2026 ECNP Congress

PS03-3095

Cortisol awakening response and outcomes after intranasal esketamine in treatment-resistant depression

Elisa Morandin — C. Scipioni, O. Sepulcri, M. Garzitto, G. Fanelli, M. Colizzi · Unit of Psychiatry, Department of Medicine DMED- University of Udine, Udine, Italy

2026 ECNP Congress

Background

Major depressive disorder is a leading cause of disability and substantial overall functional impairment in quality of life across heterogeneous populations worldwide, and up to 30% of patients do not respond to standard pharmacological treatment. Intranasal esketamine, the S-enantiomer of ketamine and an N-methyl-D-aspartate (NMDA) receptor antagonist, can produce rapid antidepressant effects in treatment-resistant depression [1]. There is evidence linking hypothalamic–pituitary adrenal (HPA) axis dysregulation to major depressive disorder [2-3]. Also, emerging evidence suggests a role of inflammation in treatment-resistant depression. As there is a connection between stress and the immune system, we tested whether baseline cortisol awakening response (CAR), a dynamic index of HPA-axis activity, was associated with clinical and functional outcomes after esketamine treatment.

Methods

Patients with treatment-resistant depression were recruited at Udine University Hospital for an 8-week, open-label, single-arm, phase 2, investigator-initiated mechanistic trial. Treatment-resistant depression was operationally defined as non-response to at least two antidepressants, each delivered as an adequate therapeutic trial with verified adherence [4]. Patients received intranasal esketamine in increasing doses (28-56/84 mg, depending on age), twice weekly for 4 weeks, followed by once-weekly administration. Assessments at baseline and week 8 included the Montgomery-Åsberg Depression Rating Scale (MADRS), the World Health Organization Disability Assessment Schedule (WHODAS), and CAR, measured before esketamine administration). Linear mixed-effects models were fitted to assess changes over time, with random intercepts for participants. Baseline CAR was modelled as both an additive fixed effect and a time-by-CAR interaction term.

Results

A total of 24 patients with treatment-resistant depression were enrolled (mean age: 48.2±13.51 years; 50% female). The most frequent comorbidities were autism spectrum disorder (level 1) or attention-deficit/hyperactivity disorder (9 patients), anxiety disorders (3 patients), and personality disorders (2 patients). 9 patients had endocrine diseases (3 with type 2 diabetes, 7 with thyroid and/or parathyroid diseases), and 2 patients had multiple sclerosis (1 with hypothyroidism). No other clinically documented HPA axis-related diseases were recorded. Depressive symptoms and functional disability, as assessed by the MADRS and WHODAS, significantly reduced at 2 months (respectively: mean-Δ%=−29.6%, F=6.1, p=0.021; Δ%=−32.3%, F=18.6, p<0.001). Higher baseline CAR was associated with greater improvement in both MADRS and WHODAS scores (time-by-CAR interaction: χ²=5.4, p=0.020; χ²=4.7, p=0.031). Baseline CAR correlated with baseline WHODAS (r=0.485, p=0.030), but not significantly with MADRS (r=0.340, p=0.104). CAR did not change from baseline to the 2-month assessment (Δ%=+4.9%, F=0.1, p=0.782).

Conclusions

In this single-arm mechanistic trial, higher baseline CAR was associated with greater symptomatic and functional improvement after intranasal esketamine in treatment-resistant depression. These preliminary findings suggest that baseline HPA-axis activity may index variation in short-term response to NMDA-receptor antagonist treatment. Given the small sample size, open-label design, and endocrine comorbidity burden, the results should be considered hypothesis-generating and require replication in larger controlled studies.

References

  1. Daly, E. J., Singh, J. B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R. C., Thase, M. E., Winokur, A., Van Nueten, L., Manji, H., & Drevets, W. C. (2018). Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA psychiatry, 75(2), 139–148.
  2. Nunez, S. G., Rabelo, S. P., Subotic, N., Caruso, J. W., & Knezevic, N. N. (2025). Chronic Stress and Autoimmunity: The Role of HPA Axis and Cortisol Dysregulation. International journal of molecular sciences, 26(20), 9994.
  3. Anisman H. (2009). Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. Journal of psychiatry & neuroscience: JPN, 34(1), 4–20.
  4. Sforzini, L., Worrell, C., Kose, M., Anderson, I. M., Aouizerate, B., Arolt, V., Bauer, M., Baune, B. T., Blier, P., Cleare, A. J., Cowen, P. J., Dinan, T. G., Fagiolini, A., Ferrier, I. N., Hegerl, U., Krystal, A. D., Leboyer, M., McAllister-Williams, R. H., McIntyre, R. S., Meyer-Lindenberg, A., … Pariante, C. M. (2022). A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials. Molecular psychiatry, 27(3), 1286–1299.