The correlation of Esketamine with specific adverse events: a deep dive into the FAERS database

Depressive disorder affects hundreds of millions worldwide and a substantial minority of patients do not respond to standard antidepressant therapies. Existing treatments typically have a delayed onset of action and 20% to 30% of patients remain symptomatic after trials of multiple medications. Ketamine and its enantiomers, particularly esketamine, have attracted attention because of rapid antidepressant effects; esketamine nasal spray (Spravato) received FDA approval in March 2019 for treatment-resistant depression and later for adults with depression accompanied by suicidal ideation or behaviour. The drug is the S-enantiomer of ketamine and acts as a non-selective, non-competitive NMDA receptor antagonist, but its precise antidepressant mechanism and long-term safety profile remain incompletely characterised. Jiang and colleagues set out to characterise adverse event (AE) signals associated with esketamine in a real-world post-marketing database. Using FAERS reports from 2019 Q1 through 2023 Q1, the study applies disproportionality and Bayesian signal-detection methods (Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Multi-item Gamma Poisson Shrinker/EBGM) to identify preferred terms (PTs) and system organ class (SOC) associations that may be linked to esketamine use, aiming to inform clinicians and regulators about known and emergent safety signals.

The investigators performed a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) covering the period from the first quarter of 2019 to the first quarter of 2023. Search terms were "Esketamine" and "Spravato," and the dataset was limited to reports in which esketamine was listed as the primary suspected drug. Adverse events were coded to MedDRA preferred terms (PTs) and aggregated by system organ class (SOC). Descriptive statistics summarised reporter and patient characteristics (sex, age group, reporter type, country), time trends, clinical outcomes, and time-to-onset categories as available in the extraction. For signal detection, four complementary methods were applied: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN), and the Multi-item Gamma Poisson Shrinker (MGPS), with results ranked by the EBGM (empirical Bayes geometric mean) metric from the MGPS. The text notes that 2 × 2 contingency tables and calculation formulas were used, although the extraction does not provide the exact thresholds or software used. The extracted text does not clearly report certain procedural details commonly relevant to FAERS analyses, such as whether duplicate reports were removed, how concomitant drugs or comorbidities were handled, or whether any stratified analyses (for example by route of administration) were performed. The authors do state that PTs meeting all four algorithm criteria were identified and that the top PTs were ranked by EBGM.

Across 7,604,592 AE records in FAERS during the study period, 5,061 reports listed esketamine as the primary suspected drug. From these reports, 117 PTs met the study's signal-detection criteria across the four applied algorithms and were ranked by EBGM; the top 30 PTs are reported in the paper (table not present in the extraction). The strongest signal was observed for dissociation (signal strength highest by EBGM), consistent with known label information. Patient- and report-level characteristics showed that female patients accounted for 52.20% of esketamine-related reports while male patients accounted for 29.60% (the extraction does not fully account for the remaining proportion). The largest age group was 18–65 years (47.12%). Reporters were primarily doctors (35.11%), consumers (32.5%), and pharmacists (29.24%). Geographically, the United States accounted for 81.64% of reports. Time-series data indicated an annual increase in esketamine-related reports, with the first quarter of 2023 comprising 9.39% of the total. Clinical outcomes recorded in the dataset included hospitalisation or prolonged hospital stay in 19.58% of reports and death in 4.62% of reports. For reports with a known time to onset, 13.38% occurred within 60 days of starting esketamine and 9.07% within 7 days. In addition to label-consistent signals such as dissociation, sedation, nausea and elevated blood pressure, the analysis flagged several emergent or less-expected PTs. New potential signals identified by the authors include Flashback, Tachyphylaxis, and Autoscopy. High-ranking experiential states included euphoric mood, feeling of relaxation, and feeling drunk, which the authors interpret as indicators of possible misuse or addiction potential. Notably, reports of suicidal ideation and suicide attempt were relatively frequent among the esketamine-related records. The extraction also notes adverse events related to the intranasal route, for example incorrect drug monitoring procedure and nasal discomfort.

The authors contextualise their findings by reaffirming that esketamine provides rapid antidepressant effects and is more clinically established than some alternatives, but argue that its safety profile requires careful post-marketing scrutiny. They note that many high-frequency signals—dissociation, sedation, nausea, raised blood pressure—align with the product label and clinical trial experience, and emphasise the importance of monitoring for these known adverse effects. Demographic patterns in the reports are discussed as partly reflecting epidemiology: more females reported AEs, which the authors link to the higher diagnosed prevalence of depression in women, though they acknowledge multifactorial explanations including biological and reporting factors. The heavy concentration of reports from the United States is recognised as a potential source of reporting bias, since pharmacovigilance practices and public awareness vary between countries. For the novel signals, Jiang and colleagues propose mechanistic hypotheses grounded in NMDA receptor antagonism and downstream effects on glutamatergic, GABAergic, dopaminergic and serotonergic systems. They suggest that abnormal neuronal network activity could underlie flashbacks and autoscopy, while receptor-level adaptations might explain tachyphylaxis and potentially reduced long-term efficacy. The emergence of euphoric states and intoxication-like sensations is interpreted as raising concerns about abuse liability and reinforces the need for vigilance in monitoring patients for misuse. The discussion acknowledges the limitations inherent to FAERS-based disproportionality studies: spontaneous reporting is subject to under-reporting, reporting bias, variable data quality and incomplete clinical detail. The extracted text specifically notes that baseline patient characteristics were not considered in the analysis and that the method of administration (intranasal versus intravenous) was not distinguished—an important limitation because route can alter pharmacokinetics and adverse effect profiles. The authors call for future work to differentiate administration routes, to explore mechanisms behind newly identified signals, and to pursue longer-term and more personalised investigations into safety, including genetic studies.

The authors conclude that while esketamine offers significant rapid antidepressant benefits, its use is accompanied by a range of adverse events and potential risks, notably tachyphylaxis, addiction potential and risks related to suicidal ideation or attempts. Clinicians are advised to closely monitor patients and intervene promptly if adverse effects emerge. Looking forward, the authors recommend more personalised research approaches, including genetic profiling to identify biomarkers of response and susceptibility to adverse events, and further studies to clarify long-term safety and mechanisms underlying newly detected AE signals.