Psychiatry researchAug 27, 2025

Esketamine nasal spray's effects on loss of pleasure in hard-to-treat bipolar and unipolar depression

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 28, 2026

Abstract

Essence

Repeated esketamine nasal spray was linked to reduced anhedonia in treatment-resistant unipolar and bipolar depression in routine care.

Evidence

This multicenter real-world observational study of 253 patients with treatment-resistant unipolar or bipolar depression found MADRS anhedonia scores improved over 3 months with adjunctive repeated esketamine nasal spray, with T2 response rates of 38% in unipolar TRD and 51.92% in bipolar TRD.

Caveat

Because all patients received esketamine in an observational secondary analysis without a control group, the study cannot establish that esketamine caused the anhedonia improvements.

Simplified

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.

Full Text

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Funding

Competing interests

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.

PubMed

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Esketamine nasal spray's effects on loss of pleasure in hard-to-treat bipolar and unipolar depression

Abstract

Full Text

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Competing interests

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