Effectiveness of repeated Esketamine nasal spray administration on anhedonic symptoms in treatment-resistant bipolar and unipolar depression: A secondary analysis from the REAL-ESK study group
Bibliographic record
Abstract
INTRODUCTION: Anhedonia, defined as the diminished ability to experience or anticipate pleasure, is a core symptom of major depressive disorder (MDD) and bipolar depression (BD), and associated with depression severity, suicidality and poor treatment outcomes. Conventional antidepressants demonstrate limited efficacy against anhedonia. Esketamine nasal spray (ESK-NS) - a novel NMDA receptor antagonist approved for treatment-resistant depression - has demonstrated rapid antidepressant effects, though its specific impact on anhedonia remains underexplored. METHODS: This multicenter, observational, real-world study included 253 treatment-resistant patients (199 with unipolar depression/TRD; 54 with bipolar depression/B-TRD). All participants received repeated administrations of ESK-NS adjunctive to their current medication regimen. Anhedonia was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia subscale at baseline, after one month (T1), and three months (T2). Response was defined as a ≥50 % reduction in MADRS anhedonia subscale score from baseline. Adverse effects were systematically monitored. RESULTS: Significant improvements in anhedonia were observed in both TRD and B-TRD groups, and these effects were distinct from overall depressive symptom reduction (p < 0.001). Response rates at T2 were 51.92 % in B-TRD and 38 % in TRD patients. Drop-out rates were 12.96 % in B-TRD and 14 % in TRD, primarily due to inefficacy or side effects. Safety profiles were comparable between groups, with minimal incidence of manic switches (B-TRD 5.6 %, TRD 2.0 %, p = 1.000). CONCLUSION: Repeated administration of ESK-NS effectively reduces anhedonia in both unipolar and bipolar depression patients in real-world settings, suggesting a targeted, transdiagnostic anti-anhedonic effect beyond general antidepressant action.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| 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".