SPRAVATO® Esketamine Treatment Guide | Benefits, Risks & Assessment

SPRAVATO® (esketamine) is an FDA-approved nasal spray treatment for adults with treatment-resistant depression and, in conjunction with an oral antidepressant, for depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behavior. This comprehensive guide explains how SPRAVATO works, who may be considered for treatment, dosing and treatment schedules, REMS monitoring requirements, what to expect during treatment, potential benefits, side effects, contraindications, medication considerations and important safety information. It also includes a scoreable candidate-discussion questionnaire to help patients organize their treatment history and prepare for a consultation with a qualified SPRAVATO provider.

Advanced Mental Health Treatment Guide

SPRAVATO® (Esketamine) Treatment Guide

SPRAVATO® (esketamine) nasal spray is an FDA-approved, rapid-acting treatment option for certain adults with depression. This patient-centered guide explains treatment-resistant depression, how SPRAVATO works, FDA-approved uses, dosing and monitoring, possible benefits, dissociation and sedation, blood-pressure and respiratory monitoring, contraindications, medication considerations, treatment-day preparation, and a scoreable candidate-discussion questionnaire.

EsketamineSPRAVATO® Treatment-Resistant DepressionREMS Monitoring

Mark Zauss, LMHC, LPC, CCMHC, NBCC, BC-TMC, ASDCS, NATC, CCTP, CCTP II, ADHD-CCSP, C-DBT, C-PD
Educational decision-support resource. This page does not prescribe SPRAVATO, determine medical eligibility, or replace evaluation by a qualified SPRAVATO prescriber.

SPRAVATO is not the same as IV ketamine. SPRAVATO contains esketamine and is administered only as a nasal spray under direct observation in a certified healthcare setting. Racemic ketamine given intravenously, intramuscularly, orally, or sublingually is a different treatment and is generally used off-label for psychiatric conditions.

Overview FDA Uses How It Works Who May Be Considered Dosing Treatment Day What It Feels Like Safety Medication Issues Candidate Questionnaire FAQ Sources

What is SPRAVATO®?

SPRAVATO is the brand name for esketamine, a Schedule III controlled medication delivered through a single-use nasal spray device. Esketamine is one of the two mirror-image molecules that make up racemic ketamine. Although the two medications are chemically related, SPRAVATO has a specific FDA-approved formulation, dosing schedule, safety program, and monitoring framework.

Unlike conventional antidepressants that primarily act on serotonin, norepinephrine, or dopamine systems, esketamine acts mainly through the brain’s glutamate system. Its precise antidepressant mechanism is not fully established, but NMDA-receptor modulation and downstream AMPA signaling are believed to influence synaptic plasticity and communication between brain networks involved in mood regulation.

FDA-Approved Uses

Treatment-Resistant Depression (TRD)

SPRAVATO is FDA-approved for adults with treatment-resistant depression (TRD). Current U.S. labeling permits treatment either as monotherapy or together with an oral antidepressant. A qualified prescriber determines whether a patient meets the clinical criteria for TRD and whether SPRAVATO is appropriate.

MDD with Acute Suicidal Ideation or Behavior

SPRAVATO is also FDA-approved, in conjunction with an oral antidepressant, for depressive symptoms in adults with major depressive disorder (MDD) who have acute suicidal ideation or behavior. This indication does not mean SPRAVATO replaces emergency assessment, hospitalization, safety planning, or other urgent psychiatric care when clinically necessary.

Important: SPRAVATO has not been demonstrated to prevent suicide or to reduce suicidal ideation or suicidal behavior. Improvement in depressive symptoms after treatment does not eliminate the need for hospitalization, emergency evaluation, safety planning, or another higher level of psychiatric care when clinically warranted.

How May SPRAVATO Reduce Depression?

NMDA Receptor Modulation

Esketamine is a noncompetitive antagonist at the NMDA subtype of glutamate receptor. Its effects differ from conventional monoamine antidepressants and lead to downstream changes in glutamate signaling.

