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Ketamine and glutamatergic agents

TL;DR — Intravenous racemic ketamine and intranasal esketamine established that antidepressant effects can emerge within hours to days, transforming both treatment and mechanism research. Early controlled studies were small but striking (Berman 2000, PMID 10686270; Zarate 2006, PMID 16894061). In phase 3 TRD, flexible-dose esketamine plus a new oral antidepressant improved MADRS by 4.0 points more than oral antidepressant plus placebo spray at day 28 (Popova 2019, PMID 31109201); relapse-prevention evidence supports continued treatment among responders (Daly 2019, PMID 31166571). Dissociation, blood-pressure elevation, nausea, sedation, misuse potential, monitoring burden, and uncertain long-term comparative value constrain use. Dextromethorphan–bupropion extends NMDA/sigma-1 pharmacology to an oral product, but durability and mechanism-specific advantage remain incompletely resolved.

Evidence timeline

Study Design Main contribution
Berman 2000 small placebo-controlled crossover proof of rapid antidepressant effect (PMID 10686270)
Zarate 2006 randomized crossover in TRD replicated rapid effect (PMID 16894061)
Popova 2019 phase 3 esketamine + oral AD day-28 difference −4.0 MADRS points (PMID 31109201)
Daly 2019 randomized withdrawal relapse prevention among stable responders/remitters (PMID 31166571)
Phillips 2019 single/repeated/maintenance IV ketamine repeated and maintenance strategy evidence (PMID 30922101)
Anand 2023 pragmatic ketamine vs ECT noninferiority for response in nonpsychotic TRD (PMID 37224232)

Racemic ketamine versus esketamine

Feature IV racemic ketamine Intranasal esketamine
Regulatory position generally off-label for depression approved in several jurisdictions for defined TRD indications
Route monitored infusion monitored nasal administration
Evidence academic and pragmatic trials registration program plus extensions
Comparative certainty no definitive superiority standardized product, structured program

A meta-analysis suggested racemic ketamine may show larger effects than esketamine, but comparisons were largely indirect and confounded by route, dose, population, and trial design (Bahji 2021, PMID 33022440). Cochrane review supports short-term benefit for ketamine-class interventions while rating much longer-term evidence limited (Dean 2021, PMID 34510411).

Durability

Single-infusion benefit often wanes over days to weeks. Repeated administration and maintenance can sustain response in some patients, but optimal interval and stopping rules are unsettled (Phillips 2019, PMID 30922101). Randomized withdrawal with esketamine showed fewer relapses on continued esketamine plus oral antidepressant than discontinuation to placebo spray (Daly 2019, PMID 31166571); enrichment means the result applies most directly to people who first responded and tolerated treatment.

Psychotherapy after rapid response is no longer an untested concept. In a response-enriched randomized trial, 28 ketamine responders received CBT or treatment as usual: the primary MADRS group-by-time interaction was not significant, while QIDS trajectories favored CBT, leaving efficacy uncertain because the study was small (Wilkinson 2021, PMID 34186531). A later 93-person esketamine trial in major depression with suicidal ideation found that adjunctive CBT improved some suicidal-ideation and depression measures through week 18, but not the Columbia scale, MADRS suicidal-ideation item, or suicide-related events (Wilkinson 2026, PMID 42095692). The remaining gap is a well-powered, prespecified test of timing, mechanism, durability, and patient burden.

Safety and monitoring

Risk Time scale Research/clinical implication
Dissociation/perceptual change acute observation and driving restriction
BP elevation acute pre/post-dose monitoring
Nausea/sedation acute falls, aspiration, transport planning
Misuse/dependence longer term controlled access and substance-use assessment
Urinary/hepatic toxicity chronic high exposure concern long-term surveillance
Cognitive effects uncertain long term prospective measurement needed

Other glutamatergic/rapid-acting agents

Dextromethorphan–bupropion combines NMDA antagonism/sigma-1 agonism with bupropion-mediated metabolic inhibition. GEMINI showed phase 3 efficacy (Iosifescu 2022, PMID 35649167), supported by an earlier randomized comparison (Tabuteau 2022, PMID 35582785). Many NMDA-modulating candidates have failed, indicating that “glutamatergic” is not a sufficient class prediction.

The live trial registry shows ongoing tests of hydroxynorketamine (NCT06511908), AMPA involvement in anti-suicidal effects (NCT05786066), ketamine neural circuits (NCT06213324), and kappa-opioid involvement (NCT07139106); all exact records were re-fetched through ClinicalTrials.gov v2 on 2026-08-30.

