2026 ECNP Congress

PS04-4203

Immunological correlates of antidepressant response to serial oral ketamine in major depressive disorder and bipolar depression

Leo Silberbauer — B. Eggerstorfer, P. Altmann, R. Lanzenberger, G. Gryglewski · Medical University of Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria

2026 ECNP Congress

Introduction

Ketamine represents a major advancement in the pharmacological treatment of patients with major depressive disorder and bipolar depression, particularly in difficult to treat cases. However, treatment response shows considerable interindividual variability. This highlights the importance of identifying predictive markers to enable patient stratification prior to treatment initiation. Immunological factors have been increasingly implicated in the pathophysiology of depression, with evidence suggesting that peripheral and central inflammatory processes may contribute to altered neurotransmission, neuroendocrine dysregulation, and impaired neuroplasticity. These inflammatory alterations have also been linked to treatment resistance. Preliminary findings further indicate that ketamine may exert part of its rapid antidepressant effects through the modulation of immune-inflammatory pathways, including potential anti-inflammatory effects that may underlie its antidepressant efficacy [1]. Baseline inflammatory markers may therefore help identify biologically distinct subgroups of patients who are more likely to benefit from ketamine treatment.

Aims

This exploratory study aims to investigate the association between peripheral immunological parameters and treatment response following repeated oral ketamine treatment in patients suffering from major depressive disorder and bipolar depression.

Methods

A total of 23 patients (mean age ± sd: 38.3 ± 13.4; 11 female) received peroral racemic ketamine (1mg/kg bodyweight) six times over a two-week period in a double-blind trial. Venous blood samples were collected at screening and at the final study visit. Peripheral inflammatory markers, including total leukocyte count, neutrophil count, lymphocyte count, basophil count, eosinophil count, fibrinogen, C-reactive protein (CRP) were assessed. Moreover, monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) were calculated. In a subsample, cytokines and related biomarkers, including IL-10, IL-13, IL-15, IL-17A, IL-22, IL-33, IL-5, IL-6, IL-8, tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP) were analyzed using multiplex immunoassays. Results of the clinical trial were previously published elsewhere [2]. Changes in immunological parameters from baseline to the final study visit were assessed using paired t-tests. The relative reduction in the Montgomery–Åsberg Depression Rating Scale (MADRS) scores from baseline to the final study visit was correlated with immunological parameters using Spearman correlation analysis.

Results

No statistically significant differences in immunological parameters were observed between screening visit and the final study visit following repeated oral ketamine treatment. Baseline levels of IL-15 were significantly associated with the relative reduction in MADRS scores at the final visit (Spearman’s ρ= 0.76, p = 0.037).

Conclusions

Our exploratory findings suggest that immunological parameters may serve as promising biomarkers for predicting antidepressant response to ketamine. These results support the relevance of immune-inflammatory pathways in ketamines antidepressant efficacy and highlight the potential value of peripheral inflammatory markers for patient stratification. Larger, adequately powered studies are needed to confirm these preliminary observations and to further clarify the role of IL-15 and related immune mechanisms in ketamine’s antidepressant effects.

References

  1. Johnston JN, Greenwald MS, Henter ID, Kraus C, Mkrtchian A, Clark NG et al. Inflammation, stress and depression: An exploration of ketamine’s therapeutic profile. Drug discovery today 2023; 28(4): 103518.
  2. Silberbauer LR, Eggerstorfer B, Michenthaler P, Reichel S, Stimpfl T, Vanicek T et al. Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis. J Affect Disord 2026; 394(Pt A): 120466.