AMPA Signaling and Synaptic Plasticity

Research suggests that downstream AMPA-receptor activity and intracellular signaling may contribute to changes in synaptic strength and plasticity. These mechanisms are among the reasons esketamine can produce antidepressant effects on a different time course than many traditional antidepressants.

Brain-Network Effects

Studies of ketamine-class treatments suggest changes in connectivity among networks involved in self-referential thinking, emotion, salience, and executive control. These findings remain an active area of research and should not be interpreted as a simple “brain reset.”

Who May Be Considered for SPRAVATO?

A qualified prescriber determines eligibility. Discussion may be appropriate when an adult has a confirmed depressive disorder and has not improved sufficiently with appropriate prior treatment.

Possible discussion factors

Persistent moderate-to-severe depressive symptoms.
Inadequate response to appropriate antidepressant treatment trials.
Ongoing functional impairment despite psychotherapy and medication treatment.
Need to consider a treatment with a different mechanism of action.
Ability to attend a certified treatment setting and remain for monitoring.
Reliable transportation home after each treatment.

Issues requiring careful review

Blood-pressure or cardiovascular concerns.
Cerebrovascular or aneurysmal vascular disease.
History of intracerebral hemorrhage.
Substance-use disorder or elevated abuse/misuse risk.
Pregnancy or plans for pregnancy.
Severe liver impairment.
Psychosis, mania, or other diagnostic factors that may change the risk-benefit analysis.
Medications that may increase sedation or blood pressure.

SPRAVATO Dosing Schedule

SPRAVATO is self-administered by the patient using single-use nasal spray devices under the direct observation of a healthcare provider in a certified treatment setting. Each device delivers 28 mg of esketamine. For treatment-resistant depression, the recommended dose on Day 1 is 56 mg. Subsequent doses may be 56 mg or 84 mg based on effectiveness and tolerability, as determined by the prescribing clinician.

Phase	Typical frequency for treatment-resistant depression	Typical dose
Weeks 1–4 Induction	Twice weekly	56 mg or 84 mg*
Weeks 5–8	Once weekly	56 mg or 84 mg
Week 9 and after	Once weekly or every 2 weeks	56 mg or 84 mg

*The prescribing information specifies a 56 mg starting dose on Day 1 for adults with TRD, followed by individualized dosing. The goal during maintenance is generally to use the least frequent schedule that maintains response or remission. Dosing for MDD with acute suicidal ideation or behavior follows a different short-term schedule and should be reviewed with the prescribing clinician.

What Happens on a SPRAVATO Treatment Day?

Before treatment. The treatment team reviews current symptoms, medication changes, recent medical issues, blood pressure, and other safety information.

Food and liquids. Because nausea and vomiting can occur, current labeling advises avoiding food for at least 2 hours before treatment and liquids for at least 30 minutes before treatment.

Nasal medications. If a nasal decongestant or nasal corticosteroid is needed on treatment day, the prescribing information advises using it at least 1 hour before SPRAVATO.

Nasal administration. The patient administers the prescribed number of devices while being directly observed by a healthcare professional. There is a 5-minute rest between devices.

Monitoring. Blood pressure is assessed before treatment and again approximately 40 minutes after dosing, with further assessment as clinically indicated. Respiratory status is monitored, including pulse oximetry.

Minimum 2-hour observation. Patients remain under healthcare-provider observation for at least 2 hours after administration. Discharge depends on clinical stability, not simply the clock.

Transportation home. Patients should arrange transportation and must not drive, operate machinery, or engage in hazardous activities until the next day after a restful sleep.

What Can SPRAVATO Feel Like?

Dissociation

Some patients experience a temporary sense of detachment from themselves or their surroundings, altered perception of time or space, dreamlike sensations, or unusual sensory experiences. These effects are generally monitored until they have sufficiently resolved for safe discharge.

