Journal Article Annotations
2025, 3rd Quarter

Neuromodulation

Annotations by Liliya Gershengoren, MD
September, 2025

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

PUBLICATION #1 — Neuromodulation

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

Antonio Del Casale, Sara Spirito, Jan Francesco Arena, Saskia Preissner, Marina Borro, Giovanna Gentile, Martina Nicole Modesti, Robert Preissner, Stefano Ferracuti, Maurizio Simmaco.

Abstract: JAMA Psychiatry. 2025 Aug 1;82(8):810-817. doi: 10.1001/jamapsychiatry.2025.0200.

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.

Annotation

The finding:
This large retrospective cohort study examined more than 55,000 patients with treatment-resistant depression (TRD) treated with esketamine in combination with either an SSRI or an SNRI. The analysis revealed important differences between the two treatment strategies. Patients receiving esketamine combined with an SNRI experienced significantly lower rates of all-cause mortality, hospitalization, and depression relapse over a five-year period compared with those receiving esketamine combined with an SSRI. Specifically, the SNRI group had a 5.3% mortality rate versus 9.1% in the SSRI group, a 0.1% hospitalization rate versus 0.2%, and a 14.8% relapse rate compared to 21.2%. However, the SSRI group had a slight advantage in reducing suicide attempts, with an incidence of 0.3% compared to 0.5% in the SNRI group. Overall, both combinations were associated with favorable long-term outcomes and relatively low event rates, but the choice of adjunct antidepressant appeared to meaningfully influence prognosis in distinct ways

Strength and weaknesses:
The study has several notable strengths. First, it leveraged a very large, diverse dataset from the TriNetX global research network, encompassing electronic health records from more than 90 health care centers in 20 countries. This broad scope enhances the generalizability of the findings. Second, the sample size of over 55,000 patients provided the statistical power needed to detect meaningful differences between treatment groups. Third, the use of propensity score matching helped balance baseline characteristics between cohorts, reducing confounding and strengthening the validity of the comparisons. Finally, the study employed robust analytic methods, including Kaplan-Meier survival analyses and multiple measures of risk, and followed patients over a five-year period, offering valuable insights into long-term outcomes in TRD.

Despite its strengths, the study also has important limitations. Because it was observational and retrospective, the study cannot establish causal relationships between treatment combinations and outcomes. While propensity score matching reduced some sources of bias, unmeasured confounders—such as symptom severity, medication dosing, comorbidities, or physician prescribing preferences—may still have influenced results. The reliance on electronic medical record data across multiple international sites also introduces potential variability in diagnostic coding and data completeness. In addition, the study grouped SSRIs and SNRIs together by class rather than evaluating individual medications, which may obscure clinically relevant differences within each group.

Relevance:
For consultation-liaison psychiatrists, especially those managing medically ill or hospitalized patients with refractory depression, these findings highlight the importance of antidepressant selection when using esketamine. SNRIs may confer broader systemic benefits (pain modulation, functional outcomes, reduced mortality risk), which can be relevant in medically complex patients, whereas SSRIs may be preferable when acute suicidality is a prominent concern. This underscores the need for individualized, precision-based treatment planning in TRD within general medical and psychiatric hospital settings.