Esketamine
Esketamine is the S(+) enantiomer of ketamine, marketed as the intranasal spray Spravato for treatment-resistant depression and depression with acute suicidal ideation. It is a non-competitive NMDA receptor antagonist with roughly twice the anaesthetic potency of racemic ketamine and a rapid, transient antidepressant effect.
01 Overview
Esketamine received FDA approval in 2019 for treatment-resistant major depressive disorder as an adjunct to an oral antidepressant, and later for depressive symptoms with acute suicidality. It is administered under direct medical observation because of dissociation, sedation, and transient blood pressure elevation. Unlike infusion racemic ketamine, esketamine is a defined pharmaceutical with dosing protocols and a REMS programme in the US.
The antidepressant mechanism is thought to involve NMDA blockade on GABAergic interneurons producing a glutamate surge, AMPA receptor activation, and downstream synaptogenesis via BDNF/mTOR signalling. Effects on mood appear within hours but wane over days, so repeated dosing is used. Dissociative and psychotomimetic effects are the main acute burden.
02 Mechanism
Non-competitive open-channel blocker of the NMDA glutamate receptor (S-enantiomer, higher affinity than R). Downstream AMPA activation and synaptogenesis are the proposed antidepressant pathway.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Anaesthetic induction | 0.5–1 mg/kg | IV | Anaesthesia use in some countries; approx half the mg of racemic ketamine. |
| Induction (intranasal) | 56–84 mg | Insufflated | Spravato nasal spray, twice weekly during induction under supervision. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Rapid antidepressant responseReduction in depressive symptoms in treatment-resistant patients within hours to days, sustained with repeat dosing. | MADRS drop within 24h | Clinical | |
| DissociationTransient detachment, perceptual changes and altered time sense, typically resolving within 1-2 hours. | peaks ~40 min | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Dissociation and sedationAcute dissociative state and drowsiness during and after dosing. | Moderate | Most sessions | Clinical | |
| Transient hypertensionBlood pressure rises around 40 minutes post-dose, usually returning to baseline within 1.5 hours. | Moderate | Common | Clinical | |
| Abuse and dependence potentialAs a ketamine enantiomer it carries dependence liability, the reason for controlled scheduling and REMS. | Moderate | Uncommon at therapeutic use | Clinical |