Dynamic Observations And Genetic Association Analyses On Antipsychotics Induced Obesity,Dyslipidemia And Glucose Metabolism Abnormalities

ObjectiveAtypical antipsychotic drugs(AAPD)induced obesity,dyslipidemia and abnormal glucose metabolisms are serious problems in the treatment of mental disorders.The antipsychotic-induced weight gain(AIWG)is closely related to genetic factors,hower,AIWG and simple obesity are not exactly the same.The mechanism of AIWG related changes in glucose and lipid metabolisms has not been fully elucidated.In this study,we tracked 27 body weight,glucose and lipid related phenotypes after single AAPD intervention.These phenotypes were compared among first-episode patients(FEP),non first-episode patients(NFEP),and different AAPDs.Before receiving intervention of antipsychotic drugs,psychiatric patients might have some abnormal metabolisms.In order to decipher the relationships between psychosis and antipsychotics on the metabolism,we compared glucose and lipid metabolism phenotypes between FEP and healthy controls.There are significant individual differences in AIWG,which may due to different genetic backgrounds.On the other hand,only a few studies focused on the difference of genetics backgrounds between AIWG and simple obesity.In order to find the genetic markers related to AIWG,we analyzed associations among candidate gene SNPs and 160 quantitative traits in AIWG subjects.MethodsA total of 339 patients including 86 FEPs meeting the entry criteria were collected.In addition,88 normal healthy controls that matched with FEP in age and gender were recruited.All patients received a single AAPD intervention according to the clinical treatment need.One hundred thirty one(131)patients received olanzapine(OLA)treatment,while 133 patients took risperidone(RIS).Patients were followed up for 12 weeks.All patients were measured for body weight,waist,abdominal and hip circumferences at baseline,and at weeks 2,4,6,8 and 12 after the treatment.Body mass index(BMI)and waist to hip ratio(WHR)were calculated.Before and after treatment for 4,8 and 12 weeks,triglyceride(TG),high density lipoprotein(HDL),low density lipoprotein(LDL),total cholesterol(Chol),total protein(TP),albumin(ALB),fasting plasma glucose(FPG),blood creatinine(CRE),urea nitrogen(urea),Ur/Cr,serum C reactive protein(CRP),prolactin(PRL),T3,T4 and thyroid stimulating hormone(TSH)were measured for all patients.In addition,baseline plasma fasting insulin(FINS),homocysteine cysteine(Hcy),adiponectin(ADP),brain-derived nerve neurotrophic factor(BDNF)and leptin(LEP)in all the FEP were measured by enzyme linked immunosorbent assay(ELISA).At the same time,body weight and metabolism phenotypes were detected in all normal controls.The dynamic changes of each index from all patients that receiving treatment of a single AAPD were analyzed using MANOVA;Differences between FEP and NFEP,and patients accepting OLA or RIS were compared by Student’s t-test.Spearman correlation and multiple regression analyses were performed to identify factors that correlated with AIWG.Candidate genes in this study mainly came from a comparative whole genome association analysis(GWAS)for Caucasian obesity-AIWG subjects,which carried out by our project team members and colleagues.Genotyping of all SNPs were performed by Matrix assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF-MS).Quantitative genetic association and gene-gene interaction analyses were carried out in all patients,the FEP group,the OLA treatment group and the RIS treatment groupusing PLINK.Results1.TG,TP and ALB levels in the FEP group were significantly lower than healthy controls at baseline(P<0.001),while SBP and DBP were significantly higher(P<0.001);FINS and HOMA-IR were significantly higher(P<0.001),QUICKI,HOMA-ISI and G/I significantly reduced(P<0.001),suggesting insulin resistance in the FEP group;Plasma ADP decreased significantly in FEP group(P=0.023).2.There were significant influences on the body weight,BMI and WHR in psychiatric patients by the AAPD.Just after 2 weeks treatment,all body weight traits increased significantly,and continued to increase till the end of study.In groups of FEP and OLA,bodyweight,BMI and WHR increased more significantly than those patients in