Esketamine (Spravato)

What it treats

Esketamine is approved by the U.S. Food and Drug Administration to treat:

• Treatment-resistant depression in adults, used with an oral antidepressant. Treatment-resistant depression means depression that hasn't responded to at least two adequate antidepressant trials.
• Depressive symptoms in adults with major depressive disorder who have acute suicidal thoughts or behavior, used with an oral antidepressant.

Off-label uses in psychiatry are limited because the drug is only available through certified clinics under a REMS program. Off-label means a purpose the label doesn't formally list.

How it works

Esketamine acts on the glutamate system, a different family of chemical messengers from the serotonin system that SSRIs target. It blocks NMDA glutamate receptors, which sets off downstream signaling changes that appear to strengthen synapses and shift mood over hours to days.

Because the pathway is different from SSRIs, esketamine can work when SSRIs haven't. And because the changes happen faster, some people notice mood shifts within the first few doses rather than waiting weeks. Ongoing dosing seems to be needed for most people; the benefit doesn't always hold on its own.

Receptor mechanism (detail)

Esketamine is the S-enantiomer of racemic ketamine, a non-competitive NMDA receptor antagonist with higher affinity at NMDA than R-ketamine. Downstream effects include AMPA receptor activation, BDNF release, and mTOR pathway signaling, which together are thought to drive synaptic changes underlying the rapid antidepressant effect. Blockade of NMDA is also what produces the dissociative side effects.

Potency and typical dosing pattern

Ranges are typical framework only, not a prescription for any individual.

Induction (weeks 1 to 4): 56 mg on day 1, then 56 or 84 mg twice weekly. Continuation (weeks 5 to 8): 56 or 84 mg once weekly. Maintenance (week 9 onward): 56 or 84 mg every one or two weeks, dose and interval based on response. Every dose is self-administered as a nasal spray under supervision in a certified clinic.

Safety monitoring

• REMS program. Every dose is given in a Spravato-certified clinic. Patients cannot take the spray home.
• Two hours of in-clinic monitoring after each dose for sedation and dissociation.
• Blood pressure at baseline and about 40 minutes post-dose. Esketamine can cause a transient rise.
• No driving or operating heavy machinery for the rest of the day.
• Do not co-administer with sedatives (benzodiazepines, opioids), CNS depressants, or alcohol on dosing days.
• Assess suicidality and depressive symptoms at each visit.
• Bladder symptoms and dissociative symptoms worth tracking over time with long-term use.

What to expect

Common side effects

Common side effects (mostly during the dosing session) include:

• Dissociation (feeling detached, altered perception of time).
• Dizziness.
• Nausea.
• Sedation.
• Blood pressure rise.
• Headache.
• Numbness or altered taste in the nose.
• Vertigo.

Most side effects resolve within the two-hour monitoring window.

Serious side effects and warnings

Boxed warnings. Esketamine carries FDA boxed warnings for sedation and dissociation with risk of impaired driving and injury, for potential for misuse and abuse, and for suicidal thoughts and behaviors in patients under 25. That's why every dose is given under a REMS program with monitoring.

• Sedation and dissociation. Can be intense during the session; both resolve within about two hours.
• Blood pressure rise. Transient but sometimes marked; a hypertensive event can occur. Uncontrolled hypertension, unstable cardiovascular disease, and recent stroke are contraindications.
• Misuse potential. Esketamine is a Schedule III controlled substance.
• Bladder problems (ulcerative or interstitial cystitis) have been reported with long-term ketamine use, more often with recreational use.
• Suicidality in patients under 25, though esketamine is also being used specifically for acute suicidality, which changes the risk-benefit calculation.
• Pregnancy and breastfeeding. Generally avoided; effects on the fetus and infant aren't well characterized.

Sexual side effects

Sexual side effects specifically from esketamine are not a prominent feature. That said, when esketamine is used alongside an SSRI or SNRI, sexual side effects from those other drugs remain.

Weight, appetite, and sleep

Esketamine tends to be weight-neutral. Sleep is usually not directly disturbed by the dosing itself, though sleep quality often improves as depression improves.

Starting and dosing basics

This section is general background, not a dosing instruction for any individual. The plan is made by the prescriber and the certified clinic.

Esketamine is self-administered as a nasal spray under supervision at a Spravato-certified clinic. An oral antidepressant is continued alongside. Vital signs are checked before, during, and after. Patients need a ride home; driving is not allowed on dosing days.

Missed doses and interactions

Missed doses affect the treatment plan. Contact the clinic to reschedule; don't try to make up for missed sessions on your own.

Do not use sedatives, opioids, or alcohol on dosing days. Uncontrolled hypertension, aneurysmal vascular disease, and a history of intracerebral hemorrhage are contraindications. Give every prescriber and pharmacist a full list of your medications and supplements, including over-the-counter ones.

Stopping and tapering

Esketamine can be stopped without a taper. If the depression has responded, the plan for continued oral antidepressant treatment or the transition to another maintenance strategy is worth discussing.

Because ongoing esketamine is often what holds the benefit, stopping can be followed by return of depression, and that possibility is worth planning for.

Pregnancy and breastfeeding

This is an area where individual circumstances matter and the decision belongs with a clinician. Esketamine is generally avoided in pregnancy and breastfeeding when alternatives exist. Anyone who is pregnant, planning a pregnancy, or breastfeeding should talk it through with their prescriber so the specific risks and benefits can be weighed for their situation.

Cost and generic availability

Esketamine is brand-only (Spravato). Coverage typically requires prior authorization, and copays depend heavily on the insurance plan. Some manufacturer assistance programs exist. Costs also include the clinic visit for each session.

Common questions

How is esketamine different from IV ketamine? Esketamine is the S-enantiomer of ketamine, delivered as a nasal spray, and it's FDA-approved for treatment-resistant depression under a REMS program. Racemic ketamine IV is used off-label for the same purpose, isn't FDA-approved for it, and is given in different clinic settings.

How fast does it work? Some people notice mood shifts within the first few sessions. The full response is usually assessed over the first four to eight weeks.

Why is monitoring needed for two hours? Sedation, dissociation, and a blood pressure rise typically peak in the first 40 minutes and settle by two hours. The monitoring window covers that.

Can I drive to and from the clinic? You can drive there, but you can't drive home. Plan for a ride.

Is esketamine addictive? It has misuse potential, which is why it's a Schedule III drug and given only in certified clinics. Under the REMS structure, the risk is low; the drug isn't taken home.

Questions to ask your prescriber

• What are we hoping this treats, and how will we know it's working?
• What does the induction, continuation, and maintenance schedule look like for me?
• What should I plan around each session (transportation, meals, work)?
• Which of my other medications matter for dosing days?
• If we decide to stop it later, what happens next?

Sources

This guide draws on current prescribing information and public health references and current as of June 8, 2026. It is reviewed for clinical accuracy and updated as guidance changes.

• U.S. Food and Drug Administration. Esketamine (Spravato) prescribing information.
• Spravato REMS program materials.
• MedlinePlus, U.S. National Library of Medicine. Esketamine.
• American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder.
• American Psychiatric Association / ASKP consensus on the use of ketamine in mood disorders.