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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.

Ketamine and esketamine show rapid, substantial antidepressant effects in treatment-resistant depression, with several randomized trials reporting large early reductions in depression severity versus placebo or active control, and maintenance/relapse-prevention data favoring continued esketamine. Results are not fully consistent: at least one large phase 3 trial missed its primary endpoint, effects are often transient, and augmentation strategies add little. Main caveats are small samples in some trials, short follow-up, limited long-term safety data, and selective reporting.

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 ketamine infusion lowered MADRS scores more than midazolam at 24 hours (7.95-point difference) with 64% versus 28% response.
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 new antidepressant reduced MADRS more than antidepressant plus placebo at day 28 (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 RCT 297 Supports Continuing esketamine plus oral antidepressant reduced relapse risk by 51% in stable remitters and 70% in stable responders versus 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 lower 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 Expert synthesis concludes ketamine and esketamine are effective rapid-onset treatments for treatment-resistant depression, with 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 Esketamine plus standard care improved depressive symptoms at 4 and 24 hours but not at day 25, and did not reduce clinician-rated suicide risk.
Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder 2014 RCT (crossover) 41 Supports Ketamine reduced PTSD symptom severity more than midazolam at 24 hours, with secondary depressive symptom measures also assessed.
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 antidepressant did not significantly reduce MADRS versus placebo plus antidepressant at 4 weeks (difference -3.2, P=.088).
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 fell significantly within 40 minutes of a single ketamine infusion and remained improved through 4 hours.
Side-effects associated with ketamine use in depression: a systematic review. 2018 systematic review Opposes After acute dosing, psychiatric, psychotomimetic, cardiovascular, and other side effects were more frequently reported with ketamine than placebo, with selective reporting 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- and thrice-weekly IV ketamine both produced substantially greater MADRS reductions than placebo at day 15.
Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study 2015 RCT 30 Supports Both 0.20 and 0.40 mg/kg IV esketamine produced rapid, significant MADRS improvement versus placebo by day 2.
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 (dose-ranging) 99 Supports Ketamine at 0.5 and 1.0 mg/kg was superior to active placebo for rapid antidepressant effects, while lower doses showed no consistent efficacy.
Quality of Life in Patients with Treatment-Resistant Depression Treated with Intranasal Esketamine as Add-On Therapy to an SSRI—A Prospective, Comparative Study in Real-World Clinical Practice 2026 prospective observational cohort 60 Supports Both groups improved in quality of life and symptom severity, with larger absolute changes in the esketamine add-on group; authors caution this is not evidence of an isolated causal effect.
Depression: Ketamine quiets an unruly habenula. 2026 commentary Unclear Describes evidence that the ~24-hour window of ketamine's antidepressant effects coincides with reduced habenula activation and aversive learning in healthy subjects, without effect sizes or statistics.
Real-world clinical outcomes under intravenous and subcutaneous esketamine protocols for treatment-resistant depression: a multicenter, retrospective study 2026 retrospective chart review 72 Mixed IV esketamine response distribution favored IV over subcutaneous at six sessions but was not statistically significant, and categorical response did not differ at protocol endpoints; dissociation was more frequent with IV.
Esketamine alleviates the pain-depression dyad: insights from exploratory transcriptomic profiling and Wnt4-associated molecular alterations within the anterior cingulate cortex 2026 animal RCT Supports A single 15 mg/kg esketamine dose alleviated pain hypersensitivity, behavioral despair, and anhedonia in rats, associated with Wnt4-related molecular changes in the anterior cingulate cortex.
Baseline Response Criterion and Changes in Emotional Bias as Markers of Esketamine Response in Treatment-Resistant Depression 2026 observational cohort 106 Supports Esketamine responders showed early increases in emotion discrimination sensitivity and, by week 4, less negative categorization of neutral faces than non-responders; lower baseline response criterion was associated with responder status.
Longitudinal peripheral DNA methylation remodeling following ketamine-assisted psychotherapy in major depressive disorder 2026 longitudinal observational 10 Supports Depressive symptoms declined markedly after ketamine-assisted psychotherapy, alongside exploratory DNA methylation changes; authors state findings do not establish causality.
Intranasal Esketamine for Treatment-Resistant Depression: A Practical Clinical Guide to Patient Selection, Dosing, Combination Strategies and Adverse-Event Management 2026 review Unclear Argues that esketamine approval trials excluded many real-world patients and leave prescribing questions unresolved, and that evidence does not show 84 mg is more effective than 56 mg.
Ketamine administered biomedically or as psychedelic-assisted therapy in treatment-resistant depression: Differing efficacy based on depressive subtype or presence of childhood trauma? 2026 commentary Unclear Argues that ketamine efficacy should be examined by depressive subtype, reporting preliminary open-label findings that biomedical ketamine may be superior in melancholic versus non-melancholic depression, and notes psychedelic-assisted studies are lacking.
Ketamine's mechanisms of action in major depressive disorder and treatment-resistant depression: Is brain topological change a candidate convergent systems-level pathway? 2026 narrative review Unclear Argues that ketamine's antidepressant effects may be mediated by systems-level normalization of brain network topology rather than NMDA antagonism and glutamatergic signaling alone.
Augmentation strategies for intravenous ketamine in treatment-resistant depression: A systematic review and meta-analysis. 2026 systematic review and meta-analysis 346 No effect Across seven RCTs, IV ketamine was associated with antidepressant improvement, but augmentation strategies generally added no benefit (overall SMD -0.12, 95% CI -0.37 to 0.12), with low-certainty evidence.

