Genetic determinants of antipsychotic drug response

Abstract

Since their introduction, the use of antipsychotic drugs has been complicated by adverse effects. While the first generation of antipsychotic agents mainly caused motor side effects, the newer antipsychotic drugs are also associated with metabolic disturbance such as diabetes and obesity. The introduction of pharmacogenetics into antipsychotic treatment may be a promising way to improve both safety and effectiveness of therapy. The main objective of the first section of this thesis was to investigate pharmacodynamic polymorphisms as determinants of metabolic disturbances during treatment with atypical antipsychotic agents. The main objective of the second section was to investigate pharmacokinetic genetic polymorphisms as a determinant of the success rate in antipsychotic treatment and the consumption of psychiatric care. The results of the first section showed associations of the LEPR Q223R and LEP -2548 polymorphisms with obesity and dyslipidemia, dependent on other variables such as sex of the subjects, duration of treatment history and on variation in other genes (HTR2C). No convincing associations were found in a study investigating these genotypes with eating behaviour. In the second section, CYP2D6 and CYP2C19 were the two polymorphous enzymes that were investigated, because of the fact that these enzymes play an important role in the metabolism of psychotropic medication and the activity of these enzymes is to a large extent influenced by frequently occurring genetic polymorphisms. Patients were in order of increasing enzyme activity classified as poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM). An association was found of the CYP2D6 UM phenotype with length of hospitalization. Admission of patients with the CYP2D6 UM phenotype lasted twice as long (median 56 days) compared with admissions of patients with the CYP2D6 EM (median 27 days) or CYP2D6 IM phenotype (median 22 days). The CYP2C19 polymorphisms were also associated with the length of hospitalization in patients who were using an antidepressant or antipsychotic drug. CYP2D6 phenotypes were also investigated as a determinant of the success of antipsychotic treatment in a case control design, considering the use of clozapine as a proxy for non response to antipsychotic drugs of first choice. Since clozapine is prescribed only when at least two previous drug therapies were clinically unsuccessful, patients who were treated with clozapine were classified as “non-responders”. The results of this study suggested that CYP2D6 phenotype may not be a major determining factor for patients to be switched to clozapine treatment, however, a trend was observed, suggesting an inverse association between CYP2D6 activity and non-reponse. In addition the results suggest that further research is needed with a focus on the clinical consequences of the CYP2D6 ultra rapid metabolizer phenotype. In the general discussion, the findings of the thesis are placed in a broader perspective, focusing on the differences of the development of pharmacogenetic tools between pharmacodynamics and pharmacokinetics, the relevance of including non-genetic physiological determinants in pharmacogenetic research and on ethical considerations in biobanks for pharmacogenetic research. Finally, some suggestions are done on future perspectives and implications for professional roles of pharmacists, clinical chemists and physicians.