Multiple Genetic Factors in Olanzapine-Induced Weight Gain in Schizophrenia Patients

Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 09/2008; 69(9):1416-22. DOI: 10.4088/JCP.v69n0909
Source: PubMed


One of the clinically significant adverse effects of olanzapine treatment is weight gain, which shows substantial inter-individual differences and may be influenced by genetic variation. The aim of this investigation was identification of genetic risk factors associated with olanzapine-induced weight gain.
Inpatients with DSM-IV-TR schizophrenia (N = 164) were administered olanzapine for 8 to 24 (mean +/- SD = 17.9 +/- 9.4) weeks. The clinical background, body mass index (BMI), and clinical response to olanzapine were investigated. Twenty-one loci of diverse candidate genes encoding dopamine, serotonin (5-HT), histamine, and adrenergic receptors, tumor necrosis factor-alpha, ghrelin, adiponectin, and peroxisome proliferator-activated receptor gamma-2, were analyzed. The study was conducted from June 2001 to June 2003 at 4 psychiatric hospitals in Japan.
BMI increased by a mean +/- SD 4.3 +/- 10.7% after treatment with olanzapine (mean +/- SD dose = 15.5 +/- 5.8 mg/day). Olanzapine-induced weight gain correlated negatively with baseline BMI and positively with clinical global improvement and the length of olanzapine treatment (p < .0001), but it did not correlate with the daily dose of olanzapine, concomitant antipsychotics, sex, age, or smoking. Four genetic variants, the 102T allele of HTR2A, the 825T allele of GNB3, the 23Cys allele of HTR2C, and the 64Arg/Arg genotype of ADRB3, were significantly associated with olanzapine-induced weight gain. Stepwise regression analysis revealed that the baseline BMI predicted 12.5% of the weight gain, and the 2 latter genetic factors added 6.8%. The patients with double and triple genetic risk factors showed 5.1% and 8.8% BMI increases, respectively, during olanzapine treatment, whereas the patients with a single or no risk factor showed approximately a 1% BMI increase.
We identified genetic variants of 5-HT(2A) and 5-HT(2C) receptors, the G-protein beta-3 subunit, and the adrenergic receptor beta-3, as genetic risk factors for olanzapine-induced weight gain, and they showed additive genetic effects on weight gain.

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    • "Candidate genes extensively investigated are related with the pharmacological action of atypical antipsychotics. For examples, polymorphisms of serotonin receptor 2C2-4) and 2A genes,3) histamine receptor H1 gene,5) dopamine receptor D26,7) and D4 genes,8) adrenergic receptor α2A9) and β310) genes have been explored. However, most of these studies have not identified any genetic polymorphism that accounts for a significant proportion of the inter-individual variability. "
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    ABSTRACT: Fat-mass and obesity-associated (FTO) gene is known to be involved in the pathophysiology of obesity and a single-nucleotide polymorphism (SNP) rs9939609 of FTO gene is repeatedly confirmed to be associated with body mass index (BMI) and obesity. The aim of this study is to elucidate effects of FTO gene polymorphism on BMI in Japanese patients with schizophrenia and healthy subjects. Three hundred fifty one patients with schizophrenia and 342 age- and sex-matched healthy subjects participated in the study. Information on BMI and antipsychotic medication was also collected from patients and healthy subjects. Genotype of the FTO SNP rs9939609 was determined by TaqMan SNP Genotyping Assays. There was no significant difference in BMI between patients and healthy subjects. No significant difference in BMI was observed among any medications. We observed no significant difference in rs9939609 allele frequencies between patients and healthy subjects. There was a significant difference in BMI between healthy subjects with risk (AA or TA) genotypes and those with TT genotype. We also observed a significant positive correlation between the number of risk allele (A allele) and BMI in healthy subjects. Our study suggested that FTO rs9939609 polymorphism might have some impacts on the BMI in healthy subjects, but might not have same impacts on the BMI of patients with schizophrenia.
    Clinical Psychopharmacology and Neuroscience 12/2012; 10(3):185-9. DOI:10.9758/cpn.2012.10.3.185
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    • "Other candidates that have demonstrated replicated positive associations with weight gain on antipsychotic drugs include the α2A adrenoceptor gene26) and two factors relating to synaptic transmission: SNAP2527) and the G-protein beta3 subunit (GNB3) genes.28,29) Evidence for an effect of HTR2A SNPs on antipsychotic-induced weight gain has been inconsistent, although a study carried out on patients treated with olanzapine showed that a combination of HTR2A and HTR2C SNPs with SNPs in GNB3 and the beta3 adrenoceptor gene were associated with olanzapine-induced weight gain, with significant additive effects.30) Brain-derived neurotrophic factor (BDNF) has a role in the regulation of food intake and there is a reported association of the functional val66met SNP in males.31) "
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    ABSTRACT: Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.
    Clinical Psychopharmacology and Neuroscience 08/2012; 10(2):71-7. DOI:10.9758/cpn.2012.10.2.71
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    • "Clinical studies also support the role of low DA in driving food intake, with antipsychotic medications that block dopaminergic activity causing patients to overeat and become obese (Blouin et al. 2008; Kluge et al. 2007). While this pharmacological effect could also occur through the blockade of serotonin or histamine receptors (Theisen et al. 2007; Ujike et al. 2008), the involvement of D2 receptors is supported by evidence that humans with specific variant alleles for these receptors exhibit greater weight gain on antipsychotic medication (Hong et al. 2010; Muller et al. 2010). Further, other studies of humans with alleles for the D2 receptor and the DA transporter show a positive correlation with overeating and binge eating of foods high in fat and sucrose (Eny et al. 2009; Shinohara et al. 2004). "
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    ABSTRACT: Consummatory behavior is driven by both caloric and emotional need, and a wide variety of animal models have been useful in research on the systems that drive consumption of food and drugs. Models have included selective breeding for a specific trait, manipulation of gene expression, forced or voluntary exposure to a substance, and identification of biomarkers that predict which animals are prone to overconsuming specific substances. This research has elucidated numerous brain areas and neurochemicals that drive consummatory behavior. Although energy homeostasis is primarily mediated by the hypothalamus, reinforcement is more strongly mediated by nuclei outside the hypothalamus, in mesocorticolimbic regions. Orexigenic neurochemicals that control food intake can provide a general signal for promoting caloric intake or a more specific signal for stimulating consumption of a particular macronutrient, fat, carbohydrate, or protein. The neurochemicals involved in controlling fat ingestion--galanin, enkephalin, orexin, melanin-concentrating hormone, and the endocannabinoids--show positive feedback with this macronutrient, as these peptides both increase fat intake and are further stimulated by its intake. This positive association offers some explanation for why foods high in fat are so often overconsumed. Consumption of ethanol, a drug of abuse that also contains calories, is similarly driven by the neurochemical systems involved in fat intake, according to evidence that closely relates fat and ethanol consumption. Further understanding of the systems involved in consummatory behavior will enable the development of effective therapies for the treatment of both overeating and drug abuse.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 03/2012; 53(1):35-58. DOI:10.1093/ilar.53.1.35 · 2.39 Impact Factor
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