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{{MedTemplate
{{MedTemplate
| generic            = Esketamine
| brand           = Spravato
| brand             = Spravato
| classes         = NMDA receptor antagonist (uncompetitive), dissociative
| structure          =
| mechanism       = The S-enantiomer of racemic ketamine. Uncompetitive NMDA receptor antagonist (binds open channel). Proposed antidepressant mechanism: NMDA blockade on GABA interneurons disinhibits glutamate burst → AMPA receptor activation → BDNF/VEGF release → mTOR-mediated synaptogenesis and dendritic spine formation within hours. Also binds sigma-1, opioid receptors (controversial μ-opioid contribution to antidepressant effect debated).
| classes           = Dissociative, Anesthetic, Antidepressant
| uses           = Treatment-resistant depression (TRD) in adults, as adjunct to oral antidepressant (FDA-approved March 2019). Depressive symptoms in adults with MDD with acute suicidal ideation or behavior (FDA-approved Aug 2020).
| mechanism         = NMDA receptor antagonist (S-enantiomer of ketamine)
| starting_dose   = Induction (TRD): 56 mg intranasal twice weekly × 4 weeks. Maintenance: 56-84 mg once weekly × 4 weeks, then 56-84 mg every 1-2 weeks. For acute suicidality: 84 mg twice weekly × 4 weeks. Administered under medical supervision in REMS-certified site.
| uses               =  
| preparations   = 28 mg/device (each dose uses 2 devices)
| starting_dose     =  
| fda_max         = 84 mg per session
| preparations       =  
| routes         = Intranasal (under direct medical supervision)
| fda_max           =  
| onset           = Within hours of first administration
| routes             =  
| duration       = Acute effect ~24 hours; cumulative effect builds with repeated dosing
| onset             =  
| halflife       = ~7-12 hours
| duration           =  
| bioavailability = ~48% intranasal
| halflife           =  
| pregnancy       = Avoid; may cause fetal harm
| bioavailability   =  
| legal           = Rx, Schedule III (US). REMS program required.
| pregnancy         =  
| intro           = '''Esketamine''' (brand name Spravato) is the S-enantiomer of ketamine, FDA-approved as an intranasal medicine for treatment-resistant depression (March 2019) and for major depression with acute suicidal ideation or behavior (August 2020). The S-enantiomer has approximately 4-fold higher NMDA receptor affinity than the R-enantiomer; Spravato delivers it via a nasal spray under direct medical supervision in a REMS-certified setting due to risks of dissociation, sedation, and abuse.
| legal             =  
 
| intro             =  
Mechanism: uncompetitive NMDA receptor antagonism on GABA interneurons disinhibits glutamatergic output, leading to AMPA receptor activation, BDNF/VEGF release, and rapid synaptogenesis through mTOR pathway activation. Antidepressant onset within hours is striking compared to monoaminergic antidepressants (4-6 weeks). Patients must be monitored ≥2 hours after dose due to dissociation, sedation, and blood pressure elevation.
| pharmacokinetics  =
| pharmacodynamics= Uncompetitive NMDA receptor antagonist with channel-trapping action. Sigma-1 receptor binding. Possible weak μ-opioid agonism (mechanism contribution debated; naltrexone-blockade studies have given conflicting results).
| pharmacodynamics   =  
| effects        = Dissociation, sedation, dizziness, nausea, vertigo, blood pressure elevation, anxiety, sedation. Long-term risks include abuse/dependence, cognitive effects.
| indications        =  
| interactions     = <pharmaInteractions/>
| dosing            =
| effects           =
| interactions       = <pharmaInteractions/>
| pregnancy_details  =
| monitoring        =
| counseling        =
| anecdotes          =
| seealso            =
| references        =
}}
}}


[[Category:Anesthetics]]
[[Category:Anesthetics]]
[[Category:Arylcyclohexylamines]]
[[Category:Dissociative Anesthetics]]
[[Category:General (IV) Anesthetics]]
[[Category:NMDA receptor antagonists]]
[[Category:Antidepressants]]
[[Category:Dissociatives]]

Latest revision as of 05:02, 23 May 2026

NMDA receptor antagonist (uncompetitive), dissociative
Esketamine
Spravato
Esketamine (brand name Spravato) is the S-enantiomer of ketamine, FDA-approved as an intranasal medicine for treatment-resistant depression (March 2019) and for major depression with acute suicidal ideation or behavior (August 2020). The S-enantiomer has approximately 4-fold higher NMDA receptor affinity than the R-enantiomer; Spravato delivers it via a nasal spray under direct medical supervision in a REMS-certified setting due to risks of dissociation, sedation, and abuse. Mechanism: uncompetitive NMDA receptor antagonism on GABA interneurons disinhibits glutamatergic output, leading to AMPA receptor activation, BDNF/VEGF release, and rapid synaptogenesis through mTOR pathway activation. Antidepressant onset within hours is striking compared to monoaminergic antidepressants (4-6 weeks). Patients must be monitored ≥2 hours after dose due to dissociation, sedation, and blood pressure elevation.

Experience

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Problems

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Titration strategies

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Effects

Dissociation, sedation, dizziness, nausea, vertigo, blood pressure elevation, anxiety, sedation. Long-term risks include abuse/dependence, cognitive effects.

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Pharmacodynamics

Uncompetitive NMDA receptor antagonist with channel-trapping action. Sigma-1 receptor binding. Possible weak μ-opioid agonism (mechanism contribution debated; naltrexone-blockade studies have given conflicting results).

Interactions

Fluoxetine via Category:Antidepressants👤 exp n/a/5 outcome n/a (n=1)⚕️ exp 1.0/5 outcome +33.0 (n=1)

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Summary
Classes
NMDA receptor antagonist (uncompetitive), dissociative
Common uses
Treatment-resistant depression (TRD) in adults, as adjunct to oral antidepressant (FDA-approved March 2019). Depressive symptoms in adults with MDD with acute suicidal ideation or behavior (FDA-approved Aug 2020).
Pharmacy
Starting dose
Induction (TRD): 56 mg intranasal twice weekly × 4 weeks. Maintenance: 56-84 mg once weekly × 4 weeks, then 56-84 mg every 1-2 weeks. For acute suicidality: 84 mg twice weekly × 4 weeks. Administered under medical supervision in REMS-certified site.
Preparations
28 mg/device (each dose uses 2 devices)
US FDA Max
84 mg per session
Pharmacology
Routes
Intranasal (under direct medical supervision)
Onset
Within hours of first administration
Duration
Acute effect ~24 hours; cumulative effect builds with repeated dosing
Half-life
~7-12 hours
Bioavailability
~48% intranasal
Pregnancy
Avoid; may cause fetal harm
Legal status
Rx, Schedule III (US). REMS program required.
Purported mechanism
The S-enantiomer of racemic ketamine. Uncompetitive NMDA receptor antagonist (binds open channel). Proposed antidepressant mechanism: NMDA blockade on GABA interneurons disinhibits glutamate burst → AMPA receptor activation → BDNF/VEGF release → mTOR-mediated synaptogenesis and dendritic spine formation within hours. Also binds sigma-1, opioid receptors (controversial μ-opioid contribution to antidepressant effect debated).
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