. 2026 pilot study 26 Mixed Patients commonly reported auditory and visual discomfort during ketamine treatment and most were open to virtual reality; in five patients who used VR during an esketamine session, glasses wearers had difficulty and reported nausea, and all showed reduced altered-state scores.
A circuit dissection of perception-action decoupling in S-ketamine-induced hallucination-like states. 2026 preclinical experimental study Mixed S-ketamine induced auditory false alarms and behavioral disorganization in mice through dissociable striatal pathways, and dexmedetomidine restored pathway-level temporal dynamics without simply suppressing activity.
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 treatment days), but depression worsened again by three months (BDI 20).
Cognitive effects of ketamine and esketamine treatment for major depressive and bipolar disorder: a systematic review. 2026 systematic review 2441 Mixed Single-dose ketamine or esketamine showed inconsistent cognitive effects in randomized trials, with some domain improvements, null findings, and reports of impaired memory recall and processing speed.
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 During six months of intranasal esketamine, obsessive-compulsive symptoms improved alongside depression (MADRS 38 to 17; Y-BOCS 33 to 14), though the authors state the observation cannot distinguish a direct anti-obsessional effect from nonspecific factors.
384. S-ketamine, but not R-ketamine, increases the spontaneous firing rate and the AMPA-evoked response of pyramidal neurons in the rat prefrontal cortex 2026 preclinical electrophysiological study Supports S-ketamine and ifenprodil increased spontaneous firing of medial prefrontal cortex neurons, and ketamine and S-ketamine increased responsiveness to AMPA, which the authors propose may underlie rapid antidepressant effects.
507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review 2026 case study 1 Opposes The authors describe a temporal association between about three years of intranasal esketamine maintenance and subsequent ketamine use disorder escalating to 2-3 g/day, while noting causality cannot be inferred from a single case.

Points of agreement

  • Multiple randomized trials and reviews agree that esketamine produces rapid antidepressant effects in treatment-resistant depression, with onset within hours to days.
  • Maintenance esketamine plus an oral antidepressant reduces relapse risk substantially compared with discontinuation to placebo.
  • Esketamine appears non-inferior to racemic ketamine for short-term remission and superior to quetiapine augmentation for remission at week 8.
  • Common adverse events are dissociation, dizziness, nausea, and headache, generally transient and occurring on dosing days.
  • Effects on suicidality-specific outcomes are less consistent than effects on depressive symptoms.

Conflicts

  • One large trial (TRANSFORM-1) failed to show statistical significance for the primary endpoint at 4 weeks, while other trials and reviews report significant short-term benefit.
  • A meta-analysis found racemic ketamine had greater response and remission rates than esketamine, whereas a head-to-head non-inferiority trial found esketamine non-inferior to ketamine.
  • Some trials report early symptom improvement that is not sustained at later timepoints (e.g., day 25), while maintenance studies show durable benefit with continued dosing.

Gaps

  • Durability of benefit after stopping esketamine and optimal maintenance dosing schedules are not well established.
  • Long-term safety data are limited by low completion rates in open-label extension studies.
  • Whether esketamine directly reduces suicidality independent of depressive symptom improvement remains unclear.
  • Cognitive effects are inconsistent and it is uncertain whether any improvements are direct or secondary to mood response.
  • No peripheral biomarker is yet reliable for predicting response.
  • Risk of misuse and transition to ketamine use disorder is based mainly on case reports and requires systematic study.
Browse these studies in the library

Common questions

What does the research agree on about esketamine?
  • Multiple randomized trials and reviews agree that esketamine produces rapid antidepressant effects in treatment-resistant depression, with onset within hours to days.
  • Maintenance esketamine plus an oral antidepressant reduces relapse risk substantially compared with discontinuation to placebo.
  • Esketamine appears non-inferior to racemic ketamine for short-term remission and superior to quetiapine augmentation for remission at week 8.
  • Common adverse events are dissociation, dizziness, nausea, and headache, generally transient and occurring on dosing days.
  • Effects on suicidality-specific outcomes are less consistent than effects on depressive symptoms.
Where do studies on esketamine conflict?
  • One large trial (TRANSFORM-1) failed to show statistical significance for the primary endpoint at 4 weeks, while other trials and reviews report significant short-term benefit.
  • A meta-analysis found racemic ketamine had greater response and remission rates than esketamine, whereas a head-to-head non-inferiority trial found esketamine non-inferior to ketamine.
  • Some trials report early symptom improvement that is not sustained at later timepoints (e.g., day 25), while maintenance studies show durable benefit with continued dosing.
What is still unknown about esketamine?
  • Durability of benefit after stopping esketamine and optimal maintenance dosing schedules are not well established.
  • Long-term safety data are limited by low completion rates in open-label extension studies.
  • Whether esketamine directly reduces suicidality independent of depressive symptom improvement remains unclear.
  • Cognitive effects are inconsistent and it is uncertain whether any improvements are direct or secondary to mood response.
  • No peripheral biomarker is yet reliable for predicting response.
  • Risk of misuse and transition to ketamine use disorder is based mainly on case reports and requires systematic study.
How we analyze this

This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is Esketamine, 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 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

Latest monthly recap: September 2026 →

1,225 articles · 682 from the last two years · 2,037,925 participants across 595 studies reporting sample size

Common study designs

review 219 narrative review 52 systematic review 89 observational cohort 50 randomized controlled trial 147

Esketamine research by condition

Data updated

Studies whose primary subject is both Esketamine and the condition, with reviews counted by the study design extracted from each abstract. Registered trials are from ClinicalTrials.gov. This maps how much research exists, not how well anything works.

