Ketamine: A Clinical Reference

Overview

Ketamine occupies a unique position in the depression treatment landscape. Its antidepressant mechanism is distinct from all existing small-molecule antidepressants — glutamate/NMDA-mediated rather than monoamine-mediated — and its speed of onset (hours) is dramatically faster than anything else available. For patients with severe or treatment-resistant depression, particularly with suicidality, this combination is genuinely valuable.

At the same time, ketamine is not a clean story. The evidence base is strong for acute response but less robust for long-term durability. The psychoactive effects are uncomfortable for some patients. Addiction potential is real. Insurance coverage is uneven. And the "ketamine clinic" industry has expanded faster than quality standards, creating variable care across the country.

History & regulatory context

Ketamine (CI-581) was synthesized at Parke-Davis in the early 1960s as a shorter-acting derivative of phencyclidine (PCP) (Domino 2010). It received FDA approval as an anesthetic in 1970 and remains approved only for induction and maintenance of general anesthesia (IV or IM). It is a Schedule III controlled substance.

The antidepressant signal came from Berman et al. (2000), a seven-patient placebo-controlled crossover study, and was replicated by Zarate et al. (2006) at the NIMH. Murrough et al. (2013) provided the first adequately sized trial against an active placebo (midazolam). Over the following decade the field added repeated-dose trials, a phase 3 program for the S-enantiomer (esketamine), two head-to-head comparisons with ECT, and a growing set of independent re-analyses.

Regulatory timeline (FDA)

• March 5, 2019: Esketamine nasal spray (Spravato) approved for treatment-resistant depression in adults, in conjunction with an oral antidepressant, under a Risk Evaluation and Mitigation Strategy (REMS) that restricts administration to certified healthcare settings with at least 2 hours of post-dose observation.
• July 31, 2020: Supplemental approval for depressive symptoms in adults with MDD with acute suicidal ideation or behavior, with an oral antidepressant. The label states that effectiveness in preventing suicide or reducing suicidal ideation or behavior has not been demonstrated.
• February 16, 2022 and October 10, 2023: FDA compounding risk alerts on compounded ketamine products (nasal, then oral and other formulations) marketed for psychiatric disorders, often for at-home use. The 2023 alert states: “Ketamine is not FDA approved for the treatment of any psychiatric disorder,” and warns that use without provider monitoring for sedation, dissociation, and vital-sign changes “may put patients at risk for serious adverse events.”
• January 17, 2025: Label expanded so that Spravato may be used for TRD as monotherapy, without an oral antidepressant, based on a 378-patient placebo-controlled trial.

Racemic IV ketamine remains off-label for depression and is widely used. The current landscape includes REMS-certified Spravato programs, IV ketamine clinics of highly variable quality, and telehealth-based oral or sublingual ketamine prescribing that the FDA has specifically cautioned against. Each carries a different evidence, regulatory, and monitoring profile.

Indications & patient selection

FDA-approved indications (esketamine/Spravato, January 2025 label)

• Treatment-resistant depression (TRD) in adults, as monotherapy or in conjunction with an oral antidepressant
• Depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior, in conjunction with an oral antidepressant

Off-label uses of racemic ketamine, by strength of evidence

• Treatment-resistant unipolar depression — the best-supported use: multiple placebo- and midazolam-controlled trials, two randomized comparisons with ECT, and a 174-patient phase 3 trial of subcutaneous ketamine (KADS).
• Acute suicidal ideation — reductions within 24 hours in an individual-participant-data meta-analysis and in a 156-patient placebo-controlled trial (Abbar 2022); a 26-patient trial of repeated infusions in chronic suicidal ideation was negative. No trial has shown a reduction in suicide attempts or deaths.
• Bipolar depression — two small NIMH crossover trials (n = 18 and n = 15) on lithium or valproate were positive at 24 hours to 3 days; the 2021 Cochrane review rated the evidence low to very low certainty. Monitor for manic switch.
• PTSD — mixed: a 30-patient single-site trial of six infusions was positive (67% vs 20% response), but a 158-patient multicenter trial in veterans and service members found no dose-related effect on PTSD symptoms.

