Understanding Spravato® (Esketamine) for Treatment-Resistant Depression
An evidence-based overview of the FDA-approved prescription nasal spray, clinical indications, REMS safety protocols, and patient preparation guidelines.
Depression can be exhausting and relentless, especially when multiple trials of standard oral antidepressants have failed to provide meaningful relief. For adults living with Treatment-Resistant Depression (TRD), Spravato® (esketamine) offers an FDA-approved interventional pathway that operates on entirely different neurochemical pathways than traditional medications.
Administered as a nasal spray only in healthcare settings certified under its Risk Evaluation and Mitigation Strategy (REMS), Spravato is prescribed to help relieve depressive symptoms.
FDA-Approved Indications & Limitations of Use
According to the FDA-approved prescribing information (revised March 2026), SPRAVATO® (esketamine) CIII nasal spray is indicated for Treatment-Resistant Depression (TRD) in adults, as monotherapy or with an oral antidepressant, and for depressive symptoms in adults with MDD with acute suicidal ideation or behavior, in conjunction with an oral antidepressant.
- Treatment-Resistant Depression (TRD) in adults: Individuals with major depressive disorder who have not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode (the definition used in the clinical studies).
- Depressive symptoms in adults with Major Depressive Disorder (MDD) with acute suicidal ideation or behavior: Used in conjunction with an oral antidepressant, with labeled dosing of twice weekly for 4 weeks, after which the prescriber evaluates whether to continue.
The effectiveness of Spravato in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of Spravato does not preclude the need for hospitalization if clinically warranted, even if patients report improvement after an initial dose. Spravato is not approved as an anesthetic agent.
How Esketamine Differs from Traditional Antidepressants
Traditional antidepressants, such as SSRIs (Prozac, Lexapro, Zoloft) and SNRIs (Cymbalta, Effexor), work primarily on monoamine neurotransmitters such as serotonin and norepinephrine. These medications usually take four to eight weeks of daily use to work.
In contrast, esketamine is the S-enantiomer of ketamine and acts as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. The FDA-approved label states that the mechanism of its antidepressant effect is unknown. Researchers think that blocking NMDA receptors may lead to a brief increase in glutamate activity, the release of Brain-Derived Neurotrophic Factor (BDNF), and the formation of new synaptic connections (synaptogenesis) in brain regions that regulate mood, but this is still being studied.
What to Expect: Patient Preparation & Clinical Protocol
Because esketamine can cause sedation, dissociative sensations (such as feeling detached from one's body or surroundings), respiratory depression and temporary increases in blood pressure, the FDA requires that it be self-administered under the direct observation of a healthcare provider in a REMS-certified healthcare setting.
Pre-Treatment Instructions
- Fasting: Do not eat for at least 2 hours before your session to prevent nausea.
- Hydration: Avoid liquids for at least 30 minutes prior to dosing.
- Nasal Sprays: If you use nasal steroids or decongestants, administer them at least 1 hour before Spravato.
- Arranged Ride: You will need someone to drive you home; do not drive until the next day after a restful sleep.
In-Office Monitoring Protocol
- Baseline Vitals: Blood pressure and pulse are assessed before self-administration.
- Supervised Self-Dosing: The patient self-administers the nasal spray under staff direction.
- At Least 2 Hours of Observation: A healthcare provider monitors you, including your breathing with pulse oximetry, until you are clinically stable and ready to leave.
- Post-Dose Vitals: Blood pressure is checked at about 40 minutes after the dose and afterward as clinically needed.
Typical Treatment Schedule for Treatment-Resistant Depression
The FDA-approved prescribing information recommends the following schedule for TRD; your prescriber individualizes dosing based on response and tolerability:
Two treatment sessions per week (56 mg or 84 mg). Benefit is evaluated at the end of this phase to decide whether to continue.
One treatment session per week (56 mg or 84 mg) while your response is monitored.
One session every week or every two weeks, individualized to the least frequent schedule that maintains response.
Contraindications & Clinical Safety Screening
Spravato is contraindicated in patients with aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels), arteriovenous malformations, a history of intracerebral hemorrhage, or known hypersensitivity to esketamine, ketamine, or any of the product's other ingredients. The prescribing information also directs prescribers to carefully assess people with other heart or blood vessel conditions before prescribing.
To find out whether Spravato may be appropriate for you, ask our office about eligibility and next steps. Spravato® is offered at our Orland Park and Willowbrook offices.