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:

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Molecular Psychiatry volume 12, pages 474–482 (2007)Cite this article

Abstract

Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidone's may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Muller DJ, Muglia P, Fortune T, Kennedy JL . Pharmacogenetics of antipsychotic-induced weight gain. Pharmacol Res 2004; 49: 309–329.

    Article  CAS  Google Scholar 

  2. Correll CU, Malhotra AK . Pharmacogenetics of antipsychotic-induced weight gain. Psychopharmacology 2004; 174: 477–489.

    Article  CAS  Google Scholar 

  3. Ruaño G, Zöllner S, Goethe JW . Drug-induced metabolic syndrome (DIMS) in psychiatry: a diagnostic need uniquely suited to pharmacogenomics. In: Wong SHY, Linder MW, Valdes Jr R (eds). Pharmacogenomics and Proteomics: Enabling the Practice of Personalized Medicine. AACC Press: Washington, DC, 2006, pp 277–282.

    Google Scholar 

  4. Meyer JM . Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001; 21: 369–374.

    Article  CAS  Google Scholar 

  5. Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R . Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002; 159: 561–566.

    Article  Google Scholar 

  6. Koro CE, Fedder DO, L'Italien GJ, Weiss SS, Magder LS, Kreyenbuhl J et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population-based nested case-control study. BMJ 2002; 325: 243.

    Article  CAS  Google Scholar 

  7. Gianfrancesco FD, Grogg AL, Mahmoud RA, Wang RH, Nasrallah HA . Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry 2002; 63: 920–930.

    Article  CAS  Google Scholar 

  8. Kornegay CJ, Vasilakis-Scaramozza C, Jick H . Incident diabetes associated with antipsychotic use in the United Kingdom general practice research database. J Clin Psychiatry 2002; 63: 758–762.

    Article  Google Scholar 

  9. Linnet K . Glucuronidation by cDNA-expressed human UDP-glucuronyltransferases and human liver microsomes. Hum Psychopharmacol 2002; 17: 233–238.

    Article  CAS  Google Scholar 

  10. Markowitz JS, Brown CS, Moore TR . Atypical antipsychotics Part I: pharmacology, pharmacokinetics and efficacy. Ann Pharmacother 1999; 33: 73–85.

    Article  CAS  Google Scholar 

  11. Ereshefsky L . Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry 1996; 57 (Suppl 11): 12–25.

    CAS  PubMed  Google Scholar 

  12. Ganguli R, Brar JS, Ayrton Z . Weight gain over 4 months in schizophrenia patients: a comparison of olanzapine and risperidone. Schizophr Res 2001; 49: 261–267.

    Article  CAS  Google Scholar 

  13. Bork J, Rogers T, Wedlund P, de Leon J . A pilot study of risperidone metabolism: the role of cytochrome P450 2D6 and 3A. J Clin Psychiatry 1999; 60: 469–476.

    Article  CAS  Google Scholar 

  14. Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M . Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 1992; 149: 68–72.

    Article  CAS  Google Scholar 

  15. Lamberti JS, Bellnier T, Schwarzkopf SB . Weight gain among schizophrenic patients treated with clozapine. Am J Psychiatry 1992; 149: 689–690.

    Article  CAS  Google Scholar 

  16. Fitzgerald PB, Scaffidi A, Morris MJ, de Castella AR, Kulkarni J . The relationship of changes in leptin, neuropeptide Y and reproductive hormone to antipsychotic-induced weight gain. Hum Psychopharmacol Clin Exp 2003; 18: 551–557.

    Article  CAS  Google Scholar 

  17. Palik E, Birkas KD, Faludi G, Karadi I, Cseh K . Correlation of serum ghrelin levels with body mass index and carbohydrate metabolism in patients treated with atypical antipsychotics. Diabetes Res Clin Pract 2005; 68 (Suppl 1): S60–S64.

