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A Systematic Review of Antipsychotic Drug Effects on Human Gene Expression Related to Risk Factors for Cardiovascular Disease

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A Systematic Review of Antipsychotic Drug Effects on Human Gene Expression Related to Risk Factors for Cardiovascular Disease The Pharmacogenomics Journal (2014) 14, 446–451 & 2014 Macmillan Publishers Limited All rights reserved 1470-269X/14 www.nature.com/tpj ORIGINAL ARTICLE A systematic review of antipsychotic drug effects on human gene expression related to risk factors for cardiovascular disease DL Foley and A Mackinnon Psychosis is associated with an elevated risk for cardiovascular disease. We reviewed evidence for a causal association between experimentally controlled antipsychotic drug exposure and a change in the expression of genes relevant to cardiovascular disease in human cell lines. Reports from SCOPUS - V.4 (Elsevier) and MEDLINE (ISI) were assessed for global or candidate gene expression analysis, tissue and cell type, tissue source or cell line, antipsychotic drug and dosage, length of drug exposure and statistically significant fold change in gene expression after drug exposure; 29 eligible studies analysed gene expression in the brain, eye (as a model of neuronal cells), heart, kidney (as a model of any cell), liver, pancreas or skin. Antipsychotic drugs alter the expression of numerous genes related to cardiovascular health, including genes under the control of the sterol regulatory element binding protein transcription factors that control lipid and fatty acid biosynthesis. The Pharmacogenomics Journal (2014) 14, 446–451; doi:10.1038/tpj.2014.8; published online 11 March 2014 INTRODUCTION Other genetic mechanisms may explain a larger proportion of Cardiovascular disease is the leading cause of death worldwide1 and cardiovascular risk associated with antipsychotics. Drugs bind to individuals with schizophrenia are twice as likely to die from transcription factors and thereby alter the expression of the genes cardiovascular disease as the wider community.2 Risk factors begin under their control. Antipsychotics could alter cardiovascular risk to change within several weeks of first exposure to antipsychotics profile by targeting the transcription of genes associated with and include a visible change in body weight and clinically signi- cardiovascular health. The cumulative effect of a treatment- ficant changes in cholesterol, triglyceride and glucose levels.3,4 The induced gene expression cascade could generate a large change impact on quality of life is profound.5,6 Randomized clinical trials in risk profile and is also consistent with the time course of 13 have established that the degree of change varies by drug and antipsychotic drug effects. Treatment-induced genetic effects duration of exposure.4 Cigarette smoking, a poor diet and may be an important aspect of antipsychotic drug action that sedentariness are prevalent among individuals with psychosis but influences the development of cardiovascular side effects but the the cumulative effect of lifestyle risk factors cannot explain the rapid relevant literature has not previously been reviewed. changes observed after the first exposure to antipsychotic drugs; The aim of this study is to systematically review evidence for there appears to be a direct effect of the antipsychotics themselves. antipsychotic drug effects on human gene expression associated One possible explanation is a direct effect of antipsychotics on with risk factors for cardiovascular disease. neuronal receptor binding profiles. Antipsychotics modulate neuro- nal receptors,7 altering appetite, satiety and peripheral meta- bolism as well as neurotransmission.8 All antipsychotics modulate dopamine (especially dopamine 2) receptors in the brain. Clozapine MATERIALS AND METHODS and olanzapine also modulate serotonin, glutamate, histamine, Original studies of antipsychotic drug effects on human gene expression alpha-adrenergic and muscarinic receptors7 and are associated with related to cardiovascular risk were selected for review. Only studies using the greatest weight gain.9 Weight gain has been associated with an experimentally controlled dose of a single antipsychotic drug for a known period of time were included to ensure accurate attribution of the antipsychotic blockade (antagonism) of serotonin receptor 1A and cause of any observed change in gene expression. Drug dose was selected 2C (HTR1A, HTR2C), histamine 1 (HRH1, previously known as H1)and 7 based on cell viability and estimated clinical relevance by study authors. dopamine receptor 2. Diabetes has been associated with Any study using human cell lines or tissue was eligible. Autopsy and living antipsychotic antagonism of muscarinic receptor 3 (CHRM1, whole-person studies were excluded because lifetime exposure to drugs, previously known as M1).7 Histamine and muscarinic receptor multiple