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Background and Importance Intranasal esketamine has been recently approved for the management of treatment-resistant major depressive disorder.Aim and Objectives This study aimed to evaluate whether intranasal esketamine use met funding criteria and its combination with selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs) in adults aged 18–74 years unresponsive to at least three antidepressant strategies. Efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS scale) at baseline and treatment end. Outcomes were classified as failure (<30% reduction), partial response (30–50%), or remission (score ≤10). Safety was evaluated by the percentage of patients experiencing adverse effects.Material and Methods This retrospective observational study included patients treated with intranasal esketamine at a tertiary hospital (December 2021–March 2024). Data collected were: age, sex, SSRI/SNRI combination, prior treatments, treatment duration, MADRS score, and adverse effects. Qualitative variables were reported as frequencies and percentages, and quantitative as median and interquartile range (IQR).Results A total of 30 patients were included: 19 (63.3%) completed treatment, 10 (33.3%) remained under treatment, and 1 (3.3%) awaited evaluation. Median treatment duration was 8 months (IQR: 0–13). 15 patients (50%) were women, and median age was 56 years (IQR: 28–76). 24 patients (80%) had received ≥3 previous antidepressant lines. The median number of esketamine sessions was 24 (IQR: 2–34), and 13 (43.3%) received treatment for >6 months. Almost all (90%) received intranasal esketamine with an SSRI or SNRI, most frequently venlafaxine (51.8%). Regarding efficacy, 13 (43.3%) showed no response, 4 (13.3%) partial response, and 5 (16.6%) remission; data were unavailable for 8 (26.6%). Regarding safety, the following adverse effects were reported: dizziness in 25 patients (83.3%), headache in 6 patients (20%), dissociation in 2 patients (6.6%), nausea and drowsiness, both in 11 patients (36.6%), vertigo in 1 patient (3.3%), and increased blood pressure in 10 patients (33.3%).Conclusion and Relevance The use of intranasal esketamine in our hospital generally aligns with the established funding criteria. In terms of efficacy, although a significant proportion of patients did not achieve remission, a notable number showed partial responses. Regarding safety, while esketamine may represent a valid therapeutic option, its efficacy and safety profile should be carefully evaluated on a case-by-case basis.Conflict of Interest No conflict of interest