Introduction
Esketamine nasal spray (Spravato), the S-enantiomer of racemic ketamine, received FDA approval in March 2019 for treatment-resistant depression (TRD) in adults, and subsequently in August 2020 for the treatment of major depressive disorder (MDD) with acute suicidal ideation or behavior. As the first FDA-approved glutamatergic antidepressant, esketamine represents a mechanistically distinct therapeutic option. Unlike racemic IV ketamine, Spravato is administered under a restricted distribution system known as the Risk Evaluation and Mitigation Strategy (REMS) program, which mandates specific clinical procedures and post-administration monitoring.
REMS Program Requirements
Certified Healthcare Settings
Spravato must be administered exclusively in healthcare settings certified under the Spravato REMS program. Certification requires that the facility demonstrate the ability to monitor patients for a minimum of two hours following each administration, maintain resuscitation equipment on site, and ensure that healthcare providers are trained in the recognition and management of dissociation, sedation, and hemodynamic changes. The medication is never dispensed for home use.
Provider and Pharmacy Certification
Prescribers must enroll in the REMS program and complete the associated training. Pharmacies dispensing Spravato must also be REMS-certified. Each treatment session requires documentation that the patient has been observed for the required monitoring period and meets discharge criteria before leaving the facility.
Approved Indications and Dosing
Treatment-Resistant Depression
For TRD, Spravato is prescribed as an adjunct to a newly initiated oral antidepressant. The dosing schedule is structured in distinct phases:
Induction Phase (Weeks 1-4): Patients receive 56 mg or 84 mg intranasally twice per week. Treatment is typically initiated at 56 mg for the first session, with titration to 84 mg at the second session based on tolerability. Each dose is delivered using the proprietary nasal spray device, with 56 mg requiring two devices (each delivering 28 mg, one spray per nostril per device) and 84 mg requiring three devices.
Maintenance Phase (Weeks 5-8): Dosing frequency is reduced to once weekly at 56 mg or 84 mg, based on clinical response and tolerability.
Extended Maintenance (Week 9 onward): Frequency may be further reduced to once weekly or once every two weeks, at either 56 mg or 84 mg. The lowest effective frequency should be used to maintain remission. Clinicians should periodically reassess the need for continued therapy.
MDD with Acute Suicidal Ideation or Behavior
For this indication, Spravato is administered at 84 mg twice weekly for four weeks, in conjunction with standard-of-care oral antidepressant therapy. Following the four-week treatment course, the evidence base for continued esketamine therapy beyond this period is limited for this specific indication, and clinical judgment should guide decisions regarding treatment extension.
Administration Procedure
Pre-Administration Preparation
Patients should be instructed to avoid food for at least two hours and liquids for at least 30 minutes prior to administration. If the patient is using an intranasal corticosteroid or nasal decongestant, these should be administered at least one hour before Spravato. Blood pressure should be measured before dosing. Clinicians should withhold administration if systolic blood pressure exceeds 140 mmHg or diastolic pressure exceeds 90 mmHg, and reassess whether proceeding is clinically appropriate.
Self-Administration Under Supervision
The patient self-administers each spray under direct observation of a healthcare provider. For each device, the patient inserts the nozzle into one nostril, occludes the opposite nostril, breathes in through the nose while pressing the plunger, and then switches to the other nostril for the second spray from the same device. A five-minute rest period with the head slightly tilted back is observed between devices to allow for mucosal absorption. The patient should avoid blowing the nose for the duration of the dosing session.
Post-Dose Monitoring
Two-Hour Observation Period
Following administration, patients must be monitored in the clinical setting for a minimum of 120 minutes. Vital signs, including blood pressure, should be assessed at approximately 40 minutes and again at the end of the observation window. If blood pressure remains significantly elevated at the two-hour mark, continued monitoring and appropriate medical management are required.
Dissociation and Sedation Assessment
The Clinician-Administered Dissociative States Scale (CADSS) may be used to quantify dissociative symptoms during the monitoring period, though its routine use is at the clinician's discretion. Sedation levels should be assessed throughout the observation window. Patients should not be discharged until they are alert, oriented, and hemodynamically stable. Driving and operation of machinery are prohibited until the following day after a restful sleep.
Clinical Considerations and Safety
Contraindications
Spravato is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformation, or a history of intracerebral hemorrhage. It should not be used in patients with known hypersensitivity to esketamine, ketamine, or any excipients in the formulation.
Drug Interactions
Concurrent use of CNS depressants, including benzodiazepines, opioids, and alcohol, may potentiate sedation. Psychostimulants and monoamine oxidase inhibitors (MAOIs) may increase the hypertensive effects of esketamine. Clinicians should review the patient's full medication list at each visit and counsel patients regarding avoidance of alcohol and sedating substances on treatment days.
Long-Term Monitoring
Ongoing assessment should include regular depression rating scales (PHQ-9 or MADRS), monitoring for signs of substance misuse or diversion, evaluation for urinary tract symptoms (dysuria, frequency, urgency), and periodic cognitive assessment in patients receiving extended maintenance therapy. Any emergence of psychotic symptoms or persistent perceptual disturbances warrants treatment discontinuation and thorough psychiatric reassessment.
References
- MedlinePlus: Esketamine Nasal Spray Drug Information — National Library of Medicine comprehensive prescribing information for Spravato (esketamine) nasal spray
- DailyMed: FDA Drug Label Information — National Library of Medicine database for official FDA-approved Spravato labeling
- FDA MedWatch: Safety Information and Adverse Event Reporting — FDA safety reporting system for esketamine adverse events
- NIMH: Depression Overview — National Institute of Mental Health information on treatment-resistant depression and novel interventions
Share