Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Ruaño, Gualberto; Goethe, John W.; Caley, Charles F.; Woolley, Stephen B.; Holford, Theodore R.; Kocherla, Mohan; Windemuth, Andreas; León, José de

doi:10.1038/sj.mp.4001944

Cited by 58 publications

(45 citation statements)

References 60 publications

(56 reference statements)

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“…307 As the first marketed atypical antipsychotics are becoming off-patent and less expensive generic forms are available, it is also possible that pharmacogenetic testing for weight gain may become cost-effective. 308 In summary, the authors believed that future tests predicting antipsychotic response may need to include clinical and genetic variables to classify patients more accurately.…”

Section: Prediction Of Side Effectsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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Section: Prediction Of Side Effectsmentioning

confidence: 99%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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“…The association between AgRP, fat mass and appetite have been examined and were found to be disrupted in olanzapine-treated patients, but not in patients treated with ziprasidone [132]. Although an early study by Ruano and colleagues reported that a polymorphism (rs1468271) in the NPY gene had no association with body weight gain in patients treated with olanzapine and risperidone [133], a recent study by Tiwari and colleagues suggested a significant association between the SNPs rs16147, rs5573, and rs5574 in NPY and weight gain in clozapine and olanzapine-treated patients [134]. The same authors also revealed an association of rs6837793, near NPY 5 R, with the weight gain profile in patients treated with risperidone, which supported the role of the NPY system in SGAinduced weight gain.…”

Section: The Role Of Npy and Agrp In Sga-induced Weight Gainmentioning

confidence: 99%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

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“…A subsequent 9-month study in 75 neuroleptic-naïve Spanish schizophrenia patients found that the 2448A polymorphism did not predict short term weight gain (over 6 months), but was associated with 9 month weight gain (Templeman et al, 2005). Most recently, 29 single nucleotide polymorphisms (SNP) from 13 candidate genes were examined in a cross-sectional study of 67 olanzapine-and 101 risperidone-treated patients, including a SNP in the leptin receptor gene (rs8179183) associated with body weight in nonpsychiatric subjects (Ruano et al, 2007). Among this group of genetic markers, the leptin receptor SNP rs8179183 was found to have the strongest association with weight, and was significantly associated with weight profiles for the risperidone cohort (p<.001).…”

Section: Genetic Studiesmentioning

confidence: 99%

Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin

Jin

Meyer

Mudaliar

et al. 2008

Schizophrenia Research

131

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Background-Many adverse effects of atypical antipsychotic treatment are associated with antagonism of monoamine receptors; however, data indicate that important metabolic effects, such as hypertriglyceridemia and impairment in glucose/insulin homeostasis, may not be related to these mechanisms, leading investigators to explore alternative hypotheses. Promising candidates include a possible impact of antipsychotics on peptide hormonal regulators of metabolic control such as leptin, ghrelin, and adiponectin. The purpose of this review is to summarize recent data on changes in these hormones during atypical antipsychotic treatment.

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Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Cited by 58 publications

References 60 publications

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin

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