Reasonable candidates

• Moderate-to-severe unipolar or bipolar depression with inadequate response to at least two adequate antidepressant trials in the current episode
• Severe depression with significant functional impairment or suicidal ideation where speed of onset matters
• Medically stable, with controlled blood pressure and no aneurysmal vascular disease, arteriovenous malformation, or history of intracerebral hemorrhage
• Capacity for informed consent, including an understanding that benefit is often temporary and that maintenance treatment may be needed
• Able to arrange transportation and post-treatment supervision (no driving until the next day after a restful sleep)

Contraindications

The esketamine label lists only three contraindications (aneurysmal vascular disease or arteriovenous malformation; history of intracerebral hemorrhage; hypersensitivity to esketamine, ketamine or excipients) and treats most other issues as warnings requiring assessment. The lists below are our program's screening criteria and are deliberately more conservative.

Absolute / strong relative contraindications (program criteria)

• Uncontrolled hypertension (our threshold: consistently >160/100; the esketamine label advises weighing delay when pre-dose blood pressure exceeds about 140/90)
• Unstable cardiovascular disease, recent MI, uncontrolled arrhythmia
• Intracranial aneurysm or recent intracranial hemorrhage
• Active psychosis or a primary psychotic disorder (the esketamine label calls for careful assessment and treatment only if benefit outweighs risk)
• Active substance use disorder, particularly ketamine or PCP (boxed warning for abuse and misuse)
• Pregnancy (fetal harm in animal studies, including developmental neurotoxicity; insufficient human data; esketamine is not recommended in pregnancy)
• Severe hepatic impairment
• Hypersensitivity to ketamine, esketamine or excipients

Relative contraindications / increased monitoring

• Controlled but significant cardiovascular disease
• History of severe dissociative or panic responses to substances
• Bipolar I with recent manic/mixed episode
• Severe hepatic/renal dysfunction (affects clearance)
• Increased intraocular or intracranial pressure (the Ketalar label advises caution; human data on ketamine and intracranial pressure are reassuring)
• Benzodiazepine use (may reduce efficacy; consider tapering if possible)

Medication interactions that reduce efficacy

• Benzodiazepines: observational data suggest a blunted and shorter antidepressant response with concomitant benzodiazepines (Andrashko 2020, n = 47); consider tapering or minimizing doses around infusions when feasible. They also add to sedation (esketamine label).
• Lamotrigine: evidence is mixed; in healthy volunteers, lamotrigine pretreatment reduced ketamine's dissociative and psychotomimetic effects but increased its immediate mood-elevating effect (Anand 2000). Not by itself a reason to withhold treatment.
• Naltrexone: Williams et al. 2018 suggests opioid-receptor antagonism interferes with antidepressant efficacy

Routes & formulations

Racemic ketamine is a 50:50 mixture of R-ketamine and S-ketamine enantiomers. Spravato is pure S-ketamine (esketamine). S-ketamine is the more potent enantiomer at the NMDA receptor and as an anesthetic (reported 3–5 fold; Peltoniemi 2016, Ebert 1997); R-ketamine has shown antidepressant-like effects in animal studies. One small randomized trial (n = 63) found a single IV esketamine infusion non-inferior to IV racemic ketamine at 24 hours (Correia-Melo 2020); no randomized trial has compared esketamine nasal spray with IV racemic ketamine.

Protocols & dosing

Standard IV ketamine induction protocol (TRD)

Spravato (esketamine) protocol

Pharmacology

Values from the Ketalar (ketamine injection) and Spravato (esketamine) prescribing information and the cited pharmacokinetic papers: Clements 1982 (IM and oral bioavailability), Yanagihara 2003 (three volunteers) and Chong 2009 (six patients) for oral, sublingual and nasal racemic ketamine. Onset and duration figures are for anesthetic doses.

Mechanism of action

Ketamine's antidepressant mechanism is multifaceted and not fully resolved. Zanos and Gould (2018) reviewed several non-exclusive hypotheses; four are summarized here (they also discuss inhibition of burst firing in the lateral habenula).

The basic pharmacology

Ketamine acts at three receptor types with relevance to antidepressant effects:

• NMDA receptor — antagonist (primary mechanism of interest)
• AMPA receptor — indirect agonist via downstream glutamate release
• Opioid receptor — ketamine activates the opioid system; in a small crossover study (12 completers, stopped early at interim analysis) naltrexone pre-treatment markedly blunted the antidepressant effect but not the dissociation (Williams et al. 2018)

NMDA receptor background

NMDA receptors are ligand-gated, glutamatergic ion channels. They have 7 known subunits (GluN1, GluN2A-D, GluN3A-B). Typical configuration: 2 GluN1 + 2 GluN2 subunits. NMDA activation requires both glutamate binding and post-synaptic depolarization (typically from AMPA activation) to release the magnesium block and allow Ca²⁺ influx.

