-759C>T Polymorphism of the HTR2C Gene is Associated with Second Generation Antipsychotic-Induced Weight Gain in Female Patients with Schizophrenia

Abstract

Introduction: The HTR2C gene is an important candidate in pharmacogenetic studies of antipsychotic-induced weight gain (AIWG). However, inconsistent results have been obtained. The present study investigated the association between -759C>T, functional polymorphism of the HTR2C receptor, and AIWG.

Methods: A prospective cohort of 48 female inpatients with schizophrenia and related illness treated according to normal clinical practice with second generation antipsychotics (SGAs) risperidone, clozapine, quetiapine, and olanzapine were evaluated. Patients were weighted at admission and again at 6 weeks of hospitalization. Weight gain was defined as an increase≥7% of baseline weight. The association between polymorphisms HTR2C and weight gain was evaluated. Multiple logistic regression was run to determine potential confounders.

Results: Patients with the T allele at position -759 (TT or CT) gained less weight as compared to patients who did not have the allele. This association was not affected by possible confounding factors such as age, baseline BMI, and prior psychopharmacological treatment.

Discussion: The T allele at position -759 protects against AIWG in female patients with schizophrenia.

Key words

second generation antipsychotic - weight gain - HTR2C gene - schizophrenia

• References

• 1 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
• 2 Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry 2002; 63: 1121-1128
• 3 Weiden PJ, Mackell JA, McDonnell DD. Obesity as a risk factor for antipsychotic noncompliance. Schizophr Res 2004; 66: 51-57
• 4 Shams TA, Muller DJ. Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep 2014; 16: 473
• 5 Daray FM, Maffia PC, Rothlin RP et al. Pharmacogenetics in psychiatry: how far are we from clinical application?. Vertex 2012; 23: 299-309
• 6 Stahl SM, Mignon L, Meyer JM. Which comes first: atypical antipsychotic treatment or cardiometabolic risk?. Acta Psychiatr Scand 2009; 119: 171-179
• 7 Tecott LH, Sun LM, Akana SF et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 1995; 374: 542-546
• 8 Gebhardt S, Theisen FM, Haberhausen M et al. Body weight gain induced by atypical antipsychotics: an extension of the monozygotic twin and sib pair study. J Clin Pharm Ther 2010; 35: 207-211
• 9 Wehmeier PM, Gebhardt S, Schmidtke J et al. Clozapine: weight gain in a pair of monozygotic twins concordant for schizophrenia and mild mental retardation. Psychiatry Res 2005; 133: 273-276
• 10 Theisen FM, Cichon S, Linden A et al. Clozapine and weight gain. Am J Psychiatry 2001; 158: 816
• 11 Hill MJ, Reynolds GP. Functional consequences of two HTR2C polymorphisms associated with antipsychotic-induced weight gain. Pharmacogenomics 2011; 12: 727-734
• 12 Hill MJ, Reynolds GP. 5-HT2C receptor gene polymorphisms associated with antipsychotic drug action alter promoter activity. Brain Res 2007; 1149: 14-17
• 13 Reynolds GP, Hill MJ, Kirk SL. The 5-HT2C receptor and antipsychoticinduced weight gain – mechanisms and genetics. J Psychopharmacol 2006; 20: 15-18
• 14 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
• 15 Reynolds GP. Weight gain, antipsychotic drug treatment and pharmacogenomics. Pharmacogenomics 2002; 3: 567-570
• 16 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
• 17 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
• 18 Ryu S, Cho EY, Park T et al. -759 C/T polymorphism of 5-HT2C receptor gene and early phase weight gain associated with antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 673-677
• 19 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
• 20 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
• 21 Godlewska BR, Olajossy-Hilkesberger L, Ciwoniuk M et al. Olanzapine-induced weight gain is associated with the -759C/T and -697 G/C polymorphisms of the HTR2C gene. Pharmacogenomics J 2009; 9: 234-241
• 22 Lane HY, Liu YC, Huang CL et al. Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 2006; 26: 128-134
• 23 Tsai SJ, Hong CJ, Yu YW et al. -759C/T genetic variation of 5HT(2C) receptor and clozapine-induced weight gain. Lancet 2002; 360: 1790
• 24 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
• 25 Park YM, Cho JH, Kang SG et al. Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and olanzapine-induced weight gain among Korean schizophrenic patients. J Clin Pharm Ther 2008; 33: 55-60
• 26 Ujike H, Nomura A, Morita Y et al. Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study. J Clin Psychiatry 2008; 69: 1416-1422
• 27 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
• 28 Mulder H, Franke B, Arends J et al. The association between HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia. Journal of clinical psychopharmacology 2007; 27: 338-343
• 29 Mulder H, Cohen D, Scheffer H et al. HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. Journal of clinical psychopharmacology 2009; 29: 16-20
• 30 Reynolds GP, Templeman LA, Zhang ZJ. The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1021-1028
• 31 Yuan X, Yamada K, Ishiyama-Shigemoto S et al. Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes. Diabetologia 2000; 43: 373-376
• 32 Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med 2011; 17: 97-107
• 33 Lett TA, Wallace TJ, Chowdhury NI et al. Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 2012; 17: 242-266
• 34 Brennan MD. Pharmacogenetics of second-generation antipsychotics. Pharmacogenomics 2014; 15: 869-884
• 35 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
• 36 Kuzman MR, Medved V, Bozina N et al. The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients. Psychiatry Res 2008; 160: 308-315
• 37 Sicard MN, Zai CC, Tiwari AK et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics 2010; 11: 1561-1571
• 38 Zhang JP, Malhotra AK. Pharmacogenetics of antipsychotics: recent progress and methodological issues. Expert Opin Drug Metab Toxicol 2013; 9: 183-191