Comparative Efficacy of Esketamine Nasal Spray Versus Quetiapine Extended Release as Adjunctive Treatments for Treatment-Resistant Depression: A Systematic Review
Neha Ather, Mashal Zahid, Mohammad Hassan, Maryam Zahid, Nouraiz Abbas, Taimoor Rasheed, Hafsa Ahsun, Muhammad Saad Khan, Muhammad Mohsin Khan
Annals of Clinical Psychiatry July 29, 2026 DOI: 10.1177/10401237261473589 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant depression |
| Interventions | Esketamine nasal spray Quetiapine extended-release |
| Topics | Depression Esketamine |
| Key findings | Esketamine nasal spray demonstrated superior efficacy over quetiapine extended-release in achieving clinical response, remission, and functional improvements at weeks 8 and 32, with no significant differences in serious adverse events or mortality. |
Abstract
Background: Depression remains a leading cause of disability and suicide worldwide, with treatment-resistant depression (TRD) affecting nearly 30% of individuals diagnosed with major depressive disorder. Esketamine nasal spray (NS) and quetiapine extended-release (XR) are both approved as adjunctive therapies for TRD; however, direct head-to-head comparisons are limited.
Method: A systematic review following PRISMA guidelines was registered on PROSPERO. PubMed, Cochrane Central, and Web of Science were searched for RCTs comparing esketamine NS and quetiapine XR. Two reviewers independently assessed bias (Cochrane RoB 2) and extracted data. Findings were synthesized narratively.
Result: A total of six studies met inclusion criteria. Esketamine demonstrated superior efficacy over quetiapine in achieving clinical response, remission, and improvements in functional outcomes at weeks 8 and 32. There were no significant differences between the two treatments in terms of serious adverse events or mortality.
Conclusion: Esketamine nasal spray exhibited greater and more sustained antidepressant effects compared to quetiapine in the treatment of TRD. Its favorable efficacy and tolerability profile suggest its potential as a preferred adjunctive treatment. Further research is warranted to explore its long-term safety, real-world effectiveness, and performance across diverse populations.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |