Antipsychotics' effects on blood levels of cytokines in schizophrenia: A meta-analysis

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Abstract

Objectives

Evidence-based medicine suggests that schizophrenia is associated with an inflammatory syndrome, but the extent to which this syndrome is normalized by antipsychotic treatment has yet to be determined.

Methods

A systematic quantitative review of the effects of antipsychotics on peripheral cytokine levels in schizophrenia was performed, using follow-up studies providing in vivo cytokine assessments before and after treatment.

Results

We retrieved 23 studies (total of 762 subjects) which showed that antipsychotic treatment significantly increases plasma levels of soluble interleukin-2 receptor and reduces the plasma levels of interleukin-1β and interferon-γ.

Conclusions

These results show that antipsychotics produce anti-inflammatory effects in schizophrenia.

Introduction

The incidence rates of schizophrenia are on the order of 12 to 15 per 100,000 person-years (McGrath et al., 2008). This mental disorder is associated with poor outcome, and significant and persistent impairment (Newman et al., 2012). Schizophrenia is a heterogeneous disorder and its etiology remains incompletely elucidated. Among possible causes, immunological factors have been increasingly implicated in its pathogenesis and course (Benros et al., 2012). The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neuroplasticity and neurotransmission (Benros et al., 2012). Alterations in cytokine levels in schizophrenia have been repeatedly described (Potvin et al., 2008, Miller et al., 2011). The effect of antipsychotics on cytokine levels remains, as yet, incompletely explored. A few groups have recently published reviews which concluded that antipsychotics have anti-inflammatory effects in schizophrenia that may be related to antipsychotic response, and in some cases, pro-inflammatory effects that may be related to important side effects, such as weight gain (Drzyzga et al., 2006, Tourjman et al., 2012). In order to further clarify the extent of these effects, we conducted a meta-analysis of antipsychotic-induced cytokine changes in schizophrenia.

Section snippets

Search strategies

A systematic search was performed in the electronic databases PubMed and EMBASE using the keywords “antipsychotic” and “inflammation” or “cytokine” or “interleukin” or “inflammatory markers” or “IFN” or “TGF” or “TNF”. This search identified studies before January 1st, 2013. Additionally, studies were identified by cross-referencing.

Selection criteria

Studies were included if they met the following criteria: (a) had involved subjects with DSM/ICD schizophrenia-spectrum disorder; (b) had employed a pre–post design

Database

This literature search uncovered 71 potential articles. After initial assessment, 48 articles were excluded for the following reasons: in vitro studies, add-on treatment with drugs other than antipsychotics supposed to affect the immune system, incomplete data or non-parametric statistics, and the measure of other immune markers. The final database included 23 studies for a total of 762 subjects (mean age ± SD: 35 ± 6.8 years; mean % of female: 45; n = 21 studies). The follow-up assessment of the

Discussion

This meta-analysis confirms that antipsychotic treatment increases peripheral sIL-2R levels in schizophrenia, as previously observed by others (Drzyzga et al., 2006, Miller et al., 2011). Despite significant heterogeneity across studies, the data cumulated here also demonstrates in a quantitative manner that antipsychotic treatment leads to decreases in IL-1β and IFN-γ levels in schizophrenia-spectrum disorders, and possibly to increases in IL-12. Although treatment with clozapine seems to be

Role of funding source

The funding source played no role in the preparation of the current manuscript.

Contributors

VT, SP and EK provided the justification for the meta-analysis. VT, SFF and MEK performed the search of the literature. SFF, MEK, and MR participated in data extraction. MR performed the statistical analyses. VT, SP and PFP wrote the manuscript. EK supervised each step of the meta-analysis.

Conflict of interest

In the last 3 years, Dr Potvin held grants from the Canadian Institutes of Health Research, the FRQ-S, Eli Lilly, Servier Institutes, and the MDEIE. He has been an invited speaker for Eli Lilly. Dr Tourjman held grants from Sunovion, Shire, Bristol-Myers-Squibb, Pfizer, Eli Lilly, AstraZeneca, Cephalon and Teva. She has been an invited speaker for AstraZeneca, Eli Lilly, Lundbeck, Shire and Janssen-Ortho. Dr Kouassi held grants from AstraZeneca.

Acknowledgments

This work is supported by grants from the Fonds de Recherche du Québec — Santé (FRQS) to SP and EK. SP is a holder of a Junior 1 researcher award from the FRQS, and is a supported member from the Centre de recherche de l'Institut Universitaire en Santé Mentale de Montréal.

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