Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
World Health Organization. 2011. http://www.who.int/mediacentre/factsheets/fs310/en/index.html.
Saha S, Chant D, McGrath J . A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry 2007; 64: 1123–1131.
The Lancet. No mental health without physical health. Lancet 2011; 377: 611.
Foley DL, Morley KI . Systematic review of early cardiometabolic outcomes of the first treated episode of psychosis. Arch Gen Psychiatry 2011; 68: 609–616.
Heald A . Physical health in schizophrenia: a challenge for antipsychotic therapy. Eur Psychiatry 2010; 25 (Suppl 2): S6–11.
Gentile S . A systematic review of quality of life and weight gain-related issues in patients treated for severe and persistent mental disorders: focus on aripiprazole. Neuropsychiatr Dis Treat 2009; 5: 117–125.
Nasrallah HA . Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008; 13: 27–35.
Teff KL, Kim SF . Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism. Physiol Behav 2011; 104: 590–598.
Roerig JL, Steffen KJ, Mitchell JE . Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 2011; 25: 1035–1059.
Lett TAP, Wallace TJM, Chowdhury NI, Tiwari AK, Kennedy JL, Müller DJ . Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 2012; 17: 242–266.
Lee SH, DeCandia TR, Ripke S, Yang J . Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ); International Schizophrenia Consortium (ISC); Molecular Genetics of Schizophrenia Collaboration (MGS), Sullivan PF, Goddard ME et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 2012; 44: 247–250.
Girard SL, Xiong L, Dion PA, Rouleau GA . Where are the missing pieces of the schizophrenia genetics puzzle? Curr Opin Genet Dev 2011; 21: 310–316.
Thomas EA . Molecular profiling of antipsychotic drug function: convergent mechanisms in the pathology and treatment of psychiatric disorders. Mol Neurobiol 2006; 34: 109–128.
Tummers B Data Thief 111. 2006. http://datathief.org/.
Fernø J, Raeder MB, Vik-Mo AO, Skrede S, Glambek M, Tronstad KJ et al. Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action? Pharmacogenomics J 2005; 5: 298–304.
Polymeropoulos MH, Licamele L, Volpi S, Mack K, Mitkus SN, Carstea ED et al. Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia. Schizophr Res 2009; 108: 134–142.
Barak Y, Ron IG, Sirota P, Sobe T, Slor H . The effect of chlorpromazine and haloperidol on DNA transcription. Int Clin Psychopharmacol 1996; 11: 193–197.
Fernø J, Skrede S, Vik-Mo AO, Håvik B, Steen VM . Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs. BMC Neurosci 2006; 7: 69–79.
Vik-Mo AO, Fernø J, Skrede S, Steen VM . Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS- and liver cells. BMC Pharmacol 2009; 9: 10–16.
Yang LH, Chen TM, Yu ST, Chen YH . Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells. Pharmacol Res 2007; 56: 202–208.
Aubry JM, Schwald M, Ballmann E, Karege F . Early effects of mood stabilizers on the Akt/GSK-3beta signaling pathway and on cell survival and proliferation. Psychopharmacology 2009; 205: 419–429.
Chana G, Lucero G, Salaria S, Lozach J, Du P, Woelk C et al. Upregulation of NRG-1 and VAMP-1 in human brain aggregates exposed to clozapine. Schizophr Res 2009; 113: 273–276.
Bernstein HG, Ernst T, Lendeckel U, Bukowska A, Ansorge S, Stauch R et al. Reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia. J Psychiatr Res 2009; 43: 1095–1105.
Park SW, Lee JG, Ha EK, Choi SM, Cho HY, Seo MK et al. Differential effects of aripiprazole and haloperidol on BDNF-mediated signal changes in SH-SY5Y cells. Eur Neuropsychopharmacol 2009; 19: 356–362.
Lee JG, Cho HY, Park SW, Seo MK, Kim YH . Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 1001–1006.
Schmidt AJ, Hemmeter UM, Krieg JC, Vedder H, Heiser P . Impact of haloperidol and quetiapine on the expression of genes encoding antioxidant enzymes in human neuroblastoma SH-SY5Y cells. J Psychiatr Res 2009; 43: 818–823.
Shin SY, Choi BH, Ko J, Kim SH, Kim YS, Lee YH . Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells. Cell Signal 2006; 18: 1876–1886.
Kang J, Chen X-L, Rampe D . The antipsychotic drugs sertindole and pimozide block erg3, a human brain K+ channel. Biochem Biophys Res Commun 2001; 286: 499–504.
Su Z, Martin R, Cox BF, Gintant G . Mesoridazine: an open-channel blocker of human ether-a-go-go-related gene K+ channel. J Mol Cell Cardiol 2004; 36: 151–160.
Deslauriers J, Lefrançois M, Larouche A, Sarret P, Grignon S . Antipsychotic-induced DRD2 upregulation and its prevention by α-lipoic acid in SH-SY5Y neuroblastoma cells. Synapse 2011; 65: 321–331.
Bernstein HG, Lendeckel U, Dobrowolny H, Stauch R, Steiner J, Grecksch G et al. Beacon-like/ubiquitin-5-like immunoreactivity is highly expressed in human hypothalamus and increased in haloperidol-treated schizophrenics and a rat model of schizophrenia. Psychoneuroendocrinology 2008; 33: 340–351.
