Exploring The Potential Predictive Value Of Bilirubin-Related Indexes In Lipid Disturbances Of Schizophrenia

Background and aim: Schizophrenia is a devastating brain disorder that affects approximately 1% of the population worldwide.With beneficial effects and compliance,atypical antipsychotic drugs(AAPD)have rapidly become the first-line clinical drug to treat schizophrenia.However,schizophrenia gradually develops abnormal glucose and lipid metabolism when receiving AAPD,and they have a strong possibility to suffer from type 2 diabetes,obesity,and metabolic syndrome compared to the normal population.Therefore,it is an urgent problem to be solved in the clinical treatment of schizophrenia that includes predicting the risk of metabolic disorders,contracting comorbid diseases,and improving quality of life.Recent studies suggested that bilirubin has antioxidant effects and lipid metabolism-regulating effects in vitro and in vivo,and associated with many metabolic disorders.Based on this,this study retrospectively studied the relationship between serum bilirubin levels,AAPD,and lipid metabolism parameters in patients with schizophrenia,and prospectively explored the predictive value of bilirubin metabolism-related gene mutations on the risk of lipid metabolism disturbances to provide a theoretical basis for the rational and accurate clinical selection of AAPD.Methods: This study is divided into retrospective analysis and genetic analysis.Inclusion criteria: patients diagnosed with schizophrenia according to DSM-5 diagnostic criteria;age 18-65 years old;female without pregnancy;never smoking or alcoholism;without severe liver diseases,such as viral hepatitis,other liver cirrhosis,drug-induced liver damage,and liver cancer;receiving AAPD for ≥2 weeks;without AAPD treatment for ≥1 month before admission;ALT and AST<100 IU/L,TBIL< 34.2 μmol/L.The clinical data of 603 patients with schizophrenia were retrospectively analyzed.The Kruskal–Wallis H test or the Mann–Whitney U test were used to analyze the differences between the groups,including the differences in the biochemical parameters of seizure frequency subgroups,the effect of AAPD on schizophrenia,and the effect of bilirubin levels in patients,as well as the correlation analysis of bilirubin and lipid metabolism parameters.A total of 349 patients with schizophrenia were analyzed to collect clinical data and obtained blood samples on admission.Bilirubin metabolic regulation genes(HMOX1,UGT1A1,SLCO1B1)and lipid metabolism pathway genes(PGRMC1,INSIG1,INSIG2,SREBP1,SREBP2)were sequenced by multiplex PCR target capture technology.The Kruskal–Wallis H test or Mann–Whitney U test was used to analyze the effects of gene mutations on the relevant biochemical levels,and generalized multifactor dimensionality reduction(GMDR)software was used to analyze the gene interaction between bilirubin metabolism genes and lipid metabolism pathway genes.Logistic regression analysis was used to analyze the value of bilirubin levels and common gene mutations on lipid metabolism disturbances.Results: retrospective analysis shows results as follows:1.The risk of lipid metabolism disorder in male schizophrenia patients was 21.6%,which was higher than that in female schizophrenia patients,which was 13.16%.2.Considering the number of episodes in schizophrenia comprehensively,bilirubin and triglycerides were different in both subgroups of male and female schizophrenia.However,as the number of episodes(≥4)increased,schizophrenia bilirubin levels decreased,while triglyceride levels increased.3.AAPD type and mode of administration(alone or in combination)had no significant effect on the three bilirubin levels,but bilirubin levels decreased after accepting AAPD treatment.4.Schizophrenia patients have a significantly increased risk for elevated triglycerides and decreased HDL-CH,especially decreased HDLCH.About 80% of male schizophrenia patients and about 50% of female schizophrenia patients are changed.5.In both male and female schizophrenia patients with bilirubin levels in patients without lipid metabolism disturbances were higher than those in patients with lipid metabolism disturbances.Three bilirubin levels in female schizophrenia patients and direct bilirubin in male schizophrenia patients were significantly different between the two groups.Genetic analysis shows results as follows:1.There is no interaction between the number of seizures and bilirubin metabolism gene polymorphisms and lipid metabolism gene polymorphisms,and the number of seizures has no effect on total bilirubin and TG,while the genetic polymorphism affects the above two.2.Genetic polymorphism in lipid metabolism had no significant effect on lipid metabolism parameters,and there was no gene-gene interaction with bilirubin metabolic regulation genes.3.UGT1A1*6 variants were significantly associated with increased bilirubin levels,especially total bilirubin levels.The mutant type of bilirubin gene has a lower probability of lipid metabolism disturbances than the wild type,especially in male schizophrenia,and the mutant type with lipid metabolism disturbances is about 50% compared to the wild type.This phenomenon was not found in female schizophrenia patients.4.Logistic regression analysis showed that bilirubin genetic polymorphism was a protective factor for lipid metabolism disturbances,especially UGT1A1*6 mutations.And women in this subgroup have little opportunity to develop lipid metabolism disturbances.In the moderately abnormal subgroup,UGT1A1*6 mutation was a protective factor in lipid metabolism disturbances.Conclusion: Bilirubin levels in schizophrenia patients were negatively correlated with lipid metabolism parameters,especially TG and CHOL.AAPD type and mode of administration(alone or combination)had no significant effect on the three bilirubin levels.The mutant type of bilirubin gene has a lower probability of abnormal lipid metabolism than the wild type,especially in male schizophrenia,which suggests that bilirubin levels in men may be more closely related to lipid metabolism disturbances.Higher levels of bilirubin have a certain protective effect on preventing lipid metabolism disturbances,and UGT1A1*6 variation has played a role in protecting lipid metabolism parameters in schizophrenia patients.