The relationship between immune and cognitive dysfunction in mood and psychotic disorder: a systematic review and a meta-analysis

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Abstract

Background

In psychotic and mood disorders, immune alterations are hypothesized to underlie cognitive symptoms, as they have been associated with elevated blood levels of inflammatory cytokines, kynurenine metabolites, and markers of microglial activation. The current meta-analysis synthesizes all available clinical evidence on the associations between immunomarkers (IMs) and cognition in these psychiatric illnesses.

Methods

Pubmed, Web of Science, and Psycinfo were searched for peer-reviewed studies on schizophrenia spectrum disorder (SZ), bipolar disorder (BD), or major depressive disorder (MDD) including an association analysis between at least one baseline neuropsychological outcome measure (NP) and one IM (PROSPERO ID:CRD42021278371). Quality assessment was performed using BIOCROSS. Correlation meta-analyses, and random effect models, were conducted in Comprehensive Meta-Analysis version 3 investigating the association between eight cognitive domains and pro-inflammatory and anti-inflammatory indices (PII and AII) as well as individual IM.

Results

Seventy-five studies ( n = 29,104) revealed global cognitive performance (GCP) to be very weakly associated to PII ( r = −0.076; p = 0.003; I ² = 77.4) or AII ( r = 0.067; p = 0.334; I ² = 38.0) in the combined patient sample. Very weak associations between blood–based immune markers and global or domain-specific GCP were found, either combined or stratified by diagnostic subgroup (GCP x PII: SZ: r = −0.036, p = 0.370, I ² = 70.4; BD: r = −0.095, p = 0.013, I ² = 44.0; MDD: r = −0.133, p = 0.040, I ² = 83.5). We found evidence of publication bias.

Discussion

There is evidence of only a weak association between blood-based immune markers and cognition in mood and psychotic disorders. Significant publication and reporting biases were observed and most likely underlie the inflation of such associations in individual studies.

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The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Matthew J L Page, Joanne E McKenzie, Patrick Bossuyt … (2025)

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

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Cochrane Handbook for Systematic Reviews of Interventions

Julian P.T. Higgins, James Thomas, Jacqueline Chandler … (2020)

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Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.

Brian Miller, Peter Buckley, Wesley Seabolt … (2011)

Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls (p = .01). Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.