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Home/Research/Esketamine/Depressive Disorders

Esketamine for Depressive Disorders

91 papers and 72 clinical trials exploring esketamine as a treatment for depressive disorders.

Blossom tracks 91 papers and 72 clinical trials examining esketamine as a treatment for depressive disorders. Esketamine acts primarily as a nmda receptor antagonist. The papers and trials below are sorted by recency, and reported adverse events and dosing protocols are summarised in the linked overviews.

Esketamine Depressive DisordersAdverse eventsDose summary
Compounddissociative

Esketamine

Esketamine (Spravato) is the S-enantiomer of ketamine, approved as an intranasal treatment for treatment-resistant depression and MDD with acute suicidal ideation. It is administered under clinical supervision with post-dose monitoring and has reached over $1.6 billion in annual sales.

Full Esketamine profile
IndicationAround 280 million people live with depression worldwide

Depressive Disorders

Depression is the flagship indication for psychedelic and rapid-acting psychiatry, and the place where the field has gone furthest: an approved drug (esketamine), the first Phase 3 win for a classic psychedelic, and several striking trials of psilocybin for major depression. But it is also where the honest caveats bite hardest. The most rigorous recent analyses suggest much of psilocybin’s apparent edge comes from patients knowing they got the drug, and a head-to-head against a standard antidepressant was not significant on its main measure. This is the umbrella page for the depression family; the resistant, general and bipolar forms each have their own.

Full Depressive Disorders profile
Safety summary

Esketamine for Depressive Disorders: adverse events

Esketamine safety reports for Depressive Disorders most often include dizziness, headache, nausea, paresthesia among the source-backed named adverse events currently normalized in Blossom.

8 source papers|136 named AE rows|Top events: dizziness, headache, nausea
View adverse eventsView adverse events
Dose summary

Esketamine for Depressive Disorders: dose summaries

Esketamine clinical studies for Depressive Disorders include 24 structured dose rows across 20 linked trials. Common source-reported dose patterns include 84 mg, 0.2 mg/kg, 56 mg. Interpret these as descriptive trial protocols, not treatment recommendations.

32 source papers|24 dose rows|Patterns: 84 mg, 0.2 mg/kg, 56 mg
View dosingView dosing

Academic Research

91 papers
Open Accessindividual

Sex- and Age-Stratified Differences in Antidepressant Response to Intranasal Esketamine in Treatment-Resistant Depression: A Secondary Analysis of the REAL-ESK Study

This secondary analysis of the REAL-ESK study (n=210) examined intranasal esketamine in people with treatment-resistant depression and found that depression scores fell over three months in routine care. Men had slightly better antidepressant outcomes than women overall, while safety and stopping rates were similar between sexes.

Published
June 25, 2026
Journal
Clinical Neuropsychopharmacology and Addiction
Authors
Persico, L., d'Andrea, G., Cavallotto, C., Panichella, S., Santeusanio, A., Di Tullio, A., D'Angola, M., Rosati, A., Inserra, A., Tamagnini, G., Di Puorto, C., Salvi, V., Tripodi, B., De Berardis, D., Martiadis, V., Piccirillo, M., Raffone, F., Vannucchi, T., Barra, A., Lupi, M., Miotti, L., Di Cesare, A., Pettorruso, M.
Open Accessmeta

Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials

This randomised clinical trial programme included a phase 1 crossover study (n=26) and a phase 2 placebo-controlled trial (n=122) testing oral prolonged-release ketamine for treatment-resistant depression. The oral tablet caused far less dissociation and cardiovascular change than intranasal esketamine, but it did not meet the main depression outcome at day 21, although some short-term symptom improvement was seen after the first dose.

Published
June 24, 2026
Journal
JAMA Network Open
Authors
Walter, M., zu Eulenburg, C., Damyanova, A., Schmid, K., Schwienbacher, I., Papanastasiou, E., Maiboe, K., Arvastson, L., Strote, C., Gehrlach, D., Eriksson, H.
Open Accessindividual

Real-world effectiveness and safety of intranasal esketamine for treatment-resistant depression: data from the enTRD registry

This retrospective registry study (n=176) of adults with treatment-resistant depression (TRD) at a Vienna outpatient clinic found that supervised intranasal esketamine induction was associated with a marked drop in clinician-rated depressive symptoms, with 27.2% reaching remission and 57.4% responding by the end of induction. Suicidal ideation fell significantly and tolerability was acceptable, with adverse events in 34.7% and few discontinuations.

