Peripheral low-grade inflammation in depression is increasingly seen as a therapeutic target. We aimed to establish the prevalence of low-grade inflammation in depression, using different C-reactive ...protein (CRP) levels, through a systematic literature review and meta-analysis.
We searched the PubMed database from its inception to July 2018, and selected studies that assessed depression using a validated tool/scale, and allowed the calculation of the proportion of patients with low-grade inflammation (CRP >3 mg/L) or elevated CRP (>1 mg/L).
After quality assessment, 37 studies comprising 13 541 depressed patients and 155 728 controls were included. Based on the meta-analysis of 30 studies, the prevalence of low-grade inflammation (CRP >3 mg/L) in depression was 27% (95% CI 21-34%); this prevalence was not associated with sample source (inpatient, outpatient or population-based), antidepressant treatment, participant age, BMI or ethnicity. Based on the meta-analysis of 17 studies of depression and matched healthy controls, the odds ratio for low-grade inflammation in depression was 1.46 (95% CI 1.22-1.75). The prevalence of elevated CRP (>1 mg/L) in depression was 58% (95% CI 47-69%), and the meta-analytic odds ratio for elevated CRP in depression compared with controls was 1.47 (95% CI 1.18-1.82).
About a quarter of patients with depression show evidence of low-grade inflammation, and over half of patients show mildly elevated CRP levels. There are significant differences in the prevalence of low-grade inflammation between patients and matched healthy controls. These findings suggest that inflammation could be relevant to a large number of patients with depression.
Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between ...schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.
Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and ...treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.
Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the ...mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.
Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review.
Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia.
Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
•Patients with depression show reduced variability in pro-inflammatory immune measures.•Patients with depression show increases in pro-inflammatory immune markers mean levels, and reductions in ...anti-inflammatory IL-4.
The magnitude and variability of cytokine alterations in depression are not clear.
To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation.
Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined.
Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected.
Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis.
Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR).
A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g = 0.71; 95%CI: 0.50–0.92; p < 0.0001); IL-3 (g = 0.60; 95%CI: 0.31–0.89; p < 0.0001); IL-6 (g = 0.61; 95%CI: 0.39–0.82; p < 0.0001); IL-12 (g = 1.18; 95%CI: 0.74–1.62; p < 0.0001); IL-18 (g = 1.97; 95%CI: 1.00–2.95; p < 0.0001); sIL-2R (g = 0.71; 95%CI: 0.44–0.98; p < 0.0001); and TNFα (g = 0.54; 95%CI: 0.32–0.76; p < 0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR = 0.85; 95%CI: 0.75–0.98; p = 0.02); IL-12 (CVR = 0.61; 95%CI: 0.46–0.80; p < 0.01); and sIL-2R (CVR = 0.85; 95%CI: 0.73–0.99; p = 0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α.
Depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution.
Sustainable zero cement-based one-part ambient cured alkali-activated engineered composites (AAECs) are developed. The durability and microstructural characteristics of developed AAECs using 2% v/v ...polyvinyl alcohol (PVA) fibers, silica sand, binary or ternary combinations of precursors (fly ash class C ‘FA-C’, fly ash class F ‘FA-F’ and ground granulated blast furnace slag ‘GGBFS’) and two types of powder form alkaline reagents (Type 1 and Type 2) are evaluated compared to conventional engineered cementitious composites (ECCs) and alkali-activated mortars (AAMs) without fiber. AAECs developed satisfactory compressive strength ranging from 34 MPa to 46 MPa. Expansion/shrinkage and mass change (loss/gain) behaviors are affected by binary/ternary combination of source materials, reagent types and curing regimes (water or ambient) for both AAMs and AAECs. The binary (FA-C + GGBFS) and reagent 2 (calcium hydroxide + sodium sulfate) composites demonstrated lower shrinkage due to formation of crystalline C-A-S-H/C-S-H binding phases than their ternary (FA-C + FA-F + GGBFS) and reagent 1 (calcium hydroxide + sodium metasilicate) counterparts which formed amorphous N-C-A-S-H/N-A-S-H phases. The matrix densification due to the formation of reaction products and fiber-induced micro-confinement leads to lower shrinkage and mass change of AAECs compared to their AAM counterparts. Composites exhibited lower or comparable secondary sorptivity indices compared to control ECC, indicating their superior permeation performance. All AAECs had a relative dynamic modulus of elasticity (RDME) greater than 90% at 300 cycles (comparable to control ECC), exhibiting satisfactory freeze–thaw resistance with reagent 2 mixes showing better performance compared to those with reagent 1. The production feasibility of strain hardening AAECs with powder form reagents having satisfactory mechanical and durability properties is confirmed.
