The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts.

BACKGROUND: Growing evidence indicates high comorbid anxiety and depression in patients with asthma. However, the mechanisms underlying this comorbid condition remain unclear. The aim of this study was to investigate the role of inflammation in comorbid anxiety and depression in three asthma patient cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project. METHODS: U-BIOPRED was conducted by a European Union consortium of 16 academic institutions in 11 European countries. A subset dataset from subjects with valid anxiety and depression measures and a large blood biomarker dataset were analysed, including 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy non-smokers (HC). The Hospital Anxiety and Depression Scale was used to measure anxiety and depression and a series of inflammatory markers were analysed by the SomaScan v3 platform (SomaLogic, Boulder, Colo). ANOVA and the Kruskal-Wallis test were used for multiple-group comparisons as appropriate. RESULTS: There were significant group effects on anxiety and depression among the four cohort groups (p < 0.05). Anxiety and depression of SAn and SAs groups were significantly higher than that of MMA and HC groups (p < 0.05. There were significant differences in serum IL6, MCP1, CCL18, CCL17, IL8, and Eotaxin among the four groups (p < 0.05). Depression was significantly associated with IL6, MCP1, CCL18 level, and CCL17; whereas anxiety was associated with CCL17 only (p < 0.05). CONCLUSIONS: The current study suggests that severe asthma patients are associated with higher levels of anxiety and depression, and inflammatory responses may underlie this comorbid condition.

Immune-endocrine biomarkers associated with mental health: A 9-year longitudinal investigation from the Hertfordshire Ageing Study.

BACKGROUND: The study of neural-endocrine-immune system interactions has led to substantial advances in our understanding of neuropsychiatric disorders. Growing evidence reveals the pivotal roles of inflammatory cytokines signalling the brain to produce neurochemical, neuroendocrine, and neuroimmune changes which affect mood and behaviour. Ageing is accompanied by the development of low-grade systemic inflammation which may promote changes in the neural systems predisposing to geriatric depression via the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the longitudinal associations between baseline values and conditional changes (independent of baseline) in immune-endocrine biomarkers and mental health status in a population-based cohort of older adults. METHODS: Data from 347 subjects (200 men, 147 women) who participated in the Hertfordshire Ageing Study at baseline (1994/5, mean age 67.3 years) and at 9-year follow-up were analysed. Serum samples for analysis of inflammatory and endocrinological measures were collected at baseline and follow-up. At follow-up, depression (Hospital Anxiety and Depression Scale) and mental health (Short Form-36 questionnaire) were assessed. Baseline values and changes in biomarkers in relation to risk of high depression scores (top sex-specific third) and low mental health scores (bottom sex-specific third) were examined using logistic regression. RESULTS: Lower baseline cortisol was related to greater risk of high depression scores; higher baseline cortisol: dehydroepiandrosterone sulphate ratio (men only) and higher baseline C-reactive protein (CRP) (women only) were related to greater risk of poor mental health scores. In addition, greater decline in cortisol was related to increased risk of high depression scores among men. These relationships were robust (p < 0.05) after controlling for sex, age, BMI, smoking, alcohol consumption and number of systems medicated. CONCLUSION: This study provides further evidence of the role of the HPA axis and inflammation in older adults with poor mental health. In addition, the findings highlight sex differences where increased inflammation in women and declines in cortisol in men were linked to poorer mental health. Further research is warranted to confirm these findings. This could lead to the search for potential biomarkers to stratify medications as well as developing novel intervention targets to improve mental health at older age.

Effects of SSRIs on peripheral inflammatory cytokines in patients with Generalized Anxiety Disorder.