Published
June 23, 2026
Journal
European Psychiatry
Authors
Preiss, M., Popper, V., Faber, L. H. C., Baumgartner, T., Baberis-Martinez, P. M., Winkler-Pjrek, E., Gryglewski, G., Bartova, L., Kasper, S., Rujescu-Balcu, D., Pezawas, L.
Open Accessindividual

Trajectory of response to esketamine nasal spray for treatment resistant depression: findings from ESCAPE-TRD

This analysis of the randomised, open-label Phase IIIb ESCAPE-TRD study (n=676) compared esketamine nasal spray with extended-release quetiapine in treatment-resistant depression, tracking response to Week 32. Most esketamine-treated patients improved continuously, with early response linked to better long-term outcomes, and symptom resolution was greater and earlier than with quetiapine across most rated symptoms.

Published
June 16, 2026
Journal
European Psychiatry
Authors
Young, A., Bartova, L., Cardoner, N., Demyttenaere, K., Fagiolini, A., Godinov, Y., Golib Dzib, J., von Holt, C., McIntyre, R., Oliveira-Maia, A., Rive, B., Gorwood, P.
Paywallindividual

Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention: The CBT-ENDURE Randomized Trial

This randomised trial (n=93) found that adding 16 weeks of cognitive behavioural therapy to esketamine was feasible for people with major depression and suicidal ideation, and it reduced suicidal thoughts and depression scores more than esketamine with usual care alone. No difference was seen in suicide-related events.

Published
May 4, 2026
Journal
Journal of Clinical Psychiatry
Authors
Wilkinson, S. T., Kitay, B. M., Macaluso, M., Santucci, M. C., Kumpf, K., Voghell, C., Astorino, L., Hershenberg, R., Martinez-Kaigi, V., Nowell, T., Thase, M. E., Sanacora, G., Rhee, T. G.
Open Accessindividual

Repeated intranasal esketamine augmentation in treatment-resistant obsessive-compulsive disorder with comorbid major depressive disorder: a prospective case series

This prospective case series (n=8) examined repeated intranasal esketamine for people with treatment-resistant obsessive-compulsive disorder and comorbid major depressive disorder, and found clear improvement in depression and a smaller, more variable reduction in obsessive-compulsive symptoms. Depression improved earlier than OCD symptoms, and half of the participants met response criteria for each condition.

Published
April 26, 2026
Journal
BMC Psychiatry
Authors
López-Rodríguez, S., Segalàs, C., Real, E., Urretavizcaya, M., Bertolín, S., Menchón, J. M., del Pino Alonso, M.

Clinical Trials

72 trials
Not yet recruitingPhase IV

Intranasal Esketamine-dexmedetomidine Combination and Postpartum Depression

This Phase IV, randomised, double-blind, placebo-controlled trial (n=164) will assess whether intranasal esketamine combined with dexmedetomidine can reduce postpartum depressive symptoms in women with prenatal depressive symptoms. The study will evaluate parturients aged 18 years and older who screen positive for prenatal depression, with the main outcome being the prevalence of depressive symptoms at 42 days postpartum. Participants will receive either an intranasal esketamine-dexmedetomidine combination or intranasal placebo (normal saline) in a parallel design. The active treatment will use body-weight-based dosing of approximately 0.4 μg/kg dexmedetomidine and 0.2 mg/kg esketamine, delivered by nasal spray alternating between nostrils every 5 minutes until the target dose is reached, and given twice after childbirth at a 12-hour interval. The placebo will follow the same administration schedule and weight-based volume calculation.

Started
June 1, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT07639099
Not yet recruitingPhase NA

Multimodal Pharmacological Study of Clinical Cohorts for Major Depressive Disorder

This observational cohort study (n=130) will assess neurobiological changes in adults with major depressive disorder (MDD) and high suicidal risk during rapid antidepressant treatment, with a focus on suicidal tendency and the mechanisms of fast-acting antidepressant effects. Participants will be followed across electroconvulsive therapy (ECT), esketamine nasal spray, or conventional antidepressant treatment paths, with the main outcome being change in Hamilton Depression Rating Scale (HAMD-17) total score from baseline to follow-up. The study will collect data at three time points: baseline, 24 hours after the first treatment, and at remission 4–6 weeks later, with overall treatment follow-up to 8 weeks. It will compare a cohort of 70 patients receiving ECT, 30 receiving esketamine, and 30 receiving conventional medication, while also integrating clinical scales such as the C-SSRS and QIDS-SR16 with multimodal measures including whole genome sequencing, single-cell sequencing, proteomics, metabolomics, DNA methylomics, gut metagenomics, fMRI, DTI, and 32-channel resting-state EEG. Eligible participants are adults aged 18–65 years with DSM-5 MDD and suicidal ideation.

