Spravato (Esketamine) Nasal Spray: Comprehensive Clinical Guide
Core Recommendation
Spravato is reserved exclusively for treatment-resistant depression (TRD) after failure of at least 2 adequate antidepressant trials, and must be administered with mandatory 2-hour post-dose monitoring in a certified healthcare setting under REMS requirements 1, 2.
FDA-Approved Indications
Spravato has two specific FDA-approved indications 2:
- Treatment-Resistant Depression (TRD): As monotherapy or combined with an oral SSRI/SNRI in adults who have failed ≥2 adequate antidepressant trials
- Major Depressive Disorder with Acute Suicidal Ideation or Behavior (MDSI): Combined with an oral antidepressant (must be used in conjunction, not as monotherapy)
Critical caveat: While approved for MDSI, the effectiveness of esketamine in preventing suicide or reducing suicidal ideation/behavior has NOT been established 1.
Dosing Schedule
For Treatment-Resistant Depression 2:
Induction Phase (Weeks 1-4):
- Frequency: Twice weekly
- Dose: 56 mg or 84 mg
- Each dose uses 2 devices (56 mg) or 3 devices (84 mg)
Maintenance Phase (Weeks 5-8):
- Frequency: Once weekly
- Dose: 56 mg or 84 mg
Long-term Maintenance (Week 9+):
- Frequency: Every 2 weeks OR once weekly (individualized)
- Dose: 56 mg or 84 mg
Evaluate therapeutic benefit at end of induction phase (Week 4) to determine if continued treatment is warranted 2.
For MDD with Acute Suicidal Ideation/Behavior 2:
- Standard dose: 84 mg twice weekly for 4 weeks
- Reduced dose: 56 mg twice weekly (if tolerability issues)
- Must be combined with oral antidepressant
- Re-evaluate after 4 weeks - use beyond 4 weeks has not been systematically studied in this population
Administration Requirements
Pre-Administration Preparation 2:
- No food for ≥2 hours before administration
- No liquids for ≥30 minutes before administration
- Nasal corticosteroids/decongestants: Must be given ≥1 hour before Spravato
- Blood pressure screening: Do NOT administer if BP >140/90 mmHg without careful risk-benefit assessment
Device Administration 2:
- Each device delivers 28 mg esketamine (two sprays total)
- Do NOT prime the device (prevents medication loss)
- For 56 mg dose: Use 2 devices
- For 84 mg dose: Use 3 devices
- 5-minute rest required between each device
Mandatory Monitoring Parameters
REMS Requirements 1, 2:
Spravato is available ONLY through a restricted REMS program requiring:
- Pharmacy certification
- Healthcare setting certification
- Mandatory 2-hour post-dose observation at EVERY treatment session
Post-Administration Monitoring 2:
Blood Pressure:
- Reassess at approximately 40 minutes post-dose (corresponds to Cmax)
- Continue monitoring as clinically warranted
- Patient may be discharged after 2 hours ONLY if BP is decreasing and patient is clinically stable
Sedation Monitoring 2:
- 48-61% of patients develop sedation
- 0.3-0.4% experience loss of consciousness
- Use Modified Observer's Assessment of Alertness/Sedation scale (MOAA/S)
- Monitor for diminished breathing
Discharge Criteria:
- Minimum 2 hours observation
- Clinically stable
- Blood pressure decreasing/stable
- Instruct patients NOT to drive or operate machinery until the next day after restful sleep
Absolute Contraindications 2:
- Aneurysmal vascular disease (thoracic/abdominal aorta, intracranial, peripheral arterial vessels)
- Arteriovenous malformation
- History of intracerebral hemorrhage
- Hypersensitivity to esketamine or ketamine
- Do NOT administer if increase in blood pressure or intracranial pressure poses serious risk
Relative Contraindications/Cautions 2:
- Baseline hypertension (BP >140/90 mmHg): Carefully weigh risks vs. benefits
- Concomitant CNS depressants (increased sedation risk)
Positioning in Treatment Algorithm
The 2022 VA/DoD guidelines are explicit: Ketamine and esketamine are NOT recommended as initial treatment but are reserved for patients for whom previous therapies have failed or who have not tolerated previous therapies 1.
When to Consider Spravato:
- After failure of ≥2 adequate antidepressant trials in current moderate-to-severe depressive episode
- Patient has TRD with inadequate response to standard treatments
- Patient has MDD with acute suicidal ideation/behavior requiring rapid intervention
Evidence Base 1:
- Meta-analysis of 5 RCTs: Twice-weekly esketamine as augmentation improved depressive symptoms and remission rates at 28 days in TRD patients
- Benefits seen specifically in TRD patients with new or optimized antidepressant therapy
- Short-term efficacy established; long-term efficacy and safety data remain limited
Alternative Treatment Options
Before considering Spravato, ensure adequate trials of 1:
- Multiple SSRI/SNRI trials (different agents, adequate dose/duration)
- Augmentation strategies:
- Second-generation antipsychotics (e.g., quetiapine, aripiprazole)
- Lithium
- Psychotherapy (cognitive behavioral therapy, interpersonal therapy)
- Electroconvulsive therapy (ECT) - particularly for severe, refractory cases
Recent evidence suggests potential superiority hierarchy: esketamine > quetiapine > lithium, though head-to-head data remain limited 3.
Critical Clinical Pitfalls
- Do NOT use as first-line treatment - this violates guideline recommendations and FDA indication 1
- Do NOT discharge patients before 2-hour observation period - REMS violation and safety risk 2
- Do NOT allow patients to drive same day - sedation risk persists 2
- Do NOT administer without concurrent oral antidepressant in MDSI indication - FDA requires combination therapy 2
- Do NOT assume suicide prevention efficacy - this has NOT been established despite MDSI indication 1
- Do NOT continue indefinitely without reassessment - evaluate benefit at Week 4 (induction end) 2
- Do NOT administer in patients with vascular disease or hemorrhage history - absolute contraindication 2
Missed Dose Management 2:
- If no worsening of depressive symptoms: Continue current dosing schedule
- If worsening during maintenance: Consider returning to previous more frequent schedule (e.g., weekly → twice weekly)