Ketamine: A Clinical Reference
A clinician-facing reference covering ketamine for depression — routes, dosing, protocols, mechanism, evidence, and how ketamine fits alongside ECT, TMS, and other treatments. Written for psychiatrists, primary care clinicians, and therapists seeking a working knowledge of ketamine practice.
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 was first synthesized in 1962 by Calvin Stevens at Parke-Davis as part of a search for a better anesthetic than phencyclidine (PCP). Structurally, ketamine and PCP are close cousins — ketamine adds a ketone group and an amine group (hence ket + amine). FDA approval for anesthesia followed in 1970.
The antidepressant potential wasn't seriously explored until Berman et al.'s 2000 proof-of-concept study, which demonstrated robust antidepressant effects of sub-anesthetic IV ketamine. Over the next two decades, accumulating evidence culminated in FDA approval of intranasal esketamine (Spravato) in 2019 for treatment-resistant depression and 2020 for depression with suicidal ideation.
Racemic IV ketamine remains off-label for depression but is widely used. The landscape now includes a mix of FDA-approved Spravato programs, traditional IV ketamine clinics, and emerging home-based oral ketamine programs — each with different evidence, regulatory, and quality profiles.
Indications & patient selection
FDA-approved indications (esketamine/Spravato)
- Treatment-resistant depression (adults) — in conjunction with an oral antidepressant
- Major depressive disorder with acute suicidal ideation or behavior (adults)
Evidence-based off-label uses (racemic ketamine)
- Treatment-resistant major depression
- Bipolar depression (careful selection, monitor for switch)
- Acute suicidality
- PTSD (emerging evidence; less robust than for depression)
- Adjunct for severe anxiety in depressive disorders
Ideal candidates
- Moderate-to-severe unipolar or bipolar depression with inadequate response to 2+ antidepressant trials
- Acute depression with significant functional impairment or suicidality
- Medically stable (good cardiovascular health, controlled blood pressure)
- Capacity for informed consent and willingness to engage with the dissociative experience
- Able to arrange transportation and post-treatment supervision
Contraindications
Absolute / strong relative contraindications
- Uncontrolled hypertension (consistently >160/100)
- Unstable cardiovascular disease, recent MI, uncontrolled arrhythmia
- Intracranial aneurysm or recent intracranial hemorrhage
- Active psychosis (current or primary psychotic disorder)
- Active substance use disorder, particularly ketamine or PCP
- Pregnancy (teratogenicity in animal models; limited human data)
- Severe hepatic impairment
- Hypersensitivity to ketamine
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)
- Thyrotoxicosis
- Increased intraocular or intracranial pressure
- Benzodiazepine use (reduces efficacy; consider tapering if possible)
Medication interactions that reduce efficacy
- Benzodiazepines: blunt antidepressant response; data suggest taper or minimize doses around infusions when feasible
- Lamotrigine: may attenuate ketamine's effects on glutamate release
- 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). R-ketamine has higher affinity for NMDA receptors but S-ketamine appears more potent acutely; head-to-head human trials have not directly compared them.
IV ketamine (racemic)
The most studied route for depression. Generic; readily available through compounding pharmacies. Typical dose: 0.5–1.0 mg/kg infused over 40–60 minutes. 100% bioavailable by definition. Clinic-based administration under physician supervision (psychiatrist, anesthesiologist, or EM physician).
Pros
- 100% bioavailability
- Weight-based precise dosing
- Can be discontinued immediately if adverse effects
- Racemic mixture (may matter; unclear)
- Strongest evidence base
Cons
- Rarely covered by insurance
- Requires IV placement and monitoring infrastructure
- ~$400–800 per infusion out-of-pocket
- Clinic-based only
Spravato (intranasal esketamine)
Pure S-enantiomer in a nasal spray device, available in 56 mg and 84 mg dose cartridges. 35–50% bioavailability via nasal mucosa. Self-administered under clinic supervision with 2-hour post-dose observation. Only ketamine formulation with FDA approval for depression.
Pros
- FDA-approved (MDD-TRD; MDD with suicidality)
- Usually covered by insurance
- No IV placement required
- Standardized delivery
- REMS monitoring program
Cons
- Fixed dosing (56 or 84 mg, no weight-based adjustment)
- Variable absorption via nasal mucosa
- Cannot be immediately terminated mid-dose
- 2-hour clinic observation required
- No direct head-to-head RCT vs IV
Oral (PO) ketamine
Compounded lozenges or rapid-dissolve tablets. 20–30% bioavailability with extensive first-pass metabolism producing norketamine (which is ~33% as potent as parent compound, so oral dosing produces a different metabolite profile than IV). Emerging use in home-based telemedicine programs.
Pros
- Home-based administration
- Low cost
- No procedure required
Cons
- Variable absorption; unreliable dosing
- Less robust evidence than IV or Spravato
- Higher abuse potential without supervision
- Quality/safety varies widely across telehealth programs
Intramuscular (IM) ketamine
93% bioavailability, typical dose 0.5–1.0 mg/kg IM. Limited clinical literature (Chilukuri et al. 2014 showed feasibility) but used in some settings as an alternative to IV. Faster onset than oral, less precise dose control than IV.
