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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

1,715 articles · 714 from the last two years · 2,493,509 participants across 933 studies reporting sample size

Common study designs

review 278 case study 63 systematic review 116 observational cohort 116 randomized controlled trial 183

Research volume by year

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1,686 studies whose primary subject is ketamine for depression since 2005

Studies about ketamine for depression per year, 2005 to 2026, peaking at 346 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 346 in 2025
Year Studies
2005 1
2006 0
2007 2
2008 3
2009 6
2010 6
2011 7
2012 4
2013 5
2014 24
2015 24
2016 46
2017 52
2018 76
2019 51
2020 73
2021 93
2022 126
2023 186
2024 238
2025 346
2026 317

Research

Synthesize the evidence →

Effects of Repeated Ketamine Infusions on Suicidal Ideation in Treatment-Resistant Depression and Associated Changes in Selected Plasma Biomarkers

Pharmacopsychiatry October 2, 2026 Masami Murao, Daiki Setoyama, Yasuyuki Matsumoto et al.

Abstract This study investigated the antisuicidal effects of repeated intravenous ketamine in patients with treatment-resistant depression and explored associations between suicidal ideation and temporal changes in selected plasma biomarkers to identify potential biomarkers. This secondary analysis of an open-label trial included outpatients with treatment-resistant depression who received four...

DOI: 10.1055/a-2959-4626 (opens in new tab)

KETAMINE VERSUS ELECTROCONVULSIVE THERAPY FOR SEVERE TREATMENT-RESISTANT DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF EFFICACY, SPEED OF RESPONSE, COGNITIVE OUTCOMES, AND SAFETY

The International Journal of Medical Science and Health Research September 29, 2026 Arby Shafara Sekundaputra

Introduction: Treatment-resistant depression (TRD) affects approximately one-third of patients with major depressive disorder and accounts for disproportionate disability and mortality. Electroconvulsive therapy (ECT) has long been the definitive intervention, whereas subanaesthetic intravenous ketamine has emerged as a rapid-acting alternative. Direct head-to-head evidence has accumulated...

DOI: 10.70070/fdkn3z10 (opens in new tab)

Multimodal predictors of response to intravenous ketamine in treatment-resistant depression: toward personalized treatment in major depressive and bipolar disorders.

CNS Spectrums September 28, 2026 Magda Malewska-Kasprzak, Filip Rybakowski, Monika Dmitrzak-Weglarz

Intravenous ketamine is a rapid-acting intervention for treatment-resistant depression (TRD) in adults with major depressive disorder and bipolar disorder (BD). While efficacy is established, a comprehensive integration of clinical, neurophysiological, biomarker, metabolic, and cognitive predictors remains lacking, limiting precision CNS-targeted therapy. To synthesize recent evidence on...

DOI: 10.1017/s1092852926101187 (opens in new tab) Full text (opens in new tab) Major depressive disorder Treatment-resistant depression Cns biomarkers Intravenous ketamine +3

Symptom-level and network analyses of ketamine treatment in treatment-resistant depression: A pooled analysis of two randomized controlled trials.

Progress in neuro-psychopharmacology & biological psychiatry September 26, 2026 Kuan-I Liu, Wei-Chen Lin, Cheng-Ta Li et al.

We examined symptom-level treatment effects and exploratory symptom networks after ketamine in treatment-resistant depression. This post hoc analysis pooled 132 participants assigned to ketamine 0.5 mg/kg or protocol-specific control (66 each) from saline-controlled 2017 and midazolam-controlled 2023 trials. Baseline- and trial-adjusted models assessed Montgomery-Åsberg Depression Rating Scale...

DOI: 10.1016/j.pnpbp.2026.111950 (opens in new tab) Full text (opens in new tab) Ketamine Treatment-resistant depression Network intervention analysis Symptom network

Ketamine for Treatment-Resistant Depression in Adolescents: Hope or Risk?

Journal of Education, Health and Sport September 24, 2026 Anna Kamosińska, Julia Pająk, Olga Sławatyniec et al.

Treatment-resistant depression (TRD) in adolescents remains a major clinical challenge because of the limited efficacy of conventional antidepressants and the high risk of suicidal behavior. Ketamine has emerged as a rapidly acting antidepressant with a unique glutamatergic mechanism, promoting neuroplasticity and reducing neuroinflammation. Clinical studies demonstrate significant symptom...

DOI: 10.12775/jehs.2026.95.73956 (opens in new tab)

Feasibility and tolerability of virtual reality during esketamine treatment: A pilot study.

Journal of Affective Disorders September 23, 2026 Erin Curran, Kristina T. Kumpf, Mina Ansari et al.

Ketamine/esketamine produce rapid antidepressant effects, with growing interest in how acute subjective experiences and the surrounding set and setting shape clinical outcomes. Little is known about how audiovisual adjustments during ketamine/esketamine treatment influence comfort, tolerability, or patient experience, despite their common use in clinical practice. Virtual reality (VR) is one...

DOI: 10.1016/j.jad.2026.122554 (opens in new tab) Full text (opens in new tab) Esketamine Set and setting Treatment resistant depression Virtual reality

Peripheral Biomarkers of Response to Ketamine and Esketamine Treatment in Unipolar Depressive Disorder—A Scoping Review

Journal of Personalized Medicine September 23, 2026 Aleksandra Metelska, Wojciech Ziemichód, Hanna Karakuła-juchnowicz

Objectives: A significant problem in the treatment of depressive disorders is the growing number of cases of so-called treatment-resistant depression (TRD). There is evidence of ketamine’s effectiveness in treating TRD, with response rates ranging from 40% to 90%. This review aimed to map available studies on peripheral biomarkers of response to ketamine and esketamine in the treatment of...

DOI: 10.3390/jpm16100488 (opens in new tab)

Modulation of GABA and glutamate by ketamine in depression: A systematic review and meta-analysis of magnetic resonance spectroscopy studies.

Neuropsychopharmacology September 21, 2026 Balwinder Singh, Hossam M Ali, Alessandro Miola et al.

Disrupted excitation-inhibition (E/I) balance involving GABA and glutamate (Glu) is implicated in the pathophysiology of depression. Ketamine, an NMDA receptor antagonist with rapid antidepressant properties, may modulate this balance, yet proton magnetic resonance spectroscopy (¹H-MRS) studies report inconsistent findings regarding the direction, magnitude, and timing of neurochemical effects....

DOI: 10.1038/s41386-026-02562-4 (opens in new tab) Full text (opens in new tab)

Default mode network functional connectivity following treatment with conventional antidepressants and (es)ketamine in major depressive disorder: A systematic review

Psychiatry Research Neuroimaging September 17, 2026 Juliana Lima Constantino, Jesca E. de Jager, Jasper O. Nuninga et al.

Antidepressant treatments, including conventional antidepressants and (es)ketamine, may reverse default mode network (DMN) resting-state functional connectivity (rsFC) alterations related to major depressive disorder (MDD). Despite these agents having distinct initial action mechanisms, both likely share downstream effects that lead to structural and functional adaptations in MDD-related neural...

DOI: 10.1016/j.pscychresns.2026.112333 (opens in new tab)

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)

Clinical trials

All ketamine for depression trials →