BACKGROUND: Extensive research into psychoneuroimmunology has led to substantial advances in our understanding of the reciprocal interactions between the central nervous system and the immune system in neuropsychiatric disorders. To date, inflammation has been implicated in the pathogenesis of depression and anxiety. The immunomodulating effects of antidepressants on depression have been reported, however, there is no evidence of the similar effects of antidepressants on anxiety. The aim of the study was to investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on peripheral inflammatory cytokines in patients with first episode generalized anxiety disorder (GAD). METHODS: A prospective cohort design was employed: 42 patients with first episode GAD were treated with either escitalopram or sertraline for 12 weeks. Anxiety was measured by the Generalized Anxiety Disorder Scale and the State Trait Anxiety Inventory, serum pro-inflammatory cytokine levels were measured by the enzyme-linked immunosorbent assay (ELISA), and CRP determined by an immunoturbidimetric method before and after SSRIs treatment RESULTS: Baseline levels of anxiety and pro-inflammatory cytokines including IL-1α, IL-6, IL-8, IL-12, IFN-γ, and CRP were significantly reduced after treatment of SSRIs (p < 0.05 in all cases). In addition, the change of anxiety measures co-vary with the change of peripheral cytokine levels (p < 0.05 in all cases). The regression model revealed that log transformed baseline levels of CRP and IL-6 predicted treatment response (p < 0.05 in both cases). CONCLUSIONS: This study is the first to investigate the effects of SSRIs on pro-inflammatory cytokines in patients with first episode GAD. The findings indicate moderate acute anti-inflammatory effects of SSRIs in GAD, and suggest that these anti-inflammatory effects may underlie anxiolytic effects of SSRIs. The study also indicates that serum levels of CRP and IL-6 may predict treatment response. However, data from randomized controlled trials is warranted to confirm these findings.

Effects of SSRIs on peripheral inflammatory markers in patients with major depressive disorder: A systematic review and meta-analysis.

INTRODUCTION: Peripheral levels of inflammatory markers are elevated in major depressive disorder (MDD). Selective serotonin reuptake inhibitors (SSRIs) affect levels of inflammatory markers in patients with MDD, but studies have reported inconsistent findings. This systematic review and meta-analysis aims to investigate the effects of SSRI treatment on peripheral levels of a range of inflammatory markers in MDD patients. METHODS: Systematic literature search (Pubmed, Web of Science, Embase, Cochrane) for studies published before November 2018. Studies were included if they used SSRI monotherapy and peripheral levels of interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured before and after treatment in patients with MDD. Meta-analysis was conducted using Comprehensive Meta-analysis (version 2). Effect sizes were calculated using bias-corrected standardized mean difference (Hedges' g) between pre- and post-treatment. Sub-group analyses, meta-regression and publication bias estimates were undertaken; sensitivity analyses were performed using different estimated pre- and post-treatment correlations and after removing poor quality studies. RESULTS: Twenty two eligible studies including 827 MDD patients were included in the meta-analysis: fifteen studies for IL-6; eleven for TNF-α; eight for IL-10; seven for IL-1ß; six for IL-4; five for IL-2; and four for IFN-γ. The pooled effect estimate indicates SSRI treatment decreased levels of pro-inflammatory markers IL-6 (Hedges' g, -0.418; 95%CI, -0.663 to -0.174; I2 = 89.412), TNF-α (Hedges' g, -0.554; 95%CI, -0.990 to -0.118; I2 = 95.438) and IL-1ß (Hedges' g = -0.574; 95%CI, -1.014 to -0.135; I2 = 91.622), and anti-inflammatory marker IL-10 (Hedges' g = -0.615; 95%CI, -0.989 to -0.242; I2 = 90.406). There were no significant treatment effects on levels of IL-2, IL-4, or IFN-γ. There was a high level of heterogeneity between studies. Sensitivity analyses indicated the robustness of the primary analyses. CONCLUSIONS: The current review and meta-analysis indicates moderate immunomodulating effects of SSRI treatment for MDD, which suggests SSRIs may owe some of their therapeutic effect to their anti-inflammatory properties. High heterogeneity across studies may limit interpretation of the findings and larger randomized clinical trials are warranted.

Peripheral proinflammatory cytokines in Chinese patients with generalised anxiety disorder.