Esketamine research by condition: studies, meta-analyses and systematic reviews, registered clinical trials, the highest trial phase, and studies from the last two years. Most studies first.
Condition Studies Meta-analyses and systematic reviews Registered trials Highest phase From the last two years
Depression 594 studies 84 meta-analyses and systematic reviews 75 registered trials up to Phase 4 344 from the last two years
Anxiety 39 studies 4 meta-analyses and systematic reviews 4 registered trials up to Phase 4 24 from the last two years

Research volume by year

Compare topics →

884 studies whose primary subject is esketamine since 2005

Studies about esketamine per year, 2005 to 2026, peaking at 261 in 2026 Bar chart: one bar per year, taller where more studies were published that year. 0 150 300 2005 2010 2015 2020 2025
2026 is partial
Show the numbers
Studies about esketamine per year, 2005 to 2026, peaking at 261 in 2026
Year Studies
2005 1
2006 0
2007 1
2008 0
2009 2
2010 0
2011 1
2012 1
2013 0
2014 0
2015 1
2016 6
2017 4
2018 17
2019 11
2020 29
2021 20
2022 50
2023 99
2024 136
2025 244
2026 261

Research

Synthesize the evidence → Search all →

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)

Targeting NMDAR2A in microglia: esketamine suppresses M1 polarization in BV2 cells.

Molecular Biology Reports October 22, 2026 Hui Li, Xiaoyuan Zhang, Yushan Luo et al.

Objective: Microglial polarization toward the M1 phenotype is a key contributor to the initiation and progression of neuroinflammatory diseases, primarily through the release of pro-inflammatory cytokines that exacerbate central nervous system-associated injury. Activation of N-methyl-D-aspartic acid receptors (NMDARs) is implicated in microglial overactivation and cytotoxicity. This study...

DOI: 10.1007/s11033-026-12874-9 (opens in new tab) Full text (opens in new tab) Esketamine Microglia Cell line Animals +12

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)

Peripartum Esketamine: A Narrative Review of Analgesia, Postpartum Depressive Symptoms, Sleep-Related Outcomes, and Safety.

Drug Design, Development and Therapy October 17, 2026 Zhaoying Zhong, Baozhen Liao, Donglan Peng et al.

Pain, depressive symptoms, and sleep disruption frequently overlap during the peripartum period, although their relationships are associative rather than established as causal. Esketamine, an N-methyl-D-aspartate receptor antagonist, has attracted interest as a peripartum intervention with potential effects on pain, mood, and sleep. This narrative review evaluates the clinical and mechanistic...

DOI: 10.2147/dddt.s646618 (opens in new tab) Full text (opens in new tab) Esketamine Humans Pain Depression, postpartum +8

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)

Real-world clinical outcomes under intravenous and subcutaneous esketamine protocols for treatment-resistant depression: a multicenter, retrospective study

Frontiers in Psychiatry October 16, 2026 Gilberto Sousa Alves, Humberto M. M. Dos Santos, Samira D Damasceno et al.

Background Esketamine is a promising therapeutic option for treatment-resistant depression (TRD). Intravenous (IV) administration is the most extensively studied parenteral route. However, subcutaneous (SC) administration may offer simpler, more scalable delivery. Multicenter real-world evidence comparing IV and SC routes of administration remains limited. Objective To report clinical outcomes...

DOI: 10.3389/fpsyt.2026.1963841 (opens in new tab)

Baseline Response Criterion and Changes in Emotional Bias as Markers of Esketamine Response in Treatment-Resistant Depression

medRxiv October 15, 2026 Chlöé Müh, Pauline Favre, Isabel Karen Lütkenherm et al. preprint

Abstract Negative emotional bias, including reduced processing of positive information and negative interpretation of ambiguous stimuli, is a core feature of depression. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects in treatment-resistant depression (TRD), reduces depressive symptoms, but its effects on distinct components of emotional...

DOI: 10.64898/2026.10.14.26365535 (opens in new tab) Full text (opens in new tab)

Intranasal Esketamine for Treatment-Resistant Depression: A Practical Clinical Guide to Patient Selection, Dosing, Combination Strategies and Adverse-Event Management

Preprints.org October 14, 2026 Domenico de Berardis, Tommaso Barlattani, Alessandro Carano et al. preprint

Intranasal esketamine has been available for treatment-resistant depression (TRD) since 2019, but the trials that led to its approval answer only some of the questions prescribers face. About 97% of trial participants had failed only one or two antidepressant classes, and patients with bipolar disorder, psychosis, obsessive–compulsive disorder, four personality disorders, moderate-to-severe...

DOI: 10.20944/preprints202610.1252.v1 (opens in new tab)

Subcutaneous Esketamine in Adolescents with Severe Depressive Episodes: A Five-Case Series

Journal of Child and Adolescent Psychopharmacology October 9, 2026 Inês Vasconcelos Sousa Magalhães, Daniel N. Lopes, Isabel de Andrade Amato et al.

OBJECTIVE: To describe the feasibility, acute tolerability, and short-term symptom trajectories of adjunctive subcutaneous esketamine in adolescents with severe depressive episodes treated in specialized outpatient care. METHODS: This observational case series included five adolescents aged 15-17 years with severe depressive symptoms, suicidal ideation and/or behavior, and insufficient response...

DOI: 10.1177/10445463261497130 (opens in new tab)

Clinical trials

All Esketamine trials →