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

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

1.Gaynes, B. N. (2009). Identifying difficult-to-treat depression: Differential diagnosis, subtypes, and comorbidities. The Journal of Clinical Psychiatry, 70 Suppl 6, 10–15. https://doi.org/10.4088/JCP.8133su1c.02

2.Martinotti, G., Dell’ Osso, B., Di Lorenzo, G., Maina, G., Bertolino, A., Clerici, M., Barlati, S., Rosso, G., Di Nicola, M., Marcatili, M., d’ Andrea, G., Cavallotto, C., Chiappini, S., De Filippis, S., Nicolò, G., De Fazio, P., Andriola, I., Zanardi, R., Nucifora, D., … Vita, A. (2023). Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression. Bipolar Disorders, 25(3), 233–244. https://doi.org/10.1111/bdi.13296

3.Martinotti, G., Vita, A., Fagiolini, A., Maina, G., Bertolino, A., Dell’ Osso, B., Siracusano, A., Clerici, M., Bellomo, A., Sani, G., d’ Andrea, G., Chiaie, R. D., Conca, A., Barlati, S., Di Lorenzo, G., De Fazio, P., De Filippis, S., Nicolò, G., Rosso, G., … di Giannantonio, M. (2022). Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study). Journal of Affective Disorders, 319, 646–654. https://doi.org/10.1016/j.jad.2022.09.043

4.Samalin, L., Rothä rmel, M., Mekaoui, L., Gaudré-Wattinne, E., Codet, M.-A., Bouju, S., & Sauvaget, A. (2022). Esketamine nasal spray in patients with treatment-resistant depression: The real-world experience in the French cohort early-access programme. International Journal of Psychiatry in Clinical Practice, 26(4), 352–362. https://doi.org/10.1080/13651501.2022.2030757