How to Administer Esketamine With Acute Suicide Risk Standard-of-Care
How should clinicians implement the ASPIRE I esketamine nasal spray treatment and monitoring approach for hospitalized adults with major depressive disorder and active suicidal ideation with intent?
When adults with major depressive disorder and active suicidal ideation with intent require emergency psychiatric care, the main clinical question is how to add a rapid-acting antidepressant strategy without relaxing suicide-risk management. This guide summarizes the study-based treatment process used alongside hospitalization and oral antidepressant treatment.
-
Start esketamine only as an add-on to comprehensive acute care
Use esketamine within the same background treatment framework studied in ASPIRE I. Comprehensive standard-of-care included initial psychiatric hospitalization and newly initiated or optimized oral antidepressant therapy, rather than esketamine alone.
-
Use the studied intranasal dosing schedule
Administer esketamine nasal spray at 84 mg twice weekly for 4 weeks. In the study, treatment days spanned the 4-week double-blind period, and all patients received intranasal treatment on this fixed twice-weekly schedule.
-
Supervise self-administration
Have the patient self-administer the nasal spray under direct supervision of site or clinical staff. In the trial, intranasal study drug was self-administered under staff supervision at each dosing session.
-
Initiate or optimize oral antidepressant therapy at day 1
Begin or optimize non-investigational oral antidepressant treatment at the time of randomization on day 1, based on clinical judgment and practice guidelines. The study allowed either monotherapy or antidepressant plus augmentation therapy, with augmentation consisting of a second antidepressant, an atypical antipsychotic, or a mood stabilizer.
-
Adjust the oral antidepressant only in the first 2 weeks
If dose titration or adjustments are needed for the background antidepressant regimen, make them during the first 2 weeks of treatment. After that point, doses were intended to remain stable during the double-blind phase.
-
Reduce to 56 mg if intolerance emerges after day 1
If the patient does not tolerate 84 mg, one dose reduction to 56 mg is permitted after day 1 and then continued thereafter. In the study, 21 patients in the esketamine group, or 18.6%, underwent this reduction, primarily on the second dosing session.
-
Monitor early antidepressant response
Assess depressive symptoms before dosing and reassess soon after the first treatment because the antidepressant effect emerged rapidly in the trial. Improvement versus placebo was observed starting at 4 hours after the first dose and remained significant at 24 hours, with a least-squares mean difference of -3.8 on MADRS at 24 hours.
-
Continue full suicide-risk management despite mood improvement
Do not use early improvement in depressive symptoms as evidence that suicidality has resolved. Both groups improved on suicidality measures, but the between-group difference on CGI-SS-r at 24 hours was not statistically significant, so hospitalization and close suicide-risk care remain essential.
-
Monitor for dissociation, sedation, and common same-day adverse events
At dosing visits, monitor adverse events, vital signs, dissociation with CADSS, and sedation with MOAA/S, as was done in the study. Common adverse events with esketamine were dizziness, dissociation, headache, nausea, and somnolence; 11.5% had an MOAA/S score of 3 or lower at any time during double-blind treatment, and most adverse events occurred on dosing days and resolved the same day.
-
Maintain hospitalization according to acute risk needs
Plan for initial psychiatric hospitalization, which was recommended for 5 days in the study, while allowing shorter or longer stays if clinically warranted. The article emphasizes that treatment occurred in an inpatient suicide-risk management context rather than as a substitute for it.
Clinical Considerations
- Esketamine showed a clear rapid antidepressant effect, but it did not demonstrate a statistically significant 24-hour advantage over placebo on clinician-rated suicidality severity.
- The observed benefits occurred in the presence of strong background intervention, including hospitalization, intensive clinical contact, oral antidepressant treatment, and frequent benzodiazepine use.
- Patients may have been functionally unblinded because esketamine has transient sedative and dissociative effects, which the authors identify as a study limitation.
- Regional differences in standard-of-care across this global trial may affect how closely local practice reproduces the study context.
Bottom Line
In ASPIRE I, esketamine was used as a supervised, twice-weekly intranasal add-on to hospitalization and newly initiated or optimized antidepressant therapy, with rapid improvement in depressive symptoms but no proven 24-hour advantage on suicidality severity over intensive standard-of-care alone.
