Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: A cohort study

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: 5.14). 09/2008; 69(9):1416-22. DOI: 10.4088/JCP.v69n0909
Source: PubMed

ABSTRACT 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.

  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 1.05 Impact Factor
  • Source
    • "Antipsychotics may induce metabolic adverse effects. Excessive weight gain is more common in treatment of second-and thirdgeneration antipsychotics, in comparison to the first generation antipsychotics (Ujike et al. 2008, Kroeze et al. 2003). This is explained by the affinity of secondand third-generation antipsychotics towards histamine H 1 receptors (Uzun et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Depression is a disorder held responsible for high morbidity in the overall population. Causes of depression vary, but lifestyle and stress can greatly contribute to its morbidity. Consumption of antidepressants is showing a trend in the economically developed countries. Apart from antidepressants, the treatment of depression can consist of other psychopharmaca. Depending on the severity of a disorder, that is - of psychotic symptoms, antipsychotics can be introduced in the treatment. Among those atypical antipsychotics have an advantage. This paper will illustrate a course of treatment of a female patient, diagnosed with psychotic depression and treated with antipsychotics (i.e. olanzapine, ziprasidone), to which she developed side effects. To each of the antypsychotics the patient developed side effechts, causing in prolonged treatment and affected its course.
    Psychiatria Danubina 03/2011; 23(1):89-91. · 0.65 Impact Factor
  • Source
    • "On the other side, receptors may be involved in the mechanism of weight gain even if they are not included in the receptor-binding profile of an antipsychotic compound. For instance, olanzapine may indirectly affect certain functions mediated by beta-adrenergic receptors even if has not a significant affinity for any of the beta-receptor subtypes [32]. (5) The dissection between central and peripheral mechanisms responsible of antipsychotics weight gain should also be considered. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Excess body weight is one of the most common physical health problems among patients with schizophrenia that increases the risk for many medical problems, including type 2 diabetes mellitus, coronary heart disease, osteoarthritis, and hypertension, and accounts in part for 20% shorter life expectancy than in general population. Among patients with severe mental illness, obesity can be attributed to an unhealthy lifestyle, personal genetic profile, as well as the effects of psychotropic medications, above all antipsychotic drugs. Novel "atypical" antipsychotic drugs represent a substantial improvement on older "typical" drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. Animal models of antipsychotic-related weight gain and animal transgenic models of knockout or overexpressed genes of antipsychotic receptors have been largely evaluated by scientific community for changes in obesity-related gene expression or phenotypes. Moreover, pharmacogenomic approaches have allowed to detect more than 300 possible candidate genes for antipsychotics-induced body weight gain. In this paper, we summarize current thinking on: (1) the role of polymorphisms in several candidate genes, (2) the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction, and (3) the state of development of animal models in this matter. We also outline major areas for future research.
    01/2011; 2011:459284. DOI:10.1155/2011/459284
Show more