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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.

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 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

886 articles · 562 from the last two years · 1,589,874 participants across 417 studies reporting sample size

Common study designs

review 179 narrative review 39 systematic review 63 observational cohort 44 randomized controlled trial 124

Research

Synthesize the evidence → Search all →

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

Annals of medicine December 1, 2026 Zheping Chen, Yaozhu Wang, Peilin Cong et al.

A double-blind randomized trial found that perioperative sub-anesthetic esketamine reduced postoperative depression and anxiety and improved sleep quality in patients undergoing acoustic neuroma surgery. The incidence of depression on postoperative day 1 was 7.7% in the esketamine group versus 31.6% in the placebo group, and on day 3 it was 0.0% versus 15.8%. Anxiety and sleep disturbances also significantly decreased. No significant differences were observed in immune function, postoperative pain scores, or adverse events between groups.

DOI: 10.1080/07853890.2026.2692804 (opens in new tab) Full text (opens in new tab) Esketamine Anxiety Depression Negative emotion +1

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 (opens in new tab) Full text (opens in new tab) 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 (opens in new tab) Full text (opens in new tab) 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 (opens in new tab) Full text (opens in new tab) Esketamine Major depressive disorder Substance use disorder Mortality +1

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 (opens in new tab) Full text (opens in new tab) Esketamine Perinatal mental health Postpartum depression Psychopharmacology

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

Brain Research Bulletin August 1, 2026 Rui Dong, Jiaxin Liu, Yumei Shen et al.

In a mouse model of trigeminal neuralgia (TN) that also shows anxiety-like behavior, esketamine (ES) given for five days dose-dependently reduced pain and anxiety. TN caused damage to neurons in the hippocampus and increased levels of the necroptosis pathway proteins RIPK1, RIPK3, and MLKL. ES treatment reversed these changes, protecting neurons and restoring dendritic spines. Adding a necroptosis activator blocked ES's effects, confirming that ES works by inhibiting the RIPK1/RIPK3/MLKL pathway. The findings highlight necroptosis as a key mechanism linking TN pain to emotional disorders and suggest ES could be repurposed as a treatment for both pain and anxiety in TN.

DOI: 10.1016/j.brainresbull.2026.111987 (opens in new tab) Full text (opens in new tab) Esketamine Hippocampus Pain-affect comorbidity Ripk1/ripk3/mlkl +1

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

Journal of Affective Disorders August 1, 2026 Ching-Hua Julie Lee, Yunzhe Qian, Weiqun Yu et al.

Compared with injectable ketamine, esketamine was linked to higher risks of suicidal ideation (24% increase), generalized anxiety disorder (55% increase), insomnia (25% increase), and cardiac arrest (57% increase). Compared with oral antidepressants in treatment-resistant depression, esketamine was associated with lower risks of suicidal ideation (11% decrease), suicide attempt (29% decrease), and generalized anxiety disorder (18% decrease), but a higher risk of cardiac arrest (109% increase). Injectable ketamine showed a more favorable safety and effectiveness profile than esketamine. Head-to-head clinical trials are needed to validate these findings.

DOI: 10.1016/j.jad.2026.121487 (opens in new tab) Full text (opens in new tab) Esketamine Major depressive disorder Treatment-resistant depression Outcomes +1

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.

Journal of Affective Disorders August 1, 2026 João Paulo Atidio, Rodrigo Simonini Delfino, Igor Saque Garios et al.

In patients with treatment-resistant depression receiving subcutaneous esketamine over six weeks, depressive symptoms improved significantly, with MADRS scores dropping by an average of 2.82 points per week. Those also taking benzodiazepines had higher depression scores throughout treatment, while lamotrigine and lithium showed no significant effect on outcomes. No medication altered the rate of improvement over time. The findings suggest benzodiazepine use may blunt the antidepressant response to esketamine, but further prospective research is needed.

DOI: 10.1016/j.jad.2026.121721 (opens in new tab) Full text (opens in new tab) Esketamine Treatment-resistant depression Benzodiazepine Lamotrigine +3

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

Research Square July 20, 2026

In a post-hoc analysis of a randomized controlled trial, esketamine was associated with a reduction in anhedonia symptoms, as measured by the Snaith-Hamilton Pleasure Scale, compared to placebo. The effect was observed in patients with treatment-resistant depression who had not responded to prior antidepressant therapy. The findings suggest that esketamine may have a specific therapeutic effect on anhedonia, a core symptom of depression characterized by loss of interest or pleasure.

DOI: 10.21203/rs.3.rs-10020524/v1 (opens in new tab)

Clinical guidance on the use of esketamine nasal spray for patients with treatment resistant depression: A European Delphi consensus report.

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology July 17, 2026 Allan H. Young, Bernhard T Baune, Beatrice Benatti et al.

A panel of 30 European psychiatrists with expertise in treatment-resistant depression (TRD) reached consensus on strategies for using esketamine nasal spray across treatment phases. During the acute phase (4-12 weeks), even modest reductions in core symptoms support continuing esketamine, especially for patients with long disease course or resistance to multiple therapies. Dose and frequency maximization (84 mg weekly) was recommended to improve acute outcomes. In the continuation phase (6-9 months), monitoring should focus on residual symptoms, functional recovery, and comorbidities. Prolonging maintenance treatment (≥12 months) depends on the degree of worsening when tapering, relapse risk, and recurrence history. Across all phases, integrating psychotherapy, optimizing antidepressants, managing comorbidities, and strengthening support networks were recommended.

DOI: 10.1016/j.euroneuro.2026.112907 (opens in new tab) Full text (opens in new tab) Esketamine nasal spray Assessment patient outcome Decision-making shared Delphi method +1

Clinical trials

All Esketamine trials →