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Ketamine for depression

Studies whose primary subject is both Ketamine and Depression, with an evidence synthesis read across the most-cited and most recent of them.

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 Ketamine, racemic ketamine, arketamine, R-ketamine, Depression, major depressive disorder, then ranked by relevance.

Across randomized trials, ketamine and esketamine produce rapid, substantial antidepressant effects in treatment-resistant depression, with response rates roughly double those of active placebo at 24 hours and continued esketamine reducing relapse risk by about half to two-thirds. Effects are largest and most consistent for intravenous ketamine and for esketamine when added to a newly initiated oral antidepressant, though some esketamine trials missed their primary endpoint and benefits for suicidality specifically are inconsistent. The main caveats are that early effects are transient, long-term safety and repeated-dose data are limited, and several trials are small.

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.
Study Design Sample size Direction Finding
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial 2013 RCT 73 Supports A single intravenous ketamine infusion produced greater improvement in depression severity than midazolam at 24 hours (MADRS 7.95 points lower; response 64% vs 28%).
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 phase 3 RCT 227 Supports Esketamine nasal spray plus a newly initiated antidepressant reduced depression severity significantly more than antidepressant plus placebo at day 28 (MADRS difference -4.0).
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression 2019 phase 3 randomized withdrawal study 297 Supports Continuing esketamine plus an oral antidepressant reduced relapse risk by 51% in stable remitters and 70% in stable responders compared with switching to placebo.
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression 2017 phase 2 RCT 67 Supports Intranasal esketamine produced a rapid, dose-related antidepressant effect, with response appearing to persist over 2 months at reduced dosing frequency.
Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation 2021 review Supports An international expert synthesis concludes ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, while noting unresolved safety, tolerability, and implementation questions.
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 RCT 68 Mixed Intranasal esketamine plus standard care improved depressive symptoms at 4 and 24 hours versus placebo but not at day 25, and did not significantly reduce clinician-rated suicide risk.
Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder 2014 RCT 41 Supports A single ketamine infusion produced a significantly greater reduction in PTSD symptom severity at 24 hours than midazolam.
Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression 2015 systematic review and meta-analysis Supports Ketamine produced a rapid but transient antidepressant effect, with high odds of response and remission at 24 hours, alongside brief psychotomimetic and dissociative effects.
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 phase 3 RCT 346 No effect Esketamine 84 mg plus an oral antidepressant did not significantly reduce depression scores versus placebo plus antidepressant at 4 weeks, though the effect size exceeded the clinically meaningful threshold.
Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder 2010 open-label trial 33 Supports Suicidal ideation scores decreased significantly within 40 minutes of a single ketamine infusion and remained improved through 4 hours postinfusion.
Side-effects associated with ketamine use in depression: a systematic review. 2018 systematic review Mixed After acute dosing, psychiatric, psychotomimetic, cardiovascular, and neurological side effects were more frequently reported with ketamine than placebo, with selective reporting bias and limited long-term safety data.
A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression 2016 RCT 67 Supports Twice-weekly and thrice-weekly intravenous ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days, with substantially greater MADRS reductions than placebo.
Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study 2015 RCT 30 Supports Both 0.20 mg/kg and 0.40 mg/kg intravenous esketamine produced rapid, significant antidepressant effects versus placebo, with dose-dependent adverse events.
Ketamine: a paradigm shift for depression research and treatment 2019 review Supports Argues that ketamine is a rapid-acting antidepressant effective for treatment-resistant mood disorders and that its mechanisms are reshaping views of depression neurobiology.
Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) 2018 RCT 99 Supports Intravenous ketamine at 0.5 mg/kg and 1.0 mg/kg was superior to active placebo for rapid antidepressant effects, while lower doses showed no consistent efficacy.
Esketamine for treatment of depression in Huntington's disease: A case report 2026 case study 1 Mixed Nasal esketamine was followed by rapid mood improvement (BDI 29 to 5 after three days), but depression worsened again by three months (BDI 20).
Chronic sensing during subcallosal cingulate deep brain stimulation captures ketamine-associated changes in major depressive disorder 2026 case study 1 Unclear Ketamine exposure and affective states both engaged subcallosal cingulate fast-band activity with distinct spectral and temporal patterns, which the authors argue supports adaptive deep brain stimulation strategies.
EFFECTS OF KETAMINE AND ESKETAMINE ON SUICIDAL IDEATION WITHIN THE FIRST 24 HOURS IN ADULTS WITH DEPRESSIVE DISORDERS: VARIABILITY IN CLINICAL FINDINGS AND INTERPRETATIVE CHALLENGES - A NARRATIVE REVIEW 2026 narrative review Mixed Intravenous ketamine may rapidly reduce suicidal ideation in selected adults, but findings were inconsistent across trials, and intranasal esketamine showed clearer early effects on depressive symptoms than on suicidality-specific outcomes.
Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder with Comorbid Treatment-Resistant Depression: A Six-Month Case Report 2026 case study 1 Supports Six months of intranasal esketamine was accompanied by reductions in depression (MADRS 38 to 17) and obsessive-compulsive symptoms (Y-BOCS 33 to 14), though the authors state the observation is hypothesis-generating.
Clinical correlates of non-responders to ketamine in terms of self-assessed life engagement among treatment-resistant depression patients. 2026 unclear Unclear The abstract does not report results; the study concerns clinical correlates of non-response to ketamine in terms of self-assessed life engagement.
301. Multimodal MRI signatures predict ketamine antidepressant response in treatment-resistant depression: a machine-learning analysis of independent clinical trials 2026 secondary analysis of two RCTs with machine learning 49 Supports A machine-learning classifier using pre-treatment multimodal MRI features predicted ketamine antidepressant response with 81.0% accuracy and 91.7% specificity in an independent testing set.
507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review 2026 case study 1 Mixed About three years of intranasal esketamine maintenance was temporally associated with subsequent ketamine use disorder escalating to 2-3 g/day, with depression initially improving (CGI-S 7 to 4) and later worsening; the authors state causality cannot be inferred.
286. Restoration by ketamine metabolites of cognitive and affective prosocial behaviors in a mouse model of depression 2026 preclinical animal study Supports Acute (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine restored prosocial behaviors abolished by chronic corticosterone, with the authors arguing reduced anterior insular cortex activity may underlie the deficits.
716. A randomised-controlled feasibility study of ketamine for the treatment of depression with anorexia nervosa 2026 feasibility RCT protocol 60 Unclear The authors propose that oral ketamine may be effective for depression in people with anorexia nervosa and describe a feasibility study design; no efficacy results are reported.
669. Imaging reward circuitry to guide precision ketamine treatment in treatment-resistant depression 2026 review Supports Argues that ketamine normalizes dysregulated anterior cingulate-centered circuits and large-scale networks, offering a circuit-level account of its rapid antidepressant and anti-anhedonic effects and supporting imaging-based biomarkers.