Rapid response, durability, and safety

Ketamine's key evidentiary contribution is temporal: symptom change can occur within hours. That observation constrains mechanism theories but does not establish the durability, optimal maintenance schedule, or necessity of dissociation.

Question Evidence direction Remaining uncertainty
IV ketamine vs placebo Randomized syntheses show large early symptom effects Small trials, crossover designs, and conspicuous allocation limit precision
Intranasal esketamine induction Phase 3 trials show modest mean MADRS separation Functional outcomes and individual absolute benefit vary
Maintenance Randomized withdrawal reduces relapse among prior responders Enrichment and withdrawal effects limit generalization
Suicidal ideation Meta-analysis supports a rapid ideation signal Attempts and deaths are too rare for efficacy conclusions
Racemic ketamine vs esketamine Comparative syntheses do not substitute for adequately powered head-to-head trials Route, dose, setting, and selection differ
Long-term harms Reviews track cognition, urinary symptoms, blood pressure, dissociation, and misuse Controlled multi-year denominators remain sparse

Dextromethorphan–bupropion extends glutamatergic pharmacology into an oral regimen, but its evidence base should not be merged with ketamine because exposure, ancillary mechanisms, blinding, and safety differ.

Additional live-search evidence ledger

The records below were added after full PubMed E-utilities retrieval on 2026-08-30. The ledger states the evidentiary role of each record and preserves the design limitation that should travel with its citation.

  • Seshadri A 2024 — Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Seshadri A 2024, PMID 38537759)

  • Elmosalamy A 2025 — Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Elmosalamy A 2025, PMID 41244961)

  • Shi ZM 2025 — Intravenous ketamine versus electroconvulsive therapy for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled trials. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Shi ZM 2025, PMID 39549887)

  • Terao I 2024 — Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: A systematic review and network meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Terao I 2024, PMID 37949235)

  • Shim SR 2026 — Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode: A Systematic Review and Meta-Analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Shim SR 2026, PMID 42090166)

  • Terao I 2025 — Comparative efficacy and safety of intravenous racemic ketamine, repetitive transcranial magnetic stimulation and electroconvulsive therapy for Stage 2 or higher treatment-resistant depression: A systematic review and network meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Terao I 2025, PMID 40590032)

  • Doty RL 2021 — Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies. Randomized comparison; population, control credibility, duration, and missingness bound transportability. (Doty RL 2021, PMID 34235612)

  • Shen Z 2024 — A meta-analysis of the effects of ketamine on suicidal ideation in depression patients. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Shen Z 2024, PMID 38858391)

  • Fountoulakis KN 2025 — Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Fountoulakis KN 2025, PMID 39876682)

  • Nikolin S 2023 — Ketamine for the treatment of major depression: a systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Nikolin S 2023, PMID 37593223)

  • Wang Z 2025 — Esketamine Nasal Spray in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Wang Z 2025, PMID 39790081)

  • Bartoli F 2017 — Ketamine as a rapid-acting agent for suicidal ideation: A meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Bartoli F 2017, PMID 28342764)

  • Wang YT 2024 — A systematic review and meta-analysis of the efficacy of ketamine and esketamine on suicidal ideation in treatment-resistant depression. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Wang YT 2024, PMID 38117332)

  • Witt K 2020 — Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Witt K 2020, PMID 31729893)

  • Chen CC 2023 — Acute Effects of Intravenous Sub-Anesthetic Doses of Ketamine and Intranasal Inhaled Esketamine on Suicidal Ideation: A Systematic Review and Meta-Analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Chen CC 2023, PMID 36942150)

  • Li J 2025 — Efficacy of racemic ketamine or esketamine monotherapy for reducing suicidal ideation in uni- or bipolar depression: a systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Li J 2025, PMID 39382685)

  • Xiong J 2021 — The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Xiong J 2021, PMID 33360864)

Open questions

  • What maintenance interval preserves benefit with the lowest cumulative risk (Daly 2019, PMID 31166571)?
  • Which acute subjective or physiological effects are necessary for antidepressant response?
  • Does racemic ketamine truly outperform esketamine in direct randomized comparison (Bahji 2021, PMID 33022440)?
  • Can non-dissociative metabolites reproduce efficacy (NCT06511908)?

