2026 ECNP Congress

PS01-1033

Baseline inflammation predicts symptomatic response to interleukin-2 in unipolar and bipolar depression

Carlo Di Carlo — D. Betelli, M. Carminati, E. Manfredi, C. Lorenzi, A. Finardi, R. Zanardi, C. Colombo, S. Poletti, R. Furlan, F. Benedetti · IRCCS Scientific Institute Ospedale San Raffaele, Psychiatry & Clinical Psychobiology- Division of Neuroscience, Milan, Italy

2026 ECNP Congress

Background: Immune dysregulation has been implicated in mood disorders, including unipolar and bipolar depression, but its clinical utility for treatment stratification remains uncertain. Peripheral inflammation has been proposed as a clinically relevant dimension for treatment stratification in depression [1]. Low-dose interleukin-2 (ld-IL2) has recently been investigated as an antidepressant potentiation strategy in unipolar and bipolar depression [2], yet it remains unclear whether baseline peripheral inflammatory activation can identify patients more likely to show symptomatic improvement.

Aims: To determine whether baseline peripheral blood transcriptomic profiles distinguish future symptomatic responders from non-responders to IL-2, and whether clinical response is accompanied by remodelling of inflammatory pathway activity.

Methods: Bulk RNA-sequencing data were analysed from a placebo-controlled cohort of 33 patients with unipolar or bipolar depression, and samples were collected at baseline, day 5 and day 60 after treatment. The cohort included 22 female and 11 male patients; sex was included as an adjustment covariate in DESeq2 models, where estimable, to reduce confounding from sex-related transcriptional differences. Symptomatic response was defined using the Montgomery-Åsberg Depression Rating Scale [3]. The cohort included 20 ld-IL-2-treated and 13 placebo-treated patients. Available samples were distributed as 20/20/14 for ld-IL-2 and 13/13/10 for placebo at baseline/day 5/day 60, respectively. Differential expression was modelled using paired longitudinal, treatment-stratified and response-stratified contrasts. Gene set enrichment analysis (GSEA) was performed across longitudinal treatment effects, responder versus non-responder comparisons and response-stratified trajectories. Weighted gene co-expression network analysis (WGCNA) was subsequently applied across 19,111 expressed genes.

Results: At day 5, symptomatic response was observed in 5/20 IL-2-treated patients and 5/13 placebo-treated patients; at day 60, response was observed in 11/14 and 5/10, respectively. IL-2 induced 914 differentially expressed genes at day 5 and 79 at day 60 at FDR<0.05, with the strongest day-5 signal in IL-2 non-responders. Direct responder versus non-responder contrasts and baseline future-response contrasts did not yield FDR-significant single genes, supporting a pathway-level rather than single-marker interpretation. GSEA indicated that future IL-2 responders were characterised at baseline by stronger inflammatory and immune-activation signatures than future non-responders, including inflammatory response, interferon-related programmes, cytokine signalling, innate immune activation, myeloid/neutrophil-associated pathways, complement-related processes and TNF/NF-κB-like activity. GSEA also showed attenuation of these inflammatory programmes by day 60 in responders, whereas non-responders showed weaker resolution. Among subjects with complete longitudinal response information, delayed conversion from non-responder at day 5 to responder at day 60 occurred in 9/14 IL-2-treated patients (64.3%) versus 3/10 placebo-treated patients (30.0%). In these IL-2 switchers, WGCNA supported the GSEA findings by identifying exploratory nominal eigengene changes in interferon/antiviral, myeloid-inflammatory, GTPase/vesicle-transport, cell-cycle and cytotoxic/immune-regulatory modules.

Conclusions: These findings support a predictive model in which elevated baseline peripheral inflammatory activation identifies patients with unipolar or bipolar depression more likely to experience symptomatic improvement following ld-IL-2 treatment. Peripheral transcriptomic profiling, particularly sex-adjusted pathway-level GSEA signatures, may help stratify patients before immunomodulatory treatment and monitor molecular trajectories associated with symptomatic response.

References

  1. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. Eur Neuropsychopharmacol. 2015 Oct;25(10):1532-43. doi: 10.1016/j.euroneuro.2015.06.007. Epub 2015 Jun 20. PMID: 26169573.
  2. Poletti S, Zanardi R, Mandelli A, Aggio V, Finardi A, Lorenzi C, Borsellino G, Carminati M, Manfredi E, Tomasi E, Spadini S, Colombo C, Drexhage HA, Furlan R, Benedetti F. Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers. Brain Behav Immun. 2024 May;118:52-68. doi: 10.1016/j.bbi.2024.02.019. Epub 2024 Feb 15. PMID: 38367846.
  3. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382. PMID: 444788.