Points of agreement

  • Multiple randomized trials and meta-analyses find ketamine produces rapid antidepressant effects in treatment-resistant depression, with response rates roughly double those of active placebo at 24 hours.
  • Esketamine nasal spray added to a newly initiated oral antidepressant reduces depression severity and, when continued, lowers relapse risk substantially.
  • Antidepressant effects of a single infusion are transient, and repeated or maintenance dosing is needed to sustain benefit.
  • Dissociative, psychotomimetic, and cardiovascular side effects are more common with ketamine than placebo, and long-term safety data are limited.

Conflicts

  • One phase 3 esketamine trial (TRANSFORM-1) missed its primary endpoint at 4 weeks, while another active-controlled trial found a significant day-28 benefit.
  • Effects on suicidality specifically are inconsistent: some trials show rapid reductions in suicidal ideation, while others find no significant difference on clinician-rated suicide risk.
  • Early antidepressant effects are robust, but durability is uncertain, with some reports of relapse or worsening after initial improvement.

Gaps

  • Long-term safety and efficacy of repeated or maintenance dosing are poorly characterized.
  • Optimal dose, dosing frequency, and route of administration remain unresolved.
  • Blinding integrity is difficult to maintain given ketamine's distinctive psychoactive effects.
  • Evidence in special populations (e.g., anorexia nervosa, Huntington's disease, comorbid substance use disorders) is limited to case reports or feasibility protocols.
  • Biomarkers for predicting response and non-response require validation in larger independent samples.
  • Comparative effectiveness against other rapid-acting or standard treatments is not well established.
Browse these studies in the library