    Article  CAS  Google Scholar 

  18. Atmaca M, Kuloglu M, Tezcan E, Ustundag B . Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J Clin Psychiatry 2003; 64: 598–604.

    Article  CAS  Google Scholar 

  19. Markham-Abedi C, de Leon J . Hypertriglyceridemia associated with direct effects of olanzapine rather than with weight gain: a case report (letter). J Clin Psychiatry 2006; 67: 1473–1474.

    Article  Google Scholar 

  20. Green AI, Patel JK, Goisman RM, Allison DB, Blackburn G . Weight gain from novel antipsychotic drugs: need for action. Gen Hosp Psychiatry 2000; 22: 224–235.

    Article  CAS  Google Scholar 

  21. Basile VS, Masellis M, McIntyre RS, Ozdemir V, Meltzer HY, Macciardi FM et al. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J Clin Psychiatry 2001; 62 (Suppl 23): 45–66.

    CAS  Google Scholar 

  22. Sussman N . The implications of weight changes with antipsychotic treatment. J Clin Psychopharmacol 2003; 23 (Suppl 1): S21–S26.

    CAS  PubMed  Google Scholar 

  23. Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999; 60: 358–363.

    Article  CAS  Google Scholar 

  24. Ruaño G, Thompson PD, Windemuth A, Smith A, Kocherla M, Holford TR et al. Physiogenomic analysis links serum creatine kinase activities during statin therapy to vascular smooth muscle homeostasis. Pharmacogenomics 2005; 6: 865–872.

    Article  Google Scholar 

  25. Ruaño G, Windemuth A, Kocherla M, Holford T, Fernandez ML, Forsythe CE et al. Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction. Nutr Met 2006; 3: 20–30.

    Article  Google Scholar 

  26. Ruaño G, Windemuth A, Holford TR . Physiogenomics: Integrating systems engineering and nanotechnology for personalized medicine. In: Bronzino JD (ed). The Biomedical Engineering Handbook, 3rd edn. CRC Press: Boca Raton, FL, 2005, pp 281–289.

    Google Scholar 

  27. Saltelli A, Chan K, Scott EM . Sensitivity Analysis. John Wiley and Sons: Chichester, 2000.

    Google Scholar 

  28. Rozek LS, Hatsukami TS, Richter RJ, Ranchalis J, Nakayama K, McKinstry LA . The correlation of paraoxonase (PON1) activity with lipid and lipoprotein levels differs with vascular disease status. J Lipid Res 2005; 46: 1888–1895.

    Article  CAS  Google Scholar 

  29. Eckhardt ER, Cai L, Sun B, Webb NR, van der Westhuyzen DR . High density lipoprotein uptake by scavenger receptor SR-BII. J Biol Chem 2004; 279: 14372–14381.

    Article  CAS  Google Scholar 

  30. Kalra SP, Kalra PS . NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy (review). Neuropeptides 2004; 38: 201–211.

    Article  CAS  Google Scholar 

  31. de Leon J, Susce MT, Pan RM, Fairchild M, Koch W, Wedlund PJ . The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 2005; 66: 15–27.

    Article  CAS  Google Scholar 

  32. Oliphant A, Barker DL, Stuelpnagel JR, Chee MS . BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques 2002; 32: S56–S61.

    Article  Google Scholar 

  33. Fan JB, Oliphant A, Shen R, Kermani B, Garcia F, Gunderson KL et al. Highly parallel SNP genotyping. Cold Spring Harb Symp Quant Biol 2003; 68: 69–78.

    Article  CAS  Google Scholar 

  34. R Development Core Team. A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2004; http://www.R-project.org.

  35. Dalgaard P . Introductory Statistics with R. Springer: New York, 2002.

    Google Scholar 

  36. Maindonald J, Braun J . Data Analysis and Graphics Using R. Cambridge University Press: Cambridge, 2003.

    Google Scholar 

  37. Faraway JJ . Linear Models with R. Chapman & Hall/CRC: Boca Raton, FL, 2004.

    Book  Google Scholar 

  38. Reinere A, Yekutiele D, Benjamini Y . Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics 2003; 19: 368–375.

    Article  Google Scholar 

  39. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Series B 1995; 57: 289–300.

