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Home/Research/Esketamine/Treatment-Resistant Depression (TRD)

Esketamine for Treatment-Resistant Depression (TRD)

58 papers and 33 clinical trials exploring esketamine as a treatment for treatment-resistant depression (trd).

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
Indication30% of individuals with depression experience treatment-resistant depression.

Treatment-Resistant Depression (TRD)

Research into psychedelics as a treatment for Treatment-Resistant Depression (TRD) is advancing rapidly, with compounds like psilocybin showing particular promise. Approximately 30% of depression sufferers experience TRD, which reflects a significant unmet need in mental health treatment.

Full Treatment-Resistant Depression (TRD) profile

Academic Research

58 papers
Open Accessindividual

Mystical Experience Induced by Esketamine Treatment: A Real-World Observational Study

This observational study (n=45) followed people with treatment-resistant depression receiving esketamine and found that psychedelic-like mystical experiences were common and varied widely between sessions. Higher mystical experience scores, especially positive mood and mystical feelings, were linked with greater improvement in depression symptoms, while dissociation was not.

Published
April 1, 2026
Journal
MedRvix
Authors
Mallevays, M., Fuet, L., Danon, M., Di Lodovico, L., Jaffré, C., Bouzeghoub, L., Mrad, S., Rousselet, A. V., Allary, L., Müh, C., Vissel, B., De Maricourt, P., Vinckier, F., Gaillard, R., Mekaoui, L., Gorwood, P., Petit, A. C., Berkovitch, L.
Open Accessindividual

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

This retrospective naturalistic study (n=178) examined whether benzodiazepines, lithium or lamotrigine altered the antidepressant effects of subcutaneous esketamine in people with treatment-resistant depression. Depression scores fell over six weeks, but benzodiazepine use was linked to higher symptom levels during treatment, while lithium and lamotrigine were not.

Published
March 31, 2026
Journal
Journal of Affective Disorders
Authors
Atidio, J. P., Delfino, R. S., Garios, I. S., de Brito, C. S. G. F., Gerheim, Y. P., de Almeida e Vasconcelos, G. M., Piloto, R., Ferro, M. D., de Souza Júnior, R. O. P., Surjan, J. C., Lacerda, A. L.
Open Accessindividual

Intranasal esketamine: real-world clinical practice in treatment-resistant depression and factors associated with treatment response

This retrospective study (n=101) of inpatients with treatment-resistant depression (TRD) found that intranasal esketamine led to significant reductions in depression severity, with 28.8% achieving response and 19.3% remission. Older age was associated with greater remission likelihood, and extended induction beyond eight sessions appeared particularly beneficial for older patients and those with psychiatric comorbidities, with no serious adverse events observed.

Published
March 17, 2026
Journal
BMC Psychiatry
Authors
Baune, B. T., Rosemann, K., Hefter, D., Tonkul, M., Kavakbasi, E.
Open Accessindividual

Effectiveness and factors associated with esketamine response during the 4-week induction period for treatment-resistant depression: post-hoc analysis of the real-world ESKALE study

This post-hoc analysis (n=128) of the French real-world ESKALE study found that intranasal esketamine produced a rapid and steadily increasing antidepressant response in patients with treatment-resistant depression over four weeks (response rate rising from 19% at week one to 47% at week four), and that experiencing dissociation during the first week of treatment may be an early indicator of a positive response.

Published
March 10, 2026
Journal
Journal of Psychiatric Research
Authors
Samalin, L., Rothärmel, M., Mekaoui, L., Sauvaget, A., Wicart, C., Gaudre-Wattine, E., Cohignac, V., Malatesta, A., Dupin, J.
Open Accessindividual

Long-term treatment with esketamine nasal spray in patients with treatment resistant depression: Results from the ESCAPE-LTE study

This Phase IV single-arm long-term extension trial (n=183) found that the vast majority of patients with treatment-resistant depression who achieved remission with esketamine nasal spray (plus an antidepressant) did not relapse over 136 weeks of treatment, with side effects largely resolving the same day and no new safety concerns identified.

Published
February 27, 2026
Journal
European Neuropsychopharmacology
Authors
Reif, A., Anıl, Y. A., Bitter, I., Buyze, J., Frey, R., Godinov, Y., Haggström, L., Kambarov, Y., Nielsen, R., Oliveira-Maia, A., von Holt, C., Cubała, W., Young, A. H., DJ, Fu.
Paywallindividual

Real-World Safety of Esketamine Nasal Spray: A Comprehensive Analysis Almost 5 Years After First Approval

This real-world safety analysis of esketamine in the United States (n=58,483 patients, 1,486,213 treatment sessions over 58 months) found that sedation, dissociation, and increased blood pressure occurred in 34.7%, 41.0%, and 0.9% of sessions respectively, with serious adverse events in <0.1-0.18% of sessions, suicide rates lower than background rates, and 210 cases of abuse/misuse reported, confirming the established safety profile with no new safety signals identified.

