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Esketamine (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.

Research indicates that esketamine, particularly as a nasal spray, is an effective rapid-acting antidepressant for treatment-resistant depression, with significant short-term improvements and reduced relapse risk, though results are mixed in some trials and long-term durability remains uncertain. It also shows promise for rapid reduction of depressive symptoms in patients with suicidal ideation, but evidence for reducing suicidality itself is inconsistent. Safety concerns include dissociative side effects and potential risks in patients with comorbid substance use disorders, and comparative effectiveness against other treatments like ketamine or quetiapine varies.

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.
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
Supports

Esketamine nasal spray plus a newly initiated antidepressant produced a significantly greater reduction in depression severity at day 28 compared with antidepressant plus placebo.

RCT Sample size: 227

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression 2019
Supports

Continuing esketamine nasal spray plus an oral antidepressant reduced the risk of relapse by 51% among stable remitters and by 70% among stable responders compared with switching to placebo.

RCT Sample size: 297

Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression 2017
Supports

Intranasal esketamine produced a rapid, dose-related antidepressant effect in treatment-resistant depression, with response appearing to persist for more than 2 months at a lower dosing frequency.

RCT Sample size: 67

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation 2021
Supports

Experts synthesize that ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, but safety, tolerability, and implementation guidance remain key considerations.

review

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
Mixed

Intranasal esketamine plus standard care led to significantly greater improvement in depressive symptoms at 4 and 24 hours compared with placebo, but not at day 25, and did not reduce clinician-rated suicide risk.

RCT Sample size: 68

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
No effect

Esketamine nasal spray added to an oral antidepressant did not significantly reduce depression scores compared to placebo plus antidepressant at 4 weeks, though the treatment effect exceeded what is considered clinically meaningful for approved antidepressants.

RCT Sample size: 346

Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study 2015
Supports

Both 0.20 mg/kg and 0.40 mg/kg doses of intravenous esketamine produced rapid and significant antidepressant effects compared to placebo in treatment-resistant depression, with the lower dose potentially offering better tolerability.

RCT Sample size: 30

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
Supports

Esketamine plus standard of care reduced depressive symptoms more than placebo plus standard of care at 24 hours in severely ill patients with MDD and active suicidal ideation.

RCT Sample size: 227

Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis 2020
Mixed

Racemic ketamine showed greater response and remission rates and lower dropouts compared with esketamine for treating depression.

systematic review and meta-analysis Sample size: 1877

Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent 2020
Mixed

Esketamine plus standard care led to greater improvement in depressive symptoms at 24 hours compared to placebo plus standard care, but did not significantly reduce the severity of suicidal ideation.

RCT Sample size: 226

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression 2020
Supports

Long-term esketamine nasal spray plus a new oral antidepressant had a manageable safety profile and sustained improvements in depression symptoms.

open-label long-term study Sample size: 802

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study 2019
Supports

Esketamine 0.5 mg/kg provides faster recovery and orientation recovery than 1 mg/kg racemic ketamine, with a lower incidence of adverse events, and is generally safe in this population.

RCT Sample size: 32

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression 2023
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 in treatment-resistant depression.

RCT Sample size: 676

Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. 2019
Supports

Esketamine 0.25 mg/kg was non-inferior to ketamine 0.5 mg/kg for remission of treatment-resistant depression 24 hours after a single intravenous infusion.

RCT Sample size: 63

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
Supports

Esketamine, but not R-ketamine, reduces dopamine D2/3 receptor binding availability in the striatum, suggesting esketamine-induced dopamine release that may relate to its psychotomimetic effects.

experimental study

Trauma re-experiencing episodes during esketamine treatment in patients with treatment-resistant depression and comorbid PTSD: a retrospective case series. 2026
Mixed

Trauma re-experiencing episodes during esketamine treatment resolved in most patients as sessions continued, and favorable clinical outcomes for both depression and PTSD were observed when treatment was maintained.

retrospective observational study Sample size: 22

Effects of sub-anesthetic doses of esketamine on immune function and postoperative negative emotions in acoustic neuroma patients: a randomized clinical trial. 2026
Supports

Perioperative sub-anesthetic esketamine reduced postoperative depression, anxiety, and sleep disturbances after acoustic neuroma surgery, but did not significantly affect early immune function or acute postoperative analgesia.

