Cardiovascular risk factors and pharmacogenetics of clozapine in schizophrenia

Sammanfattning: Background: Severe mental illness, including schizophrenia is associated with an increased risk of premature death by somatic conditions and in particular by cardiovascular events. Reducing cardiovascular risk factors in patients with psychotic disorder is urgently called for. Aim: This thesis describes frequencies of cardiovascular risk factors among patients with psychosis. Clinical and genetic factors affecting plasma concentration of clozapine and their respective relation to increased fasting glucose and waist circumference are evaluated. In the last part of the thesis, levels of three biomarkers associated with cardiovascular risk are determined among patients with psychosis. Methods: In two papers (Studies I and III), patients with psychosis recruited from outpatient clinics in Stockholm County Sweden were compared to non-psychotic control subjects from the population. Clinical and genetic factors related to plasma concentration of clozapine were explored in a sample of 113 patients on clozapine treatment (Study II). In one study (Study III), pharmacological treatment of diabetes was compared between 977 patients with psychosis and 3908 control subjects. In patients with psychosis and diabetes, factors associated with pharmacological treatment of diabetes were determined. In the last manuscript (study IV), levels of the biomarkers hsTnT, hsCRP and NT-BNP were determined in 300 patients with psychotic disorder. Results: Psychosis was associated with higher fasting glucose levels, increased waist circumference and higher frequency of smoking compared to controls. Furthermore, 50 percent of patients with psychosis fulfilled the criteria for metabolic syndrome. Both prediabetes and diabetes were approximately three times more frequent among patients with psychosis as compared to controls. Of patients with psychosis and prediabetes 77 percent also fulfilled the criteria for metabolic syndrome. Genetic variants of CYP1A2 and MDR1, and smoking were associated to lower plasma concentrations of clozapine. Levels of biomarkers, in previous studies associated with elevated cardiovascular risk, were elevated above reference values in patients with psychosis. Conclusion: Reduced conversion from prediabetes to manifest diabetes is proposed as a treatment goal for patients with psychosis. Regular therapeutic drug monitoring is advised when clozapine is used. Longitudinal evaluation of biomarkers of cardiovascular risk would add valuable information to the clinician caring for patients with psychosis.