Points of agreement

  • Multiple randomized trials and meta-analyses report rapid antidepressant effects of ketamine/esketamine in treatment-resistant depression.
  • Effects appear within hours to days of dosing.
  • Continued esketamine reduces relapse compared with discontinuation.
  • Dissociative and psychotomimetic side effects are common and transient.
  • Benefits are often transient and augmentation strategies have not reliably sustained them.

Conflicts

  • One large phase 3 trial (TRANSFORM-1) missed its primary endpoint while other esketamine trials were positive.
  • Symptom benefit in the suicide-risk trial did not persist to day 25 and did not reduce clinician-rated suicide risk.
  • Augmentation meta-analysis found no added benefit from add-on strategies despite ketamine's own efficacy.

Gaps

  • Long-term safety and effects of repeated dosing are poorly characterized.
  • Optimal dose and dosing frequency remain uncertain.
  • Many trials excluded common comorbid populations, limiting generalizability.
  • Durability of benefit beyond short follow-up is unclear.
  • Blinding integrity with psychoactive controls is uncertain.
  • Little evidence on ketamine combined with psychotherapy or on differential efficacy by depressive subtype.
Browse these studies in the library

Common questions

What does the research agree on about ketamine for depression?
  • Multiple randomized trials and meta-analyses report rapid antidepressant effects of ketamine/esketamine in treatment-resistant depression.
  • Effects appear within hours to days of dosing.
  • Continued esketamine reduces relapse compared with discontinuation.
  • Dissociative and psychotomimetic side effects are common and transient.
  • Benefits are often transient and augmentation strategies have not reliably sustained them.
Where do studies on ketamine for depression conflict?
  • One large phase 3 trial (TRANSFORM-1) missed its primary endpoint while other esketamine trials were positive.
  • Symptom benefit in the suicide-risk trial did not persist to day 25 and did not reduce clinician-rated suicide risk.
  • Augmentation meta-analysis found no added benefit from add-on strategies despite ketamine's own efficacy.
What is still unknown about ketamine for depression?
  • Long-term safety and effects of repeated dosing are poorly characterized.
  • Optimal dose and dosing frequency remain uncertain.
  • Many trials excluded common comorbid populations, limiting generalizability.
  • Durability of benefit beyond short follow-up is unclear.
  • Blinding integrity with psychoactive controls is uncertain.
  • Little evidence on ketamine combined with psychotherapy or on differential efficacy by depressive subtype.
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

