The medication may assist in easing severe, persistent depressive symptoms in adults with two complex forms of Major Depressive Disorder (MDD). It addresses the need for an approach relevant for situations requiring short-term symptomatic assistance when standard treatments have been ineffective or when a crisis requires immediate stabilization.

The medicine is used within the therapeutic domains of Treatment-Resistant Depression (TRD) and may assist with the timely easing of depressive symptoms in adults with MDD presenting with acute suicidal ideation or behavior.

This medicine is commonly used to help manage core depressive symptoms that interfere with daily functioning, such as persistent low mood and anhedonia, following trials of other appropriate treatments. It provides support that helps ease the overall symptom burden in these challenging conditions characterized by periods of heightened symptoms.

“The primary goal is providing timely symptomatic support and assisting with maintaining a sense of stability during difficult episodes.”

This therapeutic domain is also applied in clinical settings that involve acute or unstable symptom patterns associated with suicidal ideation, where its timely symptomatic support supports the process of maintaining a sense of stability and provides supportive relief when symptoms become temporarily overwhelming.

Quick Fact: Relief for Refractory Symptoms
Primary context	Management of Treatment-Resistant Depression (TRD) in adults.
Key benefit	Provides support to ease the overall symptom burden when previous treatments failed.
Acute use	Timely symptomatic support during acute suicidal ideation/behavior.

Who can and cannot use Spravato?

Eligibility for Spravato is strictly defined by regulatory documents and requires use only in adults (18 years and older) in conjunction with a concomitant oral antidepressant. The medicine is not approved for use in patients under 18 years of age.

Absolute Contraindications (Must Not Use)

The medicine is strictly contraindicated in patients with a history of:

• Aneurysmal vascular disease (including intracerebral, thoracic, or abdominal aortic aneurysms) or arteriovenous malformation (AVM).
• Intracerebral hemorrhage.
• Hypersensitivity to esketamine, ketamine, or any of the excipients.
• Conditions where an increase in blood pressure or intracranial pressure poses a serious risk.

Conditional and Special Population Restrictions

Use is not recommended for women who are pregnant or breastfeeding due to the potential for fetal harm and the presence of the medicine in human milk. It is also not recommended for patients with severe hepatic impairment (Child-Pugh Class C). Use requires caution and careful assessment in patients with moderate hepatic impairment or pre-existing cardiovascular and cerebrovascular conditions. While no dose adjustment is required for patients with mild to severe renal impairment, use in patients on dialysis is not established.

The official regulatory documents specify several pharmacodynamic (PD) and pharmacokinetic (PK) interactions for Esketamine. The PD profile details additive effects with certain substance classes, primarily affecting the central nervous and cardiovascular systems.

Co-administration with CNS Depressants, including opioids, benzodiazepines, and alcohol, is officially documented to increase the risk of severe sedation and respiratory depression. The risk of blood pressure elevation is also documented to increase when Esketamine is co-administered with Psychostimulants or Monoamine Oxidase Inhibitors (MAOIs).

Pharmacokinetic and Timing Constraints

PK interactions involve the metabolism of Esketamine by CYP2B6 and CYP3A4 enzymes:

• Exposure Reduction: Potent enzyme inducers, such as Rifampin, are documented to significantly reduce Esketamine exposure, with studies showing a 31% decrease in AUC.
• Exposure Increase: Conversely, potent inhibitors, such as Clarithromycin, lead to increased Esketamine exposure.

For populations with Severe Hepatic Impairment, use is not recommended due to formally documented increases in exposure and prolonged half-life. Additionally, administration requires specific timing separation for concurrent products:

• Nasal Corticosteroids/Decongestants: Must be administered at least 1 hour before Esketamine.
• Food/Liquids: Patients are advised to avoid food for at least 2 hours and liquids for at least 30 minutes prior to administration.

Spravato (esketamine) functions as a non-competitive antagonist of the N-methyl-D-aspartate ( NMDA) receptor. The primary molecular action involves binding to a site within the channel of the NMDA receptor, thereby blocking the influx of positive ions. This inhibition is believed to occur preferentially on NMDA receptors located on inhibitory GABAergic interneurons.

Blockade of NMDA receptors on these inhibitory cells leads to a transient disinhibition of pyramidal neurons and a surge in the release of the excitatory neurotransmitter, glutamate. The liberated glutamate preferentially targets and activates AMPA receptors. This enhanced AMPA receptor signaling drives subsequent intracellular processes, including the activation of the BDNF- TrkB pathway, which is critical for synaptogenesis and synaptic plasticity.

The system-level physiological consequence is the restoration of functional synaptic connections and modulation of neural circuitry, particularly within cortical regions associated with complex cognitive and affective regulation.

How Spravato is Used

Spravato (esketamine) is administered solely via the intranasal route using a metered-dose nasal spray device and is intended only for use as a supportive component alongside a new or continued oral antidepressant. The official administration of this medicine is characterized by a time-phased schedule and strict procedural controls.

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Official Dosing and Schedule

The usage follows a two-phase model: an initial Induction Phase and a subsequent Maintenance Phase that is customized to maintain clinical benefit. Dosing is achieved using the 28 mg device in combination to deliver either 56 mg or 84 mg.

Phase	Frequency and Dose Range (TRD)	Duration
Induction	Twice weekly; 56 mg or 84 mg	Weeks 1-4
Maintenance	Once weekly or once every two weeks; 56 mg or 84 mg	Week 5 and beyond

For Major Depressive Disorder with Acute Suicidal Ideation or Behavior (MDSI), the dose is typically 84 mg and is also administered twice weekly during the first four weeks.

