Esketamine Combined With SSRI or SNRI for Treatment-Resistant Depression.

Importance: Treatment-resistant depression (TRD) remains a critical challenge in psychiatry, with limited effective options. Esketamine, a rapid-acting antidepressant, is usually combined with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), but comparative evidence of these combinations' effectiveness in real-world settings is sparse.

Objective: To determine whether the combination of esketamine + SNRI shows differences in clinical outcomes compared to esketamine + SSRI in patients with TRD.

Design, setting, and participants: This retrospective cohort study was conducted in September 2024 using data from the TriNetX global health research network, with a 5-year time window from the first esketamine trial. TriNetX data are drawn from real-world clinical settings and use electronic medical records from more than 90 health care centers across 20 countries. Adults with TRD who were treated with esketamine combined with either an SSRI or an SNRI were eligible for inclusion.

Exposure: Treatment with esketamine combined with an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) or an SNRI (desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine).

Main outcomes and measures: The primary outcomes were all-cause mortality, hospitalization, depression relapse, and suicide attempts. Kaplan-Meier survival analysis was used to estimate survival probabilities, while risk ratios and odds ratios were calculated for all outcomes.

Results: In a population-based sample of 61 882 adult participants with TRD who were treated with esketamine combined with either an SSRI or an SNRI, 55 480 participants were selected after applying propensity score matching for age and sex. These patients were divided into 2 matched cohorts: 27 740 patients treated with esketamine + SSRI (16 007 female participants [57.7%]; mean [SD] age, 46.0 [21.3] years) and 27 740 treated with esketamine + SNRI (16 242 female participants [58.6%]; mean [SD] age, 45.9 [21.9] years). In the entire study population, the incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low throughout the study period. Patients in the esketamine + SNRI group had significantly lower all-cause mortality (5.3% vs 9.1%; P < .001), hospitalization rates (0.1% vs 0.2%; P < .001), and depression relapses (14.8% vs 21.2%; P < .001) compared to the esketamine + SSRI group, which instead showed a lower incidence of suicidal attempts (0.3% vs 0.5%; P = .04).

Conclusions and relevance: In this retrospective comparative effectiveness study, among the study sample, incidence of mortality, hospitalizations, depressive relapses, and suicide attempts was low. The esketamine + SNRI group showed lower incidence of mortality, hospitalizations, and depressive relapses, while the esketamine + SSRI group showed a slightly lower incidence of suicidal attempts.