What is the recommended Spravato (esketamine) treatment protocol for an adult with treatment‑resistant major depressive disorder who is already on a stable oral antidepressant?

Spravato Treatment Protocol for Treatment-Resistant Depression

For adults with treatment-resistant depression on a stable oral antidepressant, initiate Spravato (esketamine) nasal spray at 56 mg or 84 mg twice weekly for 4 weeks (induction phase), followed by once weekly dosing for weeks 5-8 (maintenance phase), then individualize to every 2 weeks or weekly thereafter based on response. 1

Pre-Treatment Requirements

Before initiating Spravato, verify the following contraindications are absent 1:

• Aneurysmal vascular disease (aortic, intracranial, peripheral arterial)
• Arteriovenous malformation
• History of intracerebral hemorrhage

Spravato must be administered under direct healthcare provider supervision—this is non-negotiable and mandated by the FDA label 1.

Dosing Protocol for Treatment-Resistant Depression

Induction Phase (Weeks 1-4)

• Frequency: Twice weekly
• Dose: Start with 56 mg or 84 mg
• Dosage adjustments based on efficacy and tolerability
• Evaluate therapeutic benefit at end of induction to determine continuation 1

Maintenance Phase (Weeks 5-8)

• Frequency: Once weekly
• Dose: 56 mg or 84 mg 1

Long-Term Maintenance (Week 9 onward)

• Frequency: Every 2 weeks OR once weekly
• Dose: 56 mg or 84 mg
• Individualize to the least frequent dosing that maintains remission/response 1

The evidence strongly supports extending treatment beyond initial phases. In long-term studies, patients receiving more than 19 esketamine administrations had significantly higher remission rates (70%) compared to those completing only the standard protocol 2. The SUSTAIN-3 study demonstrated safety with mean exposure of 42.9 months, with remission rates reaching 49.6% at optimization/maintenance endpoint 3.

Administration Day Protocol

Pre-Dose Requirements

Timing restrictions 1:

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

Blood pressure assessment 1:

• Check BP before dosing
• If baseline BP >140/90 mmHg, carefully weigh risks of short-term BP increases against treatment benefit
• Do not administer if BP or intracranial pressure increase poses serious risk

During Administration

Device usage 1:

• Each device delivers 28 mg esketamine
• Use 2 devices for 56 mg dose OR 3 devices for 84 mg dose
• Do not prime the device—this causes medication loss
• Allow 5-minute rest between each device

Post-Dose Monitoring (Mandatory 2-Hour Observation)

Vital sign monitoring 1:

• Monitor respiratory status for at least 2 hours (including pulse oximetry)
• Reassess BP at approximately 40 minutes post-dose (corresponds to peak concentration)
• Continue BP monitoring as clinically warranted

Discharge criteria 1:

• BP must be decreasing
• Patient must appear clinically stable for at least 2 hours
• If criteria not met, continue monitoring beyond 2 hours

Critical safety instruction: Patients must not drive or operate machinery until the next day after restful sleep 1.

Common Adverse Events and Management

The most frequent adverse events are dissociation (24-28%), dizziness (22-34%), nausea (24-34%), headache (19-37%), and dysgeusia (20%) 3, 2, 4. These are typically:

• Mild to moderate in severity
• Occur on dosing days
• Resolve within 1.5 hours post-dose 4, 5

Important clinical pearl: Absence of dissociative symptoms was associated with higher remission rates in real-world practice 2, though dissociation itself is common and generally well-tolerated.

Efficacy Expectations

Rapid onset: Significant improvement occurs within 24 hours of first dose, with mean MADRS score differences of -3.4 to -3.8 points versus placebo by day 2 6.

Sustained benefit: At day 28, esketamine demonstrates effect sizes of 0.48-0.63 compared to placebo, with MADRS score improvements of -5.1 to -6.8 points 6. Long-term data shows depression improvements persist during maintenance treatment, with mean MADRS changes of -16.4 during induction that remain stable during optimization/maintenance 4.

Relapse prevention: Continuation of esketamine reduces relapse risk by 51% in patients achieving stable remission and 70% in those achieving stable response compared to discontinuation 7.

Missed Dose Management

If treatment sessions are missed 1:

• Without symptom worsening: Continue current dosing schedule
• With symptom worsening during maintenance: Consider returning to previous more frequent schedule (e.g., from weekly back to twice weekly)

Critical Safety Monitoring

Long-term safety data from 3,777 cumulative patient-years shows 3:

• Discontinuation due to adverse events: 6.4%
• Discontinuation due to lack of efficacy: 5.3%
• No cases of interstitial cystitis or respiratory depression reported 4
• Cognitive performance generally improved or remained stable 4

The evidence from multiple phase 3 trials and real-world studies consistently demonstrates that esketamine combined with oral antidepressants provides clinically meaningful and sustained improvement in treatment-resistant depression when administered according to this protocol 1, 3, 4, 5, 7, 6.