How to Adjust Esketamine Maintenance Dosing in Treatment-Resistant Depression
How should clinicians adjust esketamine nasal spray dosing frequency over time in patients with treatment-resistant depression who respond to treatment?
Patients with treatment-resistant depression may improve during esketamine induction but still need a structured way to continue treatment while minimizing treatment burden. This guide applies to adults receiving esketamine nasal spray plus an oral antidepressant after initial response and summarizes the maintenance dosing approach used in SUSTAIN-2.
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Confirm that the patient meets the study treatment framework
Use this approach in patients with major depressive disorder without psychotic features who have treatment-resistant depression defined by nonresponse to at least 2 oral antidepressants in the current depressive episode. In SUSTAIN-2, eligible patients also had a MADRS total score of at least 22 at screening, and treatment was given with a concurrent oral antidepressant.
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Start induction with supervised twice-weekly esketamine
During the 4-week induction phase, patients self-administered esketamine nasal spray twice weekly under health care provider supervision. Starting dose was 56 mg for patients younger than 65 years and 28 mg for patients 65 years or older, with later doses adjusted based on efficacy and tolerability according to investigator judgment.
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Titrate dose within the allowed age-based range
For patients younger than 65 years, subsequent doses could be 56 mg or 84 mg. For patients 65 years or older, subsequent doses could be 28 mg, 56 mg, or 84 mg, using clinical judgment about benefit and tolerability.
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Continue responders into weekly treatment for weeks 5 to 8
Patients who responded during induction entered optimization/maintenance and continued esketamine once weekly during weeks 5 through 8 at the same dose. Response was defined as at least 50% reduction in MADRS total score.
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Use MADRS to set maintenance frequency after week 8
After the initial weekly optimization period, choose dosing frequency by algorithm. Continue weekly dosing if the MADRS total score is greater than 12, and reduce to every-other-week dosing if the MADRS total score is 12 or lower.
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Reevaluate dosing frequency every 4 weeks
Repeat MADRS-based reassessment at 4-week intervals and adjust the schedule as needed between weekly and every-other-week treatment. In the study, 24.0% of patients stayed on weekly dosing, 38.1% were maintained on every-other-week dosing, and 37.8% switched more than once between the 2 schedules.
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Continue the oral antidepressant throughout treatment
Esketamine was not used alone in this protocol. Direct-entry patients started a new oral antidepressant at induction, and transferred-entry patients continued the antidepressant already started in the prior short-term study.
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Stop esketamine in follow-up and observe after discontinuation
At the start of the follow-up phase, esketamine treatment was discontinued. Patients were encouraged to continue oral antidepressant treatment if clinically appropriate, and withdrawal symptoms were assessed at treatment end and again at weeks 1, 2, and 4 of follow-up.
Clinical Considerations
- This dosing algorithm was studied in an open-label trial without a control group.
- Direct-entry patients simultaneously started a new oral antidepressant, so sustained benefit cannot be attributed to esketamine alone.
- The study population excluded patients with clinically relevant psychiatric or medical comorbidities or substance dependence, which may limit generalizability.
- The maintenance frequency algorithm was based on MADRS total score thresholds and not on a broader individualized relapse-prevention protocol.
Bottom Line
After response to induction, maintain esketamine weekly through weeks 5 to 8, then use a MADRS threshold of 12 to choose weekly versus every-other-week dosing and reassess every 4 weeks.
