Real-world functional improvements in treatment-resistant depression: a prospective study of intranasal esketamine

Background

Treatment-resistant depression (TRD) is associated with persistent functional impairment, often extending beyond symptomatic remission and contributing to long-term disability and poor quality of life. Although intranasal esketamine has demonstrated rapid efficacy on depressive symptoms and suicidal ideation, evidence regarding its impact on real-world functioning remains limited. Functional recovery represents a therapeutic goal in TRD, given its relevance for occupational, social, and familial domains. The present study aimed to evaluate longitudinal changes in functional impairment in a real-world cohort of TRD patients treated with intranasal esketamine, and to explore the associations between functional outcomes and changes in depressive symptoms, anxiety, and suicidal ideation. Methods: This multicenter, prospective, observational study included 99 adult outpatients diagnosed with TRD and treated with intranasal esketamine across three specialized clinics in Northern Italy between January 2021 and November 2025. TRD was defined as non-response to at least two adequate antidepressant trials [1]. Esketamine was administered according to approved clinical guidelines, with twice-weekly dosing during the 4-week induction phase followed by weekly or biweekly administration during maintenance (up to 24 weeks). Functional impairment was assessed using the Sheehan Disability Scale (SDS) as the primary outcome. Secondary outcomes included depressive symptoms (MADRS), anxiety symptoms (HAM-A), and suicidal ideation (C-SSRS). Assessments were conducted at baseline, week 1, and months 1, 2, 3, and 6. Longitudinal changes were analyzed using linear mixed-effects models, while Pearson correlations and exploratory mediation analyses were performed to examine interrelationships among outcome domains. Results: At baseline, patients exhibited severe functional impairment (mean SDS: 21.8 ± 5.5). Progressive improvements were observed across all follow-up time points, with SDS scores decreasing to 9.3 ± 7.0 at month 6 (Δ = −11.96; p < .001). Functional remission rates increased steadily from 2.6% at week 1 to 41.8% at month 6, while partial remission reached 74.5%. Depressive symptoms showed a rapid reduction already at week 1 (MADRS: 31.9 to 23.8), with continued improvement through month 6 (10.4 ± 8.2). Anxiety symptoms and suicidal ideation followed a similar pattern, both demonstrating significant and sustained reductions over time (all p < .001). Notably, functional improvement followed a more gradual trajectory compared to symptomatic domains. Correlation analyses revealed strong associations between changes in depressive and anxiety symptoms (r = .741), and moderate correlations with functional improvement (r = .376 for MADRS; r = .414 for HAM-A). Improvements in suicidal ideation were also significantly associated with functional gains. Mediation analyses did not identify significant indirect effects, suggesting partially independent pathways of functional recovery. Conclusions: In our study, intranasal esketamine was associated with improvement in functional impairment alongside reductions in depressive symptoms, anxiety, and suicidal ideation. The temporal dissociation between rapid symptomatic relief and more gradual functional recovery underscores the importance of continuing treatment beyond early response and highlights the need for multidimensional outcome assessment in TRD. These findings support the role of esketamine as an effective intervention not only for symptom reduction but also for restoring real-world functioning.

References

1. McIntyre RS et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394–412.