Subunit selectivity matters: in the presence of physiological magnesium, channel blockers such as ketamine inhibit GluN2C/GluN2D-containing NMDA receptors more effectively than GluN2A/2B-containing receptors (Kotermanski and Johnson 2009), and GluN2C/2D subunits are enriched on cortical inhibitory (GABAergic) interneurons. This is one basis for the disinhibition hypothesis.

Proposed mechanisms (Zanos 2018)

A. Disinhibition hypothesis

Ketamine blocks NMDA receptors on GABAergic interneurons → reduced inhibitory tone on pyramidal neurons → glutamate release surge → AMPA activation → BDNF release → TrkB activation → mTORC1 activation → increased synaptic protein synthesis → synaptogenesis and enhanced plasticity.

The disinhibition mechanism: ketamine antagonizes NMDA receptors preferentially on GABAergic inhibitory interneurons, reducing inhibitory tone on cortical pyramidal neurons. The resulting glutamate surge activates AMPA receptors on excitatory neurons.

Downstream cascade following AMPA activation: BDNF release → TrkB activation → mTORC1 signaling → increased synaptic protein translation → synaptogenesis and synaptic plasticity.

B. Inhibition of extrasynaptic NMDA receptors

Ketamine antagonizes GluN2B-containing NMDA receptors located outside the post-synaptic density. These extrasynaptic receptors normally provide tonic suppression of protein synthesis machinery; blocking them disinhibits mTORC1 directly, driving the same plasticity cascade.

Ketamine's antagonism of extrasynaptic GluN2B NMDA receptors releases tonic inhibition of mTORC1 signaling, providing a second route to increased synaptic protein synthesis.

C. Blockade of spontaneous NMDA activation

Spontaneous (resting-state) NMDA receptor activity normally activates eEF2 kinase, which phosphorylates eEF2 and suppresses BDNF translation. Ketamine's NMDA blockade inhibits this tonic pathway, allowing BDNF translation to proceed → TrkB activation → plasticity cascade.

D. Hydroxynorketamine (HNK) metabolite pathway

Ketamine is metabolized to hydroxynorketamine (HNK) metabolites. In mice (Zanos 2016), (2R,6R)-HNK produced antidepressant-like effects that were independent of NMDA receptor inhibition and required early, sustained AMPA receptor activation; whether this reflects direct AMPA potentiation is unresolved, and the human relevance is untested. Lepack et al. 2014 showed in rodents that a BDNF-neutralizing antibody infused into the medial prefrontal cortex blocks ketamine's behavioral effects, supporting a required role for BDNF release.

Fourth proposed mechanism: the (2R,6R)-HNK metabolite acts through AMPA receptor activation independent of NMDA receptor antagonism in animal studies. This is one proposed explanation for the antidepressant-like effects of R-ketamine in preclinical models despite its lower NMDA receptor affinity than S-ketamine.

Evidence base

What the controlled trials actually show, including the ones that missed. Figures are taken from the published abstracts, open-access full texts, or the FDA label; each is linked in the references.

Single-dose randomized trials (reference arm: racemic ketamine 0.5 mg/kg IV over 40 minutes)

Repeated-dose racemic ketamine

Esketamine nasal spray: phase 3 and phase 4 trials

All industry-sponsored. Patients in the TRD trials had failed at least two antidepressants in the current episode; in TRANSFORM-1, -2 and -3 both arms also started a new oral antidepressant.

Meta-analyses and independent re-analyses

Real-world effectiveness

Suicidal ideation

• Wilkinson 2018 (individual-participant-data meta-analysis, 10 trials, 167 patients with baseline suicidal ideation): ketamine reduced clinician- and self-rated suicidal ideation within 1 day and for up to 1 week (d = 0.48–0.85), partly independent of mood change. The authors said more long-term safety and suicide-risk data were needed before clinical implementation.
• Grunebaum 2018 (n = 80, midazolam-controlled): 24-hour responders on the Scale for Suicidal Ideation 55% vs 30% (NNT 4).
• Abbar 2022 (n = 156 hospitalized suicidal patients, two infusions 24 h apart vs saline): full remission of suicidal ideas at day 3 in 63.0% vs 31.6%. The effect was driven by bipolar patients (OR 14.1); in the depressive-disorder stratum it was not significant (OR 1.3). At 6 weeks the difference was no longer significant (69.5% vs 56.3%).
• Ionescu 2019 (n = 26, chronic suicidal ideation, six infusions vs saline): negative.
• ASPIRE I and II (esketamine): faster MADRS improvement, no significant difference on the clinician-rated suicidality scale; both arms improved rapidly with hospitalization and standard care.