Protocols & dosing
Standard IV ketamine induction protocol (TRD)
Induction phase
- Dose: 0.5 mg/kg IV over 40 minutes (may increase to 0.75–1.0 mg/kg for inadequate response)
- Frequency: 2–3 times per week for 2–3 weeks (6 total infusions typical)
- Monitoring: BP, HR, SpO2, CADSS (Clinician-Administered Dissociative States Scale), PACU-like recovery until ambulatory
- Duration: Assess response weekly; 6 infusions is a reasonable trial
Maintenance phase (post-induction)
- Taper schedule: Typically weekly → every 2 weeks → every 3–4 weeks as tolerated
- Goal: Minimum effective frequency that maintains remission
- Typical maintenance interval: 2–6 weeks depending on individual response
Spravato (esketamine) protocol
Treatment-resistant depression
- Starting dose: 56 mg (day 1); may increase to 84 mg based on response/tolerability
- Weeks 1–4 (induction): Twice weekly
- Weeks 5–8 (transition): Once weekly
- Week 9+ (maintenance): Once weekly or every 2 weeks at effective dose
- Assessment: Re-evaluate therapeutic benefit at 4 weeks to determine continuation
MDD with suicidality
- Initial dose: 84 mg (reducible to 56 mg for tolerability)
- Weeks 1–4: Twice weekly
- Duration beyond 4 weeks: Not evaluated in pivotal trials; continued therapy requires clinical judgment
Pharmacology
Quick-reference values from UpToDate and primary literature. Values may vary slightly by source.
Ketamine PK/PD quick reference
Mechanism of action
Ketamine's antidepressant mechanism is multifaceted and not fully resolved. Zanos and Gould (2018) proposed four complementary mechanisms, each with supporting evidence.
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 — agonist; antidepressant effect is attenuated by naltrexone pre-treatment (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.
Ketamine's selectivity matters: ketamine shows higher affinity for GluN2D-containing NMDA receptors, which are preferentially expressed on forebrain inhibitory (GABAergic) interneurons. This selectivity is key to 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 (2R,6R)-HNK and (2S,6S)-HNK. In animal models (Zanos 2016), these metabolites produce antidepressant effects via direct AMPA receptor potentiation — independent of NMDA receptor action. Lepack et al. 2014 demonstrated BDNF is essential; BDNF knockouts and BDNF-neutralizing antibodies block the antidepressant response.
Fourth proposed mechanism: ketamine's HNK metabolites directly potentiate AMPA receptors, producing antidepressant effects independent of NMDA receptor antagonism. This pathway may explain why R-ketamine (which produces more HNK) shows durable antidepressant effects in preclinical models despite lower NMDA affinity than S-ketamine.
The convergent picture
All four proposed mechanisms converge on increased synaptic protein synthesis → synaptogenesis → enhanced plasticity. This is consistent with imaging findings: Chen et al. 2018 demonstrated increased activation in the supplementary motor area and dorsal anterior cingulate cortex following 0.5 mg/kg IV ketamine in TRD patients. Multiple mechanisms likely contribute, and their relative importance probably varies across patients.
A clinically important wrinkle: Abdallah et al. 2020 found that pre-treatment with the mTORC1 inhibitor rapamycin actually prolonged ketamine's antidepressant effects (29% remission at 2 weeks vs 7% placebo), complicating the simple "mTOR is the final common pathway" narrative. The mechanism picture remains an active area of research.
Evidence base
Proof of concept: Single-dose studies
| Study | N | Design | Key finding |
|---|---|---|---|
| Berman 2000 | 7 | RCT single-dose IV ketamine (0.5 mg/kg) vs. saline | 14-point HAMD reduction in ketamine vs. 0 in control |
| Zarate 2006 | 17 | RCT crossover; single-dose IV ketamine vs. placebo | 71% response, 29% remission at 24h; 35% sustained at 1 week |
| Murrough 2013 | 73 | RCT IV ketamine vs. active control (midazolam) | 64% response at 24h vs. 28% midazolam (MADRS); median relapse at 18 days |
| Lapidus 2014 | 20 | RCT crossover; intranasal ketamine 50 mg vs. saline | 44% response at 24h vs. 6% placebo (MADRS) |
Esketamine pivotal trials
| Study | N | Design | Key finding |
|---|---|---|---|
| Singh 2016 | 30 | RCT esketamine 0.2 / 0.4 mg/kg IV vs. placebo | MADRS reduction: 16.8 / 16.9 (active) vs. 3.8 (placebo) at 24h |
| TRANSFORM / SUSTAIN (pivotal) | >600 | Multiple Phase 3 RCTs for Spravato approval | Significant improvement in TRD vs. active placebo + antidepressant; durability shown in SUSTAIN-1 |
Meta-analyses
Ketamine vs. ECT
The most clinically important comparative question, with a growing literature. The short answer: it depends on the presentation.
