esketamine

General Information

Esketamine (Spravato) is an intranasal antidepressant option used under a REMS program for treatment-resistant depression and for depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior, in conjunction with an oral antidepressant (label).

Administration is supervised in a certified healthcare setting because sedation, dissociation, and respiratory depression can occur; the label requires post-dose monitoring for at least 2 hours (label).

Transient blood pressure increases are common; blood pressure monitoring before and after dosing is part of routine safety checks (label).

Esketamine is a controlled substance and carries an abuse and misuse warning; screening for substance use history and ongoing monitoring are common parts of practice (label/clinical).

The esketamine compare view, evidence feed, and print page help compare side-effect profiles and implementation logistics.

Esketamine is a high-resource intervention due to REMS certification requirements, on-site administration, required post-dose monitoring, and same-day driving restrictions. Access and scheduling capacity often shape use as much as clinical need (label/clinical).

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Esketamine is the S-enantiomer of ketamine and acts as an NMDA receptor antagonist. Its antidepressant effect is commonly framed in terms of downstream glutamatergic and synaptic plasticity changes rather than monoamine reuptake inhibition (label/clinical).

Rapid symptom improvement can occur in some patients, but treatment is still paired with an oral antidepressant and requires structured follow-up and monitoring (label/clinical).

• NMDA receptor antagonism (primary pharmacologic activity).
• Downstream glutamatergic signaling changes (clinical framing).

Metabolism and Pharmacokinetics

• Esketamine is primarily metabolized to noresketamine via CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19; subsequent metabolites undergo glucuronidation (label).
• After intranasal administration, plasma concentrations decline biphasically with a mean terminal half-life range of ~7 to 12 hours (label).
• Esketamine and major metabolites generally do not show strong CYP inhibition potential; modest induction of CYP2B6 and CYP3A4 is described in human hepatocytes (label).

Dosing and Administration

• Administration occurs under direct observation in a certified healthcare setting with post-dose monitoring for at least 2 hours (label/REMS).
• Treatment-resistant depression (adults): Induction is twice weekly for 4 weeks (56 mg or 84 mg), then once weekly for weeks 5–8 (56 mg or 84 mg), then every 2 weeks or once weekly for maintenance based on response (label).
• Depressive symptoms with MDD and acute suicidal ideation or behavior: 84 mg twice weekly for 4 weeks (may reduce to 56 mg twice weekly based on tolerability); benefit beyond 4 weeks is not established for this indication (label).
• The nasal spray device delivers 28 mg; 56 mg uses two devices and 84 mg uses three devices with a rest between devices during administration (label).
• The label advises avoiding food for at least 2 hours and liquids for at least 30 minutes before dosing to reduce nausea/vomiting risk (label).

Monitoring & Labs

• Observe for sedation and dissociation for at least 2 hours after dosing, with assessment of clinical stability before discharge (label/REMS).
• Respiratory status monitoring during the post-dose window (including pulse oximetry) (label).
• Blood pressure checks before dosing and during post-dose observation (label).
• Abuse/misuse risk screening and ongoing monitoring (label/clinical).
• Suicidal thoughts and behaviors monitoring during treatment changes (label).

Adverse Effects

Interactions

• Additive sedation with alcohol, benzodiazepines, opioids, and other CNS depressants; medication reconciliation is common before initiation (label/clinical).
• Psychostimulants and MAOIs can increase blood pressure; closer monitoring is typical when combinations are unavoidable (label).
• Esketamine metabolism involves CYP2B6 and CYP3A4; interaction review is prudent in complex regimens with strong inducers or inhibitors, even though major inhibition effects are not a dominant feature (label/clinical).

Other Useful Information

• A structured treatment setting is part of the therapy: certified site administration, post-dose monitoring, and documentation requirements are integral to risk mitigation (REMS/label).
• Esketamine is typically paired with an oral antidepressant and reassessment of benefit after induction is common, particularly when symptom improvement is modest (label/clinical).
• Same-day transportation planning is required because driving and hazardous activities are restricted after treatment sessions (label).

References

1. SPRAVATO (esketamine) nasal spray prescribing information — DailyMed (2025)
2. 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 — American Journal of Psychiatry (2019)
3. APA Clinical Practice Guideline for the Treatment of Depression — American Psychiatric Association (2023)Guidelinedepressionclinical
4. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology — Pharmacopsychiatry (2018)