1,775 articles · 748 from the last two years · 2,536,791 participants across 960 studies reporting sample size

Common study designs

review 286 case study 64 systematic review 122 observational cohort 117 randomized controlled trial 184

Research volume by year

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1,746 studies whose primary subject is ketamine for depression since 2005

Studies about ketamine for depression per year, 2005 to 2026, peaking at 361 in 2026 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 361 in 2026
Year Studies
2005 1
2006 0
2007 2
2008 3
2009 6
2010 7
2011 8
2012 4
2013 5
2014 24
2015 24
2016 46
2017 53
2018 82
2019 52
2020 73
2021 93
2022 126
2023 186
2024 240
2025 350
2026 361

Research

Synthesize the evidence →

Ketamine and esketamine for suicidal ideation in depression: a systematic review and meta-analysis of randomized controlled trials

Middle East Current Psychiatry November 11, 2026 Kirolos Eskandar, Amr Mousa, Kerolos Shahat

Abstract: Background: Suicidal ideation is a major clinical problem in depressive disorders, while conventional antidepressants have delayed effects. Ketamine and esketamine may provide rapid relief, but their effects on suicidal ideation, durability, suicidal behavior, and safety remain uncertain. Aim: To evaluate the efficacy, durability, suicidal-behavior outcomes, acceptability, and safety...

DOI: 10.1186/s43045-026-00683-6 (opens in new tab)

A predictive nomogram based on sub-anesthetic esketamine and clinical variables for estimating the risk of postoperative depression following laparoendoscopic single-site hysterectomy

Frontiers in Medicine November 10, 2026 Kun Shao, Weili Han, Xu Cao et al.

Objective To construct a nomogram combining sub-anesthetic esketamine administration with perioperative clinical characteristics for predicting postoperative depression in patients undergoing laparoendoscopic single-site (LESS) hysterectomy. Methods Clinical records from 326 patients who underwent LESS hysterectomy were retrospectively reviewed. Participants were randomly assigned to training (...

DOI: 10.3389/fmed.2026.1943794 (opens in new tab)

Ketamine for co-occurring chronic pain and depression: A scoping review highlighting the dual-outcome evidence gap and its treatment and research implications.

Journal of Pain November 9, 2026 Simon Asnes, Julio C Nunes, Rebecca Suh et al.

Chronic pain and depression frequently co-occur, share clinical features, and involve shared neurobiological substrates. Ketamine, an NMDA-receptor antagonist, has established antidepressant efficacy, whereas its analgesic efficacy for chronic pain remains uncertain. Given the overlap between chronic pain and depression, ketamine may serve as a potential dual-action treatment. We conducted a...

DOI: 10.1016/j.jpain.2026.106491 (opens in new tab) Full text (opens in new tab) Ketamine Treatment-resistant depression Analgesia Nmda receptor antagonist +1

Dextromethorphan-Bupropion-Esketamine Triadic Pharmacology: Molecular Targets, Enzymatic Interactions, and Risk-Benefit Assessment of a Three-Agent Combination for Treatment-Resistant Depression

International Journal of Molecular Sciences November 9, 2026 Andrea Fagiolini, Alessandro Cuomo, Giulio Corrivetti et al.

Dextromethorphan is extensively O-demethylated by cytochrome P450 2D6 (CYP2D6) to dextrorphan, and the two molecules do not share a target profile. Dextrorphan is the more potent N-methyl-D-aspartate (NMDA) channel blocker; the parent compound is the more potent serotonin transporter inhibitor; their sigma-1 affinities are comparable, so differences in sigma-1 engagement depend on exposure...

DOI: 10.3390/ijms272110036 (opens in new tab)

Intermittent theta burst stimulation to extend early ketamine response in treatment-resistant depression: A preliminary enriched randomized, double-blind, sham-controlled trial.

Psychiatry and Clinical Neurosciences November 4, 2026 Tung-Ping Su, Mao-Hsuan Huang, Wan-Chen Chang et al.