Bipolar depression and PTSD

• Bipolar depression: Diazgranados 2010 (n = 18) and Zarate 2012 (n = 15), single infusions added to lithium or valproate: 71% and 79% responded at some point during the trial vs 6% and 0% on placebo, with benefit lasting about 3 days. The 2021 Cochrane bipolar review found low-certainty evidence for response at 24 hours (two ketamine trials, 33 participants; OR 11.6, 95% CI 1.3–108) and no evidence of a remission benefit.
• PTSD: Feder 2014 (n = 41, single infusion vs midazolam) and Feder 2021 (n = 30, six infusions; response 67% vs 20%, median loss of response 27.5 days) were positive single-site trials. Abdallah 2022 (n = 158 veterans and service members, eight infusions of 0.2 or 0.5 mg/kg vs placebo) found no significant dose-related effect on PTSD symptoms, although the 0.5 mg/kg dose reduced depression scores.

Ketamine vs. ECT

Two randomized head-to-head trials reached opposite headline conclusions. Ekstrand and colleagues (2024) attribute much of the difference to who was enrolled and how ECT was delivered.

Durability & maintenance strategies

The acute response to ketamine is real but short-lived, and the durability data are the weakest part of the evidence base. After a single infusion, 35% of NIMH patients still met response criteria at 1 week (Zarate 2006) and 12.9% of 93 patients at 2 weeks (Pennybaker 2017). After a six-infusion open-label course, 8 of 9 responders relapsed a mean of 19 days later (aan het Rot 2010); a 2021 systematic review cites a typical median time to relapse of 2–4 weeks (McMullen 2021). Even after remission with ketamine or ECT in KetECT, about two-thirds relapsed within 12 months.

Strategies, by evidence

• Continued dosing (best supported): Phillips 2019 found that responders held their gains through four once-weekly maintenance infusions. SUSTAIN-1 showed that continuing esketamine after 16 weeks roughly halved relapse in stable remitters (26.7% vs 45.3%) and cut it by 70% in stable responders. McMullen 2021 (22 studies) concluded that repeat-dose IV ketamine was the only strategy shown to prolong the acute effect. A 2022 Lancet Psychiatry review of maintenance ketamine (three RCTs, eight open-label trials, 30 case series and reports) found it appears effective across routes, with tachyphylaxis, cognitive impairment, addiction and serious urinary problems seemingly uncommon, while calling for controlled long-term studies.
• Psychotherapy after ketamine (promising, unproven): Wilkinson 2021 randomized 28 responders to CBT or treatment as usual for 14 weeks. The primary outcome (MADRS group-by-time interaction) was not significant (d = 0.65, 95% CI −0.55 to 1.82); the Quick Inventory of Depressive Symptomatology favored CBT (d = 0.71). The authors described it as a proof-of-concept study needing a well-powered trial. Price 2022 (n = 154) found that a brief automated computer-based self-association training after a single infusion kept depression scores stably low over 30 days, whereas ketamine plus a sham program drifted back toward placebo levels.
• Behavioral activation: a 2023 case series only (Phillips, Blier and Talbot). Mechanistically plausible; not evidence of efficacy.
• Pharmacological augmentation: two riluzole trials failed to prevent relapse after ketamine (cited in Murrough 2013). No other pharmacological strategy has been shown to extend response (McMullen 2021).

Rapamycin: an interesting wrinkle

Abdallah 2020 pretreated 20 depressed patients with oral rapamycin 6 mg or placebo 2 hours before a ketamine infusion in a double-blind crossover, expecting mTORC1 inhibition to block the antidepressant effect. It did not change the 24-hour response, but two weeks later response (41% vs 13%) and remission (29% vs 7%) were higher after rapamycin plus ketamine. A single small crossover study; hypothesis-generating, not a clinical strategy.

