The effects of ketamine and esketamine on functional outcomes in major depressive disorder and treatment-resistant depression: A systematic review
Isabella S Ji, Morgan C H Cheng, Kayla M Teopiz, Christine E. Dri, Sabrina Wong, Gia Han Le, Taeho Greg Rhee, Hernán F Guillen-Burgos, Heidi Ka Ying Lo, Yang Jing Zheng, Roger S McIntyre
Journal of Psychiatric Research October 30, 2025 DOI: 10.1016/j.jpsychires.2025.10.056 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Peer reviewed |
|---|---|
| Population | Adults (≥18 years) with major depressive disorder or treatment-resistant depression |
| Interventions | Esketamine Ketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Depression economics Depressive symptoms Meta-analysis Anesthesia Clinical psychology Medline |
| Citations | 2 |
| Key findings | Esketamine significantly reduces functional impairment and improves workplace productivity in adults with MDD or TRD, while no controlled studies exist for ketamine. |
Abstract
Introduction: Functional impairment is commonly reported amongst individuals with major depressive disorder (MDD) or treatment-resistant depression (TRD). Extant evidence suggests that ketamine and esketamine, N-methyl-D-aspartate (NMDA) receptor antagonists and glutamatergic modulators, have shown efficacy in treating MDD/TRD. While symptom reduction remains central to treatment, many individuals with TRD continue to experience work, social and family difficulties even when mood symptoms remit. Hence, this review synthesizes evidence on the effect of es/ketamine on functional outcomes, as measured by workplace productivity and psychosocial function.
Methods: A systematic search was conducted in PubMed, OVID (Embase) and PsychInfo through February 1, 2025. Eligible studies were randomized controlled trials (RCTs) or post hoc RCT analyses in adults (≥18 years) with MDD or TRD, examining ketamine (R- or S-enantiomer, intravenous) or intranasal esketamine. Comparators included placebo, standard care, antidepressants or other active agents. Primary outcomes were functional impairment, workplace performance and related domains.
Results: No controlled studies were identified for ketamine, emphasizing a considerable gap in literature. Nine studies investigated esketamine and functional impairment. Significant mean [sd] reduction in Sheehan Disability Scale (SDS) scores were observed with esketamine (-13.6, [8.31]) versus placebo (-9.4, [8.43]). Workplace productivity also significantly improved; notably, reduced productivity loss (p = 0.0045), presenteeism (p = 0.0098), and activity impairment (p = 0.0172) relative to controls.
Conclusion: Esketamine alleviates depressive symptoms and improves functioning, notably in workplace domains. Future studies should include functional outcomes as key secondary or co-primary outcomes, reflecting the ultimate goal of recovery in TRD/MDD.
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 |