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.

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.

Authors: Chiara Gastaldon, Emanuel Raschi, John M. Kane, Corrado Barbui & Georgios Schoretsanitis

Notes

The adverse events (AEs) found in the study are higher than what was expected. In the discussion, the authors discuss the implications and possibility of an even higher reported number of adverse events in the next year.

Most concerning is the following: “This result might imply that clinical features of TRD may contribute to the risk of completed/attempted suicide. However, the relative risk of reporting suicidal ideation was 24-fold higher than for other drugs and 5–9 times higher than venlafaxine, which means an extremely serious concern that cannot be ignored, especially in males as the disproportionality was stronger.”

A possible hypothesis for these numbers could be the lack of efficacy of ketamine, and subsequent (a week later) increased/relapsed depression. Noted should also be that people with suicidal ideation were excluded from the clinical trials, but are part of the patient group.

Another study (Fu et al., 2020) that did look at suicidal ideation (SI) and the use of esketamine nasal spray, found no effect when compared to a placebo.

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