Started
May 30, 2026
Type
observational
Blinding
none
Randomized
No
Registry ID
NCT07602153
RecruitingPhase NA

ATLAS-1: Advanced Trial for Longitudinal Assessment in Salma 1

This observational study (n=5000) will examine adults with depressed mood who are receiving esketamine, conventional rTMS, or SAINT as part of routine care, with the aim of assessing the feasibility and clinical utility of predictive models of treatment response built from multimodal clinical data. It will use integrated real-world datasets to explore whether personalised tools could help guide treatment selection in depression. Participants must be 18 years or older, able to give informed consent, and prescribed one of the listed treatments in standard clinical practice. The main outcome is the Patient Health Questionnaire 9-item (PHQ-9), measured pre-treatment, post-treatment, 2 weeks after treatment, and then monthly for 12 months. Retrospective clinical and research data from existing databases may also be included, where available and authorised, to support model development and validation.

Started
March 25, 2026
Type
observational
Blinding
none
Randomized
No
Registry ID
NCT07528014
Not yet recruitingPhase I

Effect of sub - anesthetic dose of esketamine on the incidence of postoperative anxiety and depression in patients with thyroid cancer and breast cancer: A prospective, single - center clinical study

This prospective, single-centre interventional trial in China (n=196 planned; 98 per group) is a Phase 0 parallel-group study evaluating whether subanaesthetic esketamine reduces postoperative anxiety and depression in adults undergoing surgery for thyroid cancer or breast cancer. Participants are randomised to receive either an esketamine infusion prepared at 2.5 mg/ml and administered at 0.25 mg/kg/h, or 0.9% normal saline at 0.1 ml/kg/h as the control comparator. The study population includes both sexes aged 18 years and older. The primary outcome is the incidence of postoperative anxiety and depression in both groups within 72 hours after surgery. Secondary outcomes include postoperative quality of recovery, assessed using the QoR-15 at 48 hours, postoperative pain scores at 48 and 72 hours, and healthcare utilisation measures including length of hospital stay and total cost from surgery to discharge. The trial is designed to assess whether perioperative esketamine can improve early psychological and recovery outcomes in patients with cancer surgery.

Started
March 20, 2026
Type
interventional
Blinding
none
Randomized
No
Registry ID
ChiCTR2600120238
RecruitingPhase IV

Esketamine With or Without Integration Therapy for Treatment-Resistant Depression

This Phase IV, randomised, single-masked, parallel trial (n=20) will assess whether adding brief, structured preparation and integration therapy to FDA‑approved intranasal esketamine (Spravato®) improves depressive symptoms in adults aged 21–65 with treatment-resistant depression; the primary outcome is change in Montgomery‑Åsberg Depression Rating Scale (MADRS) score from baseline to the end of acute treatment at 8 weeks. Participants will be randomised to receive intranasal esketamine administered under medical supervision per FDA guidelines (twice weekly in weeks 1–4, then weekly or biweekly in weeks 5–8 based on clinical response) with standard post-dose monitoring of at least two hours. The experimental arm also receives brief, manualised preparation and integration sessions delivered by trained clinicians before and after each dosing session; the comparator arm receives esketamine with standard clinical monitoring and psychiatric care only. Key secondary measures include emotional regulation, therapeutic alliance, treatment acceptability and dissociative experiences, with exploratory assessments of participant engagement, perceived coherence of experience and satisfaction. Eligibility includes adults 21–65 with major depressive disorder meeting treatment‑resistance criteria (failure of ≥2 antidepressants) and baseline MADRS ≥30; the study is single-site and lasts approximately 8 weeks per participant.

Started
February 1, 2026
Type
interventional
Blinding
single
Randomized
Yes
Registry ID
NCT07369102
RecruitingPhase I

Subanesthetic Esketamine in Modified ECT for Severe Depression in Adolescents: Clinical and Mechanistic Study

This double-blind trial (n=220) of adolescents with severe depression will modify electroconvulsive therapy with esketamine.

Started
November 25, 2025
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT07247968

Explore further

Search all Esketamine papers Search all Depressive Disorders trials Full Esketamine profile Full Depressive Disorders profile