Genetic determinants for metabolic abnormalities

Abstract

Psychiatric patients often use psychotropic drugs. Apart from frequent problems regarding lack of efficacy, use of these drugs also often results in (severe) adverse effects. The use of (atypical) antipsychotic drugs in particular can give rise to weight gain and metabolic deregulation regarding glucose metabolism and lipolysis, resulting in an increased morbidity and mortality in these patients. However, not all patients experience these adverse effects to the same extent. This interindividual variability suggests that genetic susceptibility plays an important role. The studies in this thesis have investigated the potential impact of polymorphisms in the ADRA2A and HTR2C genes, coding for the adrenergic α2A- and serotonergic 5HT­2C-receptors respectively, on metabolic complications in patients with and without psychotropic drugs. Comparing the effects of these polymorphisms on metabolic complications between these groups of patients adds to understanding the potential modifying role of psychotropic medication on the impact of the investigated polymorphisms. The studies in this thesis show that the HTR2C 759 C/T polymorphism has been associated with prevalence of obesity in patients without antipsychotic drugs and antipsychotic-induced weight gain. Carriership of the variant 759 T-allele resulted in a more favorable metabolic profile regarding these endpoints, which appears to be independent of antipsychotic drugs. The HTR2C rs1414334 polymorphism has been associated with prevalence of the metabolic syndrome in patients using antipsychotic drugs and triglyceride concentrations in patients with and without psychotropic drugs. Carriership of the variant rs1414334 C-allele resulted in an increased prevalence of the metabolic syndrome and increased triglyceride concentrations. The effects of the rs1414334 polymorphism on triglyceride concentrations appears to be independent of antipsychotic drugs. The effects of this polymorphism on prevalence of the metabolic syndrome in patients without psychotropic drugs has not yet been investigated. Carriership of the variant 1291 G-allele of the ADRA2A 1291 C/G polymorphism appeared to be protective for the metabolic syndrome in schizophrenic patients without antipsychotic drugs at the time of the study and was associated with lower concentrations of LDL cholesterol in obese patients without psychotropic drugs. Both associations require further study. Although the genotypes of the investigated polymorphisms contribute to increased or reduced metabolic risks, these genotypes alone do not fully explain the complex metabolic abnormalities. However, combined with other potentially relevant polymorphisms (e.g. within the leptin or histaminergic system) and relevant patient factors it may be possible to take steps in the future towards the development of algorithms that can be tested in clinical practice. If these algorithms accurately predict a patients metabolic risk, using these algorithms in clinical practice might result in a better treatment regarding efficacy and occurrence of adverse effects.