groups NFEP and RIS.At baseline,there was a significant difference in body weight between FEP and NFEP(P<0.01),while no significant difference was found between the two groups in other indicators.3.After AAPD,the TP,ALB and CRE treatments,psychiatric patients have significant changes in clinical characteristics among different testing time;By the end of 4 weeks,psychiatric patients yielded significant changes in lipid profiles: TG and LDL increased,while HDL,TP and ALB decreased significantly.Compared to non first-episode patients,LDL levels of the first-episode patients increased significantly at the 12 th week(P=0.045);Compared to the RIS treatment group,LDL levels in the OLA group increased dramatically by the end of the 4th week(P<0.001).At the beginning of the treatment,CHOL of the patients taking OLA were significantly higher(P=0.003).FPG in all patients were significantly decreased after AAPD treatments,however,FPG began to rise after 8 weeks.4.First-episode and the type of antipsychotic drugs may closely related to the AIWG.Age,sex and baseline BMI might not related to AIWG.Baseline T4 and WHR were negatively correlations to AIWG,correlation coefficients were-0.154 and-0.199,respectively.Correlations remained significant after multiple regressions analyses.5.In our candidate gene association study,the BDNF gene SNP rs6265(P=0.002),BDAF gene SNP rs11030104 SNP(P=0.001),ADIPOQ gene SNP rs822396(P=0.003),and rs1501299(P=0.040)were associated with the change of WHR,meanwhile,consistent results were found for those SNPs in the OLA group.The TOX gene SNP rs11777927(P=0.009)and the ADIPOQ gene rs182052(P=0.019)were significantly associated with AIWG,CDKN2A/B gene SNP rs3731245(P=0.04)and rs2811708 SNP(P=0.039)were also associated with the AIWG;CDKN2A/B gene associations with AIWG remained significant in FEP and RIS groups.These results were still significant after age adjustments.6.Changes of lipid profiles(LDL,HDL and CHOL)after AAPD treatment were associated with a PKHD1 gene SNP rs9395706.CDKN2A/B gene SNP rs3731245 was associated with the FPG changes that induced by OLA(P=0.009).Results remained significant after age adjustment.7.Compared to patients that carried rs3731245 genotypes CC and CT,BMI of patients with the TT genotype increased more significantly(P<0.05);compared to the patients that carried the rs2811708 G allele,the BMI of the patients with the rs2811708 TT genotype increased significantly after the treatment of AAPD(P<0.05).8.Gene×gene interaction analyses showed significant epistasis among MTHFR and PCAF,EPB41L4 A,and LEPR,EPB41L4 A and TMEM18,ADIPOQ and CDKN2A/B,ADIPOQ and NRXN3,TOXand PKHD1,TOX and RPTOR,MC4 R and COMT gene SNPs for AIWG(ΔBMI)in all patients.Conclusion1.In our study,we found that there were metabolic changes in psychiatric patients even before AAPD treatments.TG,TP and ALB were significantly lower,while SBP and DBP were significantly higher.Psychiatric patients were more insulin resistance compared with healthy controls.Besides,the level of adiponectin was significantly lower in psychiatric patients when compared with healthy controls.2.Antipsychotics induced obesity,dyslipidemia,and glucose metabolisms were different from simple obesity.By the end of the 2nd week after AAPD intervention,body weight related traits increased significantly,while significant changes in lipid profiles(LDL,HDL,TG,etc.)could only be detectedby the end of the 4th week.FGP showed a decrease at beginning and then a rise afterwards.These changes were more significant in first-episode patients and patients receiving olanzapine.It is suggested that AAPD might have a long-term effect on patients’ weight gain.3.Baseline T4 and WHR levels were negatively correlated with changes in body weight after taking AAPD,and could be used as predictors of weight change after AAPD treatments.4.Genetic factors of AIWG could be different from simple obesity.We could not find associations for AIWG in some well-known obesity genes,such as FTO and MC4 R.ADIPOQ,TOX and CDKN2A/B gene polymorphisms were significantly associated with AIWG;ADIPOQ,BDNF and BDAF gene SNPs were significantly associated with the change of WHR;PKHD1 gene was significantly associated with the changes of lipids that induced by AAPD.