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

Aug 27, 2025Psychiatry research

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

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Abstract

Response rates for anhedonia reduction were 51.92% in bipolar depression patients and 38% in unipolar depression patients after three months of treatment.

Significant improvements in anhedonia were observed in both treatment-resistant unipolar and bipolar depression groups.
These improvements were distinct from overall reductions in depressive symptoms.
Drop-out rates were 12.96% in bipolar depression patients and 14% in unipolar depression patients, mainly due to inefficacy or side effects.
Safety profiles showed minimal incidence of manic switches, with rates of 5.6% in bipolar depression and 2.0% in unipolar depression.

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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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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

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