Safety & monitoring

Acute monitoring during infusion

• Blood pressure before dosing and at intervals during and after (transient rises are expected; in the esketamine trials 3–19% of treated patients had a rise of ≥40 mmHg systolic or ≥25 mmHg diastolic within 1.5 hours at least once during the first 4 weeks, vs 1–4% on placebo; peaks at about 40 minutes and lasts about 4 hours). Have an antihypertensive plan.
• Heart rate, SpO2 continuous
• CADSS (Clinician-Administered Dissociative States Scale) assessment during/after
• Emergency airway equipment available
• Dedicated staff for observation during and after infusion

Common acute side effects

• Dissociation/altered perception (expected; target effect to some degree)
• Hypertension, tachycardia
• Anxiety, sometimes with panic-like quality
• Nausea, occasionally vomiting
• Blurred vision, dizziness
• Headache (next-day, common)

What the esketamine label documents (January 2025)

• Boxed warning: sedation; dissociation; respiratory depression; abuse and misuse; suicidal thoughts and behaviors in young adults. Observation for at least 2 hours after each dose with pulse oximetry; REMS-restricted distribution.
• Sedation occurred in 48–61% of treated patients on the observer scale; 0.3–0.4% had loss of consciousness.
• Contraindications: aneurysmal vascular disease or arteriovenous malformation; history of intracerebral hemorrhage; hypersensitivity to esketamine or ketamine.
• Most common adverse reactions (≥5% and at least twice placebo). Adjunctive TRD trials: dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, feeling drunk. Monotherapy trial: dissociation, nausea, dizziness, headache, anxiety, vomiting, feeling drunk, increased blood pressure, sedation (nausea 24.8%, dissociation 24.3%, dizziness 21.7%, headache 19.0%); most events occurred on dosing days and resolved the same day.
• Driving: no driving or hazardous activity until the next day after a restful sleep.

Longer-term considerations

• Abuse potential: ketamine is a Schedule III controlled substance with a boxed warning for abuse and misuse in the esketamine label. Risk is managed by supervised administration; the FDA's 2023 alert specifically addressed unsupervised at-home use of compounded products.
• Bladder toxicity: ulcerative or interstitial cystitis has been reported with long-term off-label use, misuse or abuse of ketamine. In the esketamine trials, lower urinary tract symptoms (frequency, dysuria, urgency, nocturia, cystitis) were more common than with placebo, but no case of esketamine-related interstitial cystitis was observed in studies lasting up to a year. Ask about urinary symptoms at every maintenance visit.
• Cognitive effects: repeated misuse or abuse of ketamine has been associated with long-term cognitive and memory impairment. At treatment doses the data are reassuring but limited: cognition remained stable over 1- and 3-year open-label esketamine studies, six IV infusions did not impair a neurocognitive battery in a 15-patient series (Shiroma 2014), and in ELEKT-D ketamine-treated patients outperformed ECT-treated patients on cognitive tasks at 3 weeks with no differences among responders at 6 months.
• Reporting bias: a 2018 Lancet Psychiatry systematic review of 60 studies found that side effects after acute dosing were well documented but that long-term and repeated-dose safety were rarely assessed, and recommended large trials with long follow-up (Short 2018). A 2022 review reached similar conclusions: common effects are transient and self-limited; severe bladder pathology has not been reported at prescribed doses (Nikayin 2022).
• Liver: a 2025 analysis of the FDA Adverse Event Reporting System (Kwan 2025) found mixed disproportionality signals: relative to acetaminophen, fewer reports of hepatitis and liver injury for ketamine but more reports of abnormal liver function and hepatic cytolysis, and more reports of hepatic failure for esketamine; the authors recommended periodic liver-function tests with chronic exposure. Causality is not established. The Ketalar (ketamine injection) label added a Drug-Induced Liver Injury warning in June 2025 (section 5.6, updated March 2026): ketamine is associated with hepatobiliary dysfunction, most often cholestatic, with recurrent use including “medically supervised unapproved indications”; biliary dilatation, stricture and obstruction and sclerosing cholangitis (potentially reversible on discontinuation) have been reported; the label advises baseline liver tests including alkaline phosphatase and GGT before recurrent dosing and periodic monitoring during treatment.
• Tolerance: can develop with frequent use and may drive dose escalation; maintenance reviews describe tachyphylaxis as uncommon at usual intervals, but it is one reason to use the least frequent effective schedule.

Quality concerns in the ketamine clinic landscape

Referring a patient

Our program evaluates patients for ketamine treatment alongside other neuromodulation options (TMS, ECT) to help identify the best fit, and uses measurement-based care to decide whether treatment should continue.

