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.

Summary

Esketamine nasal spray received approval for treatment-resistant depression in March 2019. We analysed the FDA Adverse Event Reporting System (FAERS) database to detect and characterize relevant safety signals for esketamine-related adverse events, and found several signals, such as dissociation, sedation, and feeling drunk.

Introduction

The FDA approved the nasal spray formulation of esketamine for treatment-resistant depression in adults in March 2019, and the EMA approved it a few months later.

Esketamine’s marketing authorization triggered a vivid debate and many concerns, mainly because of the lack of convincing evidence on its efficacy and safety, including the risk of misuse and suicide.

The aim of this study was to analyse post-marketing safety data of esketamine nasal spray through the largest publicly available worldwide pharmacovigilance database, the FDA Adverse Event Reporting System (FAERS).

Description of Esketamine AEs

Esketamine-related adverse events (AEs) were reported in 4,381,931 patients over the first year of marketing approval, including 2,274 serious AEs in 962 patients, including 22 deaths. Age data were available for 442 patients.

139 different adverse events (AEs) were reported, with a mean time-to-onset of 20.3 days for dissociation, 173 for sedation, 119 for nausea, 75 for vomiting, 64 for depression, 63 for anxiety, 62 for increased blood pressure, 56 for dizziness, and 43 for feeling abnormal.

Safety Signals

Online supplementary Table 2 provides disproportionality estimates for the esketamine-reported AEs, and online supplementary Table 3 provides the RORs and IC values for all esketamine-reported AEs. Safety signals were detected for a large number of AEs, including dissociation, sedation, autoscopy, feeling drunk, euphoric mood, and completed suicide.

Sex Differences in Esketamine AEs

After assessing safety signals in females and males separately, the difference in therapeutic effect, drug ineffectiveness and dizziness were no longer significant.

Serious versus Non-Serious AEs

Patients with serious esketamine adverse events (AEs) had higher weight values, higher esketamine dose, higher frequency of AEs, higher age and time-to-onset of AEs, and more antidepressant, mood stabilizer, benzodiazepine, antipsychotic, or somatic medication use compared to patients with non-serious AEs.

Sensitivity Analyses

After performing the analyses using venlafaxine as a comparator for disease-related AEs, there were no safety signals detected for mental disorder, completed suicide, and suicide attempt.

Discussion

This pharmacovigilance study provides the first real-world data on the safety profile of esketamine, a recently approved medication for TRD. The study suggests that esketamine carries a clear potential for serious and unexpected AEs, and that the number of reported cases has doubled in 2020 compared to 2019.

Esketamine AEs increased in 2020, which contrasts with the Weber effect and the pattern suggested by Hoffman et al. However, notoriety bias cannot fully explain the increased number of reports.

Second, this analysis detected rare AEs, including self-injurious ideation, logorrhoea, depressive symptoms, panic attack, paranoia, ataxia, akathisia, and mania.

Our results show strong and consistent disproportionality estimates for several AEs, and the ROR estimate for dissociation for a newly marketed drug is remarkable. This result is in line with what has been found by regulatory trials.

The high reporting ratios of suicidal ideation in TRD and completed suicide could be considered a common symptom, and the relative risk of reporting suicidal ideation was 24-fold higher than for other drugs and 5 – 9 times higher than venlafaxine. Esketamine-treated patients have an increased risk of suicidal ideation, but the cause is not clear. However, in a long-term phase 3 non-randomized study, 14.5% of patients reported new occurrences of suicidal ideation, and 8 patients reported suicidal behaviour.

Although misuse was not formally reported in FAERS, euphoric mood, dissociation and related symptoms, feeling drunk, and hallucinations were found to occur immediately after administration. These effects are in line with the esketamine potential for misuse and abuse.

The comparison of serious versus non-serious AEs provides valuable contribution to target vulnerable subgroups of patients at high risk, such as females. Females using ketamine as a recreational drug were more likely to experience withdrawal symptoms, including dysphoric mood.

The results of this study should be interpreted with caution, since pharmacovigilance research has several limitations, including the inability to infer causality, barriers to reporting, quality of information, and lack of denominator. Furthermore, notoriety bias cannot be excluded, given the REMS program initiated by the FDA.

Implication for Clinical Practice and Research

These results have several implications for clinicians prescribing esketamine and patients receiving it, as well as for policy makers. Esketamine should be prescribed with extreme caution to people already at risk of suicide.

Our analysis detected rare AEs that were not reported by regulatory trials, and prescribers should be alert to these AEs and monitor patients for extended periods of time after esketamine administration.

This study showed that the safety profile of esketamine in the real-world population might be slightly different from that described in regulatory trials. More real-world research is urgently needed to better understand the safety profile of esketamine and provide an evidence-based framework for rational prescription.

Conclusions

This analysis of the FAERS database of esketamine adverse events (AEs) detected new, unexpected signals. These AEs might resemble effects of recreational drugs, and the signal for increased reporting of suicidal ideation requires urgent clarification.