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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.

Esketamine, particularly as an intranasal spray, is an effective rapid-acting treatment for treatment-resistant depression (TRD), with multiple randomized controlled trials showing significant reductions in depressive symptoms within days to weeks. However, results are not entirely consistent, as one large phase 3 trial (TRANSFORM-1) failed to meet its primary endpoint, and the evidence for its anti-suicidal effects is mixed, with some studies showing rapid improvement in suicidal ideation that may be partly independent of mood improvement. Long-term data suggest sustained efficacy and a manageable safety profile, but the evidence base is limited by relatively small sample sizes in some trials, open-label extensions, and a lack of direct comparisons with other active treatments in some contexts.

Confidence in the evidence

Moderate
  • Multiple phase 3 RCTs (n=227, 297, 346, 676) and a phase 2 RCT (n=67) provide consistent evidence for esketamine's efficacy in TRD, but one large trial (TRANSFORM-1, n=346) failed to meet its primary endpoint, introducing some inconsistency.
  • The evidence for esketamine's anti-suicidal effects is mixed: two RCTs (n=68, n=226) showed rapid improvement in depressive symptoms but not in clinician-rated suicide risk, while a real-world analysis suggested an anti-suicidal effect independent of mood improvement.
  • Long-term safety and efficacy are supported by open-label extensions (n=802, n=1148) with up to 4.5 years of follow-up, but these lack a control group, limiting causal inference.
  • A systematic review and meta-analysis (n=1877) found racemic ketamine to have greater effect sizes than esketamine, and a large emulated target trial (n>1 million) suggested esketamine may have higher risks of certain adverse events compared to injectable ketamine, raising questions about comparative effectiveness and safety.
How we rate confidence

Confidence reflects the strength of the underlying evidence, not whether the result is favorable. It weighs the number and size of studies, their design (randomized trials count for more than observational or single-case work), how consistently they point the same way, and their risk of bias.

Tiers run from Insufficient to High. High is rare in this field: small, early, or open-label studies land lower even when their direction is encouraging.

Evidence by study

Direction is each study's finding relative to your question: Supports, Opposes, No effect, Mixed, or Unclear.

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 a newly initiated antidepressant plus placebo nasal spray.

phase 3, double-blind, active-controlled, multicenter randomized controlled trial 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 patients in stable remission and by 70% among stable responders, compared with switching to placebo plus an oral antidepressant.

phase 3, multicenter, double-blind, randomized withdrawal study 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.

phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study 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

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.

randomized controlled trial 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.

randomized controlled trial 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.

randomized controlled trial Sample size: 30

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

Racemic ketamine showed greater overall 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.

randomized controlled trial 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.

phase 3, open-label, multicenter, 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.

randomized, open-label, parallel-controlled, Phase I study 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.

randomized controlled trial 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.

randomized controlled trial 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
Unclear

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

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
Supports

Improvement in depression ratings generally persisted among participants who remained in maintenance treatment, and no new safety signal was identified during long-term treatment (up to 4.5 years) using intermittent-dosed esketamine in conjunction with daily antidepressant.

open-label, long-term extension study Sample size: 1148

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

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 and narrative synthesis 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 using observational data 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

Beyond Monoamines: Ketamine, Esketamine, and Classic Psychedelics in the Treatment of Depression 2026
Supports

Ketamine and esketamine have the strongest evidence among rapid-acting antidepressant interventions for treatment-resistant depression, while psilocybin-assisted therapy shows promise but remains investigational.

review

Serum brain-derived neurotrophic factor following oral esketamine in treatment-resistant depression: Results from a randomized placebo-controlled trial. 2026
No effect

Repeated, low-dose, oral esketamine did not increase serum BDNF relative to placebo.

randomized controlled trial Sample size: 54

Is the reduction in suicidal ideation and deliberate self-harm during intranasal esketamine treatment independent of antidepressant response? A secondary, longitudinal analysis of a real-world TRD cohort with and without comorbid borderline personality disorder 2026
Supports

The within-person reduction in suicidal ideation over six months remains statistically significant after adjusting for time-varying depressive severity, indicating an anti-suicidal effect partly independent of mood improvement.

secondary analysis of a longitudinal cohort

Points of agreement

  • Esketamine, particularly intranasal, is effective for treatment-resistant depression, with multiple RCTs showing significant reductions in depressive symptoms within days to weeks.
  • Long-term open-label studies indicate sustained efficacy and a manageable safety profile with no new safety signals over up to 4.5 years.
  • Esketamine has a rapid onset of antidepressant action, often within hours to days.
  • Common adverse events include dissociation, dizziness, nausea, and headache, which are typically transient and mild to moderate.

