Cigarette Smoking,Coffee Consumption,Alcohol Intake,and Clozapine Metabolism:A Mendelian Randomization Study

Objective: Clozapine is an effective medication for treating treatment-resistant schizophrenia,but its concentration must be carefully monitored to avoid adverse reactions or suboptimal efficacy.However,the factors that influence clozapine drug concentration remain incompletely understood.Prior research has suggested that substance dependence factors,such as nicotine,alcohol,and coffee,may impact clozapine drug concentration,but this relationship has not been definitively established.Therefore,this study aims to employ Mendelian randomization analysis to explore the causal relationship between substance dependence factors and clozapine drug concentration.Methods: This study selected six substance dependence factors as exposure factors,including age of smoking initiation,cigarettes per day,smoking cessation,smoking initiation,coffee consumption,and alcohol consumption.Based on the previous genome-wide association study(GWAS)data on substance dependence-related factors,six single nucleotide polymorphisms(SNPs)related to substance dependence factors were screened and used as instrumental variables(IVs)for exposure factors.At the same time,this study used clozapine concentration,norclozapine concentration,and the ratio of clozapine to norclozapine as outcome variables.The GWAS data for clozapine and its metabolites were obtained from the CLOZUK consortium.This study used Mendelian randomization analysis to explore the relationship between the six substance dependence factors and clozapine concentration,norclozapine concentration,and the clozapine/norclozapine ratio.The main analysis methods included inverse-variance weighted(IVW),weighted median method,and MR-Egger.Sensitivity analysis was also performed to test for SNP heterogeneity and horizontal pleiotropy,and the Mendelian randomization evaluation results for each gene were combined.Results: Based on the Mendelian analysis results,this study found that early smoking initiation significantly reduced clozapine concentration(Beta=-0.14,P= 4.53E-04)and norclozapine concentration(Beta=-0.14,P= 3.33E-04).The results also showed that increased coffee consumption significantly reduced plasma clozapine concentration(Beta=-0.42,P= 1.70E-14),norclozapine concentration(Beta=-0.27,P=1.51E-07),and the ratio of clozapine to its metabolites(Beta=-0.15,P= 5.35E-07).All significant results passed Bonferroni multiple testing correction(P< 0.008).Sensitivity analysis using the weighted median and MR-Egger methods showed that the effects of early smoking initiation and coffee consumption on clozapine and its metabolites were consistent with the Mendelian randomization analysis results.In addition,sensitivity analysis did not detect significant horizontal pleiotropy or heterogeneity(P>0.05).However,other addiction substance use indicators,such as age of smoking initiation,cigarettes per day,smoking cessation,and alcohol consumption,did not have a significant causal relationship with clozapine and its metabolites.Conclusion: Individuals who start smoking early and consume large amounts of coffee need to pay close attention to clozapine drug concentration,as the concentration of clozapine and its metabolites may be lower in these populations.These study results can guide clinical physicians in adjusting treatment plans to ensure that patients achieve the best treatment outcomes.