What to include in a referral

• Primary diagnosis and target symptoms
• Medication history with doses, durations, responses (simple summary is fine)
• Prior neuromodulation (TMS, ECT) with responses
• Cardiovascular history, current BP control, any cardiac medications
• Substance use history
• Benzodiazepine use (doses, indication; we may want to taper prior to treatment)
• Suicidality assessment
• Urgency level

Who to flag as urgent

• Active suicidality in severe depression unresponsive to medications
• Severe depression with functional collapse requiring rapid response
• Post-ECT patients needing rapid bridge treatment
• Currently inpatient requiring expedited outpatient continuation

References

Primary sources for the figures on this page, organized thematically. Every entry was verified against PubMed, PubMed Central, ClinicalTrials.gov, or the FDA in September 2026.

Single-infusion trials

1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47(4):351–354. PMID: 10686270
2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63(8):856–864. PMID: 16894061
3. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013;170(10):1134–1142. PMID: 23982301
4. Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014;76(12):970–976. PMID: 24821196
5. Fava M, Freeman MP, Flynn M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 2020;25(7):1592–1603. PMID: 30283029
6. Correia-Melo FS, Leal GC, Vieira F, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: a randomized, double-blind, non-inferiority study. J Affect Disord 2020;264:527–534. PMID: 31786030

Repeated-dose ketamine

1. aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 2010;67(2):139–145. PMID: 19897179
2. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry 2016;173(8):816–826. PMID: 27056608
3. Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry 2019;176(5):401–409. PMID: 30922101
4. Shiroma PR, Thuras P, Wels J, et al. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Transl Psychiatry 2020;10(1):206. PMID: 32591498
5. Ionescu DF, Bentley KH, Eikermann M, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: a randomized, double blind, placebo controlled trial. J Affect Disord 2019;243:516–524. PMID: 30286416
6. Loo C, Glozier N, Barton D, et al. Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial. Br J Psychiatry 2023;223(6):533–541. PMID: 38108319
7. Pennybaker SJ, Niciu MJ, Luckenbaugh DA, Zarate CA Jr. Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion. J Affect Disord 2017;208:560–566. PMID: 27839782

Esketamine nasal spray trials

1. Popova V, Daly EJ, Trivedi M, et al. 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 (TRANSFORM-2). Am J Psychiatry 2019;176(6):428–438. PMID: 31109201
2. Fedgchin M, Trivedi M, Daly EJ, et al. 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). Int J Neuropsychopharmacol 2019;22(10):616–630. PMID: 31290965
3. Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression (TRANSFORM-3). Am J Geriatr Psychiatry 2020;28(2):121–141. PMID: 31734084
4. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial (SUSTAIN-1). JAMA Psychiatry 2019;76(9):893–903. PMID: 31166571
5. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry 2020;81(3):19m13191. PMID: 32412700
6. Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol 2021;24(1):22–31. PMID: 32861217
7. Reif A, Bitter I, Buyze J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression (ESCAPE-TRD). N Engl J Med 2023;389(14):1298–1309. PMID: 37792613
8. Janik A, Qiu X, Lane R, et al. Esketamine monotherapy in adults with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 2025;82(9):877–887. PMID: 40601310
9. Zaki N, Chen LN, Lane R, et al. Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: interim results of the SUSTAIN-3 study. Neuropsychopharmacology 2023;48(8):1225–1233. PMID: 37173512