Conflicts

  • One phase 3 RCT (TRANSFORM-1) failed to meet its primary endpoint, while other phase 3 RCTs showed significant efficacy, creating inconsistency in the evidence base.
  • Evidence for esketamine's anti-suicidal effects is mixed: some RCTs show rapid improvement in depressive symptoms but not in clinician-rated suicide risk, while a real-world analysis suggests an anti-suicidal effect independent of mood improvement.
  • A meta-analysis found racemic ketamine to have greater response and remission rates than esketamine, but a head-to-head RCT found esketamine non-inferior to ketamine.
  • A large emulated target trial found esketamine associated with higher risks of suicidal ideation and cardiac arrest compared with injectable ketamine, but lower risks of suicidal ideation and suicide attempt compared with oral antidepressants.

Gaps

  • Durability of response beyond 1-4.5 years is not well studied in controlled trials.
  • Comparative effectiveness against other active treatments (e.g., rTMS, other augmentation strategies) is limited to a few studies.
  • Optimal dosing, frequency, and duration of treatment are not fully established, especially for long-term maintenance.
  • Efficacy and safety in special populations (e.g., comorbid PTSD, substance use disorders, bipolar depression, pregnant/postpartum women) are understudied.
  • Mechanisms of action, including the role of BDNF and dopamine release, are not fully elucidated in humans.
  • Real-world effectiveness and safety data are limited by potential confounding and lack of blinding in observational studies.
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

852 articles · 551 from the last two years · 1,582,999 participants across 397 studies reporting sample size

Common study designs

review 178 narrative review 39 systematic review 59 observational cohort 44 randomized controlled trial 118

Research

Synthesize the evidence → Search all →

Psychopathological descriptive model of hallucinogenic/psychedelic drugs effect in the treatment of depression and addictions

Nestor Girala

The efficacy of hallucinogenic drugs (ayahuasca, psilocybin, LSD, ketamine) in treating depression and addictions is accompanied by intense emotional states and mystical-type experiences, including feelings of oneness, transcendence, ineffability, and awe. These common psychopathological elements may mediate the drugs' therapeutic action. The paper reviews literature on subjective experiences during such treatments and compares them with other life-changing experiences, discussing the evolutionary value of these emotions for group cohesiveness and the recalibration of cognitions and emotions.

DOI: 10.14293/s2199-1006.1.sor-.ppfvg0c.v1

Psychedelic Therapy: A Primer for Primary Care Clinicians – Part VII. Ketamine

Viviana D. Evans, Alejandro Arenas, Kenneth Shinozuka et al. preprint

Ketamine, originally a dissociative anesthetic, is now used for treatment-resistant depression and major depressive disorder with suicidal ideation. A single intravenous infusion shows antidepressant effects within hours, with a large effect size on depression scores. It also reduces PTSD symptom severity and suicidal ideation in emergency settings. However, therapeutic effects often subside within weeks, requiring repeated doses. Risks include temporary or persistent memory impairment, cardiovascular issues, liver toxicity, and bladder inflammation. Ketamine's opioid-sparing effect improves postoperative pain management.

DOI: 10.31234/osf.io/dtb6a

Ketamine and Esketamine for Suicidal Ideation: A Stratified Evidence Synthesis Across Intravenous, Intranasal, and Injection Routes (2016–2026)

SSRN Electronic Journal Michael Alvear

A synthesis of 31 studies from 2016 to 2026 finds that intravenous ketamine rapidly reduces suicidal ideation, with 63% of patients achieving full remission by Day 3 compared to 32% on placebo, effects appearing within 40 minutes. Intranasal esketamine shows inconsistent results across studies, but when confounding factors such as hospitalization floor effects, insensitive measurement, and treatment resistance are accounted for, its anti-suicidal effect becomes clear and lasts up to 18 weeks. Injection routes show promise but lack randomized trial evidence. The analysis is based on a publicly available dataset.

DOI: 10.2139/ssrn.6979838

Esketamine-induced dentate gyrus plasticity in treatment resistant depression: First-in-human evidence

Research Square Alice Le Berre

In adults with treatment-resistant depression, esketamine was associated with early microstructural changes in the dentate gyrus of the hippocampus: reduced fractional anisotropy and increased orientation dispersion index, consistent with greater dendritic complexity. Lower baseline left-dentate gyrus fractional anisotropy correlated with greater improvement at two weeks, and a decrease in fractional anisotropy over that period also correlated with improvement. These changes suggest esketamine may promote hippocampal plasticity, and baseline diffusion MRI metrics could serve as candidate biomarkers for treatment response. The study included 12 adults with treatment-resistant depression and 24 matched controls, but larger studies are needed.

