How to Monitor Long-Term Esketamine Safety in Treatment-Resistant Depression
How should clinicians monitor and respond to the main safety risks during long-term esketamine nasal spray treatment for treatment-resistant depression?
Long-term esketamine treatment raises practical concerns about blood pressure elevation, dissociation, sedation, urinary symptoms, suicidality, cognition, and misuse. This guide summarizes the monitoring structure and safety signals observed over up to 1 year of treatment in SUSTAIN-2.
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Supervise each dosing session and focus on same-day adverse effects
Monitor patients closely on dosing days because most esketamine-related treatment-emergent adverse events occurred shortly after administration, were mild or moderate, and resolved the same day. Common events were dizziness, dissociation, nausea, and headache.
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Check blood pressure before dosing and apply the protocol thresholds
Per protocol guidance, esketamine administration was not recommended if blood pressure was repeatedly greater than 140/90 mm Hg in patients younger than 65 years or greater than 150/90 mm Hg in patients 65 years or older. If blood pressure reached at least 200/120 mm Hg in patients younger than 65 years or at least 190/110 mm Hg in patients 65 years or older, esketamine treatment was discontinued.
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Recheck blood pressure after dosing during the expected peak window
In this study, mean systolic and diastolic blood pressure increases peaked at about 40 minutes after dosing and generally returned close to predose values by 1.5 hours. Acute hypertension was defined as systolic blood pressure at least 180 mm Hg or diastolic blood pressure at least 110 mm Hg and occurred in 33 of 802 patients.
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Assess dissociation soon after administration and observe until it resolves
Use postdose monitoring for dissociative symptoms because CADSS scores peaked at 40 minutes and generally resolved within 1.5 hours on the same day. Dissociation in the study included perceptual changes and feelings of disconnection from self, thoughts, feelings, space, or time.
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Monitor level of alertness for sedation
Track sedation longitudinally with an alertness/sedation assessment such as the MOAA/S used in the study. Clinically relevant sedation was defined as MOAA/S score of 3 or lower and occurred in 8.4% of patients in induction and 7.0% in optimization/maintenance; the longest period lasted 1 hour 30 minutes starting 45 minutes postdose.
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Screen for psychotic-like symptoms and suicidality over time
The study assessed psychotic and affective symptoms with the positive symptom subscale of the BPRS and suicidal ideation and behavior with the C-SSRS. Postdose psychotic-like symptoms were transient and resolved the same day, but new suicidal ideation occurred in 14.5% of patients who did not have it at baseline, and suicidal behavior was reported in 8 patients.
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Ask about urinary symptoms and follow bladder-related findings longitudinally
Monitor bladder symptoms because long-term ketamine-class exposure raises concern about cystitis, even though no case of interstitial or ulcerative cystitis occurred in this study. The protocol used the BPIC-SS, and overall scores remained low; urinary tract infection was reported in 65 patients, most urinary symptoms were mild to moderate and resolved within 2 weeks, and 5 adverse events of cystitis resolved while treatment continued.
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Reassess cognition at predose visits during maintenance
Cognitive testing in the study was performed at predose and included reaction time, learning and memory, working memory, and executive function measures. Overall performance generally improved or remained stable, but in patients 65 years or older, simple and choice reaction time slowed beginning at week 20 of optimization/maintenance while higher cognitive domains remained stable or improved.
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Watch for misuse and assess symptoms after discontinuation
The study looked for abuse-related signals and withdrawal symptoms during follow-up. There were no reports of drug seeking, overdose, or abuse, and no requests to increase dosing frequency beyond protocol or dose above 84 mg; withdrawal was assessed with the PWC-20 at treatment end and at weeks 1, 2, and 4 after stopping esketamine.
Clinical Considerations
- The study used structured rating scales and protocolized monitoring in a supervised clinical trial setting, which may not be fully replicated in routine practice.
- Patients with clinically relevant psychiatric or medical comorbidities or substance dependence were excluded, limiting generalizability of the safety profile.
- Interpretation of cognitive findings in patients 65 years or older was limited by high intraindividual variability, small sample size, lack of a control group, and possible practice effects.
- Because the trial was open label and direct-entry patients started a new oral antidepressant at the same time, some longitudinal symptom findings may reflect combined treatment effects.
Bottom Line
Long-term esketamine safety monitoring should center on supervised dosing-day observation with blood pressure checks, postdose assessment for dissociation and sedation through about 1.5 hours, and ongoing surveillance for suicidality, urinary symptoms, cognition, and discontinuation effects.
