What is the recommended dosing schedule, monitoring requirements, and contraindications for initiating Spravato (esketamine) nasal spray in an adult with treatment‑resistant major depressive disorder?

Spravato (Esketamine) for Treatment-Resistant Depression

Spravato (esketamine nasal spray) should be initiated at 56 mg or 84 mg twice weekly for 4 weeks in adults with treatment-resistant depression who have failed at least 2 adequate antidepressant trials, administered only in a certified healthcare setting with mandatory 2-hour post-dose monitoring including blood pressure and respiratory assessments. 1

Patient Selection Criteria

Before initiating Spravato, confirm the patient meets these requirements:

• Treatment resistance: Documented failure of at least 2 adequate antidepressant trials during the current moderate-to-severe depressive episode 2
• Concurrent oral antidepressant: Must be used in conjunction with an SSRI or SNRI (though recent evidence supports monotherapy efficacy) 1, 3
• No absolute contraindications present 1

Absolute Contraindications

Do not administer Spravato if the patient has:

• Aneurysmal vascular disease (thoracic/abdominal aorta, intracranial, peripheral arterial vessels)
• Arteriovenous malformation
• History of intracerebral hemorrhage
• Hypersensitivity to esketamine or ketamine 1

Dosing Schedule

For Treatment-Resistant Depression

Induction Phase (Weeks 1-4):

• Starting dose: 56 mg or 84 mg twice weekly
• For adults ≥65 years: Consider starting at 56 mg 1, 4
• Adjust based on efficacy and tolerability

Maintenance Phase (Weeks 5-8):

• 56 mg or 84 mg once weekly 1

Long-term Maintenance (Week 9 onward):

• 56 mg or 84 mg every 2 weeks OR once weekly
• Individualize to least frequent dosing that maintains remission/response 1

Critical timing note: Evaluate therapeutic benefit at the end of the 4-week induction phase to determine whether to continue treatment 1.

For MDD with Acute Suicidal Ideation/Behavior

• Standard dose: 84 mg twice weekly for 4 weeks
• May reduce to 56 mg twice weekly if tolerability issues arise
• Use beyond 4 weeks has not been systematically evaluated for this indication 1

Important caveat: Effectiveness in preventing suicide or reducing suicidal ideation/behavior has NOT been established 2, 1. Hospitalization may still be required even if initial improvement occurs.

Mandatory Monitoring Requirements

Pre-Administration Checklist

Blood Pressure Assessment:

• Measure baseline blood pressure before each dose
• If elevated (>140/90 mmHg), weigh risks of transient BP increases against treatment benefits
• Do NOT administer if BP or intracranial pressure increase poses serious risk 1

Patient Preparation:

• No food for at least 2 hours before administration
• No liquids for at least 30 minutes before administration
• If using nasal corticosteroid/decongestant, administer at least 1 hour before Spravato 1

During and Post-Administration (Minimum 2 Hours)

Respiratory monitoring:

• Continuous pulse oximetry for at least 2 hours
• Monitor for respiratory status changes 1

Blood pressure monitoring:

• Reassess at approximately 40 minutes post-dose (corresponds to peak concentration)
• Continue monitoring as clinically warranted
• Patient may be discharged only when BP is decreasing AND patient appears clinically stable for at least 2 hours 1

Observation for adverse effects:

• Most common: dissociation (24.3%), nausea (24.8%), dizziness (21.7%), headache (19.0%) 3, 5
• These effects are typically transient and resolve within the monitoring period 6, 7

Post-Discharge Instructions

• No driving or operating machinery until the next day after restful sleep 1
• This is non-negotiable due to dissociative and sedative effects

Administration Technique

• Nasal spray only - each device delivers 28 mg esketamine
• Do NOT prime the device (prevents medication loss)
• For 56 mg dose: Use 2 devices with 5-minute rest between
• For 84 mg dose: Use 3 devices with 5-minute rest between each 1

REMS Requirements

Esketamine has Risk Evaluation and Mitigation Strategy (REMS) requirements 2:

• Healthcare setting must be certified
• Pharmacy must be certified
• Administration requires direct healthcare provider supervision
• Mandatory 2-hour post-dose monitoring at each session

This distinguishes esketamine from off-label IV ketamine and reflects regulatory safety concerns.

Positioning in Treatment Algorithm

Spravato is NOT first-line treatment. 2 The 2022 VA/DoD guidelines recommend considering ketamine or esketamine only after patients have not responded to "several adequate pharmacologic trials" - meaning at least 2 adequate antidepressant trials (8-10 weeks at therapeutic dose per trial).

Evidence shows twice-weekly esketamine as augmentation to ongoing oral antidepressants improved depressive symptoms and remission rates at up to 28 days, with effects seen specifically in TRD patients 2. Recent data from a 2025 RCT demonstrates esketamine monotherapy efficacy with effect sizes of 0.48 (56 mg) and 0.63 (84 mg) at day 28 3, though FDA approval requires concurrent oral antidepressant use.

Missed Doses

• If no worsening of symptoms: Continue current schedule
• If depression worsens during maintenance: Consider reverting to previous more frequent schedule (e.g., from weekly back to twice weekly) 1

Long-Term Safety Considerations

Long-term data (up to 4.5 years) from the SUSTAIN-3 study shows no new safety signals with intermittent dosing 7. However, the 2022 VA/DoD guidelines note that long-term efficacy and safety data remain limited 2, and additional information on long-term consequences would be beneficial for future treatment decisions.

Common pitfall: Assuming esketamine can be administered in any outpatient setting. The REMS requirements mandate certified facilities with appropriate monitoring capabilities - this is not optional 2.