Download PDF
Pharmacopsychiatry 2011; 44(1): 15-20
DOI: 10.1055/s-0030-1263174
Original Paper

© Georg Thieme Verlag KG Stuttgart · New York

Association Study of Energy Homeostasis Genes and Antipsychotic-Induced Weight Gain in Patients with Schizophrenia

G. Jassim1 , 2 , J. Fernø1 , 2 , F. M. Theisen3 , M. Haberhausen3 , A. Christoforou1 , 2 , B. Håvik1 , 2 , S. Gebhardt4 , H. Remschmidt3 , C. Mehler-Wex6 , J. Hebebrand5 , S. LeHellard1 , 2 , 7 , V. M. Steen1 , 2 , 7
  • 1Department of Clinical Medicine, University of Bergen, Bergen, Norway
  • 2Dr Einar Martens’ Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  • 3Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps University, Marburg, Germany
  • 4Department of Psychiatry and Psychotherapy, Philipps University, Marburg, Germany
  • 5Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany
  • 6Department of Child and Adolescent Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany
  • 7These authors contributed equally
Further Information

Publication History

received 19.04.2010 revised 07.07.2010

accepted 23.07.2010

Publication Date:
06 September 2010 (online)

Also available at
    Permissions and Reprints

Abstract

Introduction: Marked inter-individual variation has been observed with respect to the risk of weight gain and related metabolic disturbances during antipsychotic treatment, which in part could be explained by heritability. Such adverse effects have been proposed to occur through drug-induced mechanisms involving both the central nervous system and different peripheral tissues.

Methods: We genotyped tagSNPs in several genes (ADIPOQ, PRKAA1, PRKAA2, PRKAB1, PRKAG1, PRKAG2, PRKAG3, FTO and FABP3) that regulate lipid and energy homeostasis for their possible association to antipsychotic-induced weight gain.

Results: In a sample of 160 patients of German origin with schizophrenia who had been monitored with respect to body weight, we found marked association between antipsychotic-related changes in BMI and 6 markers in the adiponectin gene (ADIPOQ).

Discussion: These findings support previous observations (in patients’ serum) that adiponectin is involved in antipsychotic-mediated metabolic adverse effects.

