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Observational Study
. 2025 Oct:352:116655.
doi: 10.1016/j.psychres.2025.116655. Epub 2025 Jul 26.

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

Giacomo d'Andrea  1 , Clara Cavallotto  2 , Mauro Pettorruso  3 , Giorgio Di Lorenzo  4 , Rosalba Carullo  1 , Domenico De Berardis  5 , Gianluca Rosso  6 , Stefano Barlati  7 , Vassillis Martiadis  8 , Gianfranco Tamagnini  9 , Fabiola Raffone  8 , Giovanna Mammarella  2 , Antonio d'Attilio  2 , Tommaso Vannucchi  10 , Marco Di Nicola  11 , Sergio De Filippis  12 , Ileana Andriola  13 , Raffaella Zanardi  14 , Angelo De Giorgi  15 , Antonino Petralia  16 , Giorgio Pigato  17 , Gianluca Serafini  18 , Bernardo Maria Dell'Osso  19 , Massimo Clerici  20 , Antonio Vita  7 ; REAL-ESK Study Group; Stefano L Sensi  31 , Roger S McIntyre  32 , Giovanni Martinotti  33
Collaborators, Affiliations
Free article
Observational Study

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

Giacomo d'Andrea et al. Psychiatry Res. 2025 Oct.
Free article

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.

Keywords: Anhedonia; Bipolar disorder; Esketamine nasal Spray; Major depressive disorder; Treatment resistant depression.

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Conflict of interest statement

Declaration of competing interest Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Bristol Myers Squibb (BMS) and Atai Life Sciences. Prof. Giorgio Di Lorenzo has been a speaker and/or a consultant for Angelini, FB-Health, Janssen-Cilag, Johnson&Johnson Innovative Medicine, Livanova, Lundbeck, Neuraxpharm, Otsuka, and Recordati. Prof. Gianluca Rosso has received advisory board, lecture or consulting fees, outside the present work, from: Angelini, Janssen, Lundbeck, Neuraxpharm, Otsuka, Rovi. Dr. Raffaella Zanardi has been a consultant/speaker for Baldacci and Italfarmaco. Dr. GiorgioPigato has received speaker/consultation/clinical trial compensation/fees from Lundbeck, Janssen, Angelini, Eli lilly Italia, Takeda, Neopharmed Gentili, Viatris, NeuraxPharm; Pfizer, AstraZeneca, Glaxo, Sanofi. Dr. Gabriele Di Salvo has been speaker for Angelini, Janssen, Lundbeck, Neuraxpharm, Dr. Ileana Andriola was a speaker at Janssen sponsored conference. Dr. Antonio Vita received grant/research support and speaker/consultant fees for Angelini, Boheringer Ingelheim, Innovapharma, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Recordati, Roche, Rovi Pharma, Takeda. Dr. Bernardo Maria Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Dr. Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. The remaining authors declare that the research was conducted without any commercial or financial relationship that could be construed as a potential conflict of interest.

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