| Study | N | Design | Finding |
|---|---|---|---|
| Anand 2023 (NEJM) | 365 | Open-label non-inferiority; IV ketamine vs. ECT in non-psychotic TRD | 55.4% response with ketamine vs. 41.2% with ECT at 3 weeks. Ketamine non-inferior to ECT. |
| Ekstrand 2021 (KetECT) | 186 | Open-label non-inferiority | 63% remission with ECT vs. 46% with ketamine. ECT superior but ketamine still effective. |
| Rhee 2022 (JAMA Psychiatry) | 340 (6 trials) | Meta-analysis | SMD −0.69 favoring ECT for acute symptom severity. ECT superior but patient-centered considerations matter. |
Clinical synthesis
The literature is not contradictory so much as nuanced. ECT retains an edge in severe, psychotic, or catatonic presentations — Anand specifically excluded psychotic depression, and Rhee's superiority finding reflects acute symptom reduction in generally more severe populations. Ketamine is a reasonable alternative in non-psychotic TRD, particularly when patients prioritize avoiding anesthesia, cognitive side effects, or the logistical burden of an ECT course.
In practice: ECT for psychotic depression, catatonia, severe inanition, or acute suicidality with severe depression. Ketamine for non-psychotic TRD where rapid onset matters but ECT is not accepted or not feasible.
Durability & maintenance strategies
Acute antidepressant response to ketamine is reliable but short-lived. Murrough et al. 2013 found a median time to relapse of 18 days after a single infusion in TRD patients. This creates the fundamental clinical challenge: how to sustain the acute response.
Strategies with evidence
- Continued infusions: Phillips 2019 showed that weekly continuation after an initial course maintains response significantly better than abrupt discontinuation. McMullen 2021 review concluded continued infusions are currently the most effective strategy for sustaining improvement.
- CBT augmentation: Wilkinson 2021 randomized CBT-augmented ketamine vs. ketamine alone, finding significantly better maintenance of response at 14 weeks.
- Behavioral activation: Phillips 2023 case series suggested behavioral activation therapy can prolong antidepressant effects; smaller evidence base but mechanistically plausible.
Rapamycin: an interesting wrinkle
Abdallah et al. 2020 pre-treated with rapamycin (mTORC1 inhibitor) before ketamine, expecting to block the antidepressant effect. Instead, rapamycin pre-treatment prolonged the response: 41% response and 29% remission at 2 weeks in the rapamycin+ketamine group vs. 13% and 7% in placebo+ketamine. The finding complicates the simple "mTOR as final common pathway" model and suggests an underappreciated role for autophagy or alternative plasticity mechanisms. Not yet a standard clinical strategy but actively researched.
Safety & monitoring
Acute monitoring during infusion
- Blood pressure every 15 minutes during infusion (ketamine typically elevates BP 10–30 mmHg systolic; manage with labetalol if needed)
- 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)
Longer-term considerations
- Abuse potential: ketamine is a DEA Schedule III controlled substance. Risk is managed by clinic-based administration; home-based oral protocols carry higher risk.
- Bladder toxicity: chronic high-dose ketamine (typically recreational, far exceeding therapeutic doses) can cause ulcerative cystitis. Therapeutic-dose risk is low but monitor for urinary symptoms in long-term maintenance.
- Cognitive effects: some longitudinal concern about chronic use; therapeutic-dose data is reassuring but not extensive.
- Tolerance: can develop with frequent use; may necessitate dose increases or drug holidays.
Quality concerns in the ketamine clinic landscape
Referring a patient
The Prisma Health Neuromodulation Program evaluates patients for ketamine treatment alongside other neuromodulation options (TMS, ECT) to help identify the best fit.
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
Prisma Health Neuromodulation Program
For ketamine referrals, consultations, or clinical questions:
Behavioral Health and Wellness Pavilion
725 Grove Road, Greenville, SC 29605
Adam Hart, MD — Medical Director, Neuromodulation Program
References
Key primary sources for ketamine in depression, organized thematically.
Proof of concept & foundational trials
- Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000;47(4):351–354. PMID: 10686270
- 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
- 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
- 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.
- 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.
- 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.
- Nikayin S, Rhee TG, Cunningham ME, et al. Evaluation of the trajectory of depression severity with ketamine and esketamine treatment. Lancet eClinicalMedicine 2023;62:102130.
Mechanism of action
- Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 2018;23(4):801–811. PMID: 29532791
- Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov 2017;16(7):472–486.
- Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016;533(7604):481–486.
- Lepack AE, Fuchikami M, Dwyer JM, et al. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 2014;18(1):pyu033.
- 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.
- 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. J Affect Disord 2018;225:709–714.
- Hansen KB, Yi F, Perszyk RE, et al. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol 2018;150(8):1081–1105.
- 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.
Durability & maintenance
- 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.
- 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.
- Phillips JL, Blier P, Talbot J. Sustaining the benefits of intravenous ketamine with behavioral activation therapy for depression: A case series. J Affect Disord Rep 2023;14:100613.
- 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.
Comparisons with ECT
- Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. N Engl J Med 2023;388(25):2315–2325. PMID: 37224232
- 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.
- 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.