drug exposures and the moderating effects of other variables antagonism has been hypothesised to explain glucose could not be controlled. abnormalities, and histamine antagonism has been hypothesised Eligible reports were retrieved from SCOPUS-V.4 (Elsevier) and to explain increased food intake and peripheral effects on MEDLINE (ISI) (from inception through August, 2013). Factors related to metabolism.8 Common DNA sequence variants could moderate cardiovascular risk profile in patients with their first treated episode of psychosis defined the search string (see Supplementary e-Table 24): effects of antipsychotics and have been reviewed in relation to 10 ‘antipsychotic gene expression’ AND (weight OR BMI OR waist OR ‘central antipsychotic-induced weight gain. Promising candidates included obesity’ OR adipose OR fat OR glucose OR insulin OR triglycerides OR variants in HTR2C and the dopamine transporter (SLC6A3, previously cholesterol OR ‘blood pressure’ OR ‘heart rate’ OR cortisol OR exercise OR known as DAT1) but these explained only a small proportion of leptin OR adiponectin OR interleukin OR VCAM OR selectin OR c-peptide observed weight gain,10 reminiscent of the small effects of common or QT interval OR creatinephosphokinase OR EKG OR grehlin OR resistan DNA sequence variants on risk for psychosis.11,12 OR visfatin OR cardiovascular). Eligible studies were divided into two sets. Orygen Youth Health Research Centre, Centre for Youth Mental Health, University of Melbourne, Parkville, Victoria, Australia. Correspondence: Dr DL Foley, Orygen Youth Health Research Centre, 35 Poplar Road, Parkville, Victoria 3052, Australia. E-mail: [email protected] Received 15 December 2013; revised 22 January 2014; accepted 31 January 2014; published online 11 March 2014 Antipsychotic effects on human gene expression DL Foley and A Mackinnon 447 Figure 1. Global gene expression studies. Global expression studies studies that could not control drug exposure experimentally, Global expression studies identified the genes with the largest change in including autopsy studies and those that combined autopsy and expression after exposure to antipsychotics, genes that were preferentially surgically removed tissue from living patients, (4) studies where an targeted by antipsychotics (Figure 1). Targeted replication studies tested if antipsychotic was considered only as a moderator of the effect of expression of those genes changed after exposure to other antipsychotics, another substance on gene expression and (5) studies where in different cell lines or tissues or over variable time periods. Global human experimental studies were described but antipsychotic- expression studies also assessed the change in total gene expression to induced gene expression was conducted only in animal cell lines. estimate the impact of antipsychotic drugs on cellular DNA repair mechanisms. This identified the degree of compromised DNA repair across all actively transcribed genes. Global expression studies in the brain Fourteen genes related to lipid and fatty acid biosynthesis were Candidate gene expression studies preferentially upregulated in a global expression analysis in glia Candidate gene studies tested apriorihypotheses about the effects of after exposure to clozapine/haloperidol.15 This was due to antipsychotics on expression changes in prespecified genes (Figure 2). These increased proteolytic cleavage of the sterol regulatory element were often associated with cell signalling pathways involving Akt that is binding protein (SREBP) transcription factors SREBP1 and SREBP2 strongly implicated in cardiovascular health and disease. These pathways are therefore briefly noted where it illustrates the connections among studies. (encoded by the SREBF1 and SREBF2 genes) that control Data extracted were global versus replication versus candidate expression of these genes, especially SREBP2. SREBP2 expression analysis, tissue and cell type, tissue source or cell line, preferentially activates the genes that control the synthesis and antipsychotic drug and dosage, length of drug exposure, gene for which uptake of cholesterol (Figure 1, Supplementary Table 1). data were reported, expression-fold change in that gene after drug Genes under the control of SREBP were also preferentially exposure and the associated standard error and exact P-value when upregulated in a second global expression analysis in glia and in 14 reported (Supplementary Tables 1 and 2). DataThief III version 1.6 was (a model for) neurons, across 18 different antipsychotics: used to extract data points from published bar charts and graphs if the aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, numeric fold change was not reported. The HUGO Gene Nomenclature iloperidone, loxapine, mesoridazine, molindone, olanzapine, Committee database was used to define gene symbols and names in perphenazine, promazine, quetiapine, risperidone, thioridazine,
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