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Contextual Use Requirements

Administration must occur under the direct supervision of a healthcare professional in an appropriate clinical setting. Patients are required to remain in the facility for observation for at least two hours after the medicine is administered.

Patients should avoid consuming food for at least two hours and liquids for at least 30 minutes prior to use. During the procedure, a 5-minute rest period is required between the use of each nasal spray device to allow for proper absorption.

Population-Specific Use

Specific dosing rules are detailed for certain populations: for older adults (65 years), a lower initial dose of 28 mg is indicated in some regions. Furthermore, the maximum dose of 84 mg should be used with caution in patients with moderate hepatic impairment; the medicine is not recommended for those with severe impairment.

Spravato: Recent Clinical Evidence

Clinical research on esketamine (marketed as Spravato) has primarily focused on its use, alongside an oral antidepressant, for adults with treatment-resistant depression (TRD) and for depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior.

Efficacy and Onset of Effect

Randomized, controlled trials (RCTs) demonstrated a statistically significant reduction in depressive symptoms (as measured by the Montgomery-Åsberg Depression Rating Scale, or MADRS) compared to placebo plus an oral antidepressant.

A key finding across short-term studies is the rapid onset of changes in depressive symptoms, with improvements often noted within 24 hours of the first dose. This is in contrast to the typical onset timeline observed with traditional oral antidepressants.

Recent phase 4 data also supported the use of esketamine as a monotherapy (without a concurrent oral antidepressant) for adults with TRD, showing significant improvement in MADRS scores versus placebo at four weeks.

Long-Term Safety and Maintenance

Long-term extension studies, such as SUSTAIN-3, evaluated the sustained use of esketamine for up to six years in conjunction with an oral antidepressant. The data from these studies indicate the durability of the treatment effect, with a statistically significant delay in the time to relapse among stable responders and remitters compared to the placebo group.

The safety profile across long-term and short-term trials remained consistent. Most common adverse events (such as dissociation, dizziness, and sedation) were generally transient, occurring and resolving on the day of administration. Long-term studies monitored safety outcomes, including cardiovascular, hepatic, and renal parameters.

Common questions about Spravato (FAQ)

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Q: What is Spravato (esketamine) used to treat?

A: Spravato (esketamine) nasal spray is approved by the FDA for adults with two specific conditions:

• Treatment-Resistant Depression (TRD): This is for adults who have tried at least two different antidepressant medications taken by mouth, at an adequate dose and duration, without an improvement in their symptoms.
• Major Depressive Disorder (MDD) with acute suicidal ideation or behavior: Spravato is used in combination with an oral antidepressant for this indication. Treatment for this condition always involves comprehensive standard-of-care care, which includes hospitalization and optimization of oral antidepressant therapy.

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Q: Is Spravato the same as ketamine?

A: No, Spravato is not the same as ketamine.

• The active ingredient in Spravato is esketamine, which is a specific form (S-enantiomer) of the drug ketamine.
• Spravato is an FDA-approved prescription nasal spray specifically for the treatment of depression. It is administered in a certified healthcare setting.
• Ketamine is a derivative but is not FDA-approved to treat depression. Both esketamine and ketamine are classified as Schedule III controlled substances under the U.S. Controlled Substances Act.

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Q: How is Spravato administered, and where can I take it?

A: Spravato is a nasal spray that is self-administered by the patient under the direct supervision of a healthcare provider at a certified healthcare setting.

• It cannot be taken at home or purchased directly from a standard pharmacy.
• Because of risks such as sedation, dissociation, and increased blood pressure, Spravato is only available through a restricted program called the SPRAVATO REMS (Risk Evaluation and Mitigation Strategy) Program.
• Patients must remain in the healthcare setting for at least two hours after administration for monitoring by a healthcare professional until they are clinically stable and ready to leave.

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Q: How quickly does Spravato start to work?

A: Spravato may offer a relatively rapid onset of effect compared to traditional oral antidepressants, which often take several weeks.

• Clinical studies have shown that some patients experience a significant reduction in depressive symptoms within the first four weeks of treatment.
• The full therapeutic benefit and overall progress are assessed over a period of weeks, and the treatment plan is adjusted based on the patient's individual response.

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Q: What are the most common side effects of Spravato?

A: The most commonly observed side effects that may occur during or shortly after treatment include:

• Dissociation (a feeling of being disconnected from yourself, thoughts, feelings, or surroundings)
• Dizziness
• Nausea or Vomiting
• Sedation (feeling sleepy or drowsy)
• Increased Blood Pressure (temporary increase)
• Headache

These side effects are typically temporary and usually resolve by the end of the two-hour monitoring period at the certified treatment center.

SPRAVATO nasal spray storage and disposal are governed by official regulations for a Schedule III controlled substance.

Storage & Disposal Scope	Requirement
Standard Storage Temperature	Must be stored in a refrigerator at 2 C to 8 C (36 F to 46 F).
Prohibited Environment	Do not freeze.
Temporary Stability Limit	Can be stored outside the refrigerator for a single cumulative period of up to 14 days (up to 25 C), then must be discarded.
Security & Handling	Must be stored in a secure place and kept out of the sight and reach of children; limited to certified healthcare settings.
Disposal Requirement	Used, unused, and expired devices must be discarded immediately by a healthcare professional as per regulations for controlled substance waste. Do not dispose of in household waste or wastewater.