How to Choose Maintenance IV Ketamine or Esketamine for TRD
How should clinicians compare maintenance intravenous ketamine and intranasal esketamine for adults with treatment-refractory depression?
Adults with treatment-refractory depression who improve during acute ketamine-based treatment often need ongoing maintenance, and visit frequency can strongly affect feasibility, cost, and adherence. This study offers real-world data clinicians can use when discussing expected durability, symptom trajectory, and monitoring demands for maintenance IV ketamine versus intranasal esketamine.
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Confirm that the patient matches the studied maintenance population
Apply these comparisons to adults 18 years or older with treatment-refractory depression who had major depressive disorder or bipolar disorder diagnosed by DSM-5 criteria. In this study, treatment-refractory depression meant failure to respond to at least 2 adequate depression treatments in the current episode, including antidepressants, mood stabilizers for bipolar depression, atypical antipsychotics, electroconvulsive therapy, or transcranial magnetic stimulation. The cohort excluded patients with psychotic disorders, substance use disorder within 6 months except nicotine and caffeine, cognitive disorders, and primary psychiatric disorders other than mood disorders.
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Discuss expected durability between maintenance sessions
Tell patients that IV ketamine was associated with longer intervals between maintenance treatments than intranasal esketamine in this observational cohort. Mean treatment intervals were 18.9 days for IV ketamine versus 10.8 days for intranasal esketamine, with an incidence rate ratio of 1.8 favoring IV ketamine. The longest maintenance cycle also lasted a median of 61 weeks with IV ketamine versus 48 weeks with intranasal esketamine, with median treatment counts of 14 and 28, respectively.
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Review likely symptom course over maintenance
Explain that baseline maintenance-phase depressive symptom severity did not significantly differ between groups, but trajectories diverged over time in this cohort. Pretreatment QIDS-SR scores were flatter with IV ketamine and trended upward with intranasal esketamine, especially after 1 year. At year 1, mean QIDS-SR was 7.6 with IV ketamine and 11.7 with intranasal esketamine.
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Compare monitoring and day-of-treatment logistics
Counsel patients that intranasal esketamine was administered under FDA REMS requirements with 2-hour mandatory monitoring, while post-treatment monitoring after IV ketamine in this clinic typically lasted 30 to 60 minutes. During treatment, SpO2 and pulse were measured approximately every 5 minutes for IV ketamine and every 40 to 60 minutes for intranasal esketamine, while blood pressure was recorded approximately every 5 to 20 minutes for IV ketamine and every 40 to 60 minutes for intranasal esketamine. For both treatments, patients were discharged with a responsible adult and advised not to drive for the rest of the day.
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Do not assume a major cardiopulmonary safety advantage for either option from this study
Use the study's safety findings to frame expectations cautiously rather than to declare one treatment safer. The probability of SpO2 below 92% was near zero in both groups, 0.007 for IV ketamine and 0.003 for intranasal esketamine, and systolic blood pressure trajectories were relatively stable with both treatments. Pulse changes differed modestly at baseline maintenance, with mean change 4.4 for IV ketamine and 5.9 for intranasal esketamine.
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Include access and preference in the final treatment choice
This study's treatment allocation was based on patient preference or insurance coverage rather than randomization, and the authors note that in their sample it mostly came down to patient preference. Use that same practical framing in counseling, especially because IV ketamine is off-label for treatment-refractory depression whereas intranasal esketamine is FDA approved. When patients are choosing between options, incorporate durability, visit burden, monitoring time, and coverage realities into shared decision-making.
Clinical Considerations
- This was a single-site observational study, so the results show associations rather than definitive causal differences between treatments.
- The sample size was small, particularly for the intranasal esketamine group.
- Patients continued or modified psychotropic medications and psychotherapy as part of usual care, so treatment interactions could not be isolated.
- Vital signs were monitored more frequently during IV ketamine than intranasal esketamine, which could affect detection of abnormalities.
Bottom Line
For adults with treatment-refractory depression who need maintenance treatment, this cohort supports counseling that IV ketamine was associated with longer treatment intervals and more stable depressive symptoms over time than intranasal esketamine.
