This real-world safety analysis of esketamine in the United States (n=58,483 patients, 1,486,213 treatment sessions over 58 months) found that sedation, dissociation, and increased blood pressure occurred in 34.7%, 41.0%, and 0.9% of sessions respectively, with serious adverse events in <0.1-0.18% of sessions, suicide rates lower than background rates, and 210 cases of abuse/misuse reported, confirming the established safety profile with no new safety signals identified.
Abstract of Real-World Safety of Esketamine Nasal Spray
“Objective: The objective of this study was to comprehensively examine the real-world safety of esketamine using 58 months of postapproval data in the United States.
Methods: U.S. safety data from patient monitoring forms submitted to the esketamine Risk Evaluation and Mitigation Strategy (REMS) program and reports submitted to the Janssen U.S. Global Medical Safety (US-GMS) database were evaluated (March 5, 2019, to January 5, 2024). Patient characteristics, use and dosage patterns, adverse events of interest (actively solicited reports of sedation, dissociation, and increased blood pressure), and serious adverse events following esketamine administration were described. The incidence of suicidality and drug abuse/misuse was also evaluated.
Results: Most patients were 26–55 years of age (64.3%) and female (61.1%). A total of 1,486,213 outpatient treatment sessions were completed by 58,483 patients who had at least one esketamine treatment session. Sedation, dissociation, and increased blood pressure were reported in 34.7%, 41.0%, and 0.9% of sessions, respectively. Serious adverse events were reported in <0.1% and 0.18% of treatment sessions in REMS and US-GMS, respectively; suicide rates were lower than background rates; and 210 incidences of all-cause abuse/misuse were reported.
Conclusions: Analysis of almost 5 years of real-world use of esketamine in the United States remains consistent with the established safety profile from clinical studies and current product labeling. No new safety signals were identified.”
Authors: Gerard Sanacora, Muhammad Ahmed, Brianne Brown, Patricia Cabrera, Teodora Doherty, Mai Himedan, David M. Kern, Lisa Lim, Oliver Lopena, Ronaldo R. Naranjo, Isaac Nuamah, Amir Sarayani, Ibrahim Turkoz & Hannah E. Bowrey
Summary of Real-World Safety of aEsketamine Nasal Spray
Sanacora and colleagues set out to characterise the real-world safety of esketamine nasal spray in the United States using nearly five years of post-approval data, focusing on adverse events that matter in clinic: sedation, dissociation, blood pressure increases, suicidality, and any signal of abuse or misuse. The backdrop is familiar: major depressive disorder (MDD) affects a large share of adults, a substantial fraction meet criteria for treatment-resistant depression (TRD), and durable remission with conventional antidepressants remains uncommon. Esketamine nasal spray—initially approved in 2019 as an adjunct for TRD, subsequently for depressive symptoms with acute suicidal ideation or behaviour (2020), and most recently as TRD monotherapy (2025)—offers rapid antidepressant effects but carries risks that require structured risk-mitigation.
A key point in the introduction is the distinction between ketamine and esketamine nasal spray. Ketamine is a racemic mixture (R/S-ketamine) often used off-label without uniform registries or standardised monitoring; esketamine nasal spray is the (S)-enantiomer delivered under a formal Risk Evaluation and Mitigation Strategy (REMS) programme. Because of these pharmacological and regulatory differences, safety profiles should not be assumed identical. The authors therefore leverage the REMS infrastructure—mandatory enrolment, supervised in-clinic dosing with at least two hours of observation, and required post-session reporting—to examine real-world outcomes at scale.
Methods
Data sources: REMS and US-GMS
Find this paper
https://pubmed.ncbi.nlm.nih.gov/40926574/
Paywall | Google Scholar | Backup | 🕊
Cite this paper (APA)
Sanacora, G., Ahmed, M., Brown, B., Cabrera, P., Doherty, T., Himedan, M., ... & Bowrey, H. E. (2025). Real-World Safety of Esketamine Nasal Spray: A Comprehensive Analysis Almost 5 Years After First Approval. American Journal of Psychiatry, appi-ajp.