Inflammatory monocyte gene signature predicts beneficial within group effect of simvastatin in patients with schizophrenia spectrum disorders in a secondary analysis of a randomized controlled trial

Mareike Aichholzer, Shiral S. Gangadin, Iris E.C. Sommer, Annemarie Wijkhuis, Lot D. de Witte, René S. Kahn, Sabine Bahn, Hemmo A. Drexhage, Carmen Schiweck*

*Corresponding author for this work

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Abstract

Immune dysregulation has been reported in schizophrenia spectrum disorders (SSD). In the past decade, several trials using anti-inflammatory agents for treatment of SSD have been completed, with so far limited success. One such anti-inflammatory agent used is simvastatin. A recent, large-scale, randomized controlled trial with simvastatin augmentation failed to show improvement in the predefined primary outcome. However, baseline inflammatory profiles were not taken into account. Here we employed a data-driven clustering approach to investigate whether patients with an inflammatory monocyte gene signature respond better to add-on simvastatin treatment than those without such a signature, over a treatment period of 2 years. In 61 patients (60 randomized, 1:1 placebo:simvastatin) and healthy controls, a previously validated monocyte gene expression signature was assessed using quantitative polymerase chain reaction. Resulting delta cycle threshold values were used to identify patient clusters. Two major patient clusters with either up- or downregulated pro-inflammatory factors were detected. Linear mixed models showed a significant three-way interaction between the inflammatory cluster, treatment, and time for psychotic symptoms. Only patients treated with simvastatin who were in the inflammatory group, showed a consistent improvement: symptom severity gradually decreased after 3 months and reached significance after 12 and 24 months compared to baseline (p.adj<0.05). The effects were small, and overall between-group effects were not significant. Here, we show that patient stratification based on inflammatory gene expression might be useful to select appropriate treatment augmentation for patients with SSD, highlighting the need for precision medicine approaches. Our findings corroborate the results of the primary analyses, showing that in the overall group, simvastatin was not effective; however, at the individual level the treatment might make a difference.

Original languageEnglish
Article number100551
JournalBrain, Behavior, and Immunity - Health
Volume26
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding:
This work was supported by the European Commission: EU 7th Framework program (grant number EU-FP7-CP-IP-2008-222963 ), European Union's Horizon 2020 research and innovation programme (grant agreement No 754740 and grant agreement No H2020-SC1-2016-2017/H2020-SC1-2017 -Two-Stage-RTD), the Cock-Hadders Foundation (projectcode: 2021-03 ) and the Dutch Research Council (ZonMW; grant number: 40-00812-98-12154 ).

Publisher Copyright:
© 2022 The Authors

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