Esketamine

Mechanism of action

◎NMDA glutamate receptor (GluN1/GluN2)Esketamine

ⓘ The figure shows esketamine (S-ketamine) in the channel pore of the human GluN1–GluN2A NMDA receptor, with glycine and glutamate.

Esketamine is the S-enantiomer of ketamine and blocks the NMDA glutamate receptor channel. The leading explanation of its fast antidepressant effect is that blocking NMDA receptors on inhibitory interneurons causes a burst of glutamate release, AMPA receptor activation and growth-factor signalling (BDNF) that restores synapses in mood circuits. The same channel block produces dissociation, sedation and a rise in blood pressure.

1. Blocks the NMDA receptor channel
2. Glutamate burst activates AMPA receptors
3. BDNF signalling rebuilds synapses in mood circuits
4. Side effects: dissociation, sedation, raised blood pressure

Indications

• Treatment-resistant depression in adults, alone or with an oral antidepressant Major depressive disorder →
• Depressive symptoms in adults with suicidal thoughts or actions, with an oral antidepressant Suicidal behaviour and suicide risk →

Adverse effects

Common

• Dissociation (feeling detached from body or surroundings), dizziness, vertigo
• Nausea, vomiting
• Sleepiness, feeling drunk
• Unusual or metallic taste; nasal discomfort
• Raised blood pressure for some hours after a dose

Contraindications

• Aneurysmal blood-vessel disease (brain, chest, abdomen, limbs) or arteriovenous malformation
• History of bleeding in the brain

Key interactions

Alcohol, benzodiazepines, opioids and other CNS depressants

More sedation.

Nasal corticosteroids or decongestants

Used at least one hour before the dose.

What is monitored

• Blood pressure before and after each dose
• Sedation, dissociation and breathing during observation
• Mood and suicidal thoughts
• Signs of misuse

Administration and safety

• Self-given nasal spray under direct supervision in a certified health-care setting (restricted programme).
• The patient is observed for at least two hours after each dose until stable.
• No food for about two hours and no drink for about half an hour beforehand, to limit nausea.
• No driving or machinery until the next day after a restful sleep; someone else takes the patient home.

Pregnancy and breastfeeding

Avoided in pregnancy: animal data suggest it may harm the fetus; it is not used while breastfeeding.

Nursing care

• Before: measure blood pressure; delay the dose if it is too high.
• During: watch for dissociation, sedation and breathing; remeasure blood pressure.
• Before discharge: confirm the patient is stable and has a ride.
• Ask about mood, suicidal thoughts and urinary symptoms at each visit.

Pharmacokinetics

Absorption

Nasal spray; each device gives one spray per nostril.

Onset and duration

Antidepressant effect can begin within days, faster than oral antidepressants.

Test yourself

Think of the answer, then tap the question to see it.

Add to my cards (3)

More Pharmacology questions →

Connections

← Back to the class: Atypical antidepressants

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Esketamine Nasal Spray: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2025); Structure of the human GluN1-GluN2A NMDA receptor in complex with S-ketamine, glycine and glutamate (RCSB Protein Data Bank, 2021); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

Spotted a mistake?We are always improving for the community. Tell us what is wrong and our team will review it.Report a mistake

Send

Representative model, for educational purposes only.