What are the latest guidelines for prescribing esketamine (generic name) for treatment-resistant depression?

Latest Guidelines for Prescribing Esketamine

Patient Selection Criteria

Esketamine nasal spray (Spravato®) should be reserved exclusively for adults with treatment-resistant depression who have failed at least 2 adequate antidepressant trials of different mechanisms of action at appropriate doses for at least 4 weeks each. 1, 2

Defining Treatment-Resistant Depression

• Patients must have failed 2 established (licensed) antidepressants for major depressive disorder with different mechanisms of action according to the Neuroscience-based Nomenclature (NbN) 3
• Each antidepressant trial must be at minimum approved dosage for at least 4 weeks duration 3
• Improvement must be less than 25% on validated scales (MADRS or clinical records) for both medications 3
• Failed psychotherapy courses do not count toward the definition of treatment-resistant depression but should be documented 3
• Discontinuation before 4 weeks without clear evidence of non-response should not be considered treatment failure 3

Critical FDA Limitation

• Esketamine's effectiveness in preventing suicide or reducing suicidal ideation/behavior has NOT been established, despite its approval for major depressive disorder with acute suicidal ideation or behavior 1

Dosing and Administration Protocol

Induction Phase (Weeks 1-4)

• Start with 56 mg intranasal twice weekly 2
• May titrate up to 84 mg starting with the second dose based on efficacy and tolerability 2
• Must be administered in conjunction with a newly initiated oral antidepressant (duloxetine, escitalopram, sertraline, or extended-release venlafaxine) 2
• At Day 28, approximately 67% of patients require the 84 mg dose 2

Maintenance Phase (Week 5 onwards)

• Weeks 5-8: Weekly dosing 4
• After Week 8: Weekly or every 2 weeks based on response 4

Recent Monotherapy Evidence

• A 2025 randomized clinical trial demonstrated esketamine monotherapy (without concurrent oral antidepressant) showed significant efficacy at both 56 mg and 84 mg doses, with effect sizes of 0.48 and 0.63 respectively 5
• However, FDA approval still requires concurrent oral antidepressant therapy 2

Mandatory Monitoring Requirements

During Each Treatment Session

• Blood pressure monitoring is required due to hypertensive effects 1, 2
• Monitor for dissociative symptoms during and after administration 1
• Monitor for sedation and potential respiratory depression 1
• Pulse oximetry is recommended within the post-dose observation period to detect respiratory depression 6
• Post-dose observation period is mandatory before patient discharge 6

Ongoing Surveillance

• Monitor for abuse and misuse potential throughout treatment 1
• Assess for development of substance use disorder 1
• Watch for urologic toxicity with chronic administration 1
• Evaluate neurocognitive effects with long-term use 1

Expected Efficacy Timeline

• Most treatment effect occurs within 24 hours of the first dose 2
• Significant improvement in depressive symptoms persists for 3-7 days after single-dose administration 1
• Both esketamine and placebo groups continue to improve between 24 hours and Day 28, with the difference generally remaining stable 2
• At Day 28, esketamine plus oral antidepressant showed a mean difference of -4.0 points on MADRS compared to placebo (95% CI: -7.3 to -0.6) 2

Adverse Event Profile and Management

Most Common Adverse Events (Week 1)

• Nausea: 24.8% 5
• Dissociation: 24.3% 5
• Dizziness: 21.7% 5
• Headache: 19.0% 5
• Dysgeusia, somnolence, vertigo, and increased blood pressure also occur 7

Temporal Pattern of Adverse Events

• Adverse events are highest in Week 1 and decrease substantially with ongoing treatment 4
• Events that occur more frequently during Week 1 (twice > once) are more likely to recur after the first week 4
• The majority of adverse events are mild to moderate in severity 4
• Initial occurrences and subsequent recurrences remain mostly mild or moderate 4

Respiratory Depression

• No respiratory depression events occurred in Phase 3 clinical trials 6
• Postmarketing incidence is extremely low: approximately 1 case per 20,000 treatment sessions 6
• Symptoms are manageable and resolve with minor supportive measures 6
• Pulse oximetry monitoring is recommended during the post-dose observation period 6

Addiction and Craving Potential

• Case reports document drug-seeking behaviors and craving symptomatology in esketamine-treated patients 8
• If craving develops, slow esketamine de-titration combined with bupropion has been effective 8
• Literature on addictive potential shows contradictory findings, requiring vigilant monitoring 8

Contraindications and Special Populations

Not Indicated For

• Initial treatment of depression (must fail 2 adequate trials first) 1
• Conversion disorder (no evidence, different pathophysiology) 9
• Patients who have not failed adequate antidepressant trials 1

Bipolar Depression Considerations

• Reserve for bipolar patients who have failed at least 2 adequate antidepressant trials 10
• Mood stabilizers (particularly lithium) should be prioritized and used concurrently 10
• Risk of manic switch is heightened during maintenance phase 10
• Intensified monitoring for hypomanic/manic symptoms is necessary during maintenance treatment 10

Long-Term Safety Limitations

• The most significant limitation is the absence of long-term safety and efficacy data for esketamine in major depressive disorder 1
• Concerns requiring ongoing surveillance include neurocognitive effects, urologic toxicity, and substance use disorder development 1
• Acute effects typically last only 3-7 days, necessitating ongoing treatment 10