RCT Sample size: 77

Prescribing bias and adverse outcomes of esketamine in major depression comorbid substance. 2026
Opposes

Esketamine users with comorbid substance use disorder had higher risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality compared to esketamine users without substance use disorder.

retrospective cohort study Sample size: 30670

Comparing transcranial magnetic stimulation and esketamine treatment response trajectories in resistant depression. 2026
Supports

Intranasal esketamine was associated with faster antidepressant and anti-suicidal response than rTMS, but overall efficacy at 90 days was similar.

retrospective analysis Sample size: 372

Ketamine and esketamine for the prevention of postpartum depression: A systematic review and network meta-analysis, with an integrated evidence synthesis. 2026
Supports

Ketamine and esketamine treatment may be associated with a reduced risk of developing postpartum depression, but the quality of the data was low to very low.

systematic review with network meta-analysis Sample size: 36

Role of concomitant benzodiazepines, lithium, and lamotrigine in modulating the antidepressant effects of subcutaneous esketamine in patients with treatment-resistant depressive episodes: A retrospective naturalistic study. 2026
Mixed

Concomitant benzodiazepine use was associated with higher depressive symptom severity during subcutaneous esketamine treatment, while lamotrigine and lithium showed no significant association with outcomes.

observational cohort Sample size: 178

Comparative effectiveness and safety of esketamine versus injectable racemic ketamine and oral antidepressants for major depressive disorder: A population-based target trial emulation. 2026
Mixed

Esketamine was associated with higher risks of suicidal ideation, generalized anxiety disorder, insomnia, and cardiac arrest compared with injectable ketamine, but lower risks of suicidal ideation, suicide attempt, and generalized anxiety disorder compared with oral antidepressants, although with a higher risk of cardiac arrest.

emulated target trial Sample size: 1089419

Esketamine alleviates trigeminal neuralgia and anxiety-like behaviors in mice by inhibiting RIPK1/RIPK3/MLKL-mediated necroptosis. 2026
Supports

Esketamine alleviates pain and anxiety in a mouse model of trigeminal neuralgia by inhibiting hippocampal necroptosis via the RIPK1/RIPK3/MLKL pathway.

animal study

(Es)ketamine in functional neurological disorder: a systematic review 2026
Unclear

The current evidence base is insufficient to establish the efficacy of (Es)ketamine for functional neurological disorder, though improvements in functional symptoms have been reported across several presentations.

systematic review

Esketamine's Therapeutic Effect on Anhedonia: A Post-hoc of a Randomized Controlled Trial 2026
Supports

Esketamine reduced anhedonia symptoms compared to placebo in patients with treatment-resistant depression.

RCT post-hoc analysis

Points of agreement

  • Esketamine is effective for rapid reduction of depressive symptoms in treatment-resistant depression, with significant improvements at early timepoints (hours to days).
  • Esketamine nasal spray combined with an oral antidepressant reduces relapse risk in patients who achieve remission or response.
  • Esketamine is generally well-tolerated with common transient adverse events like dissociation, nausea, and dizziness.
  • Esketamine shows benefit for depressive symptoms in patients with suicidal ideation, though effects on suicidality itself are less consistent.

Conflicts

  • One phase 3 trial (TRANSFORM-1) failed to show statistical significance for the primary endpoint, while other trials showed significant benefit.
  • Meta-analysis found racemic ketamine superior to esketamine for response and remission, but a non-inferiority trial found esketamine non-inferior to ketamine.
  • Studies on suicidal ideation show mixed results: some show improvement in depressive symptoms but not in clinician-rated suicide risk, while others show no significant difference in suicidality severity.
  • Real-world comparative studies show esketamine associated with higher risks of certain adverse outcomes compared to injectable ketamine, but lower risks compared to oral antidepressants.

Gaps

  • Long-term durability of esketamine's antidepressant effects beyond one year is not well established.
  • Comparative effectiveness against other augmentation strategies (e.g., rTMS, quetiapine) is limited to few studies with mixed results.
  • Safety and efficacy in special populations (e.g., comorbid substance use disorder, PTSD, postpartum women) require more research.
  • Optimal dosing, frequency, and duration of esketamine treatment are not fully defined.
  • Most studies are short-term (4-8 weeks) with limited follow-up; long-term safety data are sparse.
  • Blinding in some trials is compromised by the psychoactive effects of esketamine.
Browse these studies in the library
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.

