Pharmacogenetics of schizophrenia

Abstract

Patients display significant differences in response to therapeutic agents which may be caused by a variety of factors. Among them, genetic components presumably play a major role. Pharmacogenetics is the field of research that attempts to unravel the relationship between genetic variation affecting drug metabolism (pharmacokinetic level) or drug targets (pharmacodynamic level) and interindividual differences in pharmacoresponse. In schizophrenia, pharmacokinetic studies have shown the role of genetic variants of the cytochrome P450 enzymes CYP2D6, CYP2C19, and CYP2C9 in the metabolism of neuroleptic drugs. At the level of the drug target, variants of the dopamine D3 and D4, and 5-HT2A and 5-HT2C receptors have been examined. A general problem of pharmacogenetic studies in schizophrenia is the high number of controversial findings which may be related to the lack of standardized phenotype definition. Recently, guidelines for an exact and comparable phenotype characterization have been proposed and will aid in designing and evaluating pharmacogenetic studies in the future. The final goal of pharmacogenetic studies-making a prediction of drug response at the level of the individual patient-will require a simultaneous look at a large number of response-determining genetic variants by applying the tools of pharmacogenomics, e.g. large-scale Single Nucleotide Polymorphism (SNP) detection and genotyping.

Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies

“…Several prior association studies have examined the relationship between 5-HT 2A receptor SNPs and atypical antipsychotic drug response. 11,34 Most of the patients in the aforementioned studies met the criteria for treatment refractoriness or intolerance to typical antipsychotic therapy. 35 The H452Y variant is the most widely studied 5-HT 2A receptor SNP.…”

The Impact of Drug and Gene Interaction on the Antipsychotic Medication for Schizophrenia

“…Since genetic factors influence the phenotypic responses to drugs, an increasing number of researchers are involved in identifying schizophrenic genetic factors for the disorder and treatment responses for commonly known neuroleptic drugs [15,16]. This is where the field of pharmacogenetics plays a major role.…”

“…Pharmacogenetics focuses on the relationship between the pharmacokinetic level or the pharmacodynamic level and interindividual differences [15]. The pharmacokinetics focuses on the way drugs being metabolized based on individual genetic differences, while pharmacodynamics is to elucidate the differences in responses among individuals [15]. Pharmacogenetics also focuses on variations found in the human genome and in the different ways in which individuals respond to drugs based on genetic factors [17].…”

“…Despite the fact that there is a large variety of available medications, as many as 30-50% of the patients with treatment of antidepressants and antipsychotics will not adequately respond to treatment [16]. In order to predict drug response at the personal level, genetic variants that determine drug effects need to be identified [15]. Therefore, pharmacogenetics is to understand individual differences within humans to help identify potential variants in order to help formulate an individualized care for patients using antipsychotic medications [8].…”

Farmacogenética de inibidores seletivos de recaptação de serotonina: uma revisão

“…Mais de 70 variações neste gene já foram identificadas, embora apenas algumas possuam relevância clínica. Exemplos são os alelos CYP2D6*3A, CYP2D6*4B, CYP2D6*5, os quais estão relacionados com o fenótipo de metabolizadores lentos, e o alelo CYP2D6*2, relacionado com o fenótipo de metabolizadores rápidos 21,22 . A freqüência com que esses fenótipos ocorrem é bastante variável dentre diferentes etnias, podendo variar de 1% da população em asiáticos, até 8% em africanos, para metabolizadores lentos, e de 1% em Suecos a 29% em Africanos, para metabolizadores rápidos (Tabela 1).…”