In an adult with treatment‑resistant major depressive disorder (failed ≥2 antidepressant trials) who cannot undergo electroconvulsive therapy, how should ketamine (intravenous racemic) or intranasal esketamine be used—including indications, dosing regimen, monitoring, contraindications, and alternative treatments?

Ketamine and Esketamine for Treatment-Resistant Depression

Direct Recommendation

For adults with treatment-resistant major depressive disorder (failed ≥2 adequate antidepressant trials) who cannot undergo ECT, use intranasal esketamine 56-84 mg or intravenous racemic ketamine as augmentation to an ongoing oral antidepressant, with mandatory 2-hour post-dose monitoring in a healthcare setting. 1, 2

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Patient Selection Criteria

Defining Treatment-Resistant Depression

• Treatment resistance requires documented failure of at least 2 adequate antidepressant trials at appropriate doses and durations during the current depressive episode. 1, 3
• Explicitly confirm adequate dose and duration for each failed trial in documentation. 3
• Neither ketamine nor esketamine should be used as initial treatment—this represents inappropriate use. 1, 4

Contraindications (Absolute)

• Aneurysmal vascular disease (thoracic/abdominal aorta, intracranial, peripheral arterial vessels) or arteriovenous malformation. 2
• History of intracerebral hemorrhage. 2
• Hypersensitivity to esketamine or ketamine. 2
• Situations where acute blood pressure or intracranial pressure increases pose serious risk. 2

Relative Contraindications Requiring Risk-Benefit Assessment

• Baseline hypertension (systolic >140 mmHg or diastolic >90 mmHg) requires careful consideration of short-term blood pressure increases versus treatment benefit. 2

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Dosing Regimens

Intranasal Esketamine (FDA-Approved)

Induction Phase (Weeks 1-4):

• Administer 56 mg or 84 mg twice weekly. 2
• Use 2 devices for 56 mg dose or 3 devices for 84 mg dose (each device delivers 28 mg). 2
• Allow 5-minute rest between each device. 2

Maintenance Phase (Weeks 5-8):

• Administer 56 mg or 84 mg once weekly. 2

Extended Maintenance (Week 9 onward):

• Administer 56 mg or 84 mg every 2 weeks or once weekly based on individual response. 2
• Evaluate evidence of therapeutic benefit at end of induction phase (week 4) to determine need for continuation. 2

Intravenous Racemic Ketamine (Off-Label)

• Single subanesthetic-dose IV infusion produces rapid improvement (within 24 hours) with effects lasting 3-7 days when added to ongoing antidepressant treatment. 1, 5
• Twice-weekly dosing during induction improves symptoms and remission rates up to 28 days. 1

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Administration Protocol

Pre-Administration Requirements

• Patients must avoid food for at least 2 hours before administration. 2
• Patients must avoid liquids for at least 30 minutes before administration. 2
• If nasal corticosteroid or decongestant needed, administer at least 1 hour before esketamine. 2
• Patients must continue or initiate a second-generation oral antidepressant alongside ketamine/esketamine. 1, 2

During Administration

• Do not prime the nasal spray device before use to prevent medication loss. 2
• Esketamine is available only through a restricted REMS program requiring administration under medical supervision. 2, 5

Post-Administration Monitoring (Mandatory)

• Observe patient for at least 2 hours after each treatment session until clinically stable and safe to leave. 2, 5
• Measure blood pressure at approximately 40 minutes post-dose (corresponds with peak concentration). 2
• Continue monitoring blood pressure as clinically warranted. 2
• Patient may be discharged only if blood pressure is decreasing and patient appears clinically stable for at least 2 hours. 2
• Monitor for sedation, dissociative symptoms, and respiratory depression. 1, 2

Post-Discharge Instructions

• Instruct patients not to drive or operate machinery until the next day after restful sleep. 2

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Monitoring Requirements

Acute Monitoring (Each Session)

• Blood pressure monitoring at 40 minutes and as needed (48-61% of patients develop sedation; 0.3-0.4% experience loss of consciousness). 2, 5
• Assess for dissociative symptoms, nausea, dizziness, headache, vertigo, somnolence. 2, 6

Ongoing Assessment

• Use validated depression scales (PHQ-9, MADRS, HAM-D) to document therapeutic benefit from baseline to current visit. 3
• A reduction in PHQ-9 score of at least 50% represents treatment response threshold. 3
• Monitor for rare adverse effects including panic attacks, mania, ataxia, akathisia, self-harm ideation, increased talkativeness. 6

Long-Term Surveillance Concerns

• Potential for abuse and misuse. 1
• Unknown neurocognitive effects with long-term use. 1
• Possible urologic toxicity with chronic administration. 1
• Risk of substance use disorder development. 1
• The most significant limitation is absence of long-term safety and efficacy data for both formulations in MDD. 1

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Expected Outcomes

Efficacy Timeline

• Significant improvement in depressive symptoms occurs within 24 hours after single-dose ketamine administration. 1, 5
• Effects persist for 3-7 days with single-dose IV ketamine. 1, 5
• Esketamine as augmentation therapy improves symptoms and remission rates up to 28 days with twice-weekly dosing. 1
• Recent monotherapy trial showed effect sizes of 0.48 for 56 mg and 0.63 for 84 mg doses at day 28. 7

Response Rates

• MCID (Minimal Clinically Important Difference) achieved in 47.1% of patients. 8
• Response rate (≥50% improvement) of 26.8%. 8
• Remission rate of 15.6%. 8
• In highly treatment-resistant patients (average 8.1 antidepressant trials plus ECT in 63%), 45.9% continued treatment after 6 weeks to maintain positive effects. 8

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Management of Missed Doses

• If patient misses treatment sessions without worsening depressive symptoms, continue current dosing schedule. 2
• If patient misses sessions during maintenance with worsening depression, revert to previous dosing schedule (e.g., from weekly back to twice-weekly). 2

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Alternative Treatments When Ketamine/Esketamine Unavailable or Contraindicated

Based on 2022 VA/DoD Guidelines

• Electroconvulsive therapy remains gold standard for multiple prior treatment failures or need for rapid improvement (though patient cannot undergo ECT per scenario). 9
• Range of psychotherapy options including cognitive behavioral therapy. 9
• Bright light therapy for expanded treatment choices. 9
• Pharmacogenomics-guided antidepressant selection (though evidence still developing). 9

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Critical Safety Considerations

Suicidality Caveat

• The FDA explicitly states that effectiveness of esketamine in preventing suicide or reducing suicidal ideation/behavior has not been established. 1, 2
• While preliminary evidence suggested rapid reduction in suicidal ideation, studies had mixed results at different timepoints and were underpowered. 1
• Do not use ketamine/esketamine primarily for suicide prevention. 1

Drug Interactions

• Closely monitor for sedation with concomitant CNS depressants. 2

Common Pitfalls to Avoid

• Using ketamine/esketamine as first-line therapy without adequate antidepressant trials. 1, 4
• Failing to continue oral antidepressant during ketamine/esketamine treatment. 1
• Inadequate post-dose monitoring period (<2 hours). 2
• Allowing patients to drive or operate machinery same day as treatment. 2
• Not documenting objective improvement with validated scales for continuation decisions. 3