    Google Scholar 

  40. Benjamini Y, Hochberg Y . On the adaptive control of the false discovery rate in multiple testing with independent statistics. J Educ Behav Stat, 2000; 25: 60–83.

    Article  Google Scholar 

  41. Rosner B . Fundamentals of Biostatistics, 4th edn. Duxbury Press: Belmont, 1995.

    Google Scholar 

  42. Cleveland WS . Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc 1979; 74: 829–836.

    Article  Google Scholar 

  43. Cleveland WS, Devlin SJ . Locally weighted regression: an approach to regression analysis by local fitting. J Am Stat Assoc 1988; 83: 596–610.

    Article  Google Scholar 

  44. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004; 101: 4531–4536.

    Article  CAS  Google Scholar 

  45. Liu Y-J, Rocha-Sanchez SM, Liu PY, Long J-R, Lu Y, Elze L et al. Tests of linkage and/or association of the LEPR gene polymorphisms with obesity phenotypes in Caucasian nuclear families. Physiol Genomics 2004; 17: 101–106.

    Article  CAS  Google Scholar 

  46. Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore AI . A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women. Hum Genet 2001; 108: 233–236.

    Article  CAS  Google Scholar 

  47. Sanghera DK, Aston CE, Saha N, Kamboh MI . DNA Polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Am J Hum Genet 1998; 62: 36–44.

    Article  CAS  Google Scholar 

  48. Erlich PM, Lunetta KL, Cupples LA, Huyck M, Green RC, Baldwin CT, et al., MIRAGE Study Group. Polymorphisms in the PON gene cluster are associated with Alzheimer's disease. Hum Mol Genet 2006; 15: 77–85.

    Article  CAS  Google Scholar 

  49. Blumenthal JB, Andersen RE, Mitchell BD, Seibert MJ, Yang H, Herzog H et al. Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high-density lipoprotein cholesterol levels. Clin Genet 2002; 62: 196–202.

    Article  CAS  Google Scholar 

  50. Dallongeville J, Lussier-Cacan S, Davignon J . Modulation of plasma triglyceride levels by ApoE phenotype: a meta-analysis. J Lipid Res 1992; 33: 447–454.

    CAS  PubMed  Google Scholar 

  51. Rubinsztein DC, Easton DF . Apolipoprotein E genetic variation and Alzheimer's disease: a meta-analysis. Dement Geriatr Cogn Disord 1999; 10: 199–209.

    Article  CAS  Google Scholar 

  52. Vanhanen M, Kivipelto M, Koivisto K, Kuusisto J, Mykkanen L, Helkala EL et al. APOE-Epsilon4 is associated with weight loss in women with AD: a population-based study. Neurology 2001; 56: 655–659.

    Article  CAS  Google Scholar 

  53. The International HapMap Consortium. A haplotype map of the human genome. Nature 2005; 437: 1299–1320.

  54. American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), American Psychiatric Association (APA), North American Association for the Study of Obesity (NAASO). Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27: 596–601.

  55. Templeman LA, Reynolds GP, Arranz B, San L . Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet Genomics 2005; 15: 195–200.

    Article  CAS  Google Scholar 

  56. Ellingrod VL, Perry PJ, Ringold JC, Lund BC, Bever-Stille K, Fleming F et al. Weight gain associated with the −759C/T polymorphism of the 5HT2C receptor and olanzapine. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 76–78.

    Article  Google Scholar 

  57. Park YM, Chung YC, Lee SH, Lee KJ, Kim H, Byun YC et al. Weight gain associated with the alpha2a-adrenergic receptor-1,291 C/G polymorphism and olanzapine treatment. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 394–397.