Common questions

What does the research agree on about ketamine for depression?
  • Multiple randomized trials and meta-analyses find ketamine produces rapid antidepressant effects in treatment-resistant depression, with response rates roughly double those of active placebo at 24 hours.
  • Esketamine nasal spray added to a newly initiated oral antidepressant reduces depression severity and, when continued, lowers relapse risk substantially.
  • Antidepressant effects of a single infusion are transient, and repeated or maintenance dosing is needed to sustain benefit.
  • Dissociative, psychotomimetic, and cardiovascular side effects are more common with ketamine than placebo, and long-term safety data are limited.
Where do studies on ketamine for depression conflict?
  • One phase 3 esketamine trial (TRANSFORM-1) missed its primary endpoint at 4 weeks, while another active-controlled trial found a significant day-28 benefit.
  • Effects on suicidality specifically are inconsistent: some trials show rapid reductions in suicidal ideation, while others find no significant difference on clinician-rated suicide risk.
  • Early antidepressant effects are robust, but durability is uncertain, with some reports of relapse or worsening after initial improvement.
What is still unknown about ketamine for depression?
  • Long-term safety and efficacy of repeated or maintenance dosing are poorly characterized.
  • Optimal dose, dosing frequency, and route of administration remain unresolved.
  • Blinding integrity is difficult to maintain given ketamine's distinctive psychoactive effects.
  • Evidence in special populations (e.g., anorexia nervosa, Huntington's disease, comorbid substance use disorders) is limited to case reports or feasibility protocols.
  • Biomarkers for predicting response and non-response require validation in larger independent samples.
  • Comparative effectiveness against other rapid-acting or standard treatments is not well established.
How we analyze this

This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is Ketamine for depression, 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 Ketamine for depression 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.

The full method, including what a person does and does not review, is on the methods page.

Ask your own question in the Research Synthesis Tool

1,533 articles · 713 from the last two years · 2,152,418 participants across 814 studies reporting sample size

Common study designs

review 245 case study 50 systematic review 104 observational cohort 112 randomized controlled trial 166

Research volume by year

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1,505 studies whose primary subject is ketamine for depression since 2005

Studies about ketamine for depression per year, 2005 to 2026, peaking at 345 in 2025 Bar chart: one bar per year, taller where more studies were published that year. 0 200 400 2005 2010 2015 2020 2025
2026 is partial
Show the numbers
Studies about ketamine for depression per year, 2005 to 2026, peaking at 345 in 2025
Year Studies
2005 1
2006 0
2007 1
2008 1
2009 4
2010 3
2011 6
2012 4
2013 4
2014 17
2015 14
2016 14
2017 15
2018 21
2019 47
2020 68
2021 92
2022 120
2023 185
2024 238
2025 345
2026 305

Research

Synthesize the evidence →

Esketamine for treatment of depression in Huntington's disease: A case report

Journal of Huntington s Disease September 17, 2026 Carsten Saft, Julia Jessen, David Kiefner et al.

Depression and suicidal ideation are common in Huntington's disease (HD). We report a 60-year-old male with HD who suffered from treatment-resistant depression with intermittent suicidal thoughts for 20 years, irritability and apathy. Despite multiple trials of antidepressants, no sustained improvement was achieved. Under nasal esketamine treatment his mood improved dramatically after three...

DOI: 10.1177/18796397261489245 (opens in new tab)

EFFECTS OF KETAMINE AND ESKETAMINE ON SUICIDAL IDEATION WITHIN THE FIRST 24 HOURS IN ADULTS WITH DEPRESSIVE DISORDERS: VARIABILITY IN CLINICAL FINDINGS AND INTERPRETATIVE CHALLENGES - A NARRATIVE REVIEW

International Journal of Innovative Technologies in Social Science September 11, 2026 Marta Borkowska, Małgorzata Witaszczyk, Alicja Sołtan et al.

Background: Ketamine and esketamine have been studied as rapid-acting interventions in adults with depressive disorders and suicidal ideation, but findings vary across populations, settings, comparators, routes, and outcome measures. Aim: To examine their effects on suicidal ideation within the first 24 hours and to identify factors contributing to variability across studies. Methods: This...

DOI: 10.31435/ijitss.3(51).2026.6636 (opens in new tab)

Chronic sensing during subcallosal cingulate deep brain stimulation captures ketamine-associated changes in major depressive disorder

medRxiv September 11, 2026 Srdjan Sumarac, Tristan Lawson, Leonardo Favi Bocca et al. preprint

Ketamine and subcallosal cingulate (SCC) deep brain stimulation (DBS) have each shown antidepressant effects in treatment-resistant depression, yet how ketamine modulates SCC physiology during chronic stimulation remains poorly understood. We analyzed 5,907 hours of bilateral SCC sensing, 485 participant-triggered recordings across 193 days, 47 ketamine dosing episodes, and an in-clinic...

