Real-world effectiveness of intranasal esketamine in treatment-resistant depression in a clinically complex population

Treatment-resistant depression is associated with significant morbidity, functional impairment, and reduced response to conventional antidepressant therapies. Patients frequently present with multiple prior treatment failures and psychiatric comorbidities, contributing to a high burden of disease and limited therapeutic options. This population remains particularly challenging to treat in routine clinical practice, with persistent symptoms often leading to repeated treatment changes, increased healthcare utilisation, and reduced quality of life. Intranasal esketamine, a glutamatergic modulator acting as a non-competitive N-methyl-D-aspartate receptor antagonist, has demonstrated efficacy in randomised controlled trials. However, there remains a need for real-world data reflecting routine clinical practice, particularly in populations with greater clinical complexity and treatment resistance. The aim of this study was to evaluate the effectiveness and tolerability of intranasal esketamine in a naturalistic clinical setting.

We conducted a naturalistic observational study including 16 patients diagnosed with treatment-resistant depression treated with intranasal esketamine over a 4-week period in a specialised outpatient setting. All patients had a documented history of multiple unsuccessful antidepressant trials prior to treatment initiation, consistent with established criteria for treatment resistance. Depressive symptom severity was assessed using the Montgomery–Åsberg Depression Rating Scale at baseline and at week 4. Descriptive statistics were used to characterise the sample, and within-subject comparisons were performed to evaluate changes in depressive symptom severity over time. Response was defined as a reduction of at least 50% in Montgomery–Åsberg Depression Rating Scale score, and remission as a score of 10 or below. Adverse effects were systematically recorded and monitored at each treatment session, including dissociative and cardiovascular symptoms. Treatment administration followed standard clinical protocols, including dose titration and monitoring procedures in line with routine practice.

Mean Montgomery–Åsberg Depression Rating Scale scores decreased from 33 at baseline to 20.19 at week 4, indicating a clinically meaningful reduction in depressive symptom severity. A total of 37.5% of patients achieved response, and 25% met criteria for remission. Treatment was generally well tolerated across the treatment period. Reported adverse effects were mild and transient, with no discontinuations due to adverse events. Clinical response was heterogeneous, with some patients demonstrating limited improvement despite adequate exposure to treatment, while others showed earlier and more pronounced reductions in symptom severity during the treatment course. No unexpected safety signals were observed during the study period.

These findings suggest that intranasal esketamine may be associated with clinically meaningful improvements in depressive symptoms in a real-world population with treatment-resistant depression and high clinical complexity. However, the absence of a control group, the small sample size, and the short follow-up period limit the generalisability of these findings. These findings support the role of intranasal esketamine as a clinically meaningful treatment option in real-world treatment-resistant depression, particularly in patients with high clinical complexity and comorbidity in routine clinical practice.

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