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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, 1830 E. Monument St., Baltimore, MD 21205, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 401 N. Broadway, Baltimore, MD 21287, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Andrews
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA; Department of Neurology, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, MD 21205, USA.
authors.forename: Alexis L
authors.initials: AL
authors.lastname: Norris
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Nucifora
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA.
authors.forename: Yeewen Candace
authors.initials: YC
authors.lastname: Wu
authors.affiliation: William H. Welch Medical Library, Johns Hopkins University, 1900 E. Monument St., Baltimore, MD 21205, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wright
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA; Department of Neurology, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, 707 N. Broadway, Baltimore, MD 21205, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pevsner
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, 1830 E. Monument St., Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, 1830 E. Monument St., Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, 1830 E. Monument St., Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA. Electronic address: nucifora@jhmi.edu.
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Nucifora
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001344:Autopsy; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D003024:Clozapine / Q000627:therapeutic use*; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008297:Male; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine
keywords: Antipsychotic; Bipolar affective disorder; Microarray; Schizophrenia