Peripheral immune markers and antipsychotic non-response in psychosis

Daniela Enache,Naghmeh Nikkheslat,Dina Fathalla,B Paul Morgan,Shôn Lewis,Richard Drake,Bill Deakin,James Walters,Stephen M Lawrie,Alice Egerton,James H Maccabe,Valeria Mondelli

doi:10.1016/j.schres.2020.12.020

Abstract

BackgroundPeripheral immune markers have previously been linked to a poor response to antipsychotic medication and more severe negative symptoms at the onset of psychosis. The present study investigated the association of blood cytokines and complement markers with the presence of antipsychotic non-response and symptom severity in patients with psychosis. MethodsThis cross-sectional study recruited 94 patients with schizophrenia and other psychoses, of whom 47 were defined as antipsychotic responders and 47 as antipsychotic non-responders. In all subjects we measured plasma levels of cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, and IFN-γ), complement markers (C1-inhibitor, C3, C4, C3a, C3b, Bb, factor D, C5a, terminal complement complex) and high sensitivity C-reactive protein (hsCRP). Symptom severity was recorded using the Positive and Negative Syndrome scale for Schizophrenia (PANSS). Binary logistic regression tested each immune marker as predictor of response status while covarying for relevant socio-demographic variables. Correlation analyses tested the association between immune markers and the severity of symptoms. ResultsInterleukin (IL)-8 significantly predicted antipsychotic non-response (OR=24.70, 95% CI, 1.35–453.23, p = 0.03). Other immune markers were not associated with antipsychotic response. IL-6, IL-8, IL-10 and TNF-α significantly positively correlated with negative psychotic symptoms. ConclusionsHigher levels of IL-8 are associated with a poor response to antipsychotic treatment. Increased cytokines levels are specifically associated with more severe negative symptoms in patients with schizophrenia and other psychoses.

Highlights

One third of patients with schizophrenia meet criteria for treatment resistance (Meltzer, 1997)
In firstepisode psychosis a poor response to treatment was associated with increased levels of IL-6 and IFN-γ (Mondelli et al, 2015) whereas in the current sample of patients with established schizophrenia the association was related to increased levels of IL-8
A recent metaanalysis showed higher cerebrospinal fluid (CSF) levels of both IL-8 and IL-6 in patients with schizophrenia spectrum disorder when compared with healthy controls, supporting the idea that the elevation of the cytokines observed in peripheral blood may correspond to a central pro-inflammatory effect (Gallego et al, 2018)

Summary

Introduction

One third of patients with schizophrenia meet criteria for treatment resistance (Meltzer, 1997). One metaanalysis showed that acutely relapsed patients with schizophrenia have increased levels of peripheral interleukins (IL) including IL-6, IL8, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) but reduced levels of IL-10 when compared with healthy controls (Miller et al, 2011). In post-mortem brain tissue, markers of microglia activation, IFN-γ and TNF-α are elevated (Mondelli et al, 2017; Trepanier et al, 2016) All these studies suggest the existence of an increased peripheral and central inflammation in patients with established schizophrenia, and an association with treatment response. The present study investigated the association of blood cytokines and complement markers with the presence of antipsychotic non-response and symptom severity in patients with psychosis.

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