What are the indications, dosing schedule, monitoring requirements, contraindications, and alternative treatment options for Spravato (esketamine nasal spray) in adults with treatment‑resistant major depressive disorder?

Spravato (Esketamine Nasal Spray) for Treatment-Resistant Depression

Primary Recommendation

Spravato should be reserved exclusively for adults with treatment-resistant depression who have failed at least 2 adequate trials of different antidepressant medications, administered as augmentation to an ongoing oral SSRI or SNRI, not as monotherapy or first-line treatment. 1, 2

---

Indications

Spravato is FDA-approved for two specific populations 2:

1. Treatment-Resistant Depression (TRD): Adults who have failed ≥2 adequate antidepressant trials during the current moderate-to-severe depressive episode

   • Can be used as monotherapy OR in conjunction with oral antidepressant
   • Must document failure of at least 2 different mechanisms of action 3

2. Major Depressive Disorder with Acute Suicidal Ideation or Behavior: Adults with MDD and acute suicidal ideation/behavior

   • MUST be used in conjunction with oral antidepressant (SSRI or SNRI)
   • Critical limitation: Effectiveness in preventing suicide or reducing suicidal ideation has NOT been established 2
   • Does not replace hospitalization when clinically warranted

The 2022 VA/DoD guidelines represent a significant shift from 2016, when ketamine was recommended against outside research settings. Current evidence now supports esketamine as a treatment option specifically for patients who have not responded to several adequate pharmacologic trials 1.

---

Dosing Schedule

For Treatment-Resistant Depression 2:

Induction Phase (Weeks 1-4):

• Twice weekly administration
• Starting dose: 56 mg for adults <65 years; 28 mg for adults ≥65 years 4
• Subsequent doses: 56 mg or 84 mg (adjust based on efficacy/tolerability)

Maintenance Phase (Weeks 5-8):

• Once weekly administration
• Dose: 56 mg or 84 mg

Long-term Maintenance (Week 9 onward):

• Every 2 weeks OR once weekly (individualized to least frequent dosing maintaining remission)
• Dose: 56 mg or 84 mg
• Evaluate therapeutic benefit at end of induction phase to determine continuation 2
• Treatment recommended for ≥6 months after symptom improvement 4

For MDD with Acute Suicidal Ideation/Behavior 2:

• 84 mg twice weekly for 4 weeks (in conjunction with oral antidepressant)
• May reduce to 56 mg twice weekly if tolerability issues
• Evaluate therapeutic benefit after 4 weeks
• Use beyond 4 weeks has NOT been systematically evaluated for this indication

---

Mandatory Monitoring Requirements

Spravato is ONLY available through a REMS program requiring certified healthcare settings, pharmacies, and mandatory supervision 1, 2.

Pre-Administration Requirements:

• Blood pressure assessment: Do NOT administer if baseline BP >140/90 mmHg poses serious risk 2
• Contraindication screening: Exclude aneurysmal vascular disease, arteriovenous malformation, intracerebral hemorrhage history 2
• Patient preparation:
  • No food for ≥2 hours before administration
  • No liquids for ≥30 minutes before administration
  • Nasal corticosteroids/decongestants must be given ≥1 hour before Spravato 2

During and Post-Administration (MANDATORY 2-hour minimum observation) 2:

1. Continuous monitoring for sedation and dissociation 2

2. Respiratory status monitoring including pulse oximetry for at least 2 hours 2

3. Blood pressure reassessment:

   • At approximately 40 minutes post-dose (corresponds to Cmax) 2, 5
   • Subsequently as clinically warranted
   • Patient may be discharged only when BP decreasing and clinically stable for ≥2 hours

4. Discharge criteria: Patient must be assessed as safe to leave before discharge 2

5. Post-discharge restriction: No driving or operating machinery until next day after restful sleep 2

---

Absolute Contraindications 2

• Aneurysmal vascular disease (thoracic/abdominal aorta, intracranial, peripheral arterial vessels)
• Arteriovenous malformation
• History of intracerebral hemorrhage
• Conditions where increased blood pressure or intracranial pressure poses serious risk

---

Critical Safety Warnings 2

Black Box Warnings include:

1. Sedation risk: Mandatory monitoring
2. Dissociation/perceptual changes: Mandatory monitoring
3. Respiratory depression: Observed in post-marketing experience
4. Abuse and misuse potential: Schedule 2 controlled substance; monitor for signs of abuse
5. Suicidal thoughts/behaviors: Standard antidepressant warning for young adults

---

Alternative Treatment Options

When esketamine is not appropriate or has failed, consider these evidence-based alternatives for TRD 1:

Interventional Treatments:

1. Repetitive Transcranial Magnetic Stimulation (rTMS): Recommended for TRD with minimal adverse events; requires frequent onsite visits 1
2. Electroconvulsive Therapy (ECT): For multiple treatment failures or need for rapid improvement 1
3. Intravenous ketamine infusion: Off-label use; shows efficacy for up to 7 days when added to ongoing antidepressant 1

Pharmacological Alternatives:

• Switching to different antidepressant class (different mechanism of action per NbN classification) 3, 6
• Augmentation strategies: Adding second medication to existing antidepressant 6
• Extended-release quetiapine augmentation: Direct comparator showing inferior efficacy to esketamine (remission 17.6% vs 27.1% at week 8) 7

Psychotherapy:

• Cognitive Behavioral Therapy (CBT): ACP recommends as equivalent first-line option to antidepressants 8, 6
• Other evidence-based psychotherapies per VA/DoD guidelines 1

NOT Recommended Outside Research:

• Psilocybin/hallucinogens 1
• MDMA, cannabis, other unapproved agents 1

---

Clinical Positioning in Treatment Algorithm

Esketamine occupies a specific third-line position 1:

1. First-line: Standard antidepressants (SSRIs, SNRIs) or CBT
2. Second-line: Switch to different mechanism antidepressant OR augmentation strategy
3. Third-line: Esketamine (after ≥2 adequate antidepressant failures) OR rTMS
4. Fourth-line: ECT (for severe/refractory cases)

Key evidence: Meta-analysis of 5 RCTs showed twice-weekly esketamine augmentation improved depressive symptoms and remission rates at 28 days, but ONLY in patients with TRD who had failed ≥2 prior adequate trials 1. The 2023 ESCAPE-TRD trial demonstrated superiority over quetiapine augmentation (27.1% vs 17.6% remission at week 8) 7.

---

Critical Implementation Pitfalls

1. Do NOT use as first-line treatment: Reserved only after documented failure of ≥2 adequate antidepressant trials 1

2. Do NOT discharge prematurely: Full 2-hour monitoring is mandatory regardless of apparent clinical stability 2

3. Do NOT use for suicidality prevention: Despite approval for MDD with acute suicidal ideation, effectiveness in preventing suicide is NOT established 1, 2

4. Do NOT continue indefinitely without reassessment: Evaluate therapeutic benefit at end of induction phase (week 4) 2

5. Long-term safety unknown: Lacks long-term efficacy and safety trials; limited information on consequences of prolonged therapy 1

6. Abuse potential: Schedule 2 controlled substance; assess abuse risk before prescribing and monitor throughout treatment 2

7. Cardiovascular monitoring essential: Short-term BP increases are expected; contraindicated when BP elevation poses serious risk 2