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Try out PMC Labs and tell us what you think. Learn More. C-reactive protein CRP has been indicated to be associated with the pathogenesis of schizophrenia SZ and other psychiatric disorders. The aim of this study is to investigate whether peripheral blood CRP levels are associated with the risk of SZ.
At least two reviewers decided on Qiqihar arabic sex and extracted data from included studies. Random effects meta-analyses were performed using standardized mean difference SMD as the effect estimate of the differences in CRP levels between subjects with SZ and healthy controls. We identified 18 studies representing patients with SZ and non-SZ controls.
Our study provides evidence that higher CRP levels are associated with increased risk of SZ, especially for young adult patients less than 30 years. Further large-scale studies are strongly warranted to further confirm this association. Immune system dysfunctions and inflammatory processes have been implicated in the pathogenesis of schizophrenia SZ [ 1 — 5 ]. A vast observational studies, mainly case-control studies provide increasing evidence that patients with SZ have elevated levels of some inflammatory biomarkers, such as cytokines in plasma or serum [ 14 ]. Furthermore, evidence from epidemiologic studies implied that some autoimmune diseases contributed to the development of SZ [ 6Qiqihar arabic sex ].
As an acute-phase protein, C-reactive protein CRP is produced by some inflammatory stimula and is mainly induced by some pro-inflammatory cytokines [ 8 ]. Increased CRP levels have been reported in numerous observational studies in psychosis including SZ and in bipolar disorder [ 9 ]. Metcalf et al. Zhang et al. It has also been indicated that the increase in serum or plasma CRP levels contributes the risk of a first episode of SZ [ 9 ].
Inoshita et al.
However, several other studies reported no association between CRP levels and risk of SZ [ 11 — 13 ]. However, owing to the mixed studies combined for both case-control and cross-sectional studies in meta-analysis, we would like to update the evidence for only case-control studies published in English peer review journals. The literature search yielded citations. In summary, 18 studies recruiting patients with SZ and non-SZ controls were enrolled in this meta-analysis [ 10 — 1315 — 28 ].
Qiqihar arabic sex sample size of included studies ranged from 60 to participants. Three studies recruted participants from inpatient unit, while another three from outpatient unit, eight from both units and four from population-based samples. Seven studies enrolled patients with age of SZ onset less than 30 years and two more than 30 years. Twelve of the 18 included studies were of high quality and the remaining six studies were assessed as medium quality. Meta-analysis based on 18 studies, showed that compared with non-schizophrenics, CRP levels were moderately increased in people with SZ standardized mean difference SMD 0.
We then conducted subgroup analyses stratified by study region, sample size, clinical Qiqihar arabic sex, mean age, age of SZ onset, body mass index, adjusted controls and high-sensitivity CRP assay used or not. A bordine estimates were seen for studies for clinical setting of inpatient unit SMD 0. In this meta-analysis based on 18 case-control studies, we found that serum and plasma CRP levels were moderately increased in patients with SZ, irrespective of study region, sample size of included studies, patient mean age, age of SZ onset and patient body mass index. We noticed that patients in Asia or Africa and whose age less than 30 years were more substantially increase in CRP levels.
The potential biological mechanism for the associations between some inflammatary factors and SZ has not been fully understood. Hsuchou et al. The high levels of CRP in central nervous system has been reported to play an important part in some psychiatric dysfunctions, such as SZ [ 3031 ]. In addition, reports also showed that elevated CRP levels could influence the microcirculatory system in the blood—brain barrier, thus affecting neurotransmitter synthesis and neurotransmission [ 33 — 38 ].
Moreover, elevated CRP levels were reported to be associated with the Qiqihar arabic sex of clinical symptoms, cognitive and sensory impairments in SZ [ 39 — 42 ].
This updated literature search identified two systematic review and meta-analyses on the same topic [ 1443 ], but both of them focused on studies with mixed study de. The findings of our studies are consistent with those two meta-analyses from mixed cross-sectional studies and case—control studies Miller et al. Strength of our meta-analysis lies in the following three aspects.
Firstly, most of the included studies in the meta-analyses were cross-sectional in study de. An known limitation of a cross-sectional study is Qiqihar arabic sex exposure and outcome are generally evaluated simutaneously and we therefore cannot draw conclusions on the casual-relationship between exposure and outcome. Hence, the underlying hypothesis obtained from the meta-analyses is that the prevalance of SZ is an immediate outcome following exposure of elevated CRP levels. The investigation of the real effects caused by continuous long-term exposure may require a different study de, such as our case-control study or cohort study [ 44 ].