Sedation

Sleepiness, slowed thinking, reduced alertness, or a feeling of heaviness can occur. Because sedation can vary in intensity, patients are observed in the treatment setting for at least 2 hours after every dose and until the clinician determines they are clinically stable.

Physical sensations

Dizziness, nausea, vertigo, headache, temporary blood-pressure elevation, numbness or altered sensation, and an unusual or unpleasant taste are among commonly reported effects. The intensity and combination of effects vary from person to person and from session to session.

After treatment

Some people feel tired, slowed, “spacey,” or mildly unsteady for the remainder of the day, while others feel closer to baseline after the monitoring period. Patients should still avoid driving, operating machinery, or other hazardous activities until the next day after a restful sleep.

Dissociation is a side effect, not a requirement for benefit. A person does not need to have an intense altered-state experience for SPRAVATO to work.

SPRAVATO Safety, Boxed Warnings & REMS Monitoring

SPRAVATO is available only through the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) because of the risks of sedation, dissociation, respiratory depression, abuse, and misuse. Certified outpatient treatment settings administer SPRAVATO under direct observation, and patients are monitored for at least 2 hours after each dose. Outpatients treated through the REMS are enrolled and monitored according to program requirements.

Issue	Why it matters
Sedation	Reduced alertness or significant sleepiness can occur. Patients require observation until clinically stable.
Dissociation	Temporary perceptual changes, derealization, depersonalization, or a sense of detachment can occur.
Respiratory depression	Respiratory status must be monitored during the observation period, including pulse oximetry.
Blood-pressure increase	SPRAVATO can cause transient increases in blood pressure. BP is checked before treatment and approximately 40 minutes after dosing, with additional monitoring as needed.
Abuse and misuse	Esketamine is a Schedule III controlled substance. Clinicians should assess risk in patients with a history of substance-use disorder.
Driving impairment	Patients should not drive or operate machinery until the next day after a restful sleep.

Formal contraindications

Aneurysmal vascular disease, including thoracic or abdominal aorta, intracranial, or peripheral arterial vessels.
Arteriovenous malformation.
History of intracerebral hemorrhage.
Hypersensitivity to esketamine, ketamine, or product excipients.

Urgent symptoms: Chest pain, severe shortness of breath, symptoms suggesting stroke, severe or rapidly worsening headache, loss of consciousness, or severe psychiatric deterioration require immediate medical evaluation.

Medication and Medical Considerations

Your SPRAVATO prescriber should review all prescription medications, over-the-counter products, supplements, alcohol or substance use, and medical conditions before treatment.

CNS Depressants

Benzodiazepines, opioids, sedative-hypnotics, alcohol, and other central nervous system depressants may increase sedation when used with SPRAVATO. Patients should provide the prescriber with a complete medication and substance-use list. Medication changes should be made only with the prescribing clinician.

Psychostimulants

Psychostimulants can increase blood pressure and may require additional blood-pressure monitoring or individualized treatment planning when used with SPRAVATO. The prescriber should review stimulant dose, timing, cardiovascular history, and baseline blood pressure.

MAO Inhibitors

Monoamine oxidase inhibitors (MAOIs) may increase blood pressure and warrant careful prescriber review when SPRAVATO is being considered. Patients should not stop or alter an MAOI without medical guidance.

Pregnancy and Breastfeeding

SPRAVATO is not recommended during pregnancy. Patients who are pregnant, may become pregnant, are planning pregnancy, or are breastfeeding should discuss reproductive risks, contraception considerations, and treatment alternatives directly with the prescribing clinician.

Potential Benefits and Limitations

Potential Benefits

SPRAVATO offers an FDA-approved treatment option for adults with treatment-resistant depression whose symptoms have not improved adequately with prior treatment.
Esketamine works through the glutamate/NMDA system, providing a mechanism of action that differs from traditional antidepressants that primarily target serotonin, norepinephrine, or dopamine.
Some patients experience meaningful improvement relatively early in the treatment course, although the timing and degree of response vary.
After the induction phase, treatment frequency may be reduced to weekly or every 2 weeks when clinically appropriate.
SPRAVATO can be incorporated into a broader treatment plan that may include psychotherapy, medication management, lifestyle changes, and other evidence-based interventions.

