Rizig, M. A., McQuillin, A., Ng, A., Robinson, M., Harrison, A., Zvelebil, M., Hunt, S. P., Gurling, H. M. (2012) A gene expression and systems pathway analysis of the effects of clozapine compared to haloperidol in the mouse brain implicates susceptibility genes for schizophrenia. JOURNAL OF PSYCHOPHARMACOLOGY, 26 (9). pp. 1218-1230. ISSN 0269-8811

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Abstract

Clozapine has markedly superior clinical properties compared to other antipsychotic drugs but the side effects of agranulocytosis, weight gain and diabetes limit its use. The reason why clozapine is more effective is not well understood. We studied messenger RNA (mRNA) gene expression in the mouse brain to identify pathways changed by clozapine compared to those changed by haloperidol so that we could identify which changes were specific to clozapine. Data interpretation was performed using an over-representation analysis (ORA) of gene ontology (GO), pathways and gene-by-gene differences. Clozapine significantly changed gene expression in pathways related to neuronal growth and differentiation to a greater extent than haloperidol; including the microtubule-associated protein kinase (MAPK) signalling and GO terms related to axonogenesis and neuroblast proliferation. Several genes implicated genetically or functionally in schizophrenia such as frizzled homolog 3 (FZD3), U2AF homology motif kinase 1 (UHMK1), pericentriolar material 1 (PCM1) and brain-derived neurotrophic factor (BDNF) were changed by clozapine but not by haloperidol. Furthermore, when compared to untreated controls clozapine specifically regulated transcripts related to the glutamate system, microtubule function, presynaptic proteins and pathways associated with synaptic transmission such as clathrin cage assembly. Compared to untreated controls haloperidol modulated expression of neurotoxic and apoptotic responses such as NF-kappa B and caspase pathways, whilst clozapine did not. Pathways involving lipid and carbohydrate metabolism and appetite regulation were also more affected by clozapine than by haloperidol.

Item Type:	Article
Authors (ICR Faculty only):	Zvelebil, Marketa
All Authors:	Rizig, M. A., McQuillin, A., Ng, A., Robinson, M., Harrison, A., Zvelebil, M., Hunt, S. P., Gurling, H. M.
Additional Information:	ISI Document Delivery No.: 982CE Times Cited: 0 Cited Reference Count: 152 Rizig, Mie A. McQuillin, Andrew Aylwin Ng Robinson, Michelle Harrison, Andrew Zvelebil, Marketa Hunt, Steve P. Gurling, Hugh M. Neuroscience Research Charitable Trust; Margaret Temple (British Medical Association) schizophrenia research grant; Overseas Research Scheme (ORS-UK) award This research was funded by the Neuroscience Research Charitable Trust, a Margaret Temple (British Medical Association) schizophrenia research grant and by an Overseas Research Scheme (ORS-UK) award. The clozapine used in the 12 week experiment was a generous donation from the Novartis Pharmaceuticals Ltd. Sage publications ltd London
Uncontrolled Keywords:	Gene expression mRNA antipsychotic haloperidol clozapine atypical antipsychotic schizophrenia bipolar disorder gene ontology pathway analysis messenger-rna levels frizzled-3 fzd3 gene atypical antipsychotics prefrontal cortex protein-kinase bipolar disorder frontal-cortex epsin-4 gene weight-gain 2nd-generation antipsychotics
Research teams:	Closed research groups > Cancer Informatics
Depositing User:	Alexander Smithson
Date Deposited:	03 Sep 2012 16:40
Last Modified:	24 Dec 2013 14:38
URI:	http://publications.icr.ac.uk/id/eprint/11878

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