References

  • 1 Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature.  J Clin Psychiatry. 2001;  62 (S 07) 22-31
    PubMedSearch in Google Scholar
  • 2 Andersson U, Filipsson K, Abbott CR. et al . AMP-activated protein kinase plays a role in the control of food intake.  J Biol Chem. 2004;  279 12005-12008
    CrossrefPubMedSearch in Google Scholar
  • 3 Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research.  Mol Psychiatry. 2007;  12 707-747
    Search in Google Scholar
  • 4 Bai YM, Chen JY, Yang WS. et al . Adiponectin as a potential biomarker for the metabolic syndrome in Chinese patients taking clozapine for schizophrenia.  J Clin Psychiatry. 2007;  68 1834-1839
    CrossrefPubMedSearch in Google Scholar
  • 5 Bai YM, Chen TT, Yang WS. et al . Association of adiponectin and metabolic syndrome among patients taking atypical antipsychotics for schizophrenia: a cohort study.  Schizophr Res. 2009;  111 1-8
    CrossrefPubMedSearch in Google Scholar
  • 6 Bai YM, Lin CC, Chen JY. et al . Association of initial antipsychotic response to clozapine and long-term weight gain.  Am J Psychiatry. 2006;  163 1276-1279
    CrossrefPubMedSearch in Google Scholar
  • 7 Basile VS, Masellis M, De Luca V. et al . 759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain.  Lancet. 2002;  360 1790-1791
    PubMedSearch in Google Scholar
  • 8 Birkenaes AB, Birkeland KI, Friis S. et al . Hormonal markers of metabolic dysregulation in patients with severe mental disorders after olanzapine treatment under real-life conditions.  J Clin Psychopharmacol. 2009;  29 109-116
    CrossrefPubMedSearch in Google Scholar
  • 9 Carling D. The AMP-activated protein kinase cascade – a unifying system for energy control.  Trends Biochem Sci. 2004;  29 18-24
    CrossrefPubMedSearch in Google Scholar
  • 10 Cheung PC, Salt IP, Davies SP. et al . Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding.  Biochem J. 2000;  346 (Pt 3) 659-669
    CrossrefPubMedSearch in Google Scholar
  • 11 Correll CU, Malhotra AK. Pharmacogenetics of antipsychotic-induced weight gain.  Psychopharmacology (Berl). 2004;  174 477-489
    PubMedSearch in Google Scholar
  • 12 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. 2005;  134B 76-78
    CrossrefPubMedSearch in Google Scholar
  • 13 Ferno J, Raeder MB, Vik-Mo AO. 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
    CrossrefPubMedSearch in Google Scholar
  • 14 Ferno J, Skrede S, Vik-Mo AO. et al . 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
    CrossrefPubMedSearch in Google Scholar
  • 15 Ferno J, Vik-Mo AO, Jassim G. et al . Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver.  Psychopharmacology (Berl). 2009;  203 73-84
    CrossrefPubMedSearch in Google Scholar
  • 16 Frayling TM, Timpson NJ, Weedon MN. et al . A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.  Science. 2007;  316 889-894
    CrossrefPubMedSearch in Google Scholar
  • 17 Gregoor JG, van der Weide J, Mulder H. et al . Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication.  J Clin Psychopharmacol. 2009;  29 21-25
    CrossrefPubMedSearch in Google Scholar
  • 18 Hardie DG. AMP-activated protein kinase as a drug target.  Annu Rev Pharmacol Toxicol. 2007;  47 185-210
    CrossrefPubMedSearch in Google Scholar
  • 19 Heid IM, Henneman P, Hicks A. et al . Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: results of genome-wide association analyses including 4 659 European individuals.  Atherosclerosis. 2010;  208 412-420
    CrossrefPubMedSearch in Google Scholar
  • 20 Hivert MF, Manning AK, McAteer JB. et al . Common variants in the adiponectin gene (ADIPOQ) associated with plasma adiponectin levels, type 2 diabetes, and diabetes-related quantitative traits: the Framingham Offspring Study.  Diabetes. 2008;  57 3353-3359
    CrossrefPubMedSearch in Google Scholar
  • 21 Juutinen J, Hakko H, Meyer-Rochow VB. et al . Body mass index (BMI) of drug-naive psychotic adolescents based on a population of adolescent psychiatric inpatients.  Eur Psychiatry. 2008;  23 521-526
    CrossrefPubMedSearch in Google Scholar
  • 22 Kadowaki T, Yamauchi T, Kubota N. et al . Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.  J Clin Invest. 2006;  116 1784-1792
    CrossrefPubMedSearch in Google Scholar
  • 23 Kahn BB, Alquier T, Carling D. et al . AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism.  Cell Metab. 2005;  1 15-25
