The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill

Knight, Jennifer M.; Costanzo, Erin S.; Singh, Shiva P.; Yin, Ziyan; Szabó, Anikó; Pawar, Deepa; Hillard, Cecilia J.; Rizzo, J. Douglas; D’Souza, Anita; Pasquini, Marcelo C.; Coe, Christopher L.; Irwin, Michael R.; Drobyski, William R.

doi:10.1038/s41398-020-01164-y

Cited by 50 publications

(29 citation statements)

References 59 publications

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“…In MDD, we found some evidence to support that up-regulation of the IL-6R may be risk increasing conditioned on CRP and BMI, supporting preliminary data that blockade of IL-6R by agents such as tocilizumab may decrease depressive symptoms ( 45 ). However, data related to the antidepressant qualities of tocilizumab are conflicting ( 46 ), and randomized control trials are warranted to further investigate repurposing opportunities for IL-6 inhibition in MDD. Two recent studies also considered the effect of IL-6R signaling on the odds of depression via MR using some different GWAS than ours in some instances, with one study supporting a risk-increasing relationship between elevated IL-6R and depression ( 47 ), while the other suggested that IL-6R could be more specifically linked to suicidality rather than broad depression ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

et al. 2022

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There is a long-standing interest in exploring the relationship between blood-based biomarkers and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable serum biochemical traits to refine our understanding of causal effect in biochemical-psychiatric trait pairings. We observed widespread positive and negative genetic correlation between psychiatric disorders and biochemical traits. Causal inference was then implemented to distinguish causation from correlation, with strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders. Notably, CRP demonstrated both protective and risk-increasing effects on different disorders. Multivariable models that conditioned CRP effects on interleukin-6 signaling and body mass index supported that the CRP-schizophrenia relationship was not driven by these factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness.

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Section: Discussionmentioning

confidence: 99%

Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

et al. 2022

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“…In MDD, we found some evidence to support that upregulation of the IL-6 receptor may be risk increasing conditioned on CRP and BMI, supporting preliminary data that blockade of IL-6R by agents like tocilizumab may improve depressive symptoms (82). However, data related to the anti-depressant qualities of tocilizumab are conflicting (83), and randomised control trials are warranted to further investigate repurposing opportunities for IL- 6 inhibition in MDD. Finally, BMI demonstrated a quite robust protective effect on OCD conditioned on CRP and IL-6 signalling, in accordance with observational data that OCD is associated with reduced odds of obesity (84).…”

Section: Discussionmentioning

confidence: 99%

Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

Kiltschewskij

Geaghan

Carr

et al. 2021

Preprint

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There is a long-standing interest in exploring the relationship between blood-based biomarkers of biological exposures and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable biochemical traits measured from serum to refine our understanding of causal effect in biochemical-psychiatric trait parings. In accordance with expectation we observed widespread evidence of positive and negative genetic correlation between psychiatric disorders and biochemical traits. We then implemented causal inference to distinguish causation from correlation and found strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders, along with other putatively causal relationships involving urate and glucose. Strikingly, these analyses suggested CRP has a protective effect on three disorders including anorexia nervosa, obsessive-compulsive disorder, and schizophrenia, whilst being a risk factor for major depressive disorder. Multivariable models that conditioned CRP effects on interleukin-6 signalling and body mass index suggested that CRP-schizophrenia relationship was not likely mediated by those factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness, including factors such as CRP that are likely to constitute a causal effect and could be targets for therapeutic intervention and precision medicine.

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“…In psychiatry, interleukin (IL)-6 has been identified as a potential target in patients with depression and schizophrenia using population cohort and genetic studies 24,25 . However, patients receiving IL-6 receptor blockade (tocilizumab) as acute graftversus-host-disease prophylaxis experienced significantly more depressive symptoms 26 . This indicates that further investigation is required to test the therapeutic potential of targeting the immune system specifically in patients with depression, such as the Insight study, a proof-of-concept experimental medicine trial of tocilizumab 27 .…”

Section: Tools/technology Developmentmentioning

confidence: 99%

Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030

et al. 2021

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Neuroimmunology in the broadest sense is the study of interactions between the nervous and the immune systems. These interactions play important roles in health from supporting neural development, homeostasis and plasticity to modifying behaviour. Neuroimmunology is increasingly recognised as a field with the potential to deliver a significant positive impact on human health and treatment for neurological and psychiatric disorders. Yet, translation to the clinic is hindered by fundamental knowledge gaps on the underlying mechanisms of action or the optimal timing of an intervention, and a lack of appropriate tools to visualise and modulate both systems. Here we propose ten key disease-agnostic research questions that, if addressed, could lead to significant progress within neuroimmunology in the short to medium term. We also discuss four cross-cutting themes to be considered when addressing each question: i) bi-directionality of neuroimmune interactions; ii) the biological context in which the questions are addressed (e.g. health vs disease vs across the lifespan); iii) tools and technologies required to fully answer the questions; and iv) translation into the clinic. We acknowledge that these ten questions cannot represent the full breadth of gaps in our understanding; rather they focus on areas which, if addressed, may have the most broad and immediate impacts. By defining these neuroimmunology priorities, we hope to unite existing and future research teams, who can make meaningful progress through a collaborative and cross-disciplinary effort.

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The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill

Cited by 50 publications

References 59 publications

Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders

Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030

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