EXPLORING VORTIOXETINE COMBINATION WITH INTRANASAL ESKETAMINE: A PROMISING ALTERNATIVE TO SSRI/SNRI - INSIGHTS FROM THE REAL-ESK STUDY
Authors: Cavallotto *Clara , D'andrea Giacomo , Miuli Andrea , Marrangone Carlotta , Carullo Rosalba , Mammarella Giovanna , D'attilio Antonio , Piro Tommaso , Chiappini Stefania , Mosca Alessio , Carlo Francesco Di , Pettorruso Mauro , Martinotti Giovanni 
Published: February 2025

Abstract

Background
Treatment-Resistant Depression (TRD) affects almost 30% of patients with Major Depressive Disorder (MDD) (1). Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD in combination with a Serotonin Specific Reuptake Inhibitor/SSRI or a Serotonin-Norepinephrine Reuptake Inhibitor/SNRI. There is a lack of studies investigating the effectiveness and safety of ESK-NS in combination with other oral antidepressants. The recent surge in the utilization of ESK-NS in clinical environments (2; 3; 4) has sparked interest in conducting fresh investigations to assess the viability of integrating alternative oral antidepressants with ESK-NS.

Aims and Objectives
To assess the efficacy of Vortioxetine plus ESK-NS in mitigating depressive symptoms and emotional blunting, as well as its tolerability in TRD subjects, compared to the standard- of-care of SSRI/SNRI plus ESK-NS.

Methods
We conducted a post-hoc analysis of the REAL-ESK study. The study included twenty TRD patients: ten subjects taking Vortioxetine as the main oral antidepressant with ESK-NS and ten subjects taking SSRI or SNRI with ESK-NS. Psychometric assessments (Montgomery-Å sberg Depression Rating Scale/MADRS, Brief Psychiatric Rating Scale/BPRS) were conducted at baseline(T0), one month(T1) and three months after the treatment initiation(T2). Repeated-measures ANOVA (rm-ANOVA) was employed to gauge the impact of the treatment on the previously mentioned psychometric assessments.

Results
The combination of Vortioxetine and ESK-NS was as effective as the standard-of-care in reducing depressive symptoms (F2.36=55.768, p&lt;0.001, =0.756), with a higher effect size in reducing emotional blunting at T2 (Vortioxetine+ESK-NS, T0 vs. T2: p&lt;0.001, d=2.404; SSRI/SNRI+ESK-NS, T0 vs. T2: p=0.005, d=1.385). Furthermore, the safety and tolerability profile of the Vortioxetine+ESK-NS combination appeared to be better, with a lower rate of treatment-emergent adverse events.

Discussion and Conclusion
The combination of Vortioxetine and ESK-NS may be a valuable alternative to the standard-of-care SSRI/SNRI plus ESK-NS in TRD patients. Notably, we observed a higher effect of the Vortioxetine and ESK-NS combination compared to SSRI/SNRI plus ESK-NS in reducing emotional blunting in TRD patients. This finding underscores the potential effectiveness of this combination in addressing emotional blunting in treatment resistant subjects. In addition, vortioxetine plus ESK-NS is potentially linked to a more advantageous side effect profile, characterized by a reduced overall occurrence of treatment-emergent adverse events (TEAEs) and a diminished occurrence of reported dissociative symptoms. However, further randomized controlled trials with larger sample sizes and prospective designs are needed to confirm these findings.

References
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