| Objects1. To assess the effects of antipsychotic agents therapy on weight gain and abdominal fat deposition and distribution, on circulating leptin and insulin secretion in previously untreated patients with schizophrenia.2. To investigate whether antipsychotic agent-induced weight gain was associatited with 5-HTR2A receptor gene -1438G/A polymorphism , leptin gene -2548G/A functional polymorphism and Histamine H1 receptor 755G/T polymorphism in previously untreated Chinese Han schizophrenic subjects in trios, and to understand the interaction between 5-HTR2A receptor gene and leptin gene in APS -induced weight gain in schizophrenic patients .MethodsPart one46 Chinese Han untreated patients with schizophrenia with matched health controls (n=38) were recruited. Abdominal body fat was determined by magnetic resonance imaging(MRI), before and after 10 weeks' antipsychotic drug treatment. Body mass index(BMI), fasting and 2-hour postload plasma glucose, fasting blood concentrations of lipids, insulin and leptin were also measured.Part twoSchizophrenic patients was treated with risperidone or chlorpromazine for 10 weeks. Abdominal body fat was determined by MRI in 39 patients on admission and after 10 weeks treatment. Body weight and BMI was measured on admission and every week subsequently for all the subjects. The polymorphism of leptin gene and 5-HTR2A receptor gene was determined with PCR-RFLP technique in patients and their parents. Both case-control association study and family-based association study, including haplotype relative risk( HRR); transmission disequilibrium test( TDT ) and quantitative transmission disequilibrium tests(QTDT), were used. ResultsPart oneAs compared with the controls, untreated patients had no significantly differences in weight and body fat indicators and plasma levels of leptin as well (all P>0.05). However, after 10 weeks antipsychotic agents treatment, significant increase in body weight, BMI, SUB, IAF and the increased blood levels of 2-hour postload plasma glucose, triglycerides, cholesterol, LDL, insulin and leptin were identified(all P<0.05). In addition, increased SUB was inversely correlated with initial and 10 weeks after treatment leptin levels in plasma in the patients (P<0.05).Part two(1) No differences in genotypes(x2=0.172, v1, P>0.05) and allele(x2=0.121, vl, P>0.05) frequencies of-1438G/A polymorphism of 5-HTR2A gene were observed between subgroups. It was also found no significantly difference in weight gain between genotype group .(2) There were significant differences in the distribution of allele frequencies(x2=4.031, vl, P=0.045; OR=2.182; 95%CI: 1.009-4.772) but not in genotypes between the subgroups, which was further confirmed by HRR and TDT analysis. As compared with the patients with -2548AG/GG combined genotype, the patients with AA genotype had significant increase in weight (t=2.069, P=0.042) and SUB (t=2.58, P=0.014) .By using the QTDT, we can not found significant results for association or linkage between leptin gene and weight gain.(iii) In this study, we did not identify 755G/T polymorphism at Histamine H1 receptor gene in Chinese Han population.(iv) No evidence was found for the interaction between 5-HTR2A gene and leptin gene in APS-induced weight gain. ConclusionsPart onePatients first receiving antipsychotic drugs experience substantial weight gain, along with increased in levels of fasting lipids and 2-hour postload plasma glucose,which may provide early signs of drug-inducedmetabolic syndrome. And deposition of both subcutaneous and intra-abdominal fat reflect a loss of the normal inhibitory control of leptin on body mass.Part two(i) 5-HTR2A gene -1438G/A polymorphism was probably not associated with APS-induced weight gain in schizophrenic patients in this study.(ii) The -2548G/A polymorphism in promoter region of leptin gene associated with APS-induced weight gain and abdominal fat deposition and distribution. -2548A allele of leptin gene may be a genetic... |
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