What is the current evidence on the efficacy, dosing, administration routes, and safety of intravenous ketamine and intranasal esketamine for adult treatment‑resistant major depressive disorder?

Ketamine and Esketamine for Treatment-Resistant Depression

Direct Recommendation

Both intravenous ketamine and intranasal esketamine are effective for treatment-resistant depression, but they are reserved exclusively for patients who have failed at least 2 adequate antidepressant trials—never as first-line therapy. 1, 2, 3

Patient Selection Criteria

Treatment-resistant depression must be clearly documented before initiating ketamine-based therapies:

• Patients must have failed at least 2 antidepressants with different mechanisms of action (per Neuroscience-based Nomenclature) 3
• Each trial must be at minimum approved dosage for at least 4 weeks duration 3
• Improvement must be less than 25% on validated depression scales (PHQ-9, MADRS, HAM-D) for both medications 1, 3
• Failed psychotherapy courses do not count toward TRD definition but should be documented 3

Administration Routes and Dosing

Intravenous Ketamine

IV ketamine demonstrates efficacy at doses as low as 0.2 mg/kg, with optimal response at 0.5 mg/kg:

• Doses ≤0.2 mg/kg show treatment response 4
• Doses >0.2-0.5 mg/kg demonstrate increasing dose response 4
• Doses >0.5 mg/kg (up to 1 mg/kg) do not provide demonstrable increased benefit 4
• Single-dose effects persist for 3-7 days when added to ongoing antidepressant treatment 2, 5
• IV ketamine shows more rapid response (significant after 1 treatment) and greater overall efficacy (49.22% reduction in depression scores by eighth session) compared to intranasal esketamine 6

Intranasal Esketamine

Esketamine is FDA-approved for TRD with specific dosing parameters:

• Doses of 56-84 mg are superior to 28 mg dose 4
• Administered twice-weekly during induction phase 2
• Response reaches significance after the second treatment 6
• Results in 39.55% reduction in depression scores by eighth treatment 6
• Must be administered under medical supervision per FDA REMS requirements 5

Efficacy and Timeline

Both agents produce rapid antidepressant effects, but with different timelines:

• Significant improvement occurs within 24 hours after single-dose ketamine administration 2
• Esketamine as augmentation therapy improves symptoms and remission rates up to 28 days 1, 2
• Both treatments significantly reduce depressive symptoms and suicidal ideation by treatment endpoint in real-world settings 7
• The largest effect sizes for suicidal ideation reduction occur at 40 minutes post-administration (d = 1.05), particularly in patients with high baseline suicidal ideation (d = 2.36) 2

Critical Limitation on Suicide Prevention

The FDA explicitly states that the effectiveness of ketamine and esketamine in preventing suicide or reducing suicidal ideation/behavior has not been established 2

Concurrent Treatment Requirements

Patients must continue or initiate second-generation antidepressants alongside ketamine therapy:

• Ketamine/esketamine should be used as augmentation, not monotherapy 2
• For bipolar patients, mood stabilizers must be prioritized and used concurrently 3

Safety Monitoring Requirements

Immediate Monitoring (During and Shortly After Administration)

Blood pressure monitoring is mandatory due to hypertensive effects:

• Monitor for dissociative symptoms using validated scales (CADSS-6) 7
• Monitor for sedation and potential respiratory depression 2, 3
• Most side effects are time-dependent, mild, and transient 7, 8
• Dissociative symptoms (38%) and sedation (26%) are most frequently reported 8

Long-Term Surveillance

Ongoing monitoring is required due to absence of long-term safety data:

• Assess for abuse and misuse potential throughout treatment 3, 5
• Monitor for development of substance use disorder 3
• Surveillance for neurocognitive effects with long-term use 2, 3
• Monitor for possible urologic toxicity with chronic administration 2

Special Population Considerations

Patients with comorbid substance use disorder can be treated but require enhanced monitoring:

• Esketamine shows effectiveness and safety in TRD patients comorbid with substance use disorder 8
• No cases of abuse or misuse were reported in observational studies of SUD patients 8
• All reported side effects were time-dependent without significant sequelae 8

Common Pitfalls to Avoid

Using ketamine/esketamine as first-line therapy represents inappropriate use 2

• Do not initiate treatment without documented failure of at least 2 adequate antidepressant trials 2, 3
• Do not assume suicide prevention efficacy—this has not been established despite rapid reduction in suicidal ideation 2
• Do not use doses above 0.5 mg/kg for IV ketamine expecting greater benefit—higher doses do not improve outcomes 4
• Do not use 28 mg esketamine when 56-84 mg doses show superior efficacy 4

Evidence Quality Considerations

The 2022 VA/DoD Clinical Practice Guidelines represent a major shift from their 2016 position, now suggesting ketamine or esketamine as treatment options for TRD 2. However, the most significant limitation across all evidence is the absence of long-term safety and efficacy data for both formulations in major depressive disorder 2. The bulk of evidence comes from short-term studies in patients who have previously not responded to adequate antidepressant trials 1.