DOI: 10.64898/2026.09.08.26362080 (opens in new tab)

Clinical correlates of non-responders to ketamine in terms of self-assessed life engagement among treatment-resistant depression patients.

J Psychiatr Res September 10, 2026

Background: Major depressive and bipolar disorders are leading causes of disability, with many patients developing treatment-resistant depression (TRD/TRBD). Ketamine offers rapid symptom relief, yet recovery extends beyond symptoms. Life engagement (LE) is a key patient-centered outcome encompassing the ability to experience pleasure, function effectively, and participate in meaningful...

DOI: 10.1016/j.jpsychires.2026.09.003 (opens in new tab)

Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder with Comorbid Treatment-Resistant Depression: A Six-Month Case Report

Psychiatry International September 10, 2026 Tommaso Barlattani, Giorgio Sernia, Chiara D’Amelio et al.

Background: Evidence for repeated intranasal esketamine in obsessive–compulsive disorder (OCD) remains preliminary, particularly when OCD co-occurs with treatment-resistant depression (TRD). Methods: We report a 58-year-old woman treated with intranasal esketamine in routine clinical care for TRD; change in obsessive–compulsive symptoms was followed as a secondary observational outcome. Her...

DOI: 10.3390/psychiatryint7050207 (opens in new tab)

716. A randomised-controlled feasibility study of ketamine for the treatment of depression with anorexia nervosa

International Journal of Neuropsychopharmacology September 9, 2026 Johanna Keeler, Hubertus Himmerich, Janet Treasure et al.

Abstract Background Approximately a third of people with anorexia nervosa (AN) develop a severe and enduring form of the illness, which is often accompanied by depression. This can be a key barrier to recovery. Anti-depressant medications are less effective in treating depression in patients with acute AN, thus new pharmacological treatment options are needed. Ketamine is currently used for...

DOI: 10.1093/ijnp/pyag040.488 (opens in new tab)

301. Multimodal MRI signatures predict ketamine antidepressant response in treatment-resistant depression: a machine-learning analysis of independent clinical trials

International Journal of Neuropsychopharmacology September 9, 2026 P-C Wu, T-P Su, C-T Li et al.

Abstract Background While ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), response heterogeneity necessitates robust biomarkers to optimize clinical decision-making. Aims & Objectives To validate a machine-learning (ML) framework for predicting ketamine antidepressant response from pre-treatment multimodal neuroimaging features across independent...

DOI: 10.1093/ijnp/pyag040.042 (opens in new tab)

286. Restoration by ketamine metabolites of cognitive and affective prosocial behaviors in a mouse model of depression

International Journal of Neuropsychopharmacology September 9, 2026 Rei Yokoyama, M Matsumi, S Asano et al.

Abstract Background The execution of prosocial behaviors requires the ability to accurately understand and infer others’ affective states. Impairments in prosocial functioning have been shown to be associated with the pathology of several psychiatric disorders. In particular, individuals with depression exhibit reduced cognitive and affective responses to others’ emotions. These impairments may...

DOI: 10.1093/ijnp/pyag040.230 (opens in new tab)

507. Ketamine use disorder following intranasal esketamine for treatment-resistant depression: a case report and literature review

International Journal of Neuropsychopharmacology September 9, 2026 Y-H Chan, H-M Chang

Abstract Background Esketamine, the S-enantiomer of ketamine, is an NMDA receptor antagonist approved for treatment-resistant depression (TRD). Although regulated clinical trials suggest a low risk of misuse, concerns remain that esketamine exposure may facilitate transition to ketamine dependence, particularly in East Asia where illicit ketamine is widely available. Aims & Objectives To...

DOI: 10.1093/ijnp/pyag040.332 (opens in new tab)

669. Imaging reward circuitry to guide precision ketamine treatment in treatment-resistant depression

International Journal of Neuropsychopharmacology September 9, 2026 C Zarate

Abstract Background Ketamine produces rapid antidepressant and anti-anhedonic effects in treatment-resistant depression, but response is heterogeneous and mechanisms at the circuit level remain incompletely defined. Convergent imaging work implicates anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), and reward-related networks as key loci for ketamine’s therapeutic and...

DOI: 10.1093/ijnp/pyag040.451 (opens in new tab)

Clinical trials

All ketamine for depression trials →