Analysis of differential gene expression mediated by clozapine in human postmortem brains

Brian J. Lee, Luigi Marchionni, Carrie E. Andrews, Alexis L. Norris, Leslie G. Nucifora, Yeewen Candace Wu, Robert A. Wright, Jonathan Pevsner, Christopher A. Ross, Russell L. Margolis, Akira Sawa, Frederick C. Nucifora

Research output: Contribution to journalArticle

Abstract

Clozapine is the only medication indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to clozapine compared to other atypical antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: . GCLM, . ZNF652, and . GYPC. In addition, pathway analysis highlighted the following processes in all four studies: clathrin-mediated endocytosis, SAPK/JNK signaling, 3-phosphoinositide synthesis, and paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of clozapine, as well as the pathophysiology of schizophrenia.

Original languageEnglish (US)
JournalSchizophrenia Research
DOIs
StateAccepted/In press - Oct 28 2016

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Clozapine
Gene Expression
Brain
Antipsychotic Agents
Genes
Schizophrenia
Paxillin
Clathrin
Phosphatidylinositols
Endocytosis
Linear Models

Keywords

  • Antipsychotic
  • Bipolar affective disorder
  • Microarray
  • Schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

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title = "Analysis of differential gene expression mediated by clozapine in human postmortem brains",
abstract = "Clozapine is the only medication indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to clozapine compared to other atypical antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: . GCLM, . ZNF652, and . GYPC. In addition, pathway analysis highlighted the following processes in all four studies: clathrin-mediated endocytosis, SAPK/JNK signaling, 3-phosphoinositide synthesis, and paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of clozapine, as well as the pathophysiology of schizophrenia.",
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AU - Lee,Brian J.

AU - Marchionni,Luigi

AU - Andrews,Carrie E.

AU - Norris,Alexis L.

AU - Nucifora,Leslie G.

AU - Wu,Yeewen Candace

AU - Wright,Robert A.

AU - Pevsner,Jonathan

AU - Ross,Christopher A.

AU - Margolis,Russell L.

AU - Sawa,Akira

AU - Nucifora,Frederick C.

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AB - Clozapine is the only medication indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to clozapine compared to other atypical antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: . GCLM, . ZNF652, and . GYPC. In addition, pathway analysis highlighted the following processes in all four studies: clathrin-mediated endocytosis, SAPK/JNK signaling, 3-phosphoinositide synthesis, and paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of clozapine, as well as the pathophysiology of schizophrenia.

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