Published
October 1, 2025
Journal
American Journal of Psychiatry
Authors
Sanacora, G., Ahmed, M., Brown, B., Cabrera, P., Doherty, T., Himedan, M., Kern, D. M., Lim, L., Lopena, O., Naranjo, R. R., Nuamah, I., Sarayani, A., Turkoz, I., Bowrey, H. E.

Clinical Trials

33 trials
RecruitingPhase NA

Virtual Reality-Based Mindfulness as an Adjunct to Treatment as Usual in Treatment-Resistant Depression

This interventional trial (n=30) will evaluate the efficacy and tolerability of a virtual reality-based mindfulness intervention combined with intranasal esketamine treatment compared to esketamine treatment alone in patients with treatment-resistant major depressive disorder (TRD). Participants will be randomly assigned to receive either the combined treatment (esketamine plus mindfulness) or standard esketamine treatment as usual, with the primary aim of assessing reductions in depressive symptoms. During the 4-week induction phase, both groups will receive intranasal esketamine, with the experimental group also participating in a 10-minute virtual reality mindfulness session prior to each treatment. Following this, the maintenance phase will last from weeks 5 to 30, with participants continuing esketamine administration once weekly for four weeks, followed by biweekly sessions. Key outcome measures will include changes in depressive symptom severity, inflammatory blood parameters, tolerability, and the duration of remission, with assessments conducted at baseline, the end of the induction phase, and at 30 and 54 weeks post-treatment.

Started
September 18, 2025
Type
interventional
Blinding
none
Randomized
Yes
Registry ID
NCT07422519
RecruitingPhase IV

A Study of Esketamine Nasal Spray in Korean Participants With Treatment-resistant Depression

This open-label, single-arm Phase IV trial (n=47) will evaluate the efficacy and safety of esketamine nasal spray (flexibly dosed at 56mg or 84mg) in Korean adults with treatment-resistant depression (TRD).

Started
June 9, 2025
Type
interventional
Blinding
none
Randomized
No
Registry ID
NCT07053345
RecruitingPhase III

PCORI Comparative Effectiveness Study-Esketamine (Spravato) Vs. Ketamine-Equivalence Study

Phase III, randomised, open-label, non-inferiority study (n=400) comparing IV racemic ketamine (up to 60 mg per infusion, max 8 lifetime doses) versus intranasal esketamine (56–84 mg per dose) for treatment-resistant depression.

Started
December 1, 2024
Type
interventional
Blinding
none
Randomized
Yes
Registry ID
NCT06713616
TerminatedPhase NA

Behavioural Activation Therapy and Esketamine for Resistant Depression

Randomised, parallel-arm trial (n=6 actual) comparing concurrent behavioural activation therapy plus intranasal esketamine versus esketamine alone for treatment-resistant depressive episodes in MDD or BD.

Started
June 1, 2024
Type
interventional
Blinding
single
Randomized
Yes
Registry ID
NCT06431386
RecruitingPhase IV

Comparative Effectiveness Study of Two Forms of Ketamine for Treatment-resistant Depression (TREK)

This interventional trial, led by The George Institute, aims to compare the effectiveness of two formulations of ketamine (esketamine (Spravato®) and racemic ketamine), in treating treatment-resistant depression (TRD).

Started
April 1, 2024
Type
interventional
Blinding
single
Randomized
Yes
Registry ID
NCT06278779
RecruitingPhase III

The Effect of a Four Week Intensified Pharmacological Treatment for Major Depressive Disorder Compared to Treatment as Usual in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment. (INTENSIFY MDD)

Open-label, randomised, parallel trial with blinded raters (n=418) comparing early-intensified pharmacological treatment including esketamine or ketamine (twice-weekly for 4 weeks) plus a second-line antidepressant versus treatment as usual in adults (18–65) with MDD and first-line treatment failure.

Started
March 31, 2024
Type
interventional
Blinding
single
Randomized
Yes
Registry ID
NCT05973851

Explore further

Search all Esketamine papers Search all Treatment-Resistant Depression (TRD) trials Full Esketamine profile Full Treatment-Resistant Depression (TRD) profile