Research Article

Genetic correlates of olanzapine-induced weight gain in schizophrenia subjects from north India: role of metabolic pathway genes

Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, India.

Email the corresponding author at humgen@vsnl.com

Department of Psychiatry, Dr RML Hospital, New Delhi 110 001, India

Department of Psychaitry, School of Medicine and Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15213, USA

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Bernard Lerer

Department of Psychaitry, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem, Israel

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BK Thelma

† Author for correspondence

Department of Genetics, University of Delhi South Campus, Benito Juarez Road, New Delhi 110 021, India.

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Email the corresponding author at humgen@vsnl.com

Published Online:5 Aug 2008https://doi.org/10.2217/14622416.9.8.1055

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Abstract

Aim: Olanzapine is an efficacious drug often used as a first-line medication in the treatment for schizophrenia. However, weight gain is a notable adverse drug reaction of this medication in a proportion of patients and a major cause of noncompliance. Several hypotheses, including a contribution from hormonal, physiological and environmental factors, have been postulated. In this study, we aimed to analyze a possible association of genetic polymorphisms at four important candidate genes involved in appetite regulation and antipsychotic-induced metabolic syndrome with olanzapine-induced weight gain. Materials & methods: A total of 154 schizophrenia subjects were recruited in a systematic, 6-week, open-label trial of olanzapine. We investigated the contribution of 14 polymorphisms from four genes, namely, leptin, lipoprotein lipase, tri-acyl-glycerol lipase and citrate lyase using a binary logistic regression analysis towards olanzapine-induced weight gain. Results: rs 4731426 C/G SNP, a variant in the leptin gene, was moderately associated with median weight gain (Δ weight_m; [p = 0.05; OR: 2.2; 95% CI: 0.99–4.90]) and significantly associated with extreme weight gain (Δ weight_e [p = 0.019; OR: 11.43; 95% CI: 1.49–87.55]) when average drug dose was included in a regression model. Using in silico analysis, we found that this associated intronic SNP in the leptin gene alters the binding of zinc finger 5, a transcription factor. Conclusion: The leptin gene may be a promising candidate for olanzapine-induced weight gain. As the associations are modest, replicate studies are warranted. This approach may facilitate rationalized drug regimens.

Keywords:

Bibliography

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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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MedlineGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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MedlineGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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MedlineGoogle Scholar
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Medline CASGoogle Scholar
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MedlineGoogle Scholar
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Medline CASGoogle Scholar
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Google Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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MedlineGoogle Scholar
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Medline CASGoogle Scholar
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Google Scholar
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Google Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Google Scholar
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Medline CASGoogle Scholar
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MedlineGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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CASGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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MedlineGoogle Scholar
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Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Bibliography

