Esketamine for Depression: What does the latest meta-analysis tell us?

Title: Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis‍

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Summary

Esketamine, a nasal spray version of ketamine, has been promoted as a breakthrough treatment for treatment-resistant depression (TRD). This meta-analysis reviewed the evidence on its efficacy and safety, assessing its impact on depressive symptoms and suicidality over different timepoints. The results suggest that esketamine provides a modest antidepressant effect, comparable to existing augmentation strategies, but fails to significantly reduce suicidality. 

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What is esketamine and how is it different from ketamine?

Esketamine is the S-enantiomer of ketamine, meaning it is a chemically refined version that isolates one half of the ketamine molecule. This makes it more potent at lower doses, with a stronger binding affinity for NMDA receptors. While intravenous ketamine has been widely used in research and off-label clinical settings, esketamine was patented by Janssen Pharmaceuticals, ensuring exclusivity in its commercial use. Approved by the FDA in 2019, esketamine is marketed as a nasal spray for TRD, often used alongside traditional antidepressants. Unlike racemic ketamine, which includes both the R- and S- enantiomers and is used intravenously, esketamine’s intranasal formulation was developed for convenience and regulatory approval. However, questions remain about whether it offers significant advantages over ketamine infusions, particularly in long-term effectiveness and safety.

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What was the goal?

This meta-analysis aimed to systematically assess esketamine’s efficacy in reducing depressive symptoms and suicidality in adults with depression, particularly those with TRD. Researchers examined:

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• How esketamine compares to placebo in reducing depressive symptoms at different timepoints (up to four weeks).
• Whether it has a significant impact on suicidality, both in the short and long term.
• Potential safety concerns, including adverse events, suicidality, and mortality risks.

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By aggregating data from multiple studies, the goal was to provide a clearer picture of esketamine’s true clinical value and whether its widespread use is justified.

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What happened in the study?

• Methodology: This systematic review followed PRISMA guidelines, analyzing 87 studies from a total of 1,115 articles. 

• Timepoints Assessed:
  
  • Depression Outcomes: Up to 72 hours, and at 1, 2, and 4 weeks post-treatment.
  • Suicidality Outcomes: Measured between days 2–5 and again at week 4.

• Outcome Measures: Depression was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS) scores, while suicidality was measured based on trial-specific assessments.

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Key findings

1. Antidepressant effects
   
   1. Esketamine showed a small but statistically significant antidepressant effect at 2–4 weeks, with effect sizes between 0.15 and 0.23.
   2. The magnitude of its effect was comparable to other augmentation strategies, such as adding atypical antipsychotics to antidepressant treatments.
   3. Placebo effects were strong, and over time, many participants in the placebo arm showed similar improvements to those in the esketamine group.

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2. Effects on suicidality
   
   1. Esketamine did not significantly reduce suicidality at any assessed timepoint.
   2. Despite initial claims that esketamine could rapidly reduce suicidal ideation, this meta-analysis found no strong evidence supporting this effect.

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3. Safety concerns
   
   1. Some trials reported an increase in suicidality and mortality among esketamine users.
   2. Side effects included dissociation, increased blood pressure, dizziness, and cognitive impairment, which could impact long-term usability.
   3. Questions remain about potential misuse and dependence, given esketamine's similarity to ketamine, which has known abuse potential.‍
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4. Healthcare resource use and cost-effectiveness (Harding et al., 2025)

While the meta-analysis focuses on symptom reduction and suicidality, Harding et al. offer a complementary perspective grounded in real-world healthcare data. Using insurance claims from over 14,000 patients with major depressive disorder and acute suicidal ideation or behavior, the study compared esketamine to electroconvulsive therapy (ECT), second-generation antipsychotic augmentation, and antidepressant monotherapy.

Key findings include:
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• Hospitalization days decreased by 58% in the esketamine group compared to baseline, versus only 21% in the antipsychotic augmentation group and a 44‍
• rease in the ECT group.
• Medical costs (excluding treatment) dropped by 50% for esketamine patients — from ~$3746 to $1869 per patient per month — compared to a 22% drop in the ECT group and 17% for antipsychotic augmentation.
• Esketamine patients had the highest baseline severity, with more comorbidities and prior treatment failures, yet still saw the greatest relative improvement in both costs and acute care use.
• Just over half of patients completed at least 8 sessions, but adherence to treatment schedule was suboptimal (mean of 56.5 days to reach 8 sessions, versus the 28-day label recommendation).

These findings suggest that esketamine may not need to dramatically outperform other treatments on symptom scores to provide system-level value , particularly in high-risk populations where reducing hospital admissions and emergency care is a critical goal.

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Why is this important?

Esketamine was marketed as a revolutionary treatment for depression, particularly for individuals who did not respond to conventional antidepressants. However, this meta-analysis suggests its effects may not be as robust as initially believed.

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• The antidepressant effects are mild, and while they are statistically significant, they do not appear dramatically stronger than traditional augmentation options.
• The failure to reduce suicidality challenges one of its primary selling points.
• Safety concerns, including increased suicidality in some trials, raise questions about its risk-benefit ratio.
• Since esketamine is a patented drug, its high cost may not be justified given its relatively small clinical benefits compared to non-patented alternatives like intravenous ketamine.

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Yet, when viewed through a broader lens, esketamine’s value may lie elsewhere. Real-world research has highlighted its potential to reduce healthcare strain in high-risk populations, especially in terms of hospitalization and acute care use. These findings point to a different kind of utility, one that may not be fully captured by short-term symptom scales, but that could nonetheless shift cost-benefit considerations in settings where system-level efficiency is a clinical priority.

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Limitations

• Short-term studies: Most trials assessed outcomes up to four weeks, meaning long-term effects remain unknown.
• Heterogeneous study designs: Differences in dosage, patient populations, and methodologies could affect the findings.
• Strong placebo response: In many trials, the placebo group improved significantly, complicating interpretations of esketamine’s true effect size.
• Lack of direct comparisons with IV ketamine: More studies are needed to determine whether esketamine offers any real-world advantages over traditional ketamine infusions.

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Conclusion

Esketamine’s role in depression treatment remains complex. This meta-analysis underscores its modest clinical efficacy, limited impact on suicidality, and notable safety concerns.  all of which challenge the initial narrative of a breakthrough intervention. However, when viewed through the lens of real-world data, particularly the findings from Harding et al. (2025), a different picture emerges: esketamine may offer substantial reductions in healthcare utilization and costs. Rather than a clear-cut clinical advance, esketamine may represent a trade-off, modest symptom benefits offset by meaningful systemic advantages. Its value may lie less in outperforming other treatments on traditional clinical endpoints, and more in reducing the broader economic and resource burden of severe, treatment-resistant depression. As research evolves, so should the criteria we use to define therapeutic success.