Meta-analyses, re-analyses and real-world data

1. McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med 2015;45(4):693–704. PMID: 25010396
2. Kryst J, Kawalec P, Mitoraj AM, et al. Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials. Pharmacol Rep 2020;72(3):543–562. PMID: 32301056
3. Dean RL, Hurducas C, Hawton K, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev 2021;9(9):CD011612. PMID: 34510411
4. Dean RL, Marquardt T, Hurducas C, et al. Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder. Cochrane Database Syst Rev 2021;10(10):CD011611. PMID: 34623633
5. Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord 2021;278:542–555. PMID: 33022440
6. Nikolin S, Rodgers A, Schwaab A, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine 2023;62:102127. PMID: 37593223
7. Elmosalamy A, Tarikogullari I, Patarroyo-Rodriguez L, et al. Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Ther Adv Psychopharmacol 2025;15:20451253251394127. PMID: 41244961
8. Naudet F, Pellen C, Fodor LA, et al. Efficacy and safety of esketamine for “treatment resistant depression”: registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials. BMC Med 2025;23(1):677. PMID: 41310599
9. Naudet F, Cristea IA, Gillibert A. Questionable data and design in esketamine study. JAMA Psychiatry 2025;82(10):1053–1054. PMID: 40833773
10. Turner EH. Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval. Lancet Psychiatry 2019;6(12):977–979. PMID: 31680014
11. Alnefeesi Y, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res 2022;151:693–709. PMID: 35688035
12. Sakurai H, Jain F, Foster S, et al. Long-term outcome in outpatients with depression treated with acute and maintenance intravenous ketamine: a retrospective chart review. J Affect Disord 2020;276:660–666. PMID: 32871698
13. Martinotti G, Vita A, Fagiolini A, et al. Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and effectiveness (REAL-ESK study). J Affect Disord 2022;319:646–654. PMID: 36167246
14. Samalin L, Mekaoui L, Rothärmel M, et al. Use of esketamine nasal spray in patients with treatment-resistant depression in routine practice: a real-world French study. Depress Anxiety 2024;2024:7262794. PMID: 40226655

Suicidal ideation, bipolar depression and PTSD

1. Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry 2009;66(5):522–526. PMID: 19545857
2. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry 2018;175(2):150–158. PMID: 28969441
3. Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry 2018;175(4):327–335. PMID: 29202655
4. Abbar M, Demattei C, El-Hage W, et al. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ 2022;376:e067194. PMID: 35110300
5. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010;67(8):793–802. PMID: 20679587
6. Zarate CA Jr, Brutsche NE, Ibrahim L, et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 2012;71(11):939–946. PMID: 22297150
7. Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 2014;71(6):681–688. PMID: 24740528
8. Feder A, Costi S, Rutter SB, et al. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry 2021;178(2):193–202. PMID: 33397139
9. Abdallah CG, Roache JD, Gueorguieva R, et al. Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology 2022;47(8):1574–1581. PMID: 35046508

Comparisons with ECT

1. Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression (ELEKT-D). N Engl J Med 2023;388(25):2315–2325. PMID: 37224232 ClinicalTrials.gov NCT03113968.
2. Jha MK, Wilkinson ST, Krishnan K, et al. Ketamine vs electroconvulsive therapy for treatment-resistant depression: a secondary analysis of a randomized clinical trial. JAMA Netw Open 2024;7(6):e2417786. PMID: 38916891
3. Kumpf KT, Wilkinson ST, Hu B, et al. Comparing the cognitive effects of repeated intravenous ketamine and electroconvulsive therapy in patients with treatment-resistant depression: a secondary analysis of the ELEKT-D trial. J Clin Psychiatry 2025;86(4):25m15781. PMID: 40900112
4. Ekstrand J, Fattah C, Persson M, et al. Racemic ketamine as an alternative to electroconvulsive therapy for unipolar depression: a randomized, open-label, non-inferiority trial (KetECT). Int J Neuropsychopharmacol 2022;25(5):339–349. PMID: 35020871
5. Ekstrand J, Takamiya A, Nordenskjold A, et al. Ketamine or ECT? What have we learned from the KetECT and ELEKT-D trials? Int J Neuropsychopharmacol 2024;27(1):pyad065. PMID: 38114073
6. Rhee TG, Shim SR, Forester BP, et al. Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: a systematic review and meta-analysis. JAMA Psychiatry 2022;79(12):1162–1172. PMID: 36260324

Durability & maintenance

1. Wilkinson ST, Rhee TG, Joormann J, et al. Cognitive behavioral therapy to sustain the antidepressant effects of ketamine in treatment-resistant depression: a randomized clinical trial. Psychother Psychosom 2021;90(5):318–327. PMID: 34186531
2. Price RB, Spotts C, Panny B, et al. A novel, brief, fully automated intervention to extend the antidepressant effect of a single ketamine infusion: a randomized clinical trial. Am J Psychiatry 2022;179(12):959–968. PMID: 36128684
3. McMullen EP, Lee Y, Lipsitz O, et al. Strategies to prolong ketamine's efficacy in adults with treatment-resistant depression. Adv Ther 2021;38(6):2795–2820. PMID: 33929660
4. Smith-Apeldoorn SY, Veraart JK, Spijker J, Kamphuis J, Schoevers RA. Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Lancet Psychiatry 2022;9(11):907–921. PMID: 36244360
5. Phillips JL, Blier P, Talbot J. Sustaining the benefits of intravenous ketamine with behavioural activation therapy for depression: a case series. J Affect Disord Rep 2023;14:100613. doi:10.1016/j.jadr.2023.100613 (not MEDLINE-indexed)
6. Abdallah CG, Averill LA, Gueorguieva R, et al. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology 2020;45(6):990–997. PMID: 32092760