BACKGROUND: Inflammatory responses and inflammatory cytokines have been implicated in the pathogenesis of affective disorders, particularly major depression. Given the limited evidence relating to the potential role of proinflammatory cytokines in generalised anxiety disorder (GAD), we aimed to examine peripheral proinflammatory cytokines in Chinese patients with GAD. METHODS: A case-controlled cross-sectional study design, with recruitment of 48 patients with first episode GAD and 48 matched healthy controls. All participants completed measures of anxiety using well-established questionnaires, and serum levels of pro-inflammatory cytokines were measured using multiplex technology. RESULTS: Serum levels of CRP, IL-1α, IL-2, IL-6, IL-8, IL-12, IFN-γ, and GM-CSF were significantly higher in the GAD group in comparison to the control group (p < 0.05). Pearson correlation revealed significant positive correlations between anxiety measures and serum levels of CRP, IL-1α, IL-6, IL-8, IFN-γ, and GM-CSF (p < 0.05). LIMITATIONS: The cross-sectional study design does not permit definite conclusions on causal directions between inflammation and GAD. The study was limited to a panel of 8 cytokines and does not exclude the possibility of other important cytokines being involved. CONCLUSIONS: These findings indicate an elevated peripheral proinflammatory response, and provide further support for low grade inflammation in GAD. Further research may identify an 'inflammatory signature' for diagnosis and treatment response, and guide the search for novel pharmacological interventions.

Peripheral inflammatory cytokines and immune balance in Generalised Anxiety Disorder: Case-controlled study.

INTRODUCTION: Previous investigations have demonstrated that major depression is associated with particular patterns of cytokine signalling. The primary aim of this study was to examine peripheral pro-inflammatory and anti-inflammatory cytokines and immune balance in Generalised Anxiety Disorder (GAD). METHODS: A case-controlled cross-sectional study design was employed: 54 patients with GAD and 64 healthy controls were recruited. Participants completed self-report measures of anxiety and depression. Two pro-inflammatory and two anti-inflammatory cytokines were measured using multiplex technology. RESULTS: Case-control logistic regression analyses revealed significant differences in serum levels of IL-10, TNF-α, and IFN-γ between GAD and control groups after adjusting for age, gender, body mass index, smoking and alcohol consumption: these group differences were independent of the presence or degree of depression. Comparison of pro-inflammatory to anti-inflammatory cytokine ratios indicated that there were significantly higher ratios of TNF-α/IL10, TNF-α/IL4, IFN-γ/IL10, and IFN-γ/IL4 in the GAD group compared to the control group. CONCLUSIONS: This study is the first to investigate both pro- and anti-inflammatory cytokines and their balance in patients with GAD in comparison to healthy controls. The findings indicate a relatively increased pro-inflammatory response and decreased anti-inflammatory response and provide the first demonstration of an altered cytokine balance in GAD. Serum cytokine levels in GAD were independent of the presence of depression.

Donepezil Regulates 1-Methyl-4-phenylpyridinium-Induced Microglial Polarization in Parkinson's Disease.

1-Methyl-4-phenylpyridinium (MPP+) induces microglial activation and degeneration of dopaminergic (DAergic) neurons. Donepezil is a well-known acetylcholinesterase inhibitor used clinically to treat cognitive dysfunction in Alzheimer's disease (AD). In the present study, we tested the hypothesis that MPP+ promotes microglial M1 polarization and suppresses M2 polarization and that this can be restored by donepezil. Results indicate that MPP+ treatment in microglial BV2 cells promotes microglial polarization toward the M1 state. However, pretreatment with donepezil inhibited MPP+-induced M1 polarization in microglia by suppressing the release of interleukin (IL)-6, IL-1ß, or tumor necrosis factor (TNF)-α. Importantly, we found that MPP+ inhibited microglial M2 polarization by suppressing expression of Arg-1, Fizz1, and Ym1, which was also rescued by pretreatment with donepezil. In addition, IL-4-mediated induction of anti-inflammatory marker genes IL-10, IL-13, and transforming growth factor-ß2 (TGF-ß2) were significantly attenuated by MPP+ in BV2 cells, which was restored by pretreatment with donepezil in a concentration-dependent manner. Mechanistically, we found that the addition of MPP+ reduced the intensity of phosphorylated signal transducer and activator of transcription 6 (STAT6) but not total STAT6 in IL-4-stimulated BV2 cells. Importantly, pretreatment of microglial BV2 cells with donepezil 3 h prior to administration of MPP+ rescued the reduction of STAT6 phosphorylation induced by MPP+.