DOI: 10.21203/rs.3.rs-8196324/v1

Systematic Reviews and Meta-Analyses of Ketamine Therapy for Depression (2020–2024) A Comparative Evidence Summary

Michael Alvear preprint

More than 25 systematic reviews and meta-analyses published between 2020 and 2025 on ketamine-based therapies for depression are summarized. Intravenous (IV) ketamine, esketamine nasal spray (Spravato), and oral ketamine show differences in response rates, remission rates, speed of symptom relief, and durability of results. The report also examines research on combining ketamine with psychotherapy. The evidence is drawn from high-quality peer-reviewed studies, including randomized controlled trials and observational studies, providing a clear overview of the most reliable evidence available.

DOI: 10.31234/osf.io/tjvzr_v1

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

European journal of psychotraumatology December 1, 2026 Maud Rothärmel, Lila Mekaoui, François Kazour et al. 1 citation

In a retrospective study of 22 adults with treatment-resistant depression and comorbid post-traumatic stress disorder who received esketamine nasal spray, trauma re-experiencing episodes occurred during treatment sessions. For 16 patients (72.7%) these episodes disappeared as sessions progressed. Treatment was stopped for 6 patients (27.3%) due to re-experiencing. Among those who continued esketamine, depression response rate was 45.5% and remission 22.7%; PTSD improvement rate was 45.5% and remission 18.2%. The findings suggest esketamine can be safely administered in this comorbid population and that trauma re-experiencing does not prevent clinical improvement.

DOI: 10.1080/20008066.2025.2609425 Full text Treatment-resistant depression Esketamine nasal spray Post-traumatic stress disorder Real-life data +2

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

Journal of affective disorders November 1, 2026 Lindsay L Benster, Jordan N Kohn, Benjamin Wade et al.

In a real-world comparison of two FDA-approved treatments for treatment-resistant depression, intranasal esketamine led to faster improvement than repetitive transcranial magnetic stimulation (rTMS). Over 90 days, esketamine patients responded a median of 36 days versus 49 days for rTMS, and suicidal ideation resolved more quickly (median 9 vs. 26 days). However, by about 90 days, overall response and remission rates were similar between the groups (68.8% and 45.2% for esketamine; 59.4% and 40.1% for rTMS), suggesting a difference in speed rather than ultimate effectiveness. For rTMS, slower response was predicted by comorbid anxiety and benzodiazepine use, while former tobacco use predicted faster response. No such predictors were found for esketamine.

DOI: 10.1016/j.jad.2026.122107 Full text Esketamine Treatment-resistant depression Rtms

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

Journal of affective disorders November 1, 2026 Dian-Jeng Li, Tien-Wei Hsu, Te-Chang Changchien et al.

Patients with major depressive disorder who are prescribed esketamine have higher rates of comorbid substance use disorders compared to those treated with antidepressants or repetitive transcranial magnetic stimulation. Among esketamine users, those with a substance use disorder face greater risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality. The findings indicate a prescription bias toward patients with comorbid substance use disorders and highlight the need for careful monitoring and specialized care for this population.

DOI: 10.1016/j.jad.2026.122106 Full text Esketamine Major depressive disorder Substance use disorder Mortality +1

Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review.

Journal of affective disorders September 15, 2026 Rutger Boesjes, Claudia Oosterveld, Jeanine Kamphuis et al. 1 citation

Ketamine and its enantiomers show rapid antidepressant effects for major depressive disorder and bipolar disorder, but responses vary widely. This systematic review of 26 studies (1694 participants) found that ketamine treatment is linked to improved subjective sleep quality. Preliminary evidence suggests that baseline sleep disturbances and early sleep improvements may predict antidepressant response. Some studies also indicate beneficial effects on objective sleep and circadian rhythmicity, but this finding is tentative due to few published articles. The authors call for more research on objective circadian measures and potential synergy with chronotherapies.

DOI: 10.1016/j.jad.2026.121915 Full text Depression Ketamine Major depressive disorder Bipolar disorder +3

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

Psychiatry research September 1, 2026 Isis Lunsky, Gilmar Gutierrez, Xena Wang et al.

Postpartum depression (PPD) is common and harmful if untreated, with few effective prevention strategies. Ketamine and esketamine are rapid-acting antidepressants showing promise for PPD. This review searched five databases for peer-reviewed randomized controlled trials, pilot studies, and observational studies examining ketamine or esketamine for PPD prevention during pregnancy or postpartum, for both cesarean and vaginal deliveries. A network meta-analysis and narrative synthesis were used. Thirty-six studies were identified; five included vaginal delivery, thirty included cesarean section, and one did not specify delivery mode. Results suggested that ketamine and esketamine were well tolerated and may reduce PPD risk. However, data quality was low to very low, so results should be interpreted cautiously. More high-quality studies are needed.

DOI: 10.1016/j.psychres.2026.117221 Full text Esketamine Perinatal mental health Postpartum depression Psychopharmacology

Clinical trials

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