Ask your own question in the Research Synthesis Tool

Latest monthly recap: July 2026 →

967 articles · 601 from the last two years · 1,619,262 participants across 454 studies reporting sample size

Common study designs

review 197 narrative review 39 systematic review 68 observational cohort 49 randomized controlled trial 127

Research

Synthesize the evidence → Search all →

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)

Esketamine-based treatment, depression-specific metacognitive training, and their combination in treatment-resistant depression: 6-month trajectories of depressive symptoms and rumination in a multicenter observational study.

Eur Arch Psychiatry Clin Neurosci August 29, 2026

Esketamine-based treatment, depression-specific metacognitive training, and their combination in treatment-resistant depression: 6-month trajectories of depressive symptoms and rumination in a multicenter observational study.

DOI: 10.1007/s00406-026-02361-4 (opens in new tab)

Erratum to "Long-term treatment with esketamine nasal spray in patients with treatment resistant depression: Results from the ESCAPE-LTE study" [European Neuropsychopharmacology 107 (2026) 112801].

Eur Neuropsychopharmacol August 27, 2026 correction

Erratum to "Long-term treatment with esketamine nasal spray in patients with treatment resistant depression: Results from the ESCAPE-LTE study" [European Neuropsychopharmacology 107 (2026) 112801].

DOI: 10.1016/j.euroneuro.2026.113860 (opens in new tab)

Real-World Effectiveness and Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: A Retrospective Observational Study

Healthcare August 26, 2026 Mostafa A. Sayed Ali, Palanisamy Amirthalingam, Hanan Alshareef et al.

Background/Objectives: This study evaluated the real-world effectiveness and safety of intranasal esketamine plus oral antidepressants compared with venlafaxine-based oral antidepressant therapy in adults with moderate-to-severe treatment-resistant depression (TRD). Methods: This retrospective cohort study used electronic medical records from a mental health hospital between January 2023 and...

DOI: 10.3390/healthcare14172717 (opens in new tab)

Case report of S-ketamine as treatment option for suicidal ideation and treatment-resistant depression in adolescents with early-onset psychosis

Neuropsychiatrie August 25, 2026 Nicolas Schmelzle, Katrin Neubacher, Paul L. Plener et al.

BACKGROUND: Depressive symptoms and suicidality are highly prevalent in adolescents with early-onset psychosis (EOP) and often remain refractory to standard treatment. While S‑ketamine is an established treatment for treatment-resistant depression in adults (TRD), its use in primary psychotic disorders remains scarce due to risk of exacerbation of psychotic symptoms. CASE PRESENTATION: We...

DOI: 10.1007/s40211-026-00587-1 (opens in new tab) Full text (opens in new tab)

Profiling intranasal esketamine for adults with major depressive disorder and acute suicidal ideation or behavior: a phenotype-informed drug profile

Expert Review of Neurotherapeutics August 18, 2026 Mario Pinzi, Alessandro Cuomo, Maria Beatrice Rescalli et al.

INTRODUCTION: Acute suicidal ideation in major depressive disorder (MDD) is a psychiatric emergency requiring rapid risk assessment, containment, and treatment. Conventional monoaminergic antidepressants have delayed onset, leaving an interval during which severe depressive distress persists. Intranasal esketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist, is approved for MDD...

DOI: 10.1080/14737175.2026.2714839 (opens in new tab)

A Systematic Review of Long-term Safety Outcomes of Ketamine and Esketamine in Patients with Treatment-resistant Depression.

August 17, 2026 Tychique T. Wasolua, Morgan S Hardy, Tanner J. Bommersbach et al.

INTRODUCTION: Approximately 30-40% of patients with major depressive disorder fail to respond to conventional antidepressants. Ketamine and esketamine are increasingly used, yet synthesized data on cumulative safety remain limited. This systematic review evaluated long-term safety of both agents. METHODS: MEDLINE, PsycINFO, Embase, and Cochrane Library were searched from inception through...

DOI: 10.1159/pps/aemag005 (opens in new tab)

Clinical trials

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