Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects.
RNA‐seq
amisulpride
antipsychotic
brain derived neurotrophic factor
cardiovascular
immune
platelet derived growth factor
risperidone
selenium
side effects
tumor necrosis factor
Journal
Alzheimer's & dementia (New York, N. Y.)
ISSN: 2352-8737
Titre abrégé: Alzheimers Dement (N Y)
Pays: United States
ID NLM: 101650118
Informations de publication
Date de publication:
2020
2020
Historique:
received:
04
05
2020
revised:
09
07
2020
accepted:
28
07
2020
entrez:
1
9
2020
pubmed:
31
8
2020
medline:
31
8
2020
Statut:
epublish
Résumé
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. 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. 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). 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 32864416
doi: 10.1002/trc2.12078
pii: TRC212078
pmc: PMC7443741
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e12078Subventions
Organisme : Medical Research Council
ID : MC_PC_16072
Pays : United Kingdom
Informations de copyright
© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Déclaration de conflit d'intérêts
CB has received grants and personal fees from ACADIA Pharmaceuticals and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline, and Pfizer. DAC is an employee of Eli Lilly and Company Ltd.
Références
Lancet. 2014 Feb 8;383(9916):533-40
pubmed: 24183563
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W193-200
pubmed: 17478515
CNS Drugs. 2005;19(2):91-103
pubmed: 15697324
Cytokine Growth Factor Rev. 2004 Aug;15(4):237-54
pubmed: 15207815
Transl Psychiatry. 2019 Sep 6;9(1):220
pubmed: 31492831
Clin Ther. 2004 Aug;26(8):1261-73
pubmed: 15476907
Br J Clin Pharmacol. 2003 Mar;55(3):307-9
pubmed: 12630982
Metallomics. 2017 Jan 25;9(1):21-37
pubmed: 28009916
J Pharmacol Exp Ther. 1996 May;277(2):968-81
pubmed: 8627580
Science. 2006 Sep 29;313(5795):1929-35
pubmed: 17008526
Mov Disord Clin Pract. 2017 Mar 11;4(4):643-645
pubmed: 30713978
NPJ Schizophr. 2020 Feb 3;6(1):3
pubmed: 32015324
Transl Psychiatry. 2019 Sep 2;9(1):211
pubmed: 31477687
Eur J Pharmacol. 1994 Jul 1;259(2):137-41
pubmed: 7957607
J Pharmacol Exp Ther. 1997 Jan;280(1):83-97
pubmed: 8996185
J Psychopharmacol. 2009 Nov;23(8):909-14
pubmed: 18635700
Brain Res. 1999 Apr 17;825(1-2):161-71
pubmed: 10216183
Nat Rev Neurosci. 2006 Jun;7(6):492-500
pubmed: 16715057
Science. 2017 Sep 1;357(6354):891-898
pubmed: 28860381
Front Behav Neurosci. 2019 Jul 23;13:163
pubmed: 31396062
Biol Trace Elem Res. 2019 Jun;189(2):361-369
pubmed: 30171594
PLoS One. 2019 Jun 26;14(6):e0218937
pubmed: 31242264
PLoS One. 2011;6(7):e21800
pubmed: 21789182
Eur Neuropsychopharmacol. 2013 Apr;23(4):329-37
pubmed: 22612990
Nat Protoc. 2019 Feb;14(2):482-517
pubmed: 30664679
J Am Med Dir Assoc. 2004 Mar-Apr;5(2):129-32
pubmed: 15008183
J Mol Cell Cardiol. 2017 Sep;110:54-60
pubmed: 28736262
Neuropharmacology. 2011 Sep;61(4):761-9
pubmed: 21663752
Expert Rev Neurother. 2018 Jun;18(6):461-467
pubmed: 29764230
Lancet Neurol. 2018 Mar;17(3):213-222
pubmed: 29452684
Eur J Neurosci. 2001 Jul;14(1):135-44
pubmed: 11488957
BMC Genomics. 2012 Jan 10;13:12
pubmed: 22233519
Mol Psychiatry. 2000 Sep;5(5):558-62
pubmed: 11032392
Sci Rep. 2019 Jun 6;9(1):8336
pubmed: 31171821
BMC Genomics. 2013 Nov 07;14:765
pubmed: 24199845
Lancet Psychiatry. 2018 Jul;5(7):553-563
pubmed: 29880238