1 Baldwin DS, Montgomery SA: First clinical experience with olanzapine (LY 170053): results of an open-label safety and dose-ranging study in patients with schizophrenia. Int. Clin. Psychopharmacol.10,239–244 (1995).
Medline CASGoogle Scholar
2 Lieberman JA, Stroup TS, McEvoy JP et al.: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med.353,1209–1223 (2005).
Medline CASGoogle Scholar
3 Morozova MA, Zharkova NB, Beniashvili AG: [The experience of application of olanzapine: an atypical neuroleptic in acute schizophrenia]. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova100,37–43 (2000).
Medline CASGoogle Scholar
4 Fellows L, Ahmad F, Castle DJ, Dusci LJ, Bulsara MK, Ilett KF: Investigation of target plasma concentration – effect relationships for olanzapine in schizophrenia. Ther. Drug Monit.25,682–689 (2003).
Medline CASGoogle Scholar
5 Leucht S, Pitschel-Walz G, Abraham D, Kissling W: Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr. Res.35,51–68 (1999).
Medline CASGoogle Scholar
6 Yasuhara D, Nakahara T, Harada T, Inui A: Olanzapine-induced hyperglycemia in anorexia nervosa. Am. J. Psychiatry164,528–529 (2007).
MedlineGoogle Scholar
7 Melkersson KI, Dahl ML: Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses. Psychopharmacology170,157–166 (2003).
Medline CASGoogle Scholar
8 Allison DB, Mentore JL, Heo M et al.: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry156,1686–1696 (1999).
Medline CASGoogle Scholar
9 Osser DN, Najarian DM, Dufresne RL: Olanzapine increases weight and serum triglyceride levels. J. Clin. Psychiatry60,767–770 (1999).
Medline CASGoogle Scholar
10 Henderson DC, Cagliero E, Gray C et al.: Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am. J. Psychiatry157,975–981 (2000).
Medline CASGoogle Scholar
11 Koro CE, Fedder DO, l´Italien GJ et al.: Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case–control study. BMJ325,243 (2002).
Medline CASGoogle Scholar
12 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. Psychiatry159,561–566 (2002).
MedlineGoogle Scholar
13 Kinon BJ, Basson BR, Gilmore, JA, Tollefson GD: Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J. Clin. Psychiatry62,92–100 (2001).
Medline CASGoogle Scholar
14 Murashita M, Kusumi I, Inoue T et al.: Olanzapine increases plasma ghrelin level in patients with schizophrenia. Psychoneuroendocrinology30,106–110 (2005).
Medline CASGoogle Scholar
15 Gothelf D, Falk B, Singer Pet al.: Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. Am. J. Psychiatry159,1055–1057 (2002).
MedlineGoogle Scholar
16 Richelson E: Preclinical pharmacology of neuroleptics: focus on new generation compounds. J. Clin. Psychiatry57(Suppl. 11),4–11 (1996).
Medline CASGoogle Scholar
17 Wirshing DA, Wirshing WC, Kysar L et al.: Novel antipsychotics: comparison of weight gain liabilities. J. Clin. Psychiatry60,358–363 (1999).
Medline CASGoogle Scholar
18 Baptista T, Zarate J, Joober R et al.: Drug induced weight gain, an impediment to successful pharmacotherapy: focus on antipsychotics. Curr. Drug Targets5,279–299 (2004).
Medline CASGoogle Scholar
19 Ruetsch O, Viala A, Bardou H, Martin P, Vacheron MN: [Psychotropic drugs induced weight gain: a review of the literature concerning epidemiological data, mechanisms and management]. Encephale31,507–516 (2005).
Medline CASGoogle Scholar
20 Graham KA, Perkins DO, Edwards LJ, Barrier RC Jr, Lieberman JA, Harp JB: Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis. Am. J. Psychiatry162,118–123 (2005).
MedlineGoogle Scholar
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Medline CASGoogle Scholar
22 Blum WF: Leptin: the voice of the adipose tissue. Horm. Res.48(Suppl. 4),2–8 (1997).
Medline CASGoogle Scholar
23 Eder U, Mangweth B, Ebenbichler C et al.: Association of olanzapine-induced weight gain with an increase in body fat. Am. J. Psychiatry158(10),1719–1722 (2001).
Medline CASGoogle Scholar
24 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. Genomics15(4),195–200 (2005).
Medline CASGoogle Scholar
25 Ellingrod VL, Perry PJ, Ringold JC et al.: Weight gain associated with the -759C/T polymorphism of the 5HT2C receptor and olanzapine. Am. J. Med. Genet. B Neuropsychiatr. Genet.134(1),76–78 (2005).
Google Scholar
26 Reynolds GP, Hill MJ, Kirk SL: The 5-HT2C receptor and antipsychotic induced weight gain – mechanisms and genetics. J. Psychopharmacol.20(Suppl. 4),15–18 (2006).
MedlineGoogle Scholar
27 Bozina N, Medved V, Kuzman MR, Sain I, Sertic J: Association study of olanzapine-induced weight gain and therapeutic response with SERT gene polymorphisms in female schizophrenic patients. J. Psychopharmacol.21(7),728–734 (2007).
Medline CASGoogle Scholar
28 Park YM, Chung YC, Lee SH et al.: Weight gain associated with the α2a-adrenergic receptor -1,291 C/G polymorphism and olanzapine treatment. Am. J. Med. Genet. B Neuropsychiatr. Genet.141(4),394–397 (2006).
Google Scholar
29 Bishop JR, Ellingrod VL, Moline J, Miller D: Pilot study of the G-protein β3 subunit gene (C825T) polymorphism and clinical response to olanzapine or olanzapine-related weight gain in persons with schizophrenia. Med. Sci. Monit.12,BR47–BR50 (2006).
Medline CASGoogle Scholar
30 Müller DJ, Klempan TA, de Luca V et al.: The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia. Neurosci. Lett.379(2),81–89 (2005).
Medline CASGoogle Scholar
31 Ellingrod VL, Bishop JR, Moline J, Lin YC, Miller del D: Leptin and leptin receptor gene polymorphisms and increases in body mass index (BMI) from olanzapine treatment in persons with schizophrenia. Psychopharmacol. Bull.40,57–62 (2007).
MedlineGoogle Scholar
32 Kang SG, Lee HJ, Park YM et al.: Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain. Prog. Neuropsychopharmacol. Biol. Psychiatry32(1),160–163 (2008).
