Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study

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Abstract

Background

Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection.

Methods

We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP.

Results

Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen’s d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10).

Conclusions

These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

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Most cited references 86

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The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia

S R Kay, A Fiszbein, L A Opler (1987)

The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.

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A meta-analysis of cytokines in major depression.

Yekta Dowlati, Nathan Herrmann, Walter Swardfager … (2010)

Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls. We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references. Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-alpha, 9 for interleukin (IL)-1beta, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-gamma. There were significantly higher concentrations of TNF-alpha (p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied. This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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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.

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Author and article information

Contributors

Dimitrios Andreou: (View ORCID Profile)

Gunnar Morken: (View ORCID Profile)

Lars Tjelta Westlye: (View ORCID Profile)

Journal

Title: Schizophrenia Bulletin

Publisher: Oxford University Press (OUP)

ISSN (Print): 0586-7614

ISSN (Electronic): 1745-1701

Publication date Created: January 01 2022

Publication date Created: January 21 2022

Publication date Created: September 09 2021

Publication date Other: January 01 2022

Publication date (Print): January 21 2022

Publication date (Electronic): September 09 2021

Volume: 48

Issue: 1

Pages: 37-46

Affiliations

[1 ]Norwegian Centre for Mental Disorders Research, NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

[2 ]Vestfold Hospital Trust, Division of Mental health and Addiction, Tønsberg, Norway

[3 ]Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway

[4 ]Institute of Clinical Medicine, University of Oslo, Oslo, Norway

[5 ]K.G. Jebsen Thrombosis Research and Expertise Center, University of Troms, Tromsø, Norway

[6 ]Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

[7 ]Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden

[8 ]Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway

[9 ]Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway

[10 ]Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

[11 ]Psychosomatic and Consultation-liason Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

[12 ]Department of Mental Health, Norwegian University of Science and Technology, NTNU, Trondheim, Norway

[13 ]Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway

[14 ]Department of Psychiatry, St Olav University Hospital, Trondheim, Norway

[15 ]Department of Neuro Habilitation, Oslo University Hospital Ullevål, Oslo, Norway

[16 ]TIPS, Network for Clinical Research in Psychosis, Stavanger University Hospital, Stavanger, Norway

[17 ]Network for Medical Sciences, Faculty of Health, University of Stavanger, Stavanger, Norway

[18 ]Division of Psychiatry, Haukeland University Hospital, Bergen, Norway

[19 ]University of Bergen, Bergen, Norway

[20 ]Norwegian Centre for Mental Disorders Research, NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway

[21 ]K.G. Jebsen Center for Neurodevelopmental Disorders, Oslo, Norway

[22 ]Department of Rare Disorders and Disabilities, Oslo University Hospital, Oslo, Norway

[23 ]Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway

[24 ]Department of Psychology, University of Oslo, Oslo, Norway

[25 ]Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

Article

DOI: 10.1093/schbul/sbab106

PubMed ID: 34499169

SO-VID: 096e863c-6c5f-46ae-bf57-86db119242f7

License:

https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study

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Abstract

Background

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Results

Conclusions

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Most cited references 86

The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia

A meta-analysis of cytokines in major depression.

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

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