What are the indications, recommended dosing schedule, required administration setting, monitoring parameters, contraindications, common adverse effects, and alternative treatment options for Spravato (esketamine) nasal spray in adult patients with major depressive disorder refractory to at least two oral antidepressants?

Spravato (Esketamine) for Treatment-Resistant Depression

Indications

Spravato is FDA-approved exclusively for treatment-resistant depression (TRD) in adults who have failed at least 2 adequate antidepressant trials, and for depressive symptoms in adults with MDD who have acute suicidal ideation or behavior—always in conjunction with an oral antidepressant. 1

• TRD is defined as failure of at least 2 adequate trials of antidepressants with different mechanisms of action, each at minimum approved dosage for at least 4 weeks duration 2
• Improvement must be less than 25% on validated depression scales for both failed medications 2
• Esketamine is explicitly NOT indicated as initial treatment for depression—patients who have not failed adequate antidepressant trials should not receive esketamine 2, 1
• The FDA states that effectiveness in preventing suicide or reducing suicidal ideation/behavior has not been established 3, 1

Dosing Schedule

Treatment-Resistant Depression

Induction Phase (Weeks 1-4): 56 mg or 84 mg twice weekly 1

• Starting dose is 56 mg for adults <65 years and 28 mg for adults ≥65 years 4
• Dosage adjustments based on efficacy and tolerability 1

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 1

• Dosing frequency should be individualized to the least frequent dosing to maintain remission/response 1
• Evidence of therapeutic benefit must be evaluated at the end of the induction phase to determine need for continued treatment 1

MDD with Acute Suicidal Ideation or Behavior

84 mg twice weekly for 4 weeks in conjunction with an oral antidepressant 1

• May be reduced to 56 mg twice weekly based on tolerability 1
• Use beyond 4 weeks has not been systematically evaluated for this indication 1

Required Administration Setting

Spravato must be administered under direct supervision of a healthcare provider in a certified healthcare setting 1

• Each treatment session consists of nasal administration plus mandatory post-administration observation 1
• Patients must be observed for at least 2 hours after each dose until safe to leave 1
• Patients cannot drive or operate machinery until the next day after a restful sleep 1

Monitoring Parameters

Pre-Administration Requirements

• Blood pressure assessment before dosing—if baseline BP is elevated (>140 mmHg systolic, >90 mmHg diastolic), consider risks versus benefits 1
• Patients should avoid food for at least 2 hours before administration 1
• Patients should avoid liquids for at least 30 minutes before administration 1
• Nasal corticosteroids or decongestants must be administered at least 1 hour before Spravato 1

During and Post-Administration Monitoring

• Respiratory status monitoring for at least 2 hours, including pulse oximetry 1
• Blood pressure reassessment at approximately 40 minutes post-dose (corresponding with peak concentration) and subsequently as clinically warranted 1
• Monitor for dissociative symptoms, sedation, and potential respiratory depression 3, 2
• Patient may be discharged after 2 hours if BP is decreasing and patient appears clinically stable; if not, continue monitoring 1

Ongoing Surveillance

• Use validated depression scales (PHQ-9, MADRS, HAM-D) to assess therapeutic benefit from baseline to current visit 5
• Monitor for abuse and misuse potential throughout treatment 3, 2
• Assess for development of substance use disorder 3, 2
• Ongoing surveillance for neurocognitive effects and urologic toxicity due to absence of long-term safety data 3, 2

Contraindications

Absolute contraindications per FDA labeling: 1

• Aneurysmal vascular disease (thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation 1
• History of intracerebral hemorrhage 1
• Hypersensitivity to esketamine, ketamine, or any excipients 1
• Situations where increase in blood pressure or intracranial pressure poses serious risk 1

Common Adverse Effects

The most common treatment-emergent adverse events (≥20%) are: 6, 7

• Nausea (24.8%) 6
• Dissociation (24.3%) 6
• Dizziness (21.7%) 6, 7
• Headache (19.0%) 6
• Somnolence (≥20%) 7

Important safety considerations:

• Short-term hypertensive effects requiring blood pressure monitoring 3
• Potential for respiratory depression 3
• Risk of abuse and misuse 3
• Unknown neurocognitive effects with long-term use 3
• Possible urologic toxicity with chronic administration 3

Alternative Treatment Options

For patients with treatment-resistant depression who have failed at least 2 adequate antidepressant trials, evidence-based alternatives include: 8

Second-Step Strategies (All Have Similar Efficacy)

• Switching to another antidepressant with different mechanism of action 8
• Switching to cognitive behavioral therapy (CBT) 8
• Augmenting current antidepressant with another medication 8
• Augmenting with cognitive therapy 8

The American College of Physicians emphasizes that the more important decision is simply to try a different evidence-based approach rather than the specific second-step strategy chosen 8

First-Line Alternatives (For Less Refractory Cases)

• CBT has the most reliable evidence indicating similar treatment benefits as antidepressants with lower risks for discontinuation due to adverse events 8
• St. John's wort also has reliable evidence with lower discontinuation rates than antidepressants 8

Critical Clinical Pitfalls

Common errors to avoid:

• Using esketamine as first-line therapy represents inappropriate use 3
• Failing to document adequate dose and duration (minimum 4 weeks at therapeutic doses) for each failed antidepressant trial 5, 2
• Discharging patients before 2-hour mandatory observation period 1
• Allowing patients to drive or operate machinery on treatment day 1
• Administering when baseline blood pressure is significantly elevated without risk-benefit assessment 1
• Counting failed psychotherapy courses toward TRD definition (only failed medication trials count) 2

Recent high-quality evidence demonstrates esketamine monotherapy is effective: A 2025 JAMA Psychiatry randomized controlled trial showed both 56 mg and 84 mg doses of esketamine monotherapy significantly reduced MADRS scores compared to placebo at day 28 (effect sizes 0.48 and 0.63 respectively), with rapid onset at 24 hours post-first dose 6. This expands treatment options for patients with treatment-limiting tolerability concerns with oral antidepressants 6.