Spravato and Treatment-Resistant Depression: An Overview
What is Treatment-Resistant Depression (TRD)?
Treatment-Resistant Depression (TRD) is a form of major depressive disorder (MDD) that does not respond adequately to at least two different antidepressant medications taken at the correct dose and duration. People with TRD often experience ongoing symptoms that interfere with daily life, relationships, and work despite trying traditional treatments.
What is Spravato?
Spravato® (esketamine) is an FDA-approved noninvasive nasal spray medication for adults with:
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Treatment-resistant depression (TRD)
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Major depressive disorder with acute suicidal ideation or behavior
Spravato is typically used in combination with an oral antidepressant. The medication is self-administered under medical supervision in a certified treatment center. When TRD criteria are met, Spravato is often covered by insurance, but prior authorization is usually required. As of May 2025, patients can now choose to use Spravato with or without additional antidepressants, instead of requiring the combination.
How Does Spravato Work?
Unlike traditional antidepressants, which target serotonin and other neurotransmitters, Spravato acts on the brain’s glutamate system—a pathway involved in learning, memory, and mood. By targeting NMDA receptors, esketamine helps create new neural connections and rapidly alleviates depressive symptoms in some individuals.
Treatment Process
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Administration: Self-administered nasal spray under supervision.
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Monitoring: Due to potential side effects, patients are monitored for 2 hours after the dose. They must not drive after treatment.
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Frequency: Typically twice a week for the first 4 weeks, then weekly or biweekly as maintenance.
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Duration: Personalized, depending on response and clinical evaluations.
⚠️ Common Side Effects
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Dissociation (feeling disconnected from reality)
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Dizziness
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Nausea
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Drowsiness
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Increased blood pressure
These typically resolve shortly after the session.
⚖️ Esketamine vs. Ketamine – Understanding the Differences
| Feature | Esketamine (Spravato®) | Ketamine |
|---|---|---|
| Form | S-enantiomer of ketamine | Racemic mixture (S- and R-enantiomers) |
| Brand Name | Spravato® | Off-label (varies by clinic) |
| FDA Approval | ✅ Approved for Treatment-Resistant Depression (TRD) in 2019 | ❌ Not FDA-approved for depression (used off-label) |
| Route of Administration | Intranasal spray | Typically intravenous (IV), intramuscular injection (IM), or sublingual tablets |
| Setting | Administered in certified treatment centers with 2-hour monitoring | Typically administered in specialized clinics, monitoring protocols vary |
| Cost & Insurance | Often covered by insurance with prior authorization | Often self-pay; insurance rarely covers |
| Regulation | Strict REMS program; Schedule III controlled substance | Also, Schedule III, regulation varies more widely |
| Onset of Action | Rapid relief within hours to days | Similar rapid relief |
| Mechanism | NMDA receptor antagonist enhances glutamate activity | Same, but includes both S and R-components, which may affect results |
| Common Use Cases | Treatment-Resistant Depression, MDD with suicidality | Treatment-Resistant Depression, PTSD, chronic pain, anxiety (off-label) |
