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Peer reviewed: True, Funder: National Institute of Health Research Oxford Health Biomedical Research Centre, INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis. METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6

Background The link between inflammation and depression has been investigated extensively. Cognitive dysfunction in depression is an unmet treatment need. A better understanding of possible links between inflammation and cognition in people with depression may help to identify new treatment targets. Methods We report findings from a study comparing a range of cognitive functions between 80 depressed patients with (C-reactive protein ≥3 ​mg/L; n ​= ​37) and without (CRP, Highlights • Depressed patients with evidence of inflammation (CRP >3 ​mg/L) showed poorer neurocognitive test performance in psychomotor speed and reaction time. • Neurocognitive. performance difference between patients with and without evidence of inflammation was no longer significant after controlling for age, sex, and BMI. • The impact of depression severity and fatigue differed across cognitive domains; reaction time was affected more by fatigue scores while psychomotor speed was affected more by depressive symptoms. • Stratification of patient samples with depression according to inflammation status may provide insights into cognitive dysfunction in depression.

Depression is a major neuropsychiatric disorder common in patients with rheumatological conditions including spondyloarthritis (SpA). It is associated with higher disease activity, functional impairment, poor treatment response and quality of life in patients with musculoskeletal disorders. Using ankylosing spondylitis (AS) and psoriatic arthritis (PsA) as examples, we have reviewed the evidence regarding the burden, risk factors, potential mechanisms and clinical management of depression in spondyloarthritis. The prevalence of depression is higher in patients with AS and PsA compared with the general population, with evidence of moderate/severe depression in about 15% of patients with AS or PsA. Mild depression is even more common and estimated to be present in about 40% of patients with AS. In addition to conventional risk factors such as stressful life events and socioeconomic deprivation, increased risk of depression in SpA may be associated with disease-related factors, such as disease activity, poor quality of life, fatigue, and sleep disturbances. Emerging evidence implicates inflammation in the aetiology of depression, which could also be a shared mechanism for depression and chronic inflammatory conditions such as AS and PsA. It is imperative for clinicians to actively assess and treat depression in SpA, as this could improve treatment adherence, quality of life, and overall long-term clinical and occupational outcomes. The use of validated tools can aid recognition and management of depression in rheumatology clinics. Management of depression in SpA, especially when to refer to specialist mental health services, are discussed.

Funder: MQ: Transforming Mental Health; FundRef: https://doi.org/10.13039/501100008162; Grant(s): MQDS17/40, Funder: cambridge trust; FundRef: https://doi.org/10.13039/501100003343, Depression is a major neuropsychiatric disorder common in patients with rheumatological conditions including spondyloarthritis (SpA). It is associated with higher disease activity, functional impairment, poor treatment response and quality of life in patients with musculoskeletal disorders. Using ankylosing spondylitis (AS) and psoriatic arthritis (PsA) as examples, we have reviewed the evidence regarding the burden, risk factors, potential mechanisms and clinical management of depression in spondyloarthritis. The prevalence of depression is higher in patients with AS and PsA compared with the general population, with evidence of moderate/severe depression in about 15% of patients with AS or PsA. Mild depression is even more common and estimated to be present in about 40% of patients with AS. In addition to conventional risk factors such as stressful life events and socioeconomic deprivation, increased risk of depression in SpA may be associated with disease-related factors, such as disease activity, poor quality of life, fatigue, and sleep disturbances. Emerging evidence implicates inflammation in the aetiology of depression, which could also be a shared mechanism for depression and chronic inflammatory conditions such as AS and PsA. It is imperative for clinicians to actively assess and treat depression in SpA, as this could improve treatment adherence, quality of life, and overall long-term clinical and occupational outcomes. The use of validated tools can aid recognition and management of depression in rheumatology clinics. Management of depression in SpA, especially when to refer to specialist mental health services, are discussed.

Acknowledgements: We would like to thank Dr Mary-Ellen Lynall (University of Cambridge) for providing additional information regarding their study for our systematic review and meta-analysis., Funder: Medical Research Council Epidemiology Unit PhD Studentship, Funder: Versus Arthritis Award (Grant No. 22453), Funder: Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1), Funder: NIHR Cambridge BioResource, Funder: The MQ: Transforming Mental Health (Grant No. MQDS17/40); BMA Foundation (J. Moulton Grant 2019), INTRODUCTION: Meta-analyses implicate immune dysfunction in depression confirming increased levels of circulating immune proteins (e.g., cytokines) in depression cases compared to controls. White blood cells (WBC) both produce and are influenced by cytokines, and play key roles in orchestrating innate and adaptive immune responses, but their role in depression remains unclear. Therefore, a systematic review of studies of various WBC subsets in depression is required for a greater understanding of the nature of immune dysfunction in this illness. METHODS: We searched PubMed and PsycINFO databases (inception to 5th April 2022) and conducted a systematic review and meta-analysis of identified studies comparing absolute count and/or relative percentage of flow cytometry-derived WBC subsets between depression cases and controls. Selected studies were quality assessed. Random-effect meta-analysis was performed. RESULTS: Thirty-three studies were included and 27 studies (n = 2277) were meta-analysed. We report an increase in mean absolute counts of WBC (seven studies; standardised mean difference [SMD] = 1.07; 95% CI, 0.61-1.53; P < 0.01; I2 = 64%), granulocytes (two studies; SMD = 2.07; 95% CI, 1.45-2.68; P < 0.01; I2 = 0%), neutrophils (four studies; SMD = 0.91; 95% CI, 0.23-1.58; P < 0.01; I2 = 82%), monocytes (seven studies; SMD = 0.60; 95% CI, 0.19-1.01; P < 0.01; I2 = 66%), CD4+ helper T cells (11 studies; SMD = 0.30; 95% CI, 0.15-0.45; P < 0.01; I2 = 0%), natural killer cells (11 studies; SMD = 1.23; 95% CI, 0.38-2.08; P < 0.01; I2 = 95%), B cells (10 studies; SMD = 0.30; 95% CI, 0.03-0.57; P = 0.03; I2 = 56%), and activated T cells (eight studies; SMD = 0.45; 95% CI, 0.24-0.66; P < 0.01; I2 = 0%) in depression, compared to controls. Fewer studies reported relative percentage, indicating increased neutrophils and decreased total lymphocytes, Th1, and Th2 cells in depression. CONCLUSIONS: Depression is characterised by widespread alterations in circulating myeloid and lymphoid cells, consistent with dysfunction in both innate and adaptive immunity. Immune cells could be useful biomarkers for illness subtyping and patient stratification in future immunotherapy trials of depression, along with cytokines, other biomarkers, and clinical measures.