Open AccessWhole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects
Author(s) -
Malekizadeh Yasaman,
Williams Gareth,
Kelson Mark,
Whitfield David,
Mill Jonathan,
Collier David A.,
Ballard Clive,
Jeffries Aaron R.,
Creese Byron
Publication year - 2020
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1002/trc2.12078
Subject(s) - antipsychotic , risperidone , medicine , drug repositioning , bioinformatics , amisulpride , natalizumab , olanzapine , dementia , transcriptome , adverse effect , mechanism (biology) , pharmacology , disease , schizophrenia (object oriented programming) , biology , drug , psychiatry , gene expression , genetics , gene , philosophy , epistemology
Abstract Background Stroke/thromboembolic events, infections, and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events. Methods Whole transcriptome signatures were generated for SH‐SY5Y cells treated with amisulpride, risperidone, and volinanserin using RNA sequencing. Bioinformatic analysis was performed that scored the association between antipsychotic signatures and expression data from 415,252 samples in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) repository. Results Atherosclerosis, venous thromboembolism, and influenza NCBI GEO‐derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (eg, brain derived neurotrophic factor [BDNF], platelet derived growth factor receptor [PDGFR]‐beta, tumor necrosis factor [TNF], transforming growth factor [TGF]‐beta, selenoamino acid metabolism, and influenza infection). Conclusions These findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.