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.
Abstract of Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries
“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.“
Authors: Ilaria Ammendolia, Carmen Mannucci, Emanuela Esposito, Gioacchino Calapai, Mariaconcetta Currò, Paola Midiri, Cristina Mondello, Luigi Cardia & Fabrizio Calapai
Summary of Safety Profile and Suicidality Associated with the Use of Esketamine in the Treatment of Major Depressive Disorder in European Countries
Major depressive disorder (MDD) is a prevalent psychiatric condition, and a considerable number of individuals with this diagnosis fail to achieve sustained remission, leading to what is known as treatment-resistant depression (TRD). Although TRD lacks a universally agreed-upon definition, it is typically identified when a patient fails to respond to at least two different antidepressant therapies administered at appropriate doses and durations. TRD presents a significant clinical challenge and often necessitates alternative therapeutic strategies.
Among these strategies are drugs targeting the glutamatergic system, particularly N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine and its enantiomer, esketamine. While ketamine’s rapid antidepressant effects have garnered attention, esketamine—administered as a nasal spray—has gained regulatory approval for patients with moderate to severe TRD. Its mechanism involves transient NMDAR inhibition, resulting in increased glutamate transmission and enhancement of synaptic plasticity in mood-regulating brain regions. In 2019, esketamine was approved in Europe for use in adults who had not responded to at least two antidepressant treatments, and it may also be prescribed in emergencies to rapidly reduce depressive symptoms.
Although clinical trials reported common adverse effects such as dizziness, dissociation, nausea, and increased blood pressure, there remains a need for post-marketing surveillance. Pharmacovigilance plays a critical role in identifying adverse reactions (ARs) after a drug enters the market, using spontaneous reporting systems like EudraVigilance. The aim of this study was to analyse serious adverse reactions (SARs) reported in relation to esketamine in Europe and to compare suicidality-related outcomes with those of fluoxetine and venlafaxine.
Results
Overview of Reported Cases
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https://doi.org/10.3390/ph18050702
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Cite this paper (APA)
Ammendolia, I., Mannucci, C., Esposito, E., Calapai, G., Currò, M., Midiri, P., ... & 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.
Study details
Compounds studied
Ketamine
Topics studied
Safety
Depression
Suicidality
Study characteristics
Observational
Survey
Participants
751
Humans