Association Between Antipsychotic Drugs Receptor Occupancy And Lipid Metabolic Disturbances In First Episode Schizophrenia Patients

BackgroundSchizophrenia patients have a very complex cardiometabolic risk profiles.The risks of cardiovascular disease are increasingly being recognized as a major contributor of mortality and reduced life expectancy in patients with schizophrenia.Approximately 40%of patients with schizophrenia and related disorders have lipid abnormalities,which might be the most prevalent cardio-metabolic risk factors in this population.The prevalence of metabolic syndrome?MetS?in patients with schizophrenia is significantly associated with antipsychotic drugs.Antipsychotic drugs typically exert effects at a variety of neurotransmitter receptors(eg.H₁,M₃,D₂,5-HT_1A,5-HT_2A,5-HT_2C,alpha-1 and alpha-2).Only a few studies currently reported a positive link between receptor affinity/occupancy and weight gain.The associations between antipsychotic receptor profiles and lipid metabolic indices?e.g.,triglycerides,total cholesterol,HDL-C and LDL-C?have not been reported.ObjectiveThe aim in the study was to examine the associations between antipsychotic receptor occupancy and weight gain/lipid profile disturbances in antipsychotic-naive first-episode schizophrenia patients.Methods?1?Studies were identified searching the following databases:PubMed,PsycINFO and Web of Science?1950 to July 2019?.Additionally,references of retrieved articles,related review articles and meta-analyses were manually searched to include relevant articles.The literature with patients under 18 years old was excluded to reduce the confounding effects of sustained weight gain on outcome changes.All articles were independently reviewed,and data were extracted by two reviewers.The main outcome measures were weight gain and lipid metabolism indices.The two-tailed Spearman's rank correlation coefficients?r_s?were used for the correlation analysis and P-values of less than0.05 were considered statistically significant.All analyses were performed using SAS statistical software version 9.4?SAS Institute Inc.,Cary,NC,USA??2?A total of 996 eligible antipsychotic-naive first-episode schizophrenia patients who only accepted one antipsychotic treatment in hospital admission from the Second Affiliated Hospital of Xinxiang Medical University were selected for study from 2008 to 2011 and2015 to 2016.Demographic and clinical data,including age,gender,height,weight,blood pressure,illness duration,the duration of hospitalization,prescribed medication?dose and duration of medication?,and the biochemical indices as well as the time of measurement,were collected from the patients'records and are available for analysis.The two-tailed Spearman's rank correlation coefficients?r_s?were used to estimate the correlations of receptor occupancies of antipsychotics among these receptors.?2 tests were performed to determine if there were differences in categorical variables.Binary logistic regression models were used to estimate the associations between receptors'occupancy and outcomes.All analyses were performed using SAS statistical software version 9.4?SAS Institute Inc.,Cary,NC,USA?.A two-tailed p-value of<0.05 was considered statistically significant.Results1.Data from literature?1?histamine H₁ receptor occupancies were significantly correlated with weight gain per week?6-8W:r_s=0.59,P=0.045;6-12W:r_s=0.53,P=0.029?,as were occupancies for5-HT_1A?6-8W:r_s=-0.77,P=0.003;6-12W:r_s=-0.62,P=0.008?,?₁?6-8W:r_s=-0.81,P=0.003;6-12W:r_s=-0.67,P=0.006?,dopaminergic D2?6-12W:r_s=-0.54,P=0.025?and M₃?6-12W:r_s=0.50,P=0.042?,whereas other receptors occupancies were not.?2?histamine H₁ receptor occupancies were significantly correlated with triglyceridemia gain per week?6-8w:r_s=0.66,p=0.002;6-12w:r_s=0.58,p=0.004?,as were occupancies for M₃?6-8w:r_s=0.58,p=0.010;6-12w:r_s=0.50,p=0.015?and 5-HT_2C?6-8w:r_s=0.58,p=0.010;6-12w:r_s=0.50,p=0.015?,whereas other receptors occupancies were not.?3?The receptors were not correlated with total cholesterol gain,HDL-C gain,and LDL-C gain per week.2.Data from medical records?1?In the multivariate models,in comparison with low histamine H1 receptor occupancies?reference?,Adjusted Odds Ratio?aOR?for weight gain of at least 7%was1.90?95%CI,1.37-2.65?for high histamine H₁ receptor occupancies.Similarly,a positive association was found for muscarinic M₃?1.73,95%CI 1.25-2.40?and serotonin 5-HT_2CC receptor?aOR 1.52,95%CI 1.10-2.11?.Other receptors(5-HT_1A,5-HT_2A,?₁,?₂,D₂)were not associated with weight gain of at least 7%.?2?In the multivariate models,in comparison with low histamine H₁ receptor occupancies?reference?,Adjusted Odds Ratio?aOR?for hypertriglyceridemia was 2.35?95%CI,1.42-3.89?for high histamine H₁ receptor occupancies.Similarly,a positive association was found for muscarinic M₃?2.04,95%CI 1.24-3.34?and serotonin 5-HT_2CC receptor?a OR 1.74,95%CI 1.07-2.83?.Other receptors(5-HT_1A,5-HT_2A,?₁,?₂,D₂)were not associated with hypertriglyceridemia.?3?In the multivariate models,in comparison with low dopaminergic D2 receptor occupancies?reference?,Adjusted Odds Ratio?aOR?for?D3-hydroxybutyric acid less than the median level was 1.96?95%CI,1.40-2.74?for high dopaminergic D₂ receptor occupancies.Other receptors(?₁,?₂,H₁,M₃,5-HT_1A,5-HT_2C)were not associated with lipolysis.Furthermore,high levels of serotonin 5-HT_2AA receptor occupancy require further research.Conclusions?1?Exposure to high level of receptors'occupancy(histamine H₁,muscarinic M₃,and serotonin 5-HT_2CC receptors)was associated with increased risk of weight gain of at least7%and hypertriglyceridemia among drug-na?ve FES patients.In addition,serotonin5-HT_1A,5-HT_2A,adrenergic?₁,?₂ and dopaminergic D₂ receptors were not associated with the risk of weight gain of at least 7%and hypertriglyceridemia.?2?High level of dopaminergic D₂ receptor occupancy may suppress lipolysis,other receptor(?₁,?₂,H₁,M₃,5-HT_1A,5-HT_2C)were not associated with lipolysis.Moreover,high levels of serotonin 5-HT_2Areceptor occupancy require further research.