What evidence supports the use of intravenous ketamine versus intranasal esketamine (Spravato) in adults with treatment‑resistant major depressive disorder?

Evidence Supporting IV Ketamine Versus Intranasal Esketamine (Spravato)

For treatment-resistant depression, intranasal esketamine (Spravato) is the preferred choice over IV ketamine because it has FDA approval, stronger long-term maintenance data, and superior evidence for sustained remission beyond the acute phase. 1

Key Regulatory and Practical Distinctions

• Esketamine is FDA-approved specifically for treatment-resistant depression, while IV ketamine remains an off-label use despite widespread clinical adoption. 1
• Esketamine requires REMS certification for both the pharmacy and treatment site, with mandatory 2-hour post-administration monitoring—a regulatory burden that reflects its controlled approval pathway. 1
• Both agents are reserved exclusively for patients who have failed at least 2 adequate antidepressant trials at appropriate doses and durations; neither should be used as first-line therapy. 1, 2

Comparative Acute Efficacy

The most recent and highest-quality meta-analysis directly comparing these agents found no significant difference in acute response or remission rates:

• Pooled analysis of 7 observational studies (n=915) showed comparable response rates (OR 1.26,95% CI 0.92-1.71, p=0.15) and remission rates (OR 1.31,95% CI 0.93-1.86, p=0.12), with negligible heterogeneity. 3
• IV ketamine may offer faster onset of action, with evidence ranging from significant in one study to modest trends in two others, though this advantage is clinically marginal. 3
• A 2024 real-world observational study (n=53) confirmed that both treatments significantly reduced depressive symptoms and suicidal ideation by endpoint, with similar tolerability profiles and only mild, transient side effects. 4

Critical Advantage: Long-Term Maintenance

The decisive factor favoring esketamine is its superior evidence for sustained benefit:

• When used twice weekly as augmentation therapy, esketamine improves response and remission rates by approximately 16% at 4 weeks and has more robust evidence for long-term maintenance compared with IV ketamine. 1
• IV ketamine's antidepressant benefit from a single infusion generally wanes after about one week; without a maintenance plan, most responders relapse within two weeks after the final infusion. 1
• Meta-analyses demonstrate that esketamine as augmentation to ongoing oral antidepressants improved depressive symptoms and remission rates in TRD patients at up to 28 days of follow-up. 2, 5
• IV ketamine lacks long-term efficacy and safety studies in major depression, with most evidence limited to short-term (7-day) efficacy. 1, 2

Dosing Protocols

IV Ketamine

• Standard evidence-based dose: 0.5 mg/kg infused over 40 minutes, administered twice weekly for 4–6 infusions as add-on therapy. 1
• Meta-analysis shows efficacy at doses as low as 0.2 mg/kg, with increasing dose response at 0.5 mg/kg, but no demonstrable increased benefit at 1 mg/kg. 6
• In treatment-resistant populations, a series of six infusions yields response rates of approximately 42% and remission rates of 14–17%. 1

Intranasal Esketamine

• Efficacy increases with doses above 28 mg, with best response found between 56–84 mg for reducing depressive symptoms. 6
• Administered twice weekly with mandatory 2-hour post-dose monitoring. 1

Safety and Tolerability

• Both agents produce similar adverse effect profiles: transient dissociation, nausea, ataxia, modest blood pressure elevation, and psychotomimetic symptoms (hallucinations, nightmares) in roughly 20% and 12% of patients respectively, all resolving quickly after administration. 1, 4
• Patients receiving esketamine and those receiving IV ketamine had similar risk of developing side effects in head-to-head comparison. 4
• Long-term safety concerns for both formulations include potential for abuse and misuse, unknown neurocognitive effects with chronic use, possible urologic toxicity, and risk of substance use disorder development—all requiring ongoing surveillance. 2

Clinical Algorithm for Selection

Start with intranasal esketamine for the following reasons:

1. FDA approval provides regulatory support and standardized protocols. 1
2. Superior long-term maintenance data reduces relapse risk. 1
3. Comparable acute efficacy to IV ketamine. 3

Consider IV ketamine only when:

• Esketamine is not accessible due to REMS requirements or insurance barriers.
• Faster onset is critical (e.g., acute suicidal ideation in emergency settings, though evidence for suicide prevention remains unestablished). 1, 2
• Patient has failed esketamine trial and requires alternative glutamatergic modulation.

Critical Pitfalls to Avoid

• Never use either agent as monotherapy—the strongest evidence supports their role exclusively as augmentation to ongoing antidepressants. 1
• Do not expect sustained remission without a maintenance strategy—current data demonstrate only short-term efficacy; planning for continuation is essential. 1
• If initiating IV ketamine and achieving acute response, transition to esketamine for maintenance given its stronger long-term efficacy data. 1
• The FDA explicitly states that effectiveness in preventing suicide or reducing suicidal ideation/behavior has not been established for either agent. 2