2026 ECNP Congress

PS02-2080

Therapeutic and adverse effects of interleukin 6 receptor inhibition on depression and schizophrenia: a drug-target Mendelian randomisation study

Éimear M Foley — H.J. Jones, C. Dardani, F. Hamilton, G. Davey Smith, G.M. Khandaker · University of Bristol, MRC Integrative Epidemiology Unit, Bristol, United Kingdom

2026 ECNP Congress

Introduction

Low-grade systemic inflammation is implicated in the pathogenesis of depression and schizophrenia, with pro-inflammatory cytokines playing a central role. Meta-analytic evidence shows antidepressant effects of immunosuppression using anti-cytokine monoclonal antibodies (e.g., interleukin 6 receptor/IL-6R antagonists) in patients with chronic inflammatory conditions [1-2]. Experimental medicine trials of anti-inflammatory agents (e.g., tocilizumab) in psychiatry are ongoing [3], with early evidence suggesting possible therapeutic benefit [4]. However, triangulation of evidence remains necessary to strengthen causal inference and to assess long-term efficacy and safety of immunotherapy in psychiatry. Genetic epidemiological approaches (e.g., Mendelian randomization/MR) can inform lifetime effects of pharmacological intervention, complement trial evidence, and guide the design of future large-scale efficacy trials. Previous MR studies have linked inflammatory pathways to psychiatric outcomes [5] but have been limited by a focus on individual proteins within complex signalling pathways, reliance on diagnostic case‑control definitions rather than symptom‑specific or patient‑relevant outcomes, and a lack of examination of potential causal adverse effects.

Aims

To assess the causal effects of genetically proxied IL-6R inhibition on depression, schizophrenia, and adverse health outcomes related to immune modulation.

Methods

We conducted a two‑sample MR study using genome‑wide association study (GWAS) summary statistics from individuals of European ancestry. Genetic proxies of IL‑6R inhibition were constructed using variants in the IL‑6R gene region associated with downstream reductions in C‑reactive protein (CRP), consistent with pharmacological IL‑6R blockade. Outcomes included rheumatoid arthritis, depression, and schizophrenia, alongside symptom‑level measures capturing core affective and behavioural domains relevant to depression. To assess potential adverse effects, we examined physical health outcomes identified from clinical trials and British National Formulary guidance for anti‑IL‑6R therapies, spanning infection‑related outcomes, cardiometabolic events, gastrointestinal conditions, and circulating biomarkers influenced by immune modulation. Primary causal estimates were obtained using inverse-variance weighted MR, with complementary estimators applied to assess robustness. Results are presented as odds ratios and 95% confidence intervals, with false discovery rate correction applied for multiple testing.

Results

Genetically proxied IL‑6R inhibition showed strong protective effects on rheumatoid arthritis (0.51 [0.35-0.75]; q=0.001). For psychiatric case-control outcomes, effects on depression and schizophrenia were modest and heterogeneous. In contrast, symptom‑level analyses showed evidence for reduced liability to suicidal thoughts (0.77 [0.68-0.88]; q=0.004). Analyses of adverse outcomes demonstrated increased risk of infection‑related endpoints consistent with immunosuppression. In particular, genetically proxied IL-6R inhibition was associated with sepsis requiring critical care (1.92 [1.13-3.27]; q=0.054). Protective effects were observed for pneumonia (0.69 [0.60-0.79]; q<0.001) and bilirubin (0.88 [0.86-0.91]; q<0.001). No clear causal evidence was observed for other adverse outcomes assessed.

Conclusions

This drug‑target MR study provides genetic evidence that IL-6R inhibition is causally protective for autoimmune disease and is associated with distinct, symptom‑specific psychiatric effects. These findings highlight heterogeneity in neuroimmune mechanisms not captured by diagnostic categories alone. Increased risk of serious infection underscores the need to balance potential psychiatric benefit against established adverse immune effects when considering immunomodulatory strategies. Overall, IL-6R inhibition remains a promising therapeutic target in psychiatry and warrants carefully designed large-scale efficacy trials focused on domain and symptom-specific benefits, patient stratification, and long-term risk-benefit evaluation.

References

  1. N. Kappelmann, G. Lewis, R. Dantzer, P.B. Jones, G.M. Khandaker, Antidepressant activity of anti cytokine treatment: a systematic review and meta analysis of clinical trials in chronic inflammatory conditions, Mol. Psychiatry 23 (2018) 335–343.
  2. G.M. Wittenberg, A. Stylianou, Y. Zhang, Y. Sun, A. Gupta, P.S. Jagannatha, D. Wang, B. Hsu, M.E. Curran, S. Khan, G. Chen, E.T. Bullmore, W.C. Drevets, Effects of immunomodulatory drugs on depressive symptoms: a mega analysis of randomised, placebo controlled clinical trials in inflammatory disorders, Mol. Psychiatry 25 (6) (2020) 1275–1285.
  3. É.M. Foley, S.L. Griffiths, A. Murray, J. Rogers, F. Corsi Zuelli, H. Hickinbotham, E. Warwick, M. Wilson, M. Kaser, G.K. Murray, B. Deakin, D. Jadon, J. Suckling, N.M. Barnes, R. Upthegrove, G.M. Khandaker, PIMS Collaboration, Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double blind placebo controlled trial of single dose tocilizumab in patients with psychosis, BMJ Open 13 (2023) e067944.
  4. É.M. Foley, N. Turner, R. Margelyte, H.J. Jones, M. Kaser, G. Lewis, P.B. Jones, G.M. Khandaker, Interleukin 6 as a treatment target for depression: a proof of concept randomized clinical trial, (In press).
  5. N. Kappelmann, J. Arloth, M.K. Georgakis, D. Czamara, N. Rost, S. Ligthart, G.M. Khandaker, E.B. Binder, Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms: a genetic correlation and two sample Mendelian randomisation study, JAMA Psychiatry 78 (2) (2021) 161–170.