Integrative Analyses of Transcriptomes to Explore Common Molecular Effects of Antipsychotic Drugs

There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevan...

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Published inInternational journal of molecular sciences Vol. 23; no. 14; p. 7508
Main Authors Truong, Trang T. T., Bortolasci, Chiara C., Kidnapillai, Srisaiyini, Spolding, Briana, Panizzutti, Bruna, Liu, Zoe S. J., Kim, Jee Hyun, Dean, Olivia M., Richardson, Mark F., Berk, Michael, Walder, Ken
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 06.07.2022
MDPI
Subjects
Antipsychotics
Apoptosis
Brain
Drugs
Gene expression
Genomes
Insulin
Kinases
Peptides
Potassium
Proteins
Psychotropic drugs
Schizophrenia
Signal transduction
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Abstract There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets.
AbstractList There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets.
There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets.There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets.
There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10 , ANK2, and AKT3 , suggesting further investigation on these genes as potential novel treatment targets.
Author Spolding, Briana
Richardson, Mark F.
Liu, Zoe S. J.
Dean, Olivia M.
Panizzutti, Bruna
Berk, Michael
Truong, Trang T. T.
Kidnapillai, Srisaiyini
Kim, Jee Hyun
Walder, Ken
Bortolasci, Chiara C.
AuthorAffiliation 2 The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia
1 The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong 3220, Australia; truongtra@deakin.edu.au (T.T.T.T.); chiara.bortolasci@barwonhealth.org.au (C.C.B.); srisaiyini.kidnapillai@med.lu.se (S.K.); briana.spolding@deakin.edu.au (B.S.); b.panizzuttiparry@deakin.edu.au (B.P.); zoe.liu@deakin.edu.au (Z.S.J.L.); jee.kim@deakin.edu.au (J.H.K.); o.dean@deakin.edu.au (O.M.D.); michael.berk@deakin.edu.au (M.B.)
3 Genomics Centre, School of Life and Environmental Sciences, Deakin University, Burwood 3125, Australia; m.richardson@deakin.edu.au
4 Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville 3010, Australia
AuthorAffiliation_xml – name: 1 The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong 3220, Australia; truongtra@deakin.edu.au (T.T.T.T.); chiara.bortolasci@barwonhealth.org.au (C.C.B.); srisaiyini.kidnapillai@med.lu.se (S.K.); briana.spolding@deakin.edu.au (B.S.); b.panizzuttiparry@deakin.edu.au (B.P.); zoe.liu@deakin.edu.au (Z.S.J.L.); jee.kim@deakin.edu.au (J.H.K.); o.dean@deakin.edu.au (O.M.D.); michael.berk@deakin.edu.au (M.B.)
– name: 4 Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville 3010, Australia
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CitedBy_id crossref_primary_10_1038_s41572_023_00454_1
crossref_primary_10_1080_15622975_2024_2312475
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Snippet There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study...
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StartPage 7508
SubjectTerms Antipsychotics
Apoptosis
Brain
Drugs
Gene expression
Genomes
Insulin
Kinases
Peptides
Potassium
Proteins
Psychotropic drugs
Schizophrenia
Signal transduction
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Title Integrative Analyses of Transcriptomes to Explore Common Molecular Effects of Antipsychotic Drugs
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https://www.proquest.com/docview/2695294771
https://pubmed.ncbi.nlm.nih.gov/PMC9325239
Volume 23
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