Esketamine (US brand name Spravato™) is an antagonist of N-methyl D-aspartate (NMDA) receptors, which are one of the types of receptors to which the neurotransmitter glutamate binds. Here is some basic information about this medication. For more details, please see the pages linked to under Related Pages below.
What is esketamine?
Esketamine is an enantiomer of ketamine. Ketamine is a mixture of S-ketamine (or esketamine) and R-ketamine (or arketamine). The molecules of these two are identical in their chemical composition but are mirror images of each other. Ketamine has been available in the US since 1970 and is FDA-approved for use as a general anesthetic.
Pharmacodynamic effects
As noted above, esketamine blocks N-methyl D-aspartate (NMDA) receptors. R-ketamine does the same, but S-ketamine (esketamine) has a higher affinity for the NMDA receptor than R-ketamine.
(Optional to read: Esketamine is a “non-competitive” blocker of NMDA receptors. If you don’t know the significance of that, don’t worry. It is not important for clinicians.)
In recent years, there has been a realization that the pathophysiology of major depressive disorder does not only involve dysregulation of monoamine systems; impairments in neural connectivity are involved as well (Duman et al., 2016). Ketamine increases the release of brain-derived neurotrophic factor (BDNF), increases the formation of new synapses (synaptogenesis), and, so, improves structural connectivity in the brain.
FDA-approved indications
Esketamine nasal spray was approved by the FDA in 2019.
Currently, esketamine nasal spray (Spravato®) is indicated for the treatment of (Prescribing Information; emphasis in red added by us):
– ‘Treatment-resistant depression (TRD) in adults as monotherapy or in conjunction with an oral antidepressant‘
– ‘Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant‘
The wording of the FDA indication is amazing because it:
– Doesn’t distinguish between various types of depressive disorders
– Uses the term “treatment-resistant” depression without defining what that means in this context.
But, don’t worry—on another page on this website, we elaborate on these issues by going to the published research (see Related Pages below).
Boxed warnings
The image below shows the boxed warning from the full Prescribing Information for Spravato.
Potential side effects
Coming soon for Members only…along with a handout that can be given to patients.
REMS program
Not everyone can prescribe esketamine nasal spray. Esketamine nasal spray is only available by prescription from clinicians registered under a Risk Evaluation and Mitigation Strategy (REMS) program. This is because serious adverse events can occur due to sedation and dissociation caused by esketamine and due to the potential for abuse.
Dosage
Esketamine is intended to be given in conjunction with an oral antidepressant. Esketamine is for nasal use only. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine.
Use two devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a five-minute rest between the use of each device.
Induction Phase
Weeks 1 to 4: Administer twice per week
Day 1 starting dose: 56 mg
Subsequent doses: 56 mg or 84 mg
Maintenance Phase
Weeks 5 to 8: Administer once weekly 56 mg or 84 mg
Week 9 and over: Administer every 2 weeks or once weekly 56 mg or 84 mg
Since some patients may experience nausea and vomiting, advise patients to avoid food for at least 2 hours before administration and to avoid drinking liquids at least 30 minutes prior to administration
Dosage forms and strengths (USA)
Nasal Spray: 28 mg of esketamine per device. Each nasal spray device delivers two sprays containing a total of 28 mg of esketamine.
Important! Please refer to the full Prescribing Information (see link below) before prescribing this medication.
Related Pages
What did “treatment-resistant depression” mean in clinical trials of esketamine (Spravato®)?
Esketamine nasal spray (Spravato®): Clinical trials in “treatment-resistant depression”
News: March 5, 2019: Esketamine nasal spray approved by FDA
FDA’s announcement of the approval of Spravato
Spravato Prescribing Information
References
Fountoulakis KN, Saitis A, Schatzberg AF. Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Am J Psychiatry. 2025 Mar 1;182(3):259-275. doi: 10.1176/appi.ajp.20240515. Epub 2025 Jan 29. PMID: 39876682.
Oraee S, Alinejadfard M, Golsorkh H, Sadeghian M, Fanaei M, Centis R, D’Ambrosio L, Sotgiu G, Goudarzi H, Migliori GB, Nasiri MJ. Intranasal esketamine for patients with major depressive disorder: A systematic review and meta-analysis. J Psychiatr Res. 2024 Dec;180:371-379. doi: 10.1016/j.jpsychires.2024.11.010. Epub 2024 Nov 5. PMID: 39522447.
Ouyang Y, Li J. Efficacy of esketamine nasal spray for treatment-resistant depression: A meta-analysis of randomized controlled studies. Medicine (Baltimore). 2025 Feb 28;104(9):e41495. doi: 10.1097/MD.0000000000041495. PMID: 40020133; PMCID: PMC11875627.
Wang Z, Jiang L, Ma W, Li X, Gao Q, Lian S, Yu W. Esketamine Nasal Spray in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials. Clin Pharmacol Ther. 2025 Jan 10. doi: 10.1002/cpt.3555. Epub ahead of print. PMID: 39790081.
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