Antidepressant combos deliver improved outcomes in TRD

Combination treatment with esketamine plus either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI) is beneficial in treatment-resistant depression (TRD), with notable variations in outcomes depending on the choice of antidepressant class, as shown in a large retrospective study.

Clinical outcomes over a 5-year period, except for suicidal attempts, significantly favoured the esketamine–SNRI than the esketamine–SSRI combination, the investigators reported.

Patients who received esketamine–SSRI had a 1.7-fold higher risk of all-cause mortality (9.1 percent vs 5.3 percent; risk ratio [RR], 1.72, 95 percent confidence interval [CI], 1.62–1.83; p<0.001), threefold increased risk of hospitalization (0.2 percent vs 0.1 percent; RR, 3.01, 95 percent CI, 1.64-5.51; p<0.001), and 1.4-fold greater risk of depressive relapses (21.2 percent vs 14.8 percent; RR, 1.43, 95 percent CI, 1.36–1.50; p<0.001) compared with those who received esketamine–SNRI. [JAMA Psychiatry 2025;doi:10.1001/jamapsychiatry.2025.0200]

Nevertheless, the esketamine–SSRI group had a 30-percent lower 5-year risk of nonfatal suicide attempts (0.3 percent vs 0.5 percent; RR, 0.70, 95 percent CI, 0.50–0.98; p=0.04).

The 5-year Kaplan-Meier estimated survival probability was 91.4 percent in the esketamine–SNRI group vs 86.9 percent the esketamine–SSRI group (hazard ratio, 1.68, 95 percent CI, 1.58–1.80; p<0.001).

For the study, researchers used data from the TriNetX global health research network and established a propensity-score matched cohort of 55,480 adult patients with TRD. Of these, 27,740 were treated with esketamine–SSRI (mean age 46.0 years, 57.7 percent female) and 27,740 were treated with esketamine–SNRI (mean age 45.9 years, 58.6 percent female).

“The present research offers a global analysis of a real-world patient sample, providing the advantage of a comprehensive view of the differential outcomes of the two esketamine-containing pharmacological combinations,” the investigators said. “The findings emphasize the critical role of selecting the appropriate antidepressant partner for esketamine and tailoring treatment to an individual patient profile.”

SSRIs, as first-line antidepressants, help reduce anxiety and acute suicidal thoughts by selectively enhancing the serotonergic pathway, the investigators explained. In contrast, the dual action of SNRIs may provide broader systemic benefits, improving chronic depressive symptoms, pain, functional outcomes, and physical comorbidities—all of which potentially contributing to lower all-cause mortality, they added.

The investigators called for further research to establish the optimal use of esketamine as an add-on therapy for TRD. Randomized clinical trials are needed to compare the efficacy and tolerability of esketamine combinations, validate the observed associations, and establish causal relationships, they continued.

“Additionally, exploring the differential impact of individual SSRIs and SNRIs, rather than treating them as a uniform class, could yield a deeper understanding of the most effective combinations,” according to the investigators. “Given that TRD is associated with significant functional impairment and reduced quality of life, understanding the broader impact of esketamine-based treatments on these dimensions is crucial for guiding clinical decisions.”