Association of orexin receptor polymorphisms with antipsychotic-induced weight gain

<p><i>Objectives</i>: Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG. <i>Methods</i>: Schizophrenia or schizoaffective disorder subjects (<i>n</i> = 218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (<i>n</i> = 122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates. <i>Results</i>: Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (<i>P</i><0.05). In the replication analysis two SNPs rs3134701 (<i>P</i> = 0.043) and rs12662510 (<i>P</i> = 0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG. <i>Conclusion</i>: This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples.</p

Impact of histamine receptors H1 and H3 polymorphisms on antipsychotic-induced weight gain

<p><b>Objectives:</b> A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG.</p> <p><b>Methods:</b> We analysed 40 tagSNPs in HRH1 (<i>n</i> = 34) and HRH3 (<i>n</i> = 6) in schizophrenia/schizoaffective disorder patients (<i>n</i> = 193) primarily treated with clozapine or olanzapine for up to 14 weeks. Linear regression was used to evaluate the association between SNPs and AIWG, with baseline weight and treatment duration as covariates.</p> <p><b>Results:</b> In HRH1, a nominal association of rs7639145 with AIWG was observed in patients of European ancestry treated with either clozapine or olanzapine (<i>P</i>= 0.043; β = 1.658; <i>n</i> = 77). We observed nominal association for two HRH1 SNPs rs346074 (<i>P = </i>0.002; β = –5.024) and rs13064530 (<i>P</i>= 0.004; β = –5.158) in patients of African ancestry treated with either clozapine or olanzapine (<i>n</i> = 37). However, the above associations are not significant after correcting for multiple testing. In HRH3, we did not observe association in either ancestry.</p> <p><b>Conclusions:</b> The current study suggests that SNPs in HRH1 and HRH3 may not have a major role in AIWG.</p