    Article  Google Scholar 

  58. Lane HY, Liu YC, Huang CL, Chang YC, Wu PL, Lu CT et al. Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 2006; 26: 128–134.

    Article  CAS  Google Scholar 

  59. Chagnon YC, Merette C, Bouchard RH, Emond C, Roy MA, Maziade M . A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses. Mol Psychiatry 2004; 9: 1067–1074.

    Article  CAS  Google Scholar 

  60. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Clinical antipsychotic trials of intervention effectiveness (CATIE) investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    Article  CAS  Google Scholar 

  61. Buckley PF . Broad therapeutic uses of atypical antipsychotic medications. Biol Psychiatry 2001; 50: 912–924.

    Article  CAS  Google Scholar 

  62. Olfson M, Blanco C, Liu L, Moreno C, Laje G . Mutational trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry 2006; 63: 679–685.

    Article  Google Scholar 

  63. Ruaño G . Quo Vadis personalized medicine? Personalized Med 2004; 1: 1–7.

    Article  Google Scholar 

  64. Malhotra AK, Murphy Jr GM, Kennedy JL . Pharmacogenetics of psychotropic drug response. Am J Psychiatry 2004; 161: 780–796.

    Article  Google Scholar 

  65. Arranz MJ, Collier D, Kerwin RW . Pharmacogenetics for the individualization of psychiatric treatment. Am J Pharmacogenomics 2001; 1: 3–10.

    Article  CAS  Google Scholar 

  66. Ozdemir V, Shear NH, Kalow W . What will be the role of pharmacogenetics in evaluating drug safety and minimising adverse effects? Drug Saf 2001; 24: 75–85.

    Article  CAS  Google Scholar 

  67. Ozdemir V, Aklillu E, Mee S, Bertilsson L, Albers LJ, Graham JE et al. Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines. Expert Opin Pharmacother 2006; 7: 119–133.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported in part by NIH Small Business Innovation Research Grant 1 R43 MH073291-01 ‘Gene Markers: Antipsychotic-Induced Metabolic Syndrome’ to Genomas, Inc. Principal investigator is G Ruaño, MD, with a subcontract to J Goethe, MD. The work at the Mental Health Research Center at Eastern State Hospital was supported by internal research funding from J de Leon, MD. In the past 2 years, J de Leon, MD. has been on the advisory board of Bristol-Myers Squibb and Roche Molecular Systems Inc.; he received investigator-initiated grants from Roche Molecular Systems Inc. and the E Lilly Research Foundation; he has lectured once supported by E Lilly, once supported by Bristol–Myers Squibb, twice supported by Janssen and five times by Roche Molecular Systems Inc. We are thankful to G Pearlson, MD, Institute of Living, Hartford, CT, USA, for his contribution to our neuropsychiatric research programs. We are grateful to M Johnson, RN, MT Susce, RN, MLT, B Szarek, RN and E Murray-Carmichael, BSc, who helped with recruitment of patients and establishment of the DNA repository.

Author information

Authors and Affiliations

  1. Genomas, Inc., Hartford, CT, USA

    G Ruaño, M Kocherla & A Windemuth

  2. Institute of Living, Hartford Hospital, Hartford, CT, USA

    J W Goethe, C Caley & S Woolley

  3. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA

    T R Holford

  4. Department of Psychiatry, College of Medicine, Eastern State Hospital, Mental Health Research Center, University of Kentucky, Lexington, KY, USA

    J de Leon

Authors
  1. G Ruaño
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J W Goethe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Caley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Woolley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T R Holford
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Kocherla
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Windemuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J de Leon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J de Leon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruaño, G., Goethe, J., Caley, C. et al. Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients. Mol Psychiatry 12, 474–482 (2007). https://doi.org/10.1038/sj.mp.4001944

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001944

Keywords

This article is cited by

Search

Advanced search

Quick links