Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries: An EudraVigilance Database Analysis

Major depressive disorder (MDD) is highly prevalent and a substantial subset of patients fail to remit despite multiple pharmacological trials, a condition commonly termed treatment-resistant depression (TRD). Research into glutamatergic mechanisms, particularly antagonism of the N-methyl-D-aspartate receptor (NMDAR), led to clinical use of ketamine and its S-enantiomer, esketamine, which produces rapid antidepressant effects and was approved by the European Medicines Agency in 2019 as an intranasal formulation used together with an oral antidepressant for adults with TRD or in acute, severe depressive episodes. Pre-approval clinical trials and product labelling identified common adverse reactions including dizziness, dissociation, nausea, headache and transient increases in blood pressure, but real-world safety monitoring remains necessary to refine the drug's benefit–risk profile. This study aims to define the post-marketing safety profile of esketamine in European clinical practice by analysing spontaneous reports of suspected adverse reactions in the EudraVigilance database. In addition to descriptive characterisation, the investigators performed a disproportionality analysis using the reporting odds ratio (ROR) to compare signals of suicidality associated with esketamine against those reported for the antidepressants fluoxetine and venlafaxine, which are commonly co-prescribed with or related to esketamine's authorised use.

The researchers used the public version of the EudraVigilance database to retrieve individual case safety reports (ICSRs) that listed esketamine as the suspected medicine. The study period covered reports signalled from 1 January 2019 to 31 December 2024. Inclusion was restricted to reports originating from the European Economic Area (EEA), including the UK, that were classified as serious and had been submitted by healthcare professionals; non-serious reports, reports from non-healthcare professionals and non-EEA reports were excluded. Adverse reactions were coded and extracted according to the Medical Dictionary for Regulatory Activities (MedDRA). Each ICSR was examined and every mentioned suspected adverse reaction was counted using MedDRA Preferred Terms (PTs). To present broader patterns, PTs were also aggregated to MedDRA System Organ Class (SOC) level. Overlapping PTs were combined where appropriate to avoid double-counting. Duplicate and incomplete ICSRs were identified and removed; duplicates were sought by comparing adverse reaction, age, sex, suspected concomitant medicines and local report numbers. The investigators stratified analyses by sex and age groups to assess distributional patterns and potential confounding. A disproportionality analysis focused on suicidal ideation, suicide attempts and completed suicide was performed using the reporting odds ratio (ROR) to compare esketamine with fluoxetine and venlafaxine. Statistical analyses were descriptive and used SPSS version 29.0. The authors note that EudraVigilance contains reports of "suspected" adverse reactions and that spontaneous-report data do not establish causality.

A total of 751 ICSRs mentioning esketamine were identified for the study period; 265 of these were classified as serious (35.3%) and 486 as non-serious. Among non-serious reports, 306 (62.4%) concerned female patients and 168 male patients; serious reports showed a similar female predominance with 169 female cases (63.8%) and 96 male cases. Death was recorded in 27 of the serious cases, 18 of which were in men (66.7%). Completed suicide accounted for 17 of the deaths (63% of fatal cases), with 12 suicides in men and 5 in women (70.6% of suicide deaths in men). At the level of individual adverse reactions, the most frequently reported events were increased blood pressure, dissociation/dissociative disorder, anxiety and completed suicide. Sex-stratified analysis indicated that increased blood pressure and completed suicide were signalled more frequently in men, while dizziness was reported more often in women; most other adverse reactions showed no clear sex difference in the extracted data. Age-group analysis identified adults (18–64 years) and the elderly (65–85 years) as the groups with the largest number of reports; increased blood pressure was signalled more often in the elderly, and hallucination reports occurred only in adults in the available extraction. Non-suicide deaths unrelated to suicide made up 3.8% of serious SARs, with higher prevalence in men (2.3%) versus women (1.5%); reported fatal diagnoses included three sudden deaths and single cases of respiratory failure, pulmonary embolism and myocardial infarction. When PTs were aggregated to SOC-level groups, esketamine showed increased RORs compared with fluoxetine and venlafaxine for psychiatric disorders, vascular disorders and immune system disorders. The psychiatric category was driven chiefly by dissociation/dissociative disorders, suicidal ideation and anxiety; vascular signals were largely dizziness and hypertension; immune-system signals included several anaphylactic reactions. The extracted text reports an increased potential risk of suicidal ideation for esketamine versus fluoxetine (noted as "ROR 2.") but does not provide the complete ROR value or its 95% confidence interval in the Results section as presented here.

Ammendolia and colleagues place their findings within the ongoing debate about benefits and risks of NMDAR antagonists for depression. They note that while esketamine may offer rapid antidepressant effects and potential benefit for people with TRD, post-marketing data reveal a safety profile that differs in some respects from pre-approval clinical-trial data. In the EudraVigilance reports analysed, increased blood pressure and dissociation were among the most frequently signalled events, and psychiatric, nervous-system and vascular SOCs were prominent. The authors highlight that dissociation and transient hypertension are recognised effects of esketamine; blood-pressure rises are generally transient and peak shortly after dosing, but the present data suggest the potential for greater reporting of increased blood pressure in older patients. The discussion also summarises other safety concerns observed or signalled post-marketing, including hepatobiliary and eye disorders reported by other investigators and observed in the present dataset; the authors indicate these deserve further study but lie beyond the current paper's scope. On suicidality, the literature they review is heterogeneous: some analyses of spontaneous-report systems (notably FAERS) have shown elevated RORs for suicidal ideation associated with esketamine, while randomised trials and meta-analyses provide mixed evidence on effects against suicidality. Case reports and some long-term observations describe paradoxical worsening of depressive symptoms and suicidal ideation in a small number of patients. Using their disproportionality analysis, the investigators report a stronger association between esketamine and suicidality than for fluoxetine and venlafaxine. In the Discussion they state that the probability of association with completed suicide was about four times greater compared with fluoxetine and about five times greater compared with venlafaxine; however, they emphasise the difficulty of attribution because TRD populations already have elevated baseline rates of suicidal behaviour, and spontaneous-reporting data lack denominators and clinical context. The authors reiterate key limitations of their pharmacovigilance approach: under-reporting, variable report quality, an inability to establish causality, lack of information on confounders (comorbidities, concomitant treatments, dose and exposure duration) and the potential for remaining duplicate reports. Given these constraints, they advise caution in interpreting signals but recommend close monitoring of patients prescribed esketamine, especially those with prior suicide-related events or marked suicidal ideation.

The authors conclude that post-marketing data from EudraVigilance point to the need for increased vigilance when prescribing esketamine for depression, with particular concern about a possible elevation in the probability of suicidality. They echo regulatory guidance that patients with a history of suicide-related events or with substantial suicidal ideation prior to starting esketamine should receive heightened monitoring during treatment.