Effects of antipsychotics on bone mineral density and prolactin levels in patients with schizophrenia: a 12-month prospective study.

OBJECTIVE: Effects of conventional and atypical antipsychotics on bone mineral density (BMD) and serum prolactin levels (PRL) were examined in patients with schizophrenia. METHODS: One hundred and sixty-three first-episode inpatients with schizophrenia were recruited, to whom one of three conventional antipsychotics (perphenazine, sulpiride, and chlorpromazine) or one of three atypical antipsychotics (clozapine, quetiapine, and aripiprazole) was prescribed for 12 months as appropriate. BMD and PRL were tested before and after treatment. Same measures were conducted in 90 matched healthy controls. RESULTS: Baseline BMD of postero-anterior L1-L4 range from 1.04 ± 0.17 to 1.42 ± 1.23, and there was no significant difference between the patients group and healthy control group. However, post-treatment BMD values in patients (ranging from 1.02 ± 0.15 to 1.23 ± 0.10) were significantly lower than that in healthy controls (ranging from 1.15 ± 0.12 to 1.42 ± 1.36). The BMD values after conventional antipsychotics were significantly lower than that after atypical antipsychotics. The PRL level after conventional antipsychotics (53.05 ± 30.25 ng/ml) was significantly higher than that after atypical antipsychotics (32.81 ± 17.42 ng/ml). Conditioned relevance analysis revealed significant negative correlations between the PRL level and the BMD values after conventional antipsychotics. CONCLUSION: The increase of PRL might be an important risk factor leading to a high prevalence of osteoporosis in patients with schizophrenia on long-term conventional antipsychotic medication.

Attention processes in chronic fatigue syndrome: attentional bias for health-related threat and the role of attentional control.

Cognitive behavioural models of chronic fatigue syndrome (CFS) propose that attention processes, specifically, enhanced selective attention to health-threat related cues, may play an important role in symptom maintenance. The current study investigated attentional bias towards health-threat stimuli in CFS. It also examined whether individuals with CFS have impaired executive attention, and whether this was related to attentional bias. 27 participants with CFS and 35 healthy controls completed a Visual Probe Task measuring attentional bias, and an Attention Network Test measuring executive attention, alerting and orienting. Participants also completed self-report measures of CFS and mood symptoms. Compared to the control group, the CFS group showed greater attentional bias for health-threat words than pictures; and the CFS group was significantly impaired in executive attention. Furthermore, CFS individuals with poor executive attention showed greater attentional bias to health-threat related words, compared not only to controls but also to CFS individuals with good executive attention. Thus, this study revealed a significant relationship between attentional bias and executive attention in CFS: attentional bias to threat was primarily evident in those with impaired executive attention control. Taking account of individual differences in executive attention control in current intervention models may be beneficial for CFS.

Attentional bias towards health-threat information in chronic fatigue syndrome.

OBJECTIVE: To investigate whether individuals with chronic fatigue syndrome (CFS) show an attentional bias towards health-threat information. METHODS: Attentional bias (AB) was assessed in individuals with CFS and healthy controls using a visual probe task which presented health-threat and neutral words and pictures for 500 ms. Self-report questionnaires were used to assess CFS symptoms, depression, anxiety, and social desirability. RESULTS: Compared to a healthy control group, the CFS group showed an enhanced AB towards heath-threat stimuli relative to neutral stimuli. The AB was not influenced by the type of stimulus (pictures vs. words). CONCLUSION: The finding of an AB towards health-threat information in individuals with CFS is supportive of models of CFS which underlie cognitive behavior therapy.