The effects of ketamine and esketamine on functional outcomes in major depressive disorder and treatment-resistant depression: A systematic review
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".