Mechanism of action

1. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 2018;23(4):801–811. PMID: 29532791
2. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev 2018;70(3):621–660. PMID: 29945898
3. Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov 2017;16(7):472–486. PMID: 28303025
4. Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016;533(7604):481–486. PMID: 27144355
5. Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 2014;18(1):pyu033. PMID: 25539510
6. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry 2018;175(12):1205–1215. PMID: 30153752
7. Chen MH, Li CT, Lin WC, et al. Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: a randomized control study. J Affect Disord 2018;225:709–714. PMID: 28922734
8. Hansen KB, Yi F, Perszyk RE, et al. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol 2018;150(8):1081–1105. PMID: 30037851

History, interactions and receptor pharmacology

1. Domino EF. Taming the ketamine tiger. 1965. Anesthesiology 2010;113(3):678–684. PMID: 20693870
2. Kotermanski SE, Johnson JW. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J Neurosci 2009;29(9):2774–2779. PMID: 19261873
3. Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 1997;333(1):99–104. PMID: 9311667
4. Andrashko V, Novak T, Brunovsky M, et al. The antidepressant effect of ketamine is dampened by concomitant benzodiazepine medication. Front Psychiatry 2020;11:844. PMID: 33005153
5. Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry 2000;57(3):270–276. PMID: 10711913

Pharmacokinetics

1. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci 1982;71(5):539–542. PMID: 7097501
2. Yanagihara Y, Ohtani M, Kariya S, et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos 2003;24(1):37–43. PMID: 12516077
3. Chong C, Schug SA, Page-Sharp M, Jenkins B, Ilett KF. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: preliminary findings from a three-way randomized, crossover study. Clin Drug Investig 2009;29(5):317–324. PMID: 19366273
4. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet 2016;55(9):1059–1077. PMID: 27028535
5. Chilukuri H, Reddy NP, Pathapati RM, et al. Acute antidepressant effects of intramuscular versus intravenous ketamine. Indian J Psychol Med 2014;36(1):71–76. PMID: 24701015

Oral ketamine

1. Domany Y, Bleich-Cohen M, Tarrasch R, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry 2019;214(1):20–26. PMID: 30246667
2. Glue P, Loo C, Fam J, et al. Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Nat Med 2024;30(7):2004–2009. PMID: 38914860
3. Silberbauer LR, Eggerstorfer B, Michenthaler P, et al. Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis. J Affect Disord 2026;394(Pt A):120466. PMID: 41101490
4. Meshkat S, Haikazian S, Di Vincenzo JD, et al. Oral ketamine for depression: an updated systematic review. World J Biol Psychiatry 2023;24(7):545–557. PMID: 36651238

Safety, guidance and regulatory documents

1. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry 2018;5(1):65–78. PMID: 28757132
2. Kwan ATH, Lakhani M, Teopiz KM, et al. Hepatic adverse events associated with ketamine and esketamine: a population-based disproportionality analysis. J Affect Disord 2025;374:390–396. PMID: 39818335
3. Nikayin S, Murphy E, Krystal JH, Wilkinson ST. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin Drug Saf 2022;21(6):777–787. PMID: 35416105
4. Shiroma PR, Albott CS, Johns B, et al. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. Int J Neuropsychopharmacol 2014;17(11):1805–1813. PMID: 24963561
5. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 2017;74(4):399–405. PMID: 28249076
6. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry 2021;178(5):383–399. PMID: 33726522
7. KETALAR (ketamine hydrochloride) injection, CIII. Full prescribing information, Par Health, revised 03/2026. DailyMed
8. SPRAVATO (esketamine) nasal spray, CIII. Full prescribing information, revised 01/2025. Janssen Pharmaceuticals. FDA label (PDF). Approval history: Drugs@FDA NDA 211243 (original approval 03/05/2019; suicidality indication 07/31/2020; monotherapy indication 01/17/2025).
9. U.S. Food and Drug Administration. FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. Compounding risk alert, October 10, 2023. Archived copy (Internet Archive); the FDA's Compounding Risk Alerts index lists the alert and links to this snapshot after the original page was retired in 2026.