2026 ECNP Congress

EP01-1057

Adjunctive intranasal esketamine and changes in anhedonia in treatment-resistant depression: preliminary real-world evidence

Inês Gomes — D. Santos, G. Lima · Unidade Local de Saúde Arco Ribeirinho, Departamento de Psiquiatria e Saúde Mental, Barreiro, Portugal

2026 ECNP Congress

Background

Anhedonia, defined as the loss of interest and/or the capacity to experience pleasure in previously enjoyed activities, is one of the two cardinal symptoms required for the diagnosis of a major depressive episode. Clinically, anhedonia is associated with greater illness severity, chronicity, and increased risk of relapse, and is a robust and often independent predictor of suicidal ideation. It is also linked to persistent psychosocial impairment and frequently remains as a residual symptom even after improvement of other depressive symptoms, limiting full clinical remission**[1];. This burden is particularly pronounced in treatment-resistant depression (TRD), where anhedonia often persists despite multiple adequate antidepressant trials[2];. Moreover, conventional antidepressants, particularly SSRIs, show limited efficacy in treating anhedonic symptoms, suggesting involvement of neurobiological pathways beyond the serotonergic system, notably dopaminergic and glutamatergic mechanisms[2], [3];. Currently, no pharmacological treatments are specifically approved or indicated for anhedonia as a distinct therapeutic target, representing a critical unmet need in TRD. Intranasal esketamine, acting via NMDA receptor antagonism and glutamatergic modulation, has been proposed as a candidate with potential anti-anhedonic effects in this population; however, evidence remains limited[4]**;.

Objectives

To assess whether intranasal esketamine is associated with improvement in anhedonia in patients with TRD in a real-world setting.

Methods

We conducted a 9-week real-world, observational longitudinal pilot study including 13 consecutively recruited patients with TRD receiving intranasal esketamine as an add-on therapy. Treatment was administered twice weekly during the first 4 weeks (induction phase), followed by weekly administration thereafter (maintenance phase). Anhedonia was assessed using the patient-reported PHQ-9, focusing on item 1 (“little interest or pleasure in doing things”), which was used as a proxy measure of anhedonia, as validated anhedonia-specific scales were not systematically available. Assessments were performed at baseline, 4 weeks, and 9 weeks. As an exploratory variable, the Snaith-Hamilton Pleasure Scale (SHAPS) was used to further characterize anhedonia; however, it was not administered at consistent time points across the sample. Missing data reflected unrecorded assessments; all patients continued treatment throughout the study period. Analyses were conducted using available cases.

Results

At baseline, nearly all patients (11/13, 85%) scored at the maximum PHQ-9 item 1 score (median 3, IQR 3-3), indicating a ceiling effect. Improvements were detectable by 4 weeks, with median scores decreasing to 2 (IQR 1-3; n=8). Five patients demonstrated improvement, while the remainder remained stable, with no worsening observed. This pattern appeared to be maintained at 9 weeks (n=3). Overall depressive symptom severity showed a similar trajectory, with median PHQ-9 total score decreasing from 21 (IQR 16-24) at baseline (n=13) to 16 (IQR 12-21) at 4 weeks (n=9), and to 12.5 (IQR 10-16) at 9 weeks (n=4).

Conclusions

These preliminary findings from an ongoing real-world study provide evidence of a potential anti-anhedonic effect of intranasal esketamine in patients with TRD, with improvements detectable as early as 4 weeks, and support the feasibility of prospective controlled studies using validated anhedonia-specific measures. Limitations include the small sample size and open-label, uncontrolled design, precluding causal inferences.

References

  1. Wu, C., Mu, Q., Gao, W., & Lu, S., 2025. The characteristics of anhedonia in depression: A review from a clinically oriented perspective. Translational Psychiatry, 15, (90). https://doi.org/10.1038/s41398-025-03310-w
  2. Wang, S., Leri, F., & Rizvi, S. J., 2021. Anhedonia as a central factor in depression: Neural mechanisms revealed from preclinical to clinical evidence. Progress in Neuropsychopharmacology & Biological Psychiatry, 110, 110289. https://doi.org/10.1016/j.pnpbp.2021.110289
  3. Treadway, M. T., & Zald, D. H., 2011. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 35(3), 537–555. https://doi.org/10.1016/j.neubiorev.2010.06.006
  4. Lally, N., Nugent, A. C., Luckenbaugh, D. A., Ameli, R., Roiser, J. P., & Zarate, C. A., 2014. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Translational Psychiatry, 4, e469. https://doi.org/10.1038/tp.2014.105