Efficacy and Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Summary & key facts

Researchers combined results from 17 carefully controlled trials that enrolled about 10,000 people whose depression had not improved with standard treatments. They found that adding esketamine nasal spray to an oral antidepressant led to more people reaching a treatment response and remission and to small improvements in day-to-day functioning. However, esketamine increased the risk of dissociation (feeling detached or unreal) and raised blood pressure in some people. Overall, the drug can help people with hard-to-treat depression, but it needs careful medical monitoring and more long-term research.

Key facts:

• The review pooled data from 17 carefully controlled trials that included about 10,000 people with treatment-resistant depression.
• About 5,700 people received esketamine plus an oral antidepressant, and about 4,600 received a placebo plus an oral antidepressant.
• Across 14 trials, esketamine significantly increased the chance of a treatment response compared with placebo; the pooled statistic reported an odds ratio of about 0.51.
• Across 13 trials, esketamine also significantly increased the chance of remission compared with placebo; the pooled statistic reported an odds ratio of about 0.35.
• Functional ability (measured with a common disability scale) improved more with esketamine by about 2 points on the scale, based on four trials.
• When depression symptoms were pooled as average score changes on two common rating scales, the differences were small and not clearly statistically significant.
• Esketamine nearly doubled the risk of dissociation (people feeling detached or unreal) in nine trials.
• Esketamine raised the risk of high blood pressure by about 40% in nine trials.
• Sedation (sleepiness) and nausea were slightly more common with esketamine but those increases were not clearly statistically significant in the pooled data.
• The authors say esketamine’s benefits are meaningful for many people with hard-to-treat depression, but they also stress the need for safety monitoring and more long-term and comparative studies.

Abstract

Abstract Introduction Treatment-resistant depression (TRD) affects up to one-third of patients with major depressive disorder, leading to poor outcomes and increased suicide risk. Esketamine nasal spray, a novel glutamatergic modulator, has emerged as an adjunctive option with rapid onset of action. However, the efficacy and safety of esketamine across randomized controlled trials (RCTs) remain variably reported, necessitating a systematic synthesis. Methods We systematically searched PubMed, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov from inception to September 2025. Seventeen RCTs comprising 10,073 patients were included, of whom 5,707 received esketamine plus oral antidepressant and 4,622 received placebo plus oral antidepressant. Primary efficacy outcomes included change in depressive symptoms, response (≥50% reduction), and remission rates. Secondary outcomes were functional improvement (Sheehan Disability Scale, SDS) and safety events (dissociation, sedation, hypertension, nausea). Random-effects models were used to pool mean differences (MD), odds ratios (OR), and risk ratios (RR) with 95% confidence intervals (CI). Results Esketamine significantly improved response (OR = 0.51; 95% CI: 0.30–0.73; p < 0.001; 14 RCTs) and remission (OR = 0.35; 95% CI: 0.11–0.58; p < 0.01; 13 RCTs). Functional outcomes also favored esketamine (SDS MD = –2.27; 95% CI: –3.50 to –1.04; p < 0.01; 4 RCTs). Pooled analysis of continuous MADRS and CGI-S change showed non-significant differences (MADRS MD = –1.47; 95% CI: –3.01 to 0.07; CGI-S MD = –0.30; 95% CI: –0.75 to 0.14). Safety analysis revealed increased risk of dissociation (RR = 1.98; 95% CI: 1.68–2.28; 9 RCTs) and hypertension (RR = 1.42; 95% CI: 1.04–1.80; 9 RCTs), with non-significant elevations for sedation (RR = 1.23; 95% CI: 0.80–1.66) and nausea (RR = 1.10; 95% CI: 0.82–1.37). Conclusion Esketamine nasal spray plus oral antidepressant significantly improves treatment response, remission, and functioning in TRD patients but is associated with increased risk of dissociation and hypertension. While efficacy is robust, safety monitoring and structured clinical delivery remain essential. Further long-term and comparative effectiveness studies are warranted to define esketamine’s role in TRD management.

Topics

Digital Mental Health Interventions Olfactory and Sensory Function Studies Treatment of Major Depression

Categories

Life Sciences Neuroscience Sensory Systems

Tags

Adverse effect Anesthesia Antidepressant Clinical trial Confidence interval Depression (economics) Depressive symptoms Exacerbation Internal medicine Ketamine Major depressive disorder Medicine Meta-analysis Nasal spray Number needed to treat Odds ratio Placebo Randomized controlled trial Subgroup analysis Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Sadness or low mood