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Home/Research/Ketamine/Major Depressive Disorder (MDD)

Ketamine for Major Depressive Disorder (MDD)

211 papers and 184 clinical trials exploring ketamine as a treatment for major depressive disorder (mdd).

CompoundArylcyclohexylamine

Ketamine

A dissociative anesthetic with rapid-acting antidepressant properties, widely used in clinical settings for mood and pain disorders.

Full Ketamine profile
IndicationOver 264 million worldwide.

Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) represents a significant mental health challenge, with emerging research into the efficacy of psychedelics like psilocybin and ketamine offering new avenues for treatment. Recent studies have demonstrated the potential of these compounds to alleviate symptoms, particularly in treatment-resistant cases of MDD.

Full Major Depressive Disorder (MDD) profile

Academic Research

211 papers
Open Accessindividual

Effect of Esketamine on Depressive Symptoms in Adolescents with Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study

This double-blind Phase IIb trial (n=147) evaluated the efficacy, safety, and tolerability of esketamine nasal spray versus midazolam in reducing depressive (MDD) symptoms in adolescents at imminent risk for suicide (SI). The study finds that pooled doses of esketamine (56 and 84 mg) significantly reduce depressive symptoms at 24 hours, with common side effects including dizziness, nausea, and dissociation.

Published
January 1, 2026
Journal
Journal of the American Academy of Child & Adolescent Psychiatry
Authors
Kosik-Gonzalez, C., Chen, L. N., Lane, R., Bloch, M. H., DelBello, M., Moreno, C., Drevets, W. C., Canuso, C. M., Fu, D. J.
Paywallindividual

Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics

This rat study found that zalsupindole (third-generation psychedelic) produced robust effects on structural and functional neuroplasticity in the prefrontal cortex as well as sustained antidepressant-like responses comparable to or greater than those of ketamine, psilocybin, and DMT, despite lacking any of the acute cellular and behavioural characteristics of hallucinogenic or dissociative compounds.

Published
October 13, 2025
Journal
ACS Chemical Neuroscience
Authors
Agrawal, R., Gillie, D., Mungenast, A., Chytil, M., Engel, S., Wu, M. C., Rasmussen, K., Salinas, E., Olson, D. E.
Paywallindividual

Economic evaluation of subcutaneous ketamine injections for treatment resistant depression: A randomised, double-blind, active-controlled trial - The KADS study

This cost-utility analysis, alongside a randomised controlled trial (n=174), compared subcutaneous ketamine (twice-weekly for 4 weeks) with midazolam in treatment-resistant depression. Including midazolam costs, ketamine raised QALYs (0.435 vs 0.352) and was dominant with an 89-91 % chance of costing < $50 000/QALY, but once these comparator costs were excluded ketamine was no longer cost-effective (ICER ≈ $108 500-$251 250/QALY, ≤ 5 % probability).

Published
October 1, 2025
Journal
Journal of Affective Disorders
Authors
Chatterton, M. L., Perez, J. K., Thai, T., Faller, J., Loo, C. K., Glozier, N., Barton, D., Baune, B. T., Mills, N. T., Fitzgerald, P. B., Glue, P., Sarma, S., Hadzi-Pavlovic, D., Dong, V., Martin, D., Mitchell, P. B., Berk, M., Carter, G., Hackett, M., Hood, S., Somogyi, A. A., Rodgers, A., Mihalopoulos, C.
Open Accessindividual

Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial

In a phase 4, multicentre, double-blind randomised trial in adults with treatment‑resistant depression, intranasal esketamine monotherapy (56 mg and 84 mg) produced significant reductions in MADRS score versus placebo at day 28 (LS mean differences −5.1 and −6.8; effect sizes 0.48 and 0.63) and demonstrated rapid benefit at 24 hours. The tolerability profile was consistent with prior reports, most commonly nausea, dissociation, dizziness and headache.

Published
September 1, 2025
Journal
JAMA Psychiatry
Authors
Janik, A., Qiu, X., Lane, R., Popova, V., Drevets, W. C., Canuso, C. M., Macaluso, M., Mattingly, G. W., Shelton, R. C., Zajecka, J. M., Fu, D. J.
Paywallmeta

An Update on the Efficacy and Tolerability of Oral Ketamine for Major Depression: A Systematic Review and Meta-Analysis

This systematic review and meta-analysis of oral ketamine for major depression (10 studies; meta-analysis of three RCTs, N=161) found a significant antidepressant effect (SMD −0.75). The paper also summarises tolerability data but emphasises that the evidence base is small and further high-quality trials are needed.

Published
August 12, 2025
Journal
Psychopharmacology Bulletin
Authors
Nuñez, N. A., Joseph, B., Pahwa, M., Seshadri, A., Prokop, L. J., Kung, S., Schak, K. M., Voort, J. L. V., Frye, M. A., Singh, B.
Paywallindividual

Efficacy and safety of esketamine for smoking cessation among patients diagnosed with lung cancer and major depression disorder: A randomized, placebo-controlled clinical trial

This multicenter, randomised, placebo-controlled clinical trial (n=236) investigates the efficacy and safety of esketamine (ESK) (8x35mg) for smoking cessation in patients with lung cancer and major depressive disorder (MDD). Eight weekly intranasal ESK sessions significantly improved both self-reported (44.1%) and biologically verified (28.8%) smoking abstinence at 6-month follow-up, alongside reductions in depression, anxiety, nicotine dependence, and respiratory symptoms.