Cohen T, Sundaresh S, Levine F . Antipsychotics activate the TGFβ pathway effector SMAD3. Mol Psychiatry 2013; 18: 347–357.
Canfrán-Duque A, Casado ME, Pastor O, Sánchez-Wandelmer J, de la Peña G, Lerma M et al. Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro. J Lipid Res 2013; 54: 310–324.
Menga A, Infantino V, Iacobazzi F, Convertini P, Palmieri F, Iacobazzi V . Insight into mechanism of in vitro insulin secretion increase induced by antipsychotic clozapine: role of FOXA1 and mitochondrial citrate carrier. Eur Neuropsychopharmacol 2013; 23: 978–987.
Chen ML, Tsai TC, Wang LK, Lin YY, Tsai YM, Lee MC et al. Clozapine inhibits Th1 cell differentiation and causes the suppression of IFN-γ production in peripheral blood mononuclear cells. Immunopharmacol Immunotoxicol 2012; 34: 686–694.
Lauressergues E, Bert E, Duriez P, Hum D, Majd Z, Staels B et al. Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation? Neuropharmacology 2012; 62: 784–796.
Kiselyuk A, Farber-Katz S, Cohen T, Lee SH, Geron I, Azimi B et al. Phenothiazine neuroleptics signal to the human insulin promoter as revealed by a novel high-throughput screen. J Biomol Screen 2010; 15: 663–670.
Sussman MA, Völkers M, Fischer K, Bailey B, Cottage CT, Din S et al. Myocardial AKT: the omnipresent nexus. Physiol Rev 2011; 91: 1023–1070.
Tabarés-Seisdedos R, Dumont N, Baudot A, Valderas JM, Climent J, Valencia A et al. No paradox, no progress: inverse cancer comorbidity in people with other complex diseases. Lancet Oncol 2011; 12: 604–608.
Shimano H . Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 2001; 40: 439–452.
Shimano H . SREBPs: physiology and pathophysiology of the SREBP family. FEBS J 2009; 276: 616–621.
Zdychová J, Komers R . Emerging role of Akt kinase/protein kinase B signaling in pathophysiology of diabetes and its complications. Physiol Res 2005; 54: 1–16.
O'Neill BT, Abel ED . Akt1 in the cardiovascular system: friend or foe? J Clin Invest 2005; 115: 2059–2064.
Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V . Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry 2011; 68: 128–137.
Iliadis F, Kadoglou N, Didangelos T . Insulin and the heart. Diabetes Res Clin Pract 2011; 93 (Suppl 1): S86–S91.
Krycer JR, Sharpe LJ, Luu W, Brown AJ . The akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrin Met 2010; 21: 268–276.
Luu W, Sharpe LJ, Stevenson J, Brown AJ . Akt acutely activates the cholesterogenic transcription factor SREBP-2. Biochim Biophys Acta 2012; 1823: 458–464.
Hakem R . DNA-damage repair; the good, the bad, and the ugly. EMBO J 2008; 27: 589–605.
Patent application 20110118313http://www.faqs.org/patents/app/20110118313.
Camargo N, Smit AB, Verheijen MHG . SREBPs: SREBP function in glia-neuron interactions. FEBS J 2009; 276: 628–636.
Saher G, Brügger B, Lappe-Siefke C, Möbius W, Tozawa R, Wehr MC et al. High cholesterol level is essential for myelin membrane growth. Nat Neurosci 2005; 8: 468–475.
Guo D, Reinitz F, Youssef M, Hong C, Nathanson D, Akhavan D et al. An LXR agonist promotes GBM cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov 2011; 1: 442–456.
Steiner J, Myint AM, Schiltz K, Westphal S, Bernstein HG, Walter M et al. S100B serum levels in schizophrenia are presumably related to visceral obesity and insulin resistance. Cardiovasc Psychiatry Neurol 2010; 2010: 480707.
Remington G, Kapur S . Antipsychotic dosing: how much but also how often? Schizophr Bull 2010; 36: 900–903.
Sakai S, Ikematsu K, Matsuo A, Tsai CT, Nakasono I . Expression of C-fos, Fos-B, Fosl-1, Fosl-2, Dusp-1 and C-jun in the mouse heart after single and repeated chlorpromazine administrations. Leg Med 2010; 12: 284–288.
Vik-Mo AO, Birkenaes AB, Fernø J, Jonsdottir H, Andreassen OA, Steen VM . Increased expression of lipid biosynthesis genes in peripheral blood cells of olanzapine-treated patients. Int J Neuropsychop 2008; 11: 679–684.
Acknowledgements
We wish to acknowledge the support of the Colonial Foundation (Australia) to the Orygen Youth Health Research Centre.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
PowerPoint slides
Rights and permissions
About this article
Cite this article
Foley, D., Mackinnon, A. A systematic review of antipsychotic drug effects on human gene expression related to risk factors for cardiovascular disease. Pharmacogenomics J 14, 446–451 (2014). https://doi.org/10.1038/tpj.2014.8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2014.8
This article is cited by
-
Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review
The Pharmacogenomics Journal (2016)