What is the role of ketamine (specifically esketamine) in combination with an oral antidepressant, such as a Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin-Norepinephrine Reuptake Inhibitor (SNRI), in treating adults with treatment-resistant depression?

Ketamine Treatment with Antidepressant for Treatment-Resistant Depression

Direct Recommendation

Esketamine nasal spray (56-84 mg) combined with an oral antidepressant (SSRI or SNRI) should be used for adults with treatment-resistant depression who have failed at least 2 adequate antidepressant trials at appropriate doses and durations. 1, 2

Patient Selection Criteria

Reserve ketamine/esketamine exclusively for confirmed treatment-resistant cases:

• Patients must have documented failure of at least 2 adequate antidepressant trials (appropriate dose and duration) during the current depressive episode 1, 2
• Document baseline depression severity using MADRS or PHQ-9 before initiating treatment 3
• Do not use esketamine as initial treatment—this represents explicit guidance from major clinical practice guidelines 1

Treatment Protocol

Induction Phase (Weeks 1-4)

• Administer esketamine 56 mg or 84 mg intranasally twice weekly in conjunction with ongoing oral antidepressant 2
• The 84-mg dose demonstrates superior efficacy with an effect size of 0.63 compared to 0.48 for the 56-mg dose 4
• Expect rapid symptom improvement within 24 hours after the first dose, with statistically significant reductions in MADRS scores by day 2 4

Maintenance Phase (Week 5 onward)

• Weeks 5-8: Administer once weekly (56 mg or 84 mg) 2
• Week 9 and beyond: Administer every 2 weeks or once weekly based on sustained remission 2
• Evaluate therapeutic benefit at the end of the induction phase to determine continuation 2

Mandatory Safety Monitoring

Each treatment session requires strict adherence to monitoring protocols:

Pre-Administration Requirements

• Assess baseline blood pressure; do not administer if systolic >140 mmHg or diastolic >90 mmHg poses serious risk 2
• Patients must avoid food for at least 2 hours and liquids for at least 30 minutes before administration 2
• Administer nasal corticosteroids or decongestants at least 1 hour before esketamine if needed 2

During and Post-Administration Monitoring

• Monitor respiratory status continuously for at least 2 hours, including pulse oximetry 2
• Reassess blood pressure at approximately 40 minutes post-dose (corresponding to peak concentration) 2
• Observe for dissociative symptoms, sedation, and clinical stability for minimum 2 hours before discharge 2
• Patient cannot leave until clinically stable with decreasing blood pressure 2

Expected Outcomes and Efficacy

Esketamine combined with oral antidepressants demonstrates superior outcomes compared to alternatives:

• Remission rates reach 55.7% by week 32 with esketamine versus 36.3% with quetiapine XR 5
• Significant improvement in MADRS scores occurs as early as day 8 and persists through long-term treatment 5
• Response rates at day 28 show statistically significant reductions: -5.1 points for 56 mg and -6.8 points for 84 mg compared to placebo 4

Common Adverse Effects

Anticipate and manage the following treatment-emergent adverse events:

• Dissociation (24.3%), nausea (24.8%), dizziness (21.7%), and headache (19.0%) are most common 4
• Hypertension requiring blood pressure monitoring occurs frequently 1
• Sedation and potential respiratory depression mandate supervised administration 2
• Discontinuation due to adverse events occurs in only 4.5% of esketamine-treated patients 5

Critical Safety Warnings

The FDA mandates a Risk Evaluation and Mitigation Strategy (REMS) program due to serious risks:

• Esketamine has abuse and misuse potential; monitor for drug-seeking behaviors and craving symptoms 2, 6
• If craving develops, implement slow esketamine de-titration combined with bupropion augmentation 6
• The effectiveness in preventing suicide or reducing suicidal ideation has NOT been established 2
• Antidepressants increase risk of suicidal thoughts in young adults; closely monitor all patients 2
• Esketamine is only available through the restricted SPRAVATO REMS program 2

Contraindications

Do not administer esketamine in the following situations:

• When increased blood pressure or intracranial pressure poses serious risk 2
• Baseline blood pressure exceeding safe thresholds (>140/90 mmHg) without careful risk-benefit assessment 2

Long-Term Considerations

Recognize the limitations of current evidence:

• Long-term safety and efficacy data beyond 32 weeks remain limited 1
• Unknown neurocognitive effects with chronic use require ongoing surveillance 1
• Potential urologic toxicity with chronic administration has been reported in ketamine literature 1
• Maintenance treatment requires individualized dosing frequency to sustain remission while minimizing exposure 2

Comparison to Monotherapy

Recent evidence supports esketamine monotherapy as an alternative:

• A 2025 randomized trial demonstrated esketamine monotherapy (without oral antidepressant) significantly reduces depressive symptoms in TRD 4
• However, FDA approval and established guidelines recommend combination with oral antidepressant 2, 1
• Monotherapy may address patients with treatment-limiting tolerability to oral antidepressants 4

Practical Implementation

The 2022 VA/DoD guidelines represent a major shift, now suggesting ketamine/esketamine as viable options after multiple treatment failures, whereas their 2016 position did not include these agents 7, 1. This expansion of treatment options provides critical alternatives for patients who have exhausted traditional pharmacologic interventions, though the requirement for supervised administration and REMS enrollment creates logistical barriers 2.