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but these benefits diminish within days. Whether intermittent theta-burst stimulation (iTBS) can sustain ketamine response and whether such effects are associated with changes in large-scale brain networks are unclear. Adults with TRD who exhibited an antidepressant response to two low-dose ketamine...

DOI: 10.1111/pcn.70165 (opens in new tab) Full text (opens in new tab) Ketamine Corticostriatal Neuromodulation Thalamocortical +1

How to Give Oral Ketamine Therapy for Treatment of Resistant Depression and Suicidality: A Critical Review

Clinical Psychopharmacology and Neuroscience November 4, 2026 Mohan Dabas, Swarndeep Singh, Pankaj Verma

Objective: To critically review the empirical literature on oral ketamine dosing strategies and administration procedures; and provide pragmatic clinical considerations for its use in out-patient psychiatric settings for treatment-resistant depression and suicidality.Methods: A structured search of PubMed and Google Scholar was conducted to identify peer-reviewed studies published till April...

DOI: 10.9758/cpn.26.1453 (opens in new tab) Full text (opens in new tab)

Rapid-Acting Antidepressants: Targeting Neuroplasticity Beyond Monoamines.

Central nervous system agents in medicinal chemistry November 3, 2026 Saumya Das, Avijit Mazumder, Deepanshi Rana

Depression remains a leading cause of morbidity worldwide, with conventional monoaminergic antidepressants such as SSRIs and SNRIs limited by delayed onset and high rates of treatment resistance. Novel approaches that modulate neuroplasticity, particularly NMDA receptor antagonists like ketamine, have demonstrated rapid efficacy in treatment-resistant depression. Ketamine relieves symptoms...

DOI: 10.2174/0118715249485751261025102238 (opens in new tab) Full text (opens in new tab) Depression Ketamine Ampa potentiators Bdnf-trkb signaling +4

INTRANASAL ESKETAMINE IN TREATMENT-RESISTANT DEPRESSION: WHY DO REAL-WORLD CLINICAL PRACTICE OUTCOMES SURPASS THOSE OF CLINICAL TRIALS? A NARRATIVE REVIEW

Boletim de Conjuntura November 3, 2026 Ana Carmelita Gomes Farias, Maria Laura Vieira Martins Guimarães, Ana Carolina Ferrazi Sampaio et al.

Intranasal esketamine was approved for the treatment of treatment-resistant depression on the basis of randomized clinical trials whose effects, when pooled in meta-analyses, were of modest magnitude. In contrast, observational studies conducted in routine clinical practice have reported substantial symptom reductions and increasing remission rates over follow-up. This review aimed to...

DOI: 10.56238/bocav25n84-001 (opens in new tab)

Blood pressure elevation with ketamine and esketamine in depression: a systematic review and meta-analysis of randomised trials

Open Science Framework November 2, 2026 Karim Haffar preprint

Review title: Blood pressure elevation with ketamine and esketamine in depression: a systematic review and meta-analysis of randomised trials Type and method of review: Meta analysis Stage of review at time of this submission: Review ongoing — the protocol has been finalised and the peer-reviewed search prepared; formal screening not yet started. Review question: In Adults with depression...

DOI: 10.17605/osf.io/csarj (opens in new tab)

Working Memory Neural Correlates After Ketamine in Treatment-Resistant Depression: A Randomized Placebo-Controlled Functional Magnetic Resonance Imaging Study

Psychiatry Research Neuroimaging November 1, 2026 Adam Fijtman, Níall Lally, Jennifer W. Evans et al.

Ketamine exerts rapid antidepressant effects in treatment-resistant depression (TRD), but its impact on working memory and neural circuitry remains unclear. This secondary analysis investigated behavioral and neural changes during a working memory task post-ketamine infusion in TRD participants versus healthy volunteers (HVs). Data were previously collected from a randomized, double-blind,...

DOI: 10.1016/j.pscychresns.2026.112367 (opens in new tab)

Clinical trials

All ketamine for depression trials →