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.
G. D’andrea, C. Cavallotto, M. Pettorruso, Giorgio Di Lorenzo, Rosalba Carullo, Domenico de Berardis, Gianluca Rosso, Stefano Barlati, V. Martiadis, Gianfranco Tamagnini, F. Raffone, G. Mammarella, A. D'Attilio, T. Vannucchi, M. Nicola, S. de Filippis, I. Andriola, R. Zanardi, A. de Giorgi, A. Petralia, G. Pigato, G. Serafini, B. Dell'Osso, Massimo Clerici, A. Vita, Stefano L. Sensi, R. Mcintyre, G. Martinotti
Psychiatry Research July 26, 2025 DOI: 10.1016/j.psychres.2025.116655 via Semantic Scholar
Summary
Anhedonia, the reduced ability to experience pleasure, is a core symptom of both unipolar and bipolar depression that often responds poorly to standard antidepressants. In a real-world observational study of 253 treatment-resistant patients (199 with unipolar depression, 54 with bipolar depression), repeated doses of esketamine nasal spray added to ongoing medication significantly reduced anhedonia over three months. The effect was distinct from overall mood improvement. At three months, 51.92% of bipolar and 38% of unipolar patients showed at least a 50% reduction in anhedonia scores. Dropout rates were low (around 13–14%), and manic switches were rare. The findings suggest esketamine has a targeted, transdiagnostic anti-anhedonic effect.
Study at a glance
| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 253 |
| Population | Treatment-resistant patients with unipolar or bipolar depression |
| Keywords | Medicine Psychology |
| Citations | 16 |
| Key finding | Esketamine nasal spray significantly reduced anhedonia in both unipolar and bipolar treatment-resistant depression, with response rates of 38% and 51.92% respectively at three months. |
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.