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

Ketamine for Treatment-Resistant Depression (TRD)

190 papers and 128 clinical trials exploring ketamine as a treatment for treatment-resistant depression (trd).

CompoundArylcyclohexylamine

Ketamine

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

Full Ketamine 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

190 papers
Open Accessindividual

Blood biomarker changes and relationships after low dose oral ketamine treatment for post-traumatic stress disorder (PTSD)

This open-label trial (n=25) found that six weeks of low-dose oral ketamine treatment for PTSD was associated with small but significant decreases in both BDNF and VEGF-A blood biomarkers, which were positively correlated with each other, suggesting these two proteins may interact as part of the biological mechanism behind ketamine's effects on PTSD symptoms.

Published
March 16, 2026
Journal
Psychopharmacology
Authors
Quigley, B. L., Orr, E., Kafka, S., Hajishafiee, M., Bouças, A. P., Wellington, N., Dutton, M., Jones, M., Randall, F., Lagopoulos, J., Can, A. T., Hermens, D. F.
Open Accessindividual

The dynamics of AMPA receptors underlies the efficacy of ketamine in treatment resistant patients with depression

Using the PET tracer [11C]K-2 to image AMPAR density in vivo, the authors found that lower AMPAR availability correlates with greater illness severity and differs between patients with treatment‑resistant depression and healthy controls. Ketamine produced region‑specific changes in AMPAR density that correlated with clinical improvement and partially restored the abnormal AMPAR phenotype, supporting AMPAR dynamics as a mechanistic substrate of ketamine’s antidepressant effect in TRD.

Published
March 5, 2026
Journal
Molecular Psychiatry
Authors
Nakajima, W., Hatano, M., Ohtani, Y., Tani, H., Yatomi, T., Tsuchimoto, S., Fujimoto, Y., Eiro, T., Ichijo, S., Nakano, K., Arisawa, T., Takada, Y., Kimura, K., Abe, H., Sano, A., Nomoto-Takahashi, K., Yonezawa, K., Tomiyama, S., Nagai, N., Kusudo, K., Honda, S., Moriyama, S., Nakajima, S., Yamada, T., Iwabuchi, Y., Jinzaki, M., Yoshimura, K., Syed, S. A., Tsugawa, S., Uchida, H., Takahashi, T.
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.
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.
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.
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

128 trials
Not yet recruitingPhase II

Ketamine With Dialectical Behavioural Therapy (DBT) for Suicidality in Individuals With Treatment-Resistant Depression and Borderline Personality Disorder (KET-DBT)

This Phase II randomised, quadruple-masked trial (n=120) will study adults aged 18 to 70 years with borderline personality disorder, treatment-resistant major depressive disorder or bipolar disorder, and suicidal ideation, evaluating whether intravenous ketamine plus dialectical behavioural therapy (DBT) reduces suicidal ideation more rapidly and robustly than midazolam plus DBT. The main purpose is to assess change in suicidal ideation severity from baseline to Day 35 using the Modified Scale for Suicidal Ideation (MSSI). All participants will receive DBT for 6 months, starting before the infusions, with weekly individual sessions and the addition of weekly group sessions from Week 5. The experimental arm will receive six intravenous ketamine infusions over 1 month: the first two at 0.5 mg/kg over 40 minutes, infusions 3 and 4 flexibly dosed at 0.5 mg/kg to 0.75 mg/kg, and infusions 5 and 6 flexibly dosed at 0.5 mg/kg to 0.85 mg/kg. The comparator arm will receive six intravenous midazolam infusions over the same period: the first two at 0.02 mg/kg over 40 minutes, infusions 3 and 4 at 0.02 mg/kg to 0.03 mg/kg, and infusions 5 and 6 at 0.2 mg/kg to 0.035 mg/kg. Participants will also complete hospital visits, remote follow-up by call or videocall, and a range of mood, cognitive and behavioural assessments.

Started
June 1, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT07569198
RecruitingPhase NA

Coaching as an Adjunct to Ketamine Therapy for Treatment-Resistant Depression

This non-randomised, single-group interventional trial (n=20) will assess the feasibility and acceptability of adding psychedelic integration coaching to ongoing maintenance ketamine treatment in adults with treatment-resistant depression (TRD). The study will enrol participants already receiving maintenance intravenous ketamine or intranasal esketamine at Massachusetts General Hospital and aims to explore whether coaching can support symptom improvement and personal growth alongside existing treatment. Participants will receive 12 weekly, 50-minute one-on-one coaching sessions delivered via Zoom by trained psychedelic integration coaches. The coaching is non-clinical, collaborative and participant-directed. Over the 3-month coaching period, and again at a 1-month follow-up, participants will attend monthly study visits with brief remote assessments by a study clinician and self-report questionnaires, with visits taking about 1 to 2 hours depending on the time point. The primary outcomes are feasibility and acceptability from enrolment through Month 3.

Started
April 1, 2026
Type
interventional
Blinding
none
Randomized
No
Registry ID
NCT07563868
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

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
CompletedPhase NA

Electroconvulsive Therapy Versus Intravenous Ketamine in Treatment-Resistant Major Depressive Disorder

This randomised, open-label, parallel-group trial (n=70) will evaluate the efficacy, safety and tolerability of bitemporal electroconvulsive therapy (ECT) versus intravenous ketamine in adults with treatment-resistant major depressive disorder (TRD). The study will recruit adults aged 18-75 years with major depressive disorder who have not responded to at least two adequate antidepressant trials in the current episode and have a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 20. Participants will receive either bitemporal ECT twice weekly for 4 weeks or intravenous ketamine 0.5 mg/kg infused over 40 minutes twice weekly for 4 weeks. The primary outcome is change in MADRS score 3 weeks post-procedure. Exclusion criteria include psychotic or bipolar disorder, current substance use disorder, significant neurological disease or traumatic brain injury, uncontrolled hypertension, recent cardiovascular disease, and pregnancy or breastfeeding.

Started
July 1, 2025
Type
interventional
Blinding
none
Randomized
Yes
Registry ID
NCT07526454
RecruitingPhase II

Ketamine for the treatment of depression with anorexia nervosa

This randomised, double-blind, placebo-controlled Phase II trial (n=60) will study the feasibility, safety, and acceptability of oral ketamine (60–180 mg, administered twice weekly) as a treatment for adults with long-standing anorexia nervosa and comorbid treatment-resistant depression.

Started
June 12, 2025
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
ISRCTN26462355

Explore further

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