Esketamine Nasal Spray Reduces Anhedonia in Patients with Depression

A study showed that repeated administration of esketamine nasal spray effectively reduces anhedonia in patients with unipolar and bipolar depression.¹

“Given anhedonia’s transdiagnostic nature, our findings also suggest potential applicability of ESK-NS across various psychiatric and neurological conditions, including dual depression where clear guidelines and effective pharmacological treatments are still lacking,” wrote study investigator Giacoma d’Andrea, from the department of neurosciences, imaging and clinical Sciences at the University of Chieti-Pescara in Italy, and colleagues.¹

Anhedonia, the reduced ability to experience or anticipate pleasure, is a core symptom of major depressive disorder (MDD) and bipolar depression. It has been linked to depression severity, suicidality, and poor treatment outcomes. Despite being a core feature of depression, conventional antidepressants often fail to address anhedonia.

The US Food & Drug Administration (FDA) approved esketamine CIII nasal spray (SPREVATO), an NMDA receptor antagonist, for treatment-resistant depression on January 21, 2025.² Although trials leading up to the approval showed rapid antidepressant effects, they did not assess its impact on anhedonia. In a real-world, multicenter, observational study, investigators sought to evaluate the effects of repeated esketamine nasal spray on anhedonia in patients with unipolar and bipolar depression.¹

The study included 253 patients aged ≥ 18 years (mean age: 53 years) with treatment-resistant depression (199 with unipolar depression and 54 with bipolar depression). The unipolar and bipolar depression groups were matched based on gender, age, number of antidepressant trials, illness duration, baseline severity of MADRS total score, and MADRS anhedonia subfactor scale. The bipolar depression group had a greater number of depressive episodes (4.77 ± 4.11 vs. 3.59 ± 3.1).¹

All patients received repeated administrations of esketamine nasal spray along with their current medication regimen. The team assessed anhedonia using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, month 1, and month 3, with response defined as a ≥ 50 reduction in MADRS anhedonia subscale score from baseline.

Esketamine nasal spray provided significant improvements in anhedonia among patients with treatment-resistant depression and bipolar depression, with effects distinct from overall depressive symptom reduction (P < .001). At 3 months, 51.92% of participants with bipolar disorder and 38% with unipolar depression achieved a response. The study observed no significant differences in the antianhedonic effect when adjusting for doses (28 mg, 56 mg, or 84 mg) and diagnostic groups (P = .697).¹

The post-hoc analyses showed significant anhedonia reduction in patients with unipolar and bipolar depression at month 1 (P < .0001), with a similar amount of improvement for patients with or without bipolar. At month 3, participants continued to experience a significant reduction in anhedonia (P < .0001), with no meaningful difference between patients with unipolar or bipolar depression (P = .932).¹

Investigators observed comparable safety profiles of esketamine nasal spray among patients with unipolar and bipolar depression. Adverse events included hypertension, dissociation, sedation, manic symptoms, anxiety, dizziness, and headache. Either adverse events or efficacy led to 12.96% of patients with bipolar depression and 14% with unipolar depression to discontinue the treatment.

“This preliminary study found that ESK-NS appears to be effective in improving anhedonia, demonstrating efficacy in both MDD and BD, independent of its antidepressant effects,” investigators concluded.¹ “Given the central role of anhedonia in shaping illness severity and impairing overall functioning, the development of effective interventions targeting this symptom may be of critical importance. Despite the relevance of our results, future randomized [controlled] trial[s] utilizing [a] specific scale for anhedonia are necessary to confirm and extend these preliminary findings.”

References

1. Giacomo d’Andrea, Clara Cavallotto, Mauro Pettorruso, et al. 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. Psychiatry Research, 2025, https://doi.org/10.1016/j.psychres.2025.116655.

2. Derman, C. FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression. HCPLive. January 21, 2025. https://www.hcplive.com/view/fda-approves-esketamine-first-monotherapy-treatment-resistant-depression. Accessed August 21, 2025.