Published
August 1, 2025
Journal
Journal of Affective Disorders
Authors
Hong, C. J.

Clinical Trials

184 trials
Not yet recruitingPhase NA

Neural Mechanisms of Ketamine Antidepressant Treatment 2.0: Exploring how ketamine affects the brain function in people with difficult-to-treat depression.

This is a randomised, quadruple‑blind, placebo‑controlled mechanistic clinical trial enrolling 90 participants (60 adults with major depressive disorder, including treatment‑resistant cases, and 30 healthy controls) at the Royal Melbourne Hospital, Australia, with recruitment from February 2026 and completion expected December 2027. Participants receive a single subcutaneous administration of ketamine 0.75 mg/kg versus placebo (0.9% saline). The primary outcome is change in habenula activity measured using ultra‑high‑field 7T MRI at baseline and 24–48 hours after dosing, designed to probe rapid neural mechanisms underlying ketamine’s antidepressant effects. Secondary outcomes assess clinical and behavioural effects using the Montgomery–Åsberg Depression Rating Scale (MADRS), QIDS‑C, Snaith–Hamilton Pleasure Scale (SHAPS), GAD‑7, and objective activity monitoring by actigraphy. The protocol includes healthy controls to facilitate mechanistic comparisons between clinical and non‑clinical neural responses. The study phase is not specified in the available data. The quadruple‑blind design and saline comparator aim to isolate drug‑specific neural changes and early clinical signal following a single subcutaneous ketamine exposure in treatment‑resistant and broader MDD populations.

Started
February 2, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
ACTRN12625001087448
RecruitingPhase III

A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder (AVENUE)

This Phase III, double-blind, randomised, placebo-controlled trial (n=258) will evaluate the efficacy and safety of intranasal esketamine 84 mg in addition to comprehensive standard of care for rapidly reducing symptoms of major depressive disorder (MDD) in adolescent participants aged 12 to 17 with acute suicidal ideation or behaviour. The primary outcome is the change in depressive symptoms measured by the Children's Depression Rating Scale - Revised (CDRS-R) total score at 24 hours post-first dose. Participants will be randomly assigned to receive either intranasal esketamine (84 mg, with potential dose adjustments to 56 mg) plus oral placebo or intranasal placebo plus oral midazolam (0.0625 mg/kg) twice weekly for four weeks. The treatment will occur on specific days, with assessments conducted to monitor the efficacy and safety of the interventions. The trial is sponsored by Janssen Research & Development, LLC, with an estimated start date of January 8, 2026, and a completion date of September 15, 2031.

Started
January 8, 2026
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT07227454
Not yet recruitingPhase NA

A Study on the Rapid Antisuicidal Mechanism and Therapeutic Efficacy Prediction of Ketamine Based on Glu/GABA Metabolism in the Prefrontal-Limbic System Circuit

This non-randomised controlled interventional study (n=199) in China is evaluating the rapid anti-suicidal effects and mechanistic correlates of ketamine in adults aged 18 to 65 with major depressive disorder, with a focus on those with suicidal ideation. Participants are assigned to a major depressive disorder group without suicidal ideation (n=50, no intervention) or a major depressive disorder group with suicidal ideation (n=149) receiving intravenous ketamine. The trial is designed to investigate how ketamine influences glutamate/GABA metabolism within prefrontal-limbic circuit networks, and to identify neuroimaging markers associated with treatment response. The primary outcomes are neuroimaging-based and include comparisons between participants whose suicidal ideation decreases versus those whose ideation remains unchanged, imaging changes within the ketamine-treated group before and after treatment, and neuroimaging features that may predict ketamine’s anti-suicidal effect. Secondary outcomes assess correlations between neuroimaging features and individual symptom scores, including MADRS and HAMD ratings. The study is sponsored by Beijing Anding Hospital, Capital Medical University, and is currently pending. No phase designation or ketamine dose has been provided.

Started
September 20, 2025
Type
interventional
Blinding
none
Randomized
Yes
Registry ID
ChiCTR2500108533
RecruitingPhase III

Ketamine Augmentation of ECT in Treatment-Resistant Depression (Ketamina)

Phase III double-blind, randomised, placebo-controlled trial (n=30) testing IV ketamine 0.5 mg/kg given during ECT sessions 2, 4 and 6 in hospitalised adults with treatment-resistant MDD.

Started
July 10, 2025
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT07088380
Not yet recruitingPhase III

Evaluation of the Efficacy and Safety of Subcutaneous Ketamine in the Treatment of Depressive Episode With Suicidal Ideation and/or Behavior in Adolescents

This randomised, double-blind, placebo-controlled Phase III trial (n=60) will investigate the efficacy and safety of subcutaneous ketamine (35-70mg/70kg, twice weekly for four weeks) as an add-on treatment for adolescents experiencing a major depressive episode with suicidal ideation and/or behaviour.

Started
May 1, 2025
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT06957704
RecruitingPhase II/III

Understanding and Treating Suicidal Ideation With Ketamine

This open-label, Phase II/III trial (n=36) will study the effects of ketamine (0.5 mg/kg IV infused over 40 minutes, four infusions over two weeks) on suicidal ideation in individuals with major depressive disorder (MDD).

Started
April 8, 2025
Type
interventional
Blinding
none
Randomized
No
Registry ID
NCT06891300

Explore further

Search all Ketamine papers Search all Major Depressive Disorder (MDD) trials Full Ketamine profile Full Major Depressive Disorder (MDD) profile