Medline CASGoogle Scholar
33 Thomas P, Srivastava V, Singh A et al.: Correlates of response to olanzapine among Indians with schizophrenia. Psychiatric Res. (2008) (In press).
Google Scholar
34 Nurnberger JI Jr, Blehar MC, Kaufmann CA et al.: Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch. Gen. Psychiatry5(11),849–59; discussion 863–864 (1994).
Google Scholar
35 Deshpande SN, Mathur MN, Das SK, Bhatia T, Sharma S, Nimgaonkar VL: A Hindi version of the Diagnostic Interview for Genetic Studies. Schizophr. Bull.24,489–493 (1998).
Medline CASGoogle Scholar
36 Kay SR, Fiszbein A, Opler LA: The Positive And Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr. Bull.13,261–276 (1987).
Medline CASGoogle Scholar
37 Guy W: ECDEU Assessment Manual for Psychopharmacology (Revised Edition). Department of Health, Education and Welfare, Washington DC, USA (1976).
Google Scholar
38 Simpson GH, Angus GSW: A rating scale for extrapyramidal side effects. Acta Psychiatr. Scand. (Suppl. 212),11–19 (1970).
Google Scholar
39 Avasthi A, Kulhara P, Kakkar N: Olanzapine in the treatment of Schizophrenia: an open label comparative clinical trial from north India. Indian J. Psychiatry43(3) 257–263 (2001).
Medline CASGoogle Scholar
40 Guha P, Roy K, Sanyal D, Dasgupta T, Bhattacharya K: Olanzapine-induced obesity and diabetes in Indian patients: a prospective trial comparing olanzapine with typical antipsychotics. J. Indian Med. Assoc.103,660–664 (2005).
MedlineGoogle Scholar
41 Dossenbach M, Erol A, Kessaci M et al.: Effectiveness of antipsychotic treatments for schizophrenia: interim 6-month analysis from a prospective observational study (IC-SOHO) comparing olanzapine, quetiapine, risperidone and haloperidol. J. Clin. Psychiatry65(3),312–321 (2004).
Medline CASGoogle Scholar
42 Ruano G, Goethe JW, Caley C et al.: Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients. Mol. Psychiatry12(5),474–482 (2007).
Medline CASGoogle Scholar
43 Dahlman I, Arner P: Obesity and polymorphisms in genes regulating human adipose tissue. Int. J. Obes. (Lond.)31(11),1629–1641 (2007).
CASGoogle Scholar
44 Oswal A, Yeo GS: The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics. Obes. Rev.8,293–306 (2007).
Medline CASGoogle Scholar
45 Lindroos AK, Lissner L, Carlsson B et al.: Familial predisposition for obesity may modify the predictive value of serum leptin concentrations for long-term weight change in obese women. Am. J. Clin. Nutr.67,1119–1123 (1998).
Medline CASGoogle Scholar
46 Kraus T, Haack M, Schuld A et al.: Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am. J. Psychiatry156,312–314 (1999).
Medline CASGoogle Scholar
47 Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P: Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science269,546–549 (1995).
Medline CASGoogle Scholar
48 Schug J, Unit 2.6: Using TESS to Predict Transcription Factor Binding Sites in DNA Sequence, Current Protocols in Bioinformatics. John Wiley and Sons, NJ, USA (2003)
Google Scholar
49 Cleynen I, Brants JR, Peeters K et al.: HMGA2 regulates transcription of the Imp2gene via an intronic regulatory element in cooperation with nuclear factor-κB. Mol. Cancer Res.5,363–372 (2007).
Medline CASGoogle Scholar
50 Gorshkova EV, Kaledin VI, Kobzev VF, Merkulova TI: Lung cancer-associated SNP at the beginning of mouse K-ras gene intron 2 is essential for transcription factor binding. Bull. Exp. Biol. Med.141,731–733 (2006).
Medline CASGoogle Scholar
51 Yanagi M, Hashimoto T, Kitamura N et al.: Expression of Kruppel-like factor 5 gene in human brain and association of the gene with the susceptibility to schizophrenia. Schizophr. Res.100(1–3),291–301 (2008).
MedlineGoogle Scholar
52 Chamberlain JC, Thorn JA, Oka K, Galton DJ, Stocks J: DNA polymorphisms at the lipoprotein lipase gene: associations in normal and hypertriglyceridaemic subjects. Atherosclerosis79,85–91 (1989).
Medline CASGoogle Scholar
53 Heizmann C, Kirchgessner T, Kwiterovich PO et al.: DNA polymorphism haplotypes of the human lipoprotein lipase gene: possible association with high density lipoprotein levels. Hum. Genet.86,578–584 (1991).
Medline CASGoogle Scholar
54 Shimo-Nakanishi Y, Urabe T, Hattori N et al.: Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese. Stroke32,1481–1486 (2001).
Medline CASGoogle Scholar
55 Thorn JA, Chamberlain JC, Alcolado JC et al.: Lipoprotein and hepatic lipase gene variants in coronary atherosclerosis. Atherosclerosis85,55–60 (1990).
Medline CASGoogle Scholar
56 Li S, Chen W, Srinivasan SR, Boerwinkle E, Berenson GS: Influence of lipoprotein lipase gene Ser447Stop and β1-adrenergic receptor gene Arg389Gly polymorphisms and their interaction on obesity from childhood to adulthood: the Bogalusa Heart Study. Int. J. Obes. (Lond.)30,1183–1188 (2006).
CASGoogle Scholar
57 Mattu RK, Needham EW, Morgan R et al.: DNA variants at the LPL gene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a Welsh population. Arterioscler. Thromb.14,1090–1097 (1994).
Medline CASGoogle Scholar
58 Gerdes C, Gerdes LU, Hansen PS, Faergeman O: Polymorphisms in the lipoprotein lipase gene and their associations with plasma lipid concentrations in 40-year-old Danish men. Circulation92,1765–1769 (1995).
Medline CASGoogle Scholar
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Medline CASGoogle Scholar
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Vol. 9, No. 8

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Published online 5 August 2008

Published in print August 2008

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Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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