Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System
This study (n=962) investigated adverse events after administration of nasal esketamine (Spravato) for treatment-resistant depression (TRD). The study found increased suicidal ideation (versus antidepressants) but not suicide attempts or completions.
Authors
- Gastaldon, C.
- Raschi, E.
- Kane, J. M.
Published
Abstract
Introduction
Esketamine nasal spray received approval for treatment-resistant depression in March 2019.
Objective
Using the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020), we analysed esketamine-related adverse events (AEs) to detect and characterize relevant safety signals.
Methods
We used the consolidated case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for esketamine-related AEs with ≥4 counts. Comparisons between serious and non-serious AEs were performed using non-parametric tests.
Results
The FAERS database contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation (ROR = 1,612.64, 95% CI = 1,354.63, 1,919.79; IC = 8.19, 95% CI = 7.96, 8.35), sedation (ROR = 238.46, 95% CI = 202.98, 280.15; IC = 7, 95% CI = 6.75, 7.18), feeling drunk (ROR = 96.17, 95% CI = 61.42, 150.57; IC = 4.84, 95% CI = 4.09, 5.36), suicidal ideation (ROR = 24.03, 95% CI = 18.72, 30.84; IC = 4.31, 95% CI = 3.9, 4.61), and completed suicide (ROR = 5.75, 95% CI = 3.18, 10.41; IC = 2.25, 95% CI = 1.23, 2.94). Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine. Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, benzodiazepines, or somatic medications were more likely to suffer from serious versus non-serious AEs (χ2 = 125.29, p < 0.001, χ2 = 9.08, p = 0.003, χ2 = 8.14, p = 0.004, χ2 = 19.48, p < 0.001, χ2 = 25.62, p < 0.001, and χ2 = 16.79, p < 0.001, respectively).
Conclusions
Esketamine may carry a clear potential for serious AEs, which deserves urgent clarification by means of further prospective studies.
Research Summary of 'Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System'
Introduction
Gastaldon and colleagues introduce esketamine nasal spray as an adjunctive treatment for adults with treatment-resistant depression (TRD), noting its US FDA approval in March 2019 and subsequent approval by the European Medicines Agency. Regulatory authorities required a Risk Evaluation and Mitigation Strategy (REMS) because of concerns about misuse, dissociation and sedation. The authors point out that safety evidence available at approval came mainly from pre-marketing trials and pooled analyses, which showed higher rates of dissociation and lower acceptability versus placebo, but that rare or delayed adverse events (AEs) may not be captured by randomized controlled trials. Given these gaps, the study aims to examine post-marketing safety signals for esketamine using the FDA Adverse Event Reporting System (FAERS). The intent was to detect and characterise potential real-world AEs that might be rare, unexpected, or differ from those reported in regulatory trials, thereby informing further research and regulatory monitoring.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- APA Citation
Gastaldon, C., Raschi, E., Kane, J. M., Barbui, C., & Schoretsanitis, G. (2021). Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System. Psychotherapy and Psychosomatics, 90(1), 41-48. https://doi.org/10.1159/000510703
References (2)
Papers cited by this study that are also in Blossom
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
Zhu, W., Ding, Z., Zhang, Y. et al. · Neuroscience Bulletin (2016)
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Ammendolia, I., Mannucci, C., Esposito, E. et al. · Pharmaceuticals (2025)
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Black, J. C., Monte, A. A., Dasgupta, N. et al. · Nature Mental Health (2024)
Jiang, Y., Du, Z., Shen, Y. et al. · European Archives of Psychiatry and Clinical Neuroscience (2023)
Taillefer De Laportalière, T., Jullien, A., Yrondi, A. et al. · Psychological Medicine (2023)
Harding, F., Seynaeve, M., Keeler, J. et al. · Journal of Integrative Neuroscience (2021)
Sapkota, A., Khurshid, H., Qureshi, I. A. et al. · Cureus (2021)
Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
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