Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries: An EudraVigilance Database Analysis
This pharmacovigilance analysis (n=751) examines suspected adverse reactions (SARs) to esketamine nasal spray (Spravato) reported in the EudraVigilance database across European countries. The study identifies increased blood pressure (15.4%) and dissociation (15%) as the most common SARs, with data suggesting a potentially higher risk of suicidality with esketamine compared to fluoxetine and venlafaxine, prompting recommendations for careful monitoring of patients with a history of suicidal ideation.
Authors
- Ammendolia, I.
- Mannucci, C.
- Esposito, E.
Published
Abstract
Background/Objective: Major depressive disorder (MDD) is a common mental disorder, with a significant portion of patients developing treatment-resistant depression (TRD). Esketamine is an antagonist of the N-methyl-D-aspartate receptor indicated as a nasal spray in combination with other antidepressants for adults with TRD. Signals of suspected adverse reactions (SARs) to esketamine from the EudraVigilance database in European countries were analyzed for a more defined safety profile of this drug in the real world.
Methods
SARs to esketamine reported in the data system EudraVigilance were analyzed, and disproportionality analysis for adverse reactions indicating suicidality for esketamine, in comparison to the antidepressants fluoxetine and venlafaxine, was performed.
Results
Increases in blood pressure (15.4%) and dissociation (15.0%) were the most frequently reported SARs. The sex distribution indicates the prevalence of women, except for increased blood pressure and completed suicide, which were signaled in men, while adults (18-64 years) and elders (65-85 years) were the ages with the largest number of reported adverse reactions to esketamine. The results indicate the existence of a potential increase in the risk of suicide in depressed patients taking esketamine when compared with fluoxetine and venlafaxine.
Conclusions
Apart from carefulness due to the known limitations of pharmacovigilance research conducted by using data systems of spontaneous signals for SARs, the analysis of data points toward the need for greater attention being paid to the potential risk of suicide following the prescription of esketamine in depressed subjects. In this regard, as regulatory agencies also recommend, patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to beginning treatment should receive more careful monitoring during treatment.
Research Summary of 'Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries: An EudraVigilance Database Analysis'
Introduction
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.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- APA Citation
Ammendolia, I., Mannucci, C., Esposito, E., Calapai, G., Currò, M., Midiri, P., Mondello, C., Cardia, L., & Calapai, F. (2025). Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries: An EudraVigilance Database Analysis. Pharmaceuticals, 18(5), 702. https://doi.org/10.3390/ph18050702
References (5)
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Zanos, P., Gould, T. D. · Molecular Psychiatry (2018)
Jelen, L. A., Young, A. H., Stone, J. M. · Journal of Psychopharmacology (2020)
Castro, M., Wilkinson, S. T., Al Jurdi, R. K. et al. · CNS Drugs (2023)
Gastaldon, C., Raschi, E., Kane, J. M. et al. · Psychotherapy and Psychosomatics (2020)
Fountoulakis, K. N., Saitis, A., Schatzberg, A. F. · American Journal of Psychiatry (2025)
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