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Esketamine Combined With SSRI or SNRI for Treatment-Resistant Depression
Antonio Del Casale1,2, Sara Spirito3, Jan Francesco Arena1
1Department of Dynamic and Clinical Psychology and Health Studies, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.
JAMA Psychiatry
|April 2, 2025
Summary
Esketamine combined with serotonin-norepinephrine reuptake inhibitors (SNRIs) showed lower mortality, hospitalization, and depression relapse rates compared to selective serotonin reuptake inhibitors (SSRIs) in treatment-resistant depression. SSRIs had slightly fewer suicide attempts.
Area of Science:
- Psychiatry and Pharmacology
- Clinical Effectiveness Research
- Real-World Evidence Studies
Background:
- Treatment-resistant depression (TRD) presents a significant clinical challenge with limited therapeutic options.
- Esketamine is a rapid-acting antidepressant often used with SSRIs or SNRIs, but real-world comparative data is scarce.
Purpose of the Study:
- To compare the clinical outcomes of esketamine plus SNRI versus esketamine plus SSRI in patients with TRD.
- To evaluate differences in mortality, hospitalization, depression relapse, and suicide attempts between the two combination therapies.
Main Methods:
- Retrospective cohort study using the TriNetX global health research network (September 2024).
- Included adults with TRD treated with esketamine plus either SSRI or SNRI.
- Propensity score matching was used to create comparable cohorts (n=27,740 each).
- Kaplan-Meier analysis and risk/odds ratios assessed primary outcomes.
Main Results:
- The esketamine + SNRI group demonstrated significantly lower all-cause mortality (5.3% vs 9.1%), hospitalization rates (0.1% vs 0.2%), and depression relapses (14.8% vs 21.2%) compared to the esketamine + SSRI group.
- The esketamine + SSRI group showed a slightly lower incidence of suicide attempts (0.3% vs 0.5%).
- Overall incidence of adverse outcomes was low in both groups.
Conclusions:
- Esketamine combined with SNRIs appears to be associated with better outcomes regarding mortality, hospitalization, and relapse in TRD patients compared to SSRI combinations.
- While SSRI combinations showed a trend towards fewer suicide attempts, further research may be warranted.
- These findings contribute valuable real-world evidence for optimizing TRD treatment strategies.
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