Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A systematic review of antipsychotic drug effects on human gene expression related to risk factors for cardiovascular disease

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

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. World Health Organization. 2011. http://www.who.int/mediacentre/factsheets/fs310/en/index.html.

  2. 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.

    Article  PubMed  Google Scholar 

  3. The Lancet. No mental health without physical health. Lancet 2011; 377: 611.

    Article  Google Scholar 

  4. Foley DL, Morley KI . Systematic review of early cardiometabolic outcomes of the first treated episode of psychosis. Arch Gen Psychiatry 2011; 68: 609–616.

    Article  PubMed  Google Scholar 

  5. Heald A . Physical health in schizophrenia: a challenge for antipsychotic therapy. Eur Psychiatry 2010; 25 (Suppl 2): S6–11.

    Article  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nasrallah HA . Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008; 13: 27–35.

    Article  CAS  PubMed  Google Scholar 

  8. Teff KL, Kim SF . Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism. Physiol Behav 2011; 104: 590–598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Roerig JL, Steffen KJ, Mitchell JE . Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 2011; 25: 1035–1059.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. Thomas EA . Molecular profiling of antipsychotic drug function: convergent mechanisms in the pathology and treatment of psychiatric disorders. Mol Neurobiol 2006; 34: 109–128.

    Article  CAS  PubMed  Google Scholar 

  14. Tummers B Data Thief 111. 2006. http://datathief.org/.

  15. 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.

    Article  PubMed  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yang LH, Chen TM, Yu ST, Chen YH . Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells. Pharmacol Res 2007; 56: 202–208.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. Cohen T, Sundaresh S, Levine F . Antipsychotics activate the TGFβ pathway effector SMAD3. Mol Psychiatry 2013; 18: 347–357.

    Article  PubMed  Google Scholar 

  33. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  PubMed  Google Scholar 

  40. Shimano H . Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 2001; 40: 439–452.

    Article  CAS  PubMed  Google Scholar 

  41. Shimano H . SREBPs: physiology and pathophysiology of the SREBP family. FEBS J 2009; 276: 616–621.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    PubMed  Google Scholar 

  43. O'Neill BT, Abel ED . Akt1 in the cardiovascular system: friend or foe? J Clin Invest 2005; 115: 2059–2064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Iliadis F, Kadoglou N, Didangelos T . Insulin and the heart. Diabetes Res Clin Pract 2011; 93 (Suppl 1): S86–S91.

    Article  CAS  PubMed  Google Scholar 

  46. Krycer JR, Sharpe LJ, Luu W, Brown AJ . The akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrin Met 2010; 21: 268–276.

    Article  CAS  Google Scholar 

  47. Luu W, Sharpe LJ, Stevenson J, Brown AJ . Akt acutely activates the cholesterogenic transcription factor SREBP-2. Biochim Biophys Acta 2012; 1823: 458–464.

    Article  CAS  PubMed  Google Scholar 

  48. Hakem R . DNA-damage repair; the good, the bad, and the ugly. EMBO J 2008; 27: 589–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Patent application 20110118313http://www.faqs.org/patents/app/20110118313.

  50. Camargo N, Smit AB, Verheijen MHG . SREBPs: SREBP function in glia-neuron interactions. FEBS J 2009; 276: 628–636.

    Article  CAS  PubMed  Google Scholar 

  51. 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.

    Article  CAS  PubMed  Google Scholar 

  52. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Remington G, Kapur S . Antipsychotic dosing: how much but also how often? Schizophr Bull 2010; 36: 900–903.

    Article  PubMed  PubMed Central  Google Scholar 

  55. 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.

    Article  CAS  Google Scholar 

  56. 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.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge the support of the Colonial Foundation (Australia) to the Orygen Youth Health Research Centre.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D L Foley.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2014.8

This article is cited by

Search

Quick links