Esketamine combined with SSRI or SNRI leads to different outcomes in treatment-resistant depression

Esketamine combined with a serotonin-norepinephrine reuptake inhibitor (SNRI) reduces rates of mortality, hospitalizations, and depressive relapses, while esketamine combined with a selective serotonin reuptake inhibitor (SSRI) decreases the incidence of suicidal attempts, a real-world comparative effectiveness study on treatment-resistant depression (TRD) has shown.

Esketamine, in combination with either an SSRI or an SNRI, has emerged as a novel treatment option that provides a rapid-onset antidepressant effect for adult patients with TRD. “Determining the optimal combination to maximize therapeutic benefits while minimizing adverse effects remains an ongoing area of research,” wrote the researchers. [JAMA Psychiatry 2025;doi:10.1001/jamapsychiatry.2025.0200]

Therefore, the researchers conducted a retrospective cohort study in September 2024 using data from the TriNetX global health research network. “TriNetX data are drawn from real-world clinical settings and include electronic medical records from >90 healthcare centres across 20 countries,” noted the researchers.

After adjusting for age and gender using propensity score matching, the study included a population-based sample of 61,882 adult participants with TRD who were treated with esketamine combined with either an SSRI (mean age, 46.0 years; female, 57.7 percent) or an SNRI (mean age, 46.9 years; female, 58.6 percent).

“Given the chronic nature of TRD, the primary outcomes extend beyond merely assessing treatment response to include outcomes such as hospitalization rates, all-cause mortality, and suicide attempts,” noted the researchers.

In the overall study population, the incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low throughout the 5-year observation period. “A key finding is the low risk of suicide attempts across the entire sample, with an annual incidence of 0.08 percent, which is far below the estimated 4.66 percent in patients with TRD,” highlighted the researchers.

Notably, patients in the esketamine plus SNRI group had significantly lower risks of all-cause mortality (5.3 vs 9.1 percent; risk difference, 0.038; 95 percent confidence interval [CI], 0.034–0.042; p<0.001), hospitalizations (0.1 vs 0.2 percent; risk difference, 0.001; 95 percent CI, 0.000–0.002; p<0.001), and depression relapses (14.8 vs 21.2 percent; risk difference, 0.063; 95 percent CI, 0.055−0.072; p<0.001) compared with the esketamine plus SSRI group.

“Esketamine plus SNRI may provide broader systemic benefits through the dual action of SNRIs, improving chronic depressive symptoms, pain, functional outcomes, and physical comorbidities, which may contribute to reduced all-cause mortality,” commented the researchers.

Conversely, the 5-year risk of nonfatal suicide attempts was significantly lower with esketamine plus SSRI vs esketamine plus SNRI (0.3 vs 0.5 percent; risk difference, -0.001; 95 percent CI, -0.003 to 0.000; p=0.04).

“The fewer suicide attempts likely reflects this combination’s benefits in acute symptom management, particularly in reducing suicidal ideation and behaviours,” explained the researchers. “SSRIs, as first-line antidepressants, may selectively enhance the serotonergic pathway, decreasing anxiety and acute suicidal thoughts.”

To conclude, the study highlights the critical role of selecting an appropriate antidepressant partner for esketamine and tailoring treatment to individual patient’s profile, as the choice of antidepressant for combined use with esketamine can significantly impact clinical outcomes in TRD.