Alkali-activated engineered composites (AAECs) are cement-free composites developed using alkali activation technology, which exhibit strain hardening and multiple micro-cracking like conventional ...engineered cementitious composites (ECCs). Such AAECs are developed in this study by incorporating 2%
/
polyvinyl alcohol (PVA) fibers into alkali-activated mortars (AAMs) produced using binary/ternary combinations of fly ash class C (FA-C), fly ash class F (FA-F), and ground-granulated blast furnace slag (GGBFS) with powder-form alkaline reagents and silica sand through a one-part mixing method under ambient curing conditions. The mechanical and microstructural characteristics of eight AAECs are investigated to characterize their strain-hardening performance based on existing (stress and energy indices) and newly developed tensile/flexural ductility indices. The binary (FA-C + GGBFS) AAECs obtained higher compressive strengths (between 48 MPa and 52 MPa) and ultrasonic pulse velocities (between 3358 m/s and 3947 m/s) than their ternary (FA-C + FA-F + GGBFS) counterparts. The ternary AAECs obtained a higher fracture energy than their binary counterparts. The AAECs incorporating reagent 2 (Ca(OH)
: Na
SO
= 2.5:1) obtained a greater fracture energy and compressive strengths than their counterparts with reagent 1 (Ca(OH)
: Na
SiO
.5H
O = 1:2.5), due to additional C-S-H gel formation, which increased their energy absorption for crack propagation through superior multiple-cracking behavior. A lower fracture and crack-tip toughness facilitated the development of enhanced flexural strength characteristics with higher flexural strengths (ranging from 5.3 MPa to 11.3 MPa) and a higher energy ductility of the binary AAMs compared to their ternary counterparts. The tensile stress relaxation process was relatively gradual in the binary AAECs, owing to the formation of a more uniform combination of reaction products (C-S-H/C-A-S-H) rather than a blend of amorphous (N-C-A-S-H/N-A-S-H) and crystalline (C-A-S-H/C-S-H) binding phases in the case of the ternary AAECs. All the AAECs demonstrated tensile strain-hardening characteristics at 28 days, with significant improvements from 28% to 100% in the maximum bridging stresses for mixes incorporating 40% to 45% GGBFS at 365 days. This study confirmed the viability of producing green cement-free strain-hardening alkali-activated composites with powder-form reagents, with satisfactory mechanical characteristics under ambient conditions.
Immunopsychiatry: important facts Khandaker, G. M.; Dantzer, R.; Jones, P. B.
Psychological medicine,
10/2017, Volume:
47, Issue:
13
Journal Article
Peer reviewed
Open access
Accumulating evidence indicate a role for the immune system particularly inflammation and autoimmunity in the aetiology of major psychiatric disorders such as depression and schizophrenia. In this ...paper, we discuss some of the key advances in immunopsychiatry in order to highlight to psychiatrists and other health professionals how an increased understanding of this field might enhance our knowledge of illness mechanism and approaches to treatment. We present a brief overview of clinical research that link inflammation and autoimmunity with depression and psychosis, including potential role of inflammation in treatment response, current evidence for the effectiveness of immune-modulating treatment for depression and psychosis, and possible role of inflammation in common physical comorbidities for these disorders such as coronary heart disease and diabetes mellitus. Gaining a better understanding of the role of immune system could be paradigm changing for psychiatry. We need collaborations between clinicians and scientists to deliver high-quality translational research in order to fully realise the clinical potential of this exciting and rapidly expanding field.
Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms ...for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia.
We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38-6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36-0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37-2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85-1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant.
Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance.
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