Esketamine Adverse Events in Depression: Global Meta-Analysis

Introduction to Esketamine and Its Use in Depression

Esketamine, a derivative of ketamine, has emerged as a promising treatment for patients with treatment-resistant depression (TRD). Approved by the U.S. Food and Drug Administration (FDA) in 2019, esketamine is administered either as a nasal spray or intravenously. Despite its efficacy, concerns about adverse events have persisted, prompting a systematic review and meta-analysis to better understand these risks.

Meta-Analysis Highlights Dose-Dependent Risks

A recent meta-analysis, published on May 28, 2026, systematically evaluated the safety profile of esketamine, focusing on dose-dependent adverse events. The study included nine randomized controlled trials (RCTs) with 1,449 patients, analyzing data from various global databases. The trials assessed esketamine dosages ranging from 28 to 84 mg for nasal spray and 0.20–0.40 mg/kg for intravenous injection.

The analysis revealed that esketamine significantly increased the risk of adverse events such as nausea, dissociation, dizziness, vertigo, elevated blood pressure, and somnolence compared to controls. These risks were notably dose-dependent, with higher doses (≥56 mg or 0.40 mg/kg) posing greater risks than lower doses (≤28 mg or 0.20 mg/kg).

Geographic Variations and Implications for Clinical Practice

Interestingly, the study found geographic variations in the incidence of adverse events. Patients in international multi-regional studies experienced higher risks of nausea, somnolence, and headache compared to those in studies conducted solely in Mainland China. These findings suggest that regional factors may influence the tolerability of esketamine, which could inform international treatment guidelines and patient care strategies.

For clinicians, the study underscores the importance of precision dosing strategies. Personalized approaches that consider individual patient profiles could help balance the efficacy and tolerability of esketamine, potentially reducing the rate of treatment discontinuation due to adverse events.

Balancing Efficacy and Risks

While esketamine has been shown to improve symptoms in patients with TRD, the increased risk of adverse events cannot be overlooked. The study reported that esketamine improved the clinical response rate but also increased treatment discontinuation due to adverse events by 2.22-fold. This highlights the need for careful monitoring and individualized dosing to optimize treatment outcomes.

Future Directions and Research Needs

As the use of esketamine in clinical settings continues to grow, further research is needed to explore the mechanisms underlying its adverse effects and to refine dosing strategies. Understanding the biological and environmental factors contributing to geographic variations in adverse event risks could also enhance patient care. Future studies should aim to expand the evidence base, particularly in diverse populations, to ensure that esketamine can be used safely and effectively worldwide.