    CrossrefPubMedSearch in Google Scholar
  • 24 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 Psychiatry. 2008;  32 160-163
    CrossrefPubMedSearch in Google Scholar
  • 25 Kim SF, Huang AS, Snowman AM. et al . Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase.  PNAS. 2007;  104 3456-3459
    CrossrefPubMedSearch in Google Scholar
  • 26 Le Hellard S, Theisen FM, Haberhausen M. et al . Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?.  Mol Psychiatry. 2009;  14 308-317
    CrossrefPubMedSearch in Google Scholar
  • 27 Leucht S, Corves C, Arbter D. et al . Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.  Lancet. 2009;  373 31-41
    Search in Google Scholar
  • 28 Lieberman JA, Stroup TS, McEvoy JP. et al . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.  N Engl J Med. 2005;  353 1209-1223
    Search in Google Scholar
  • 29 Lopez M, Lage R, Saha AK. et al . Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin.  Cell Metab. 2008;  7 389-399
    CrossrefPubMedSearch in Google Scholar
  • 30 Melkersson K, Dahl ML. Adverse metabolic effects associated with atypical antipsychotics: literature review and clinical implications.  Drugs. 2004;  64 701-723
    CrossrefPubMedSearch in Google Scholar
  • 31 Miller DD, Ellingrod VL, Holman TL. et al . Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism.  Am J Med Genet B Neuropsychiatr Genet. 2005;  133B 97-100
    CrossrefPubMedSearch in Google Scholar
  • 32 Minokoshi Y, Alquier T, Furukawa N. et al . AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus.  Nature. 2004;  428 569-574
    CrossrefPubMedSearch in Google Scholar
  • 33 Opgen-Rhein C, Brandl EJ, Muller DJ. et al . Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample.  Pharmacogenomics. 2010;  11 773-780
    CrossrefPubMedSearch in Google Scholar
  • 34 Raeder MB, Ferno J, Vik-Mo AO. et al . SREBP activation by antipsychotic- and antidepressant-drugs in cultured human liver cells: relevance for metabolic side-effects?.  Mol Cell Biochem. 2006;  289 167-173
    CrossrefPubMedSearch in Google Scholar
  • 35 Reynolds GP, Zhang Z, Zhang X. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain.  Am J Psychiatry. 2003;  160 677-679
    CrossrefPubMedSearch in Google Scholar
  • 36 Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism.  Lancet. 2002;  359 2086-2087
    CrossrefPubMedSearch in Google Scholar
  • 37 Templeman LA, Reynolds GP, Arranz B. et al . 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
    CrossrefPubMedSearch in Google Scholar
  • 38 Thakore JH, Mann JN, Vlahos I. et al . Increased visceral fat distribution in drug-naive and drug-free patients with schizophrenia.  Int J Obes Relat Metab Disord. 2002;  26 137-141
    Search in Google Scholar
  • 39 Theisen FM, Hinney A, Bromel T. et al . Lack of association between the −759C/T polymorphism of the 5-HT2C receptor gene and clozapine-induced weight gain among German schizophrenic individuals.  Psychiatr Genet. 2004;  14 139-142
    CrossrefPubMedSearch in Google Scholar
  • 40 Tiwari AK, Zai CC, Meltzer HY. et al . Association study of polymorphisms in Insulin Induced Gene 2 (INSIG2) with antipsychotic-induced weight gain in European and African-American schizophrenia patients.  Hum Psychopharmacol. 2010;  25 253-259
    CrossrefPubMedSearch in Google Scholar
  • 41 Verma SK, Subramaniam M, Liew A. et al . Metabolic risk factors in drug-naive patients with first-episode psychosis.  J Clin Psychiatry. 2009;  70 997-1000
    CrossrefPubMedSearch in Google Scholar
  • 42 Yamauchi T, Kamon J, Minokoshi Y. et al . Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.  Nat Med. 2002;  8 1288-1295
    CrossrefPubMedSearch in Google Scholar
  • 43 Zhang XY, Tan YL, Zhou DF. et al . Association of clozapine-induced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population.  J Clin Psychopharmacol. 2007;  27 246-251
    CrossrefPubMedSearch in Google Scholar
  • 44 Zhang ZJ, Yao ZJ, Mou XD. et al . Association of -2548G/A functional polymorphism in the promoter region of leptin gene with antipsychotic agent-induced weight gain.  Zhonghua Yi Xue Za Zhi. 2003;  83 2119-2123
    PubMedSearch in Google Scholar

Correspondence

Prof. V. M. Steen

Center for Medical Genetics and

Molecular Medicine

Laboratory Building

Haukeland University Hospital

5021 Bergen

Norway

Phone: +47/55/975 475

Email: vidar.martin.steen@helse-bergen.no