Important Limitations

SPRAVATO does not work for everyone, and improvement cannot be guaranteed.
Some patients require ongoing maintenance treatment to sustain benefit.
Every dose must be administered in a certified healthcare setting, followed by at least 2 hours of monitoring and a clinical assessment before discharge.
Patients must arrange transportation home and should not drive, operate machinery, or perform hazardous activities until the next day after a restful sleep.
Insurance coverage, prior authorization requirements, treatment frequency, and out-of-pocket costs vary by plan and treatment center.
SPRAVATO does not replace psychotherapy, ongoing psychiatric care, safety planning, hospitalization, or emergency treatment when those interventions are clinically necessary.

Frequently Asked Questions

How quickly can SPRAVATO work?

Some patients experience improvement early in the treatment course, but response varies. Treatment is typically evaluated across the induction phase rather than judged from a single session.

Do I have to take an oral antidepressant with SPRAVATO?

For adult treatment-resistant depression, current FDA labeling permits SPRAVATO as monotherapy or with an oral antidepressant. For depressive symptoms in adults with MDD and acute suicidal ideation or behavior, it is used in conjunction with an oral antidepressant.

Can I take SPRAVATO home?

No. SPRAVATO is dispensed and administered only in a certified healthcare setting under the REMS program. It is not dispensed directly to the patient for home use.

How long will I be at the clinic?

The REMS requires monitoring for at least 2 hours after administration. Total appointment time is longer because it also includes pre-dose assessment, administration, and discharge evaluation.

Can I drive myself home?

No. Patients should arrange transportation home and should not drive or operate machinery until the next day after a restful sleep.

Is dissociation dangerous?

Dissociation is a known temporary effect and is one reason SPRAVATO is administered in a monitored setting. The treatment team assesses whether symptoms are resolving adequately before discharge.

Is SPRAVATO addictive?

Esketamine has abuse and misuse potential and is a Schedule III controlled substance. The restricted administration system and clinician monitoring are designed in part to reduce this risk. A history of substance-use disorder deserves careful individualized review.

Is SPRAVATO the same as ketamine-assisted psychotherapy?

No. SPRAVATO is an FDA-approved medication administered according to its prescribing information and REMS requirements. Psychotherapy may be used alongside treatment, but “ketamine-assisted psychotherapy” refers to a broader clinical model and should not be treated as synonymous with FDA-approved SPRAVATO treatment.

Clinical Resources & Sources

Janssen Pharmaceuticals, Inc. SPRAVATO® (esketamine) nasal spray, CIII: Prescribing Information. Current U.S. prescribing information.
SPRAVATO® REMS. REMS Program Overview. Requirements for certified healthcare settings, patient enrollment, direct observation, and post-dose monitoring.
SPRAVATO® REMS. Patient Monitoring Form — Outpatient Use Only. Includes dose documentation, blood-pressure monitoring, sedation/dissociation assessment, and the minimum 2-hour monitoring requirement.
U.S. Food and Drug Administration. SPRAVATO (esketamine) regulatory and prescribing information.
Daly, E. J., Trivedi, M. H., Janik, A., et al. (2019). Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry, 76(9), 893–903.
Popova, V., Daly, E. J., Trivedi, M., et al. (2019). Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression. American Journal of Psychiatry, 176(6), 428–438.
Fu, D. J., Ionescu, D. F., Li, X., et al. (2020). Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent. Journal of Clinical Psychiatry, 81(3).
McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., et al. (2021). Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: An international expert opinion on the available evidence and implementation. American Journal of Psychiatry, 178(5), 383–399.

Educational use: This resource is intended to improve patient understanding and preparation for discussion with a qualified prescriber. It does not provide medical clearance, prescribe medication, replace informed consent, or establish that a person should receive SPRAVATO.