References

  1. Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000. PMID 10686270
  2. Zarate CA Jr, et al. A randomized trial of an NMDA antagonist in treatment-resistant major depression. Archives of General Psychiatry. 2006. PMID 16894061
  3. Popova V, et al. Esketamine nasal spray plus oral antidepressant in TRD. American Journal of Psychiatry. 2019. PMID 31109201
  4. Daly EJ, et al. Esketamine relapse prevention. JAMA Psychiatry. 2019. PMID 31166571
  5. Phillips JL, et al. Single, repeated, and maintenance ketamine infusions. American Journal of Psychiatry. 2019. PMID 30922101
  6. Anand A, et al. Ketamine versus ECT for nonpsychotic TRD. New England Journal of Medicine. 2023. PMID 37224232
  7. Bahji A, et al. Comparative efficacy of racemic ketamine and esketamine. Journal of Affective Disorders. 2021. PMID 33022440
  8. Dean RL, et al. Ketamine and other glutamate receptor modulators for depression. Cochrane Database of Systematic Reviews. 2021. PMID 34510411
  9. Iosifescu DV, et al. Dextromethorphan-bupropion in MDD: GEMINI. Journal of Clinical Psychiatry. 2022. PMID 35649167
  10. Tabuteau H, et al. Dextromethorphan-bupropion in MDD. American Journal of Psychiatry. 2022. PMID 35582785
  11. Seshadri A, et al. Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis. Journal of affective disorders. 2024;356:379-384. PMID 38537759
  12. Elmosalamy A, et al. Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Therapeutic advances in psychopharmacology. 2025;15:20451253251394127. PMID 41244961
  13. Shi ZM, et al. Intravenous ketamine versus electroconvulsive therapy for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled trials. Journal of affective disorders. 2025;371:45-53. PMID 39549887
  14. Terao I, et al. Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: A systematic review and network meta-analysis. Journal of affective disorders. 2024;346:49-56. PMID 37949235
  15. Shim SR, et al. Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode: A Systematic Review and Meta-Analysis. JAMA psychiatry. 2026;83:714-731. PMID 42090166
  16. Terao I, et al. Comparative efficacy and safety of intravenous racemic ketamine, repetitive transcranial magnetic stimulation and electroconvulsive therapy for Stage 2 or higher treatment-resistant depression: A systematic review and network meta-analysis. PCN reports : psychiatry and clinical neurosciences. 2025;4:e70136. PMID 40590032
  17. Doty RL, et al. Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies. CNS drugs. 2021;35:781-794. PMID 34235612
  18. Shen Z, et al. A meta-analysis of the effects of ketamine on suicidal ideation in depression patients. Translational psychiatry. 2024;14:248. PMID 38858391
  19. Fountoulakis KN, et al. Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. The American journal of psychiatry. 2025;182:259-275. PMID 39876682
  20. Nikolin S, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine. 2023;62:102127. PMID 37593223
  21. Wang Z, et al. Esketamine Nasal Spray in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials. Clinical pharmacology and therapeutics. 2025;117:1637-1649. PMID 39790081
  22. Bartoli F, et al. Ketamine as a rapid-acting agent for suicidal ideation: A meta-analysis. Neuroscience and biobehavioral reviews. 2017;77:232-236. PMID 28342764
  23. Wang YT, et al. A systematic review and meta-analysis of the efficacy of ketamine and esketamine on suicidal ideation in treatment-resistant depression. European journal of clinical pharmacology. 2024;80:287-296. PMID 38117332
  24. Witt K, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: A systematic review and meta-analysis of treatment trials. The Australian and New Zealand journal of psychiatry. 2020;54:29-45. PMID 31729893
  25. Chen CC, et al. Acute Effects of Intravenous Sub-Anesthetic Doses of Ketamine and Intranasal Inhaled Esketamine on Suicidal Ideation: A Systematic Review and Meta-Analysis. Neuropsychiatric disease and treatment. 2023;19:587-599. PMID 36942150
  26. Li J, et al. Efficacy of racemic ketamine or esketamine monotherapy for reducing suicidal ideation in uni- or bipolar depression: a systematic review and meta-analysis. European archives of psychiatry and clinical neuroscience. 2025;275:1359-1371. PMID 39382685
  27. Xiong J, et al. The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Journal of psychiatric research. 2021;134:57-68. PMID 33360864
  28. Wilkinson ST, et al. Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial. Psychotherapy and Psychosomatics. 2021;90:318-327. PMID 34186531
  29. Wilkinson ST, et al. Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention: The CBT-ENDURE Randomized Trial. Journal of Clinical Psychiatry. 2026;87:25m16285. PMID 42095692