Studies on the association between genetic polymorphisms and clozapine drug response in treatment resistant schizophrenia

Abstract

Schizophrenia is a severe disabling neuropsychiatric disorder. It is almost equally prevalent in all societies around the world. The lifetime prevalence of schizophrenia is estimated around 1%. It affects men and women equally. It often starts in adolescence or in early adulthood and follows a chronic or episodic course. This research evaluated the clinical and pharmacogenetic associations predicting response to clozapine among patients with Treatment-resistant schizophrenia. A combined clinical and pharmacogenetic model was developed to predict response to clozapine. A nonparametric equation to predict serum clozapine levels, using clinical proxy measures, was also developed. The importance of varying outcome definitions for response to treatment in schizophrenia, while evaluating the pharmacogenetic associations, was demonstrated. Despite clozapine s superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost as well as variable clinical outcomes mandate a clinical need to predict its treatment response. Cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine. Antagonism of serotonin 5HT3A receptor contributes to the superior clinical efficacy of clozapine. Hence, this research investigated the associations between various clinical variables, four single nucleotide polymorphisms in CYP1A2 gene (rs2069514, rs35694136, rs2069526 and rs762551) as well as two SNP in HTR3A gene (rs1062613 and rs2276302) and treatment responses as well as adverse events of clozapine in patients with TRS. There is a need for reliable consensus research criteria to define treatment responses for future pharmacogenetic studies of schizophrenia. Such consensus criteria should go beyond a narrow focus on positive psychotic symptoms to incorporate global assessments of outcome, including cognition, functional disability and quality of life. newline newline