Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects

Yasaman Malekizadeh; Gareth Williams; Mark Kelson; David Whitfield; Jonathan Mill; David A Collier; Clive Ballard; Aaron R Jeffries; Byron Creese

doi:10.1002/trc2.12078

Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects

Yasaman Malekizadeh, Gareth Williams, Mark Kelson, David Whitfield, Jonathan Mill, David A Collier, Clive Ballard, Aaron R Jeffries, Byron Creese

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e12078
Journal	Alzheimer's and Dementia: Translational Research and Clinical Interventions
Volume	6
Issue number	1
DOIs	https://doi.org/10.1002/trc2.12078
Publication status	Published - 24 Aug 2020

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Malekizadeh, Y., Williams, G., Kelson, M., Whitfield, D., Mill, J., Collier, D. A., Ballard, C., Jeffries, A. R., & Creese, B. (2020). Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects. Alzheimer's and Dementia: Translational Research and Clinical Interventions, 6(1), Article e12078. https://doi.org/10.1002/trc2.12078

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title = "Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects",

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.",

author = "Yasaman Malekizadeh and Gareth Williams and Mark Kelson and David Whitfield and Jonathan Mill and Collier, {David A} and Clive Ballard and Jeffries, {Aaron R} and Byron Creese",

note = "{\textcopyright} 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/",

year = "2020",

month = aug,

day = "24",

doi = "10.1002/trc2.12078",

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journal = "Alzheimer's and Dementia: Translational Research and Clinical Interventions",

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Malekizadeh, Y, Williams, G, Kelson, M, Whitfield, D, Mill, J, Collier, DA, Ballard, C, Jeffries, AR & Creese, B 2020, 'Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects', Alzheimer's and Dementia: Translational Research and Clinical Interventions, vol. 6, no. 1, e12078. https://doi.org/10.1002/trc2.12078

Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects. / Malekizadeh, Yasaman; Williams, Gareth; Kelson, Mark et al.
In: Alzheimer's and Dementia: Translational Research and Clinical Interventions, Vol. 6, No. 1, e12078, 24.08.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects

AU - Malekizadeh, Yasaman

AU - Williams, Gareth

AU - Kelson, Mark

AU - Whitfield, David

AU - Mill, Jonathan

AU - Collier, David A

AU - Ballard, Clive

AU - Jeffries, Aaron R

AU - Creese, Byron

N1 - © 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/

PY - 2020/8/24

Y1 - 2020/8/24

N2 - 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.

AB - 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.

U2 - 10.1002/trc2.12078

DO - 10.1002/trc2.12078

M3 - Article

C2 - 32864416

SN - 2352-8737

VL - 6

JO - Alzheimer's and Dementia: Translational Research and Clinical Interventions

JF - Alzheimer's and Dementia: Translational Research and Clinical Interventions

IS - 1

M1 - e12078

ER -

Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects

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