Secondly, heterogeneity was noted among the included studies but we tried to for this variation by conducting sensitivity analysis. The Qiqihar arabic sex of funnel plot indicated the overestimation of the effect size due to the lack of negative studies with small sample size.
Moreover, when applying the trim and fill method, no additional hypothised negative studies with small sample size were inputed, suggesting the robustness of the meta-analysis. Thirdly, it is the first study to suggest that younger patients with SZ whose age less than 30 years were more substantially increase in CRP levels. Though this potential reason is unclear, it has been suggested to be related with a greater reactivity of the immune system in younger patients [ 45 ].
However, further large well deed studies are warrented to validate this association. Some inherent limitations do exist in our study. We report an increase in serum and plasma CRP levels in patients with SZ by pooling the eligible studies over the last decade. In our meta-analysis, we found the pooled SMD was 0. The study quality of evidence obtained from NOS score was moderate and derived from case-control studies. However, still some other confounders remained due to factors that could not be ed Qiqihar arabic sex such as physical activity, waist circumference, smoking habit, vitamin D intake, and subclinical infections.
Most studies included in our analysis did not provide such data, which could explain the heterogeneity noted in the pooled analysis.
Although subgroup analyses have been performed for some of the existing confounders, the investigated factors could only explain some of the heterogeneity. Moreover, many of the other analyses, such as dose-response relationship could not be conducted due to the lack of detailed information from original reports.
Furthermore, the possible sources of heterogeneity was explored through subgroup analyses and sensitivity analyses. However, the of these two methods did not allow us to attribute heterogeneity to any single study as the sole source of the high heterogeneity we obtained in most analyses.
Secondly, this updated meta-analysis on serum and plasma CRP levels in patients with SZ compared with non-SZ controls provided us with summary estimates originating from one type of observational study case-control study. Therefore, no definite causal conclusion can be drawn from this meta-analysis.
High serum and plasma CRP level is only one of the inflammation-related factors known to be associated with the risk of SZ. Other factors such as smoking habit and subclinical infections could also be additional related factors. Thirdly, like any meta-analysis, this one is also dependent on the quality of the included studies, and our findings need to be further confirmed by studies specifically deed to demonstrate the unclear points we raised.
Finally, the restriction of our meta-analysis to English language studies may have led to language bias with potentially relevant studies published in other languages being missed. In summary, our meta-analyses provide evidence that higher CRP levels are associated with increased risk of SZ, especially for young adult patients less than 30 years. Future studies should be focused on whether changes in CRP levels have a causal relationship with the development of SZ.
The Preferred reporting items for systematic reviews and meta-analyses PRISMA Qiqihar arabic sex was used when we performed this systematic literature review [ 46 ]. We systematically searched databases of Pubmed, EMBASE and the Cochrane Library from inception till November 1, for relevant studies, using the predefined search strategies Supplementary search strategy 1—3. We only included studies in English peer-review journals. We excluded studies with duplicate data or studies that reported CRP levels using dichotomous data ie, positive or negativeor studies without a control group.
In addition, we did not include unpublished literature due to the insufficient data obtained from these studies. Two authors Z. When discrepancies occured, a third author Qiqihar arabic sex. We extracted the following data including first author, publication yearresearch country, study subjects, clinical setting, sex, age and BMI of the study subjects, age of SZ onset, adjusted variables for controls, percent of the current Qiqihar arabic sex, CRP assay type, comorbidities and psychiatric drugs used.
If necessary, we consulted the original data from the authors of the studies to collect missing information. The Newcastle—Ottawa Scales NOS was used to assess quality of the included studies [ 47 ], which applied three domains for assessment and allocated a total score of nine points. Quality were determined by the NOS score of each study. We defined that the score of high quality with 7 or more, medium quality from 4 to 6 and low quality less than 4. The value of SMD being 0. Summary estimates in the present meta-analysis were pooled using a random-effects model due to the predictable ificant inter-study difference in the enrolled population, study de, or the treatment strategy [ 50 ].
We also estimated the of potential missing studies from a meta-analysis using the trim and fill method [ 53 Qiqihar arabic sex. Some planned subgroup analyses were performed to explore possible causes of heterogeneity and between-subgroup interactions were calculated using the chi-squared ificance test [ 54 ]. National Center for Biotechnology Information Qiqihar arabic sex, U. Journal List Oncotarget v. Published online May Author information Article notes Copyright and information Disclaimer.
Correspondence to: Guangcheng Cui, moc. Zubing Mei, moc. Received Mar 24; Accepted May 6. This is an open-access article distributed under the terms of the Creative Commons Attribution 3. This article has been cited by other articles in PMC.Qiqihar arabic sex
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Association between C-reactive protein and risk of schizophrenia: An updated meta-analysis