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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 5thApril 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.

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.

Whether depressed patients with evidence of inflammation are more appropriate candidates for immunotherapies is being tested in several clinical trials, which are selecting patients based on elevated C-reactive protein (CRP) and inflammation-related symptoms. However, studies of the clinical and phenotypic profile of depressed patients with elevated CRP are relatively scarce. We have investigated detailed clinical characteristics of 84 depressed patients, grouped as those with (CRP≥3mg/L) and without (CRP<3mg/L) inflammation. All patients met the International Classification of Diseases 10th Revision criteria for current depressive episode and had somatic symptoms of depression. We report that depressed patients with inflammation are more likely to be older (P = 0.04), have higher body mass index (P < 0.01), and be on non-selective serotonin reuptake inhibitor antidepressants (P = 0.04). After adjusting for potential confounders, the inflammation group had higher depression severity (adjusted mean difference = 8.82; 95 % CI, 3.91–13.72), somatic symptoms (adjusted mean difference = 3.25; 95 % CI, 1.58–4.92), state anxiety (adjusted mean difference = 9.25; 95 % CI, 3.82–14.67), perceived stress (adjusted mean difference = 4.58; 95 % CI, 1.98–7.18), and fatigue (adjusted mean difference = 9.71; 95 % CI, 3.09–6.33), but not anhedonia. The inflamed group also had poorer quality of life (adjusted mean difference = −0.18; 95 % CI, −0.32–0.05). At individual depressive symptom level, the inflammation group had increased guilty feelings (adjusted OR = 7.28; 95 % CI, 2.09–31.17), pessimism (adjusted OR = 5.38; 95 % CI, 1.53–22.73), concentration difficulties (adjusted OR = 4.56; 95 % CI, 1.32–19.02), and indecisiveness (adjusted OR = 4.21; 95 % CI, 1.15–18.54). Our findings highlight the clinical features associated with inflammation in depressed patients with somatic symptoms, including poor quality of life, supporting the need for intervention targeting this group. These results could also aid patient and outcome selection in future clinical trials testing immunotherapies in depression. Replication of these findings in larger samples is required.

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.