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
JAMA Psychiatry April 2, 2025 DOI: 10.1001/jamapsychiatry.2025.0200 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Retrospective cohort study Peer reviewed |
|---|---|
| Sample size | 55,480 |
| Population | Adults with treatment-resistant depression treated with esketamine combined with either an SSRI or an SNRI |
| Intervention | Esketamine combined with SSRI |
| Duration | 5-year time window from first esketamine trial |
| Topics | Depression Esketamine |
| Keywords | Depression treatment Esketamine therapy Antidepressants Mental health research Clinical outcomes |
| Citations | 17 |
| Key findings | Esketamine plus SNRI showed lower mortality, hospitalization, and depression relapse rates, while esketamine plus SSRI showed a slightly lower rate of suicide attempts. |
Abstract
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. To determine whether the combination of esketamine + SNRI shows differences in clinical outcomes compared to esketamine + SSRI in patients with TRD. 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. Treatment with esketamine combined with an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) or an SNRI (desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine). 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. 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). 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.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cited by 11
- Fast-acting approaches for treatment-resistant depression: real-world comparative effectiveness of Intranasal Esketamine versus accelerated rTMS. International Journal of Psychiatry in Clinical Practice March 11, 2026
- Intranasal esketamine for treatment-resistant depression: real-world effectiveness in electroconvulsive therapy non-responders The European Journal of Psychiatry March 7, 2026
- Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine National Science Review September 5, 2025
- Multilevel Mechanisms and Clinical Efficacy of Psilocybin in Depression Treatment: A Systematic Review International Journal of Molecular Sciences September 10, 2026
- Comparative effectiveness and safety of esketamine versus injectable racemic ketamine and oral antidepressants for major depressive disorder: A population-based target trial emulation. Journal of Affective Disorders August 1, 2026
and 6 more in the library
Cites 14
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
- Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression The Journal of Clinical Psychiatry April 20, 2020
- Novel drug developmental strategies for treatment‐resistant depression British Journal of Pharmacology November 25, 2021
and 9 more in the library