Pharmacogenetics Of Antipsychotics Research Articles

Pharmacogenetics of antipsychotics: Clinical utility and implementation

Decades of research have produced extensive evidence of the contribution of genetic factors to the efficacy and toxicity of antipsychotics. Numerous genetic variants in genes controlling drug availability or involved in antipsychotic processes have been linked to treatment variability. The complex mechanism of action and multitarget profile of most antipsychotic drugs hinder the identification of pharmacogenetic markers of clinical value. Nevertheless, the validity of associations between variants in CYP1A2, CYP2D6, CYP2C19, ABCB1, DRD2, DRD3, HTR2A, HTR2C, BDNF, COMT, MC4R genes and antipsychotic response has been confirmed in independent candidate gene studies. Genome wide pharmacogenomic studies have proven the role of the glutamatergic pathway in mediating antipsychotic activity and have reported novel associations with antipsychotic response. However, only a limited number of the findings, mainly functional variants of CYP metabolic enzymes, have been shown to be of clinical utility and translated into useful pharmacogenetic markers.Based on the currently available information, actionable pharmacogenetics should be reduced to antipsychotics’ dose adjustment according to the genetically predicted metabolic status (CYPs’ profile) of the patient. Growing evidence suggests that such interventions will reduce antipsychotics’ side-effects and increase treatment safety. Despite this evidence, the use of pharmacogenetics in psychiatric wards is minimal. Hopefully, further evidence on the clinical and economic benefits, the development of clinical protocols based on pharmacogenetic information, and improved and cheaper genetic testing will increase the implementation of pharmacogenetic guided prescription in clinical settings.

Pharmacogenetics of antipsychotics in adolescents with acute psychotic episode during first 14days after admission: effectiveness and safety evaluation.

Prediction of the antipsychotic's effectivenessis a relevant topic in the field of personalized medicine. The research design of this study is a prospective observation with posthoc analysis of associations of genetic polymorphisms with safety parameters and effectiveness of antipsychotic therapy. We observed 53 adolescents with an acute psychotic episode which were prescribed antipsychotics for 14days. We evaluated the effectiveness of antipsychotics with the Positive and Negative Symptoms Scale and the safety with the UKU Side Effects Rating Scale, Simpson-Angus Scale, and Barnes Akathisia rating scale. We genotyped CYP3A4*22 (rs2740574), CYP3A5*3 (6986A>G, rs7767746), CYP2D6*4, *9, *10 (rs3892097, rs1065852), ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), DRD2 (rs1800497), DRD4 (rs1800955), HTR2A (rs6313) by the real-time polymerase chain reaction method. We found significantly more frequent "increased dream activity" between CYP2D6 intermediate metabolizers and normal metabolizers (54 vs. 22%; p=0.043). The «increased duration of sleep» was more often observed in homozygotes TT of ABCB1 2677G>T/A (50 vs. 15.8%, p=0.006) and TT of 3435C>T (41.7 vs. 8.2%, p=0.007). We found that CYP2D6 and ABCB1 polymorphisms were associated with the safety of antipsychotics in adolescents with an acute psychotic episode.

Therapeutic drug monitoring and pharmacogenetics of antipsychotics and antidepressants in real life settings: A 5-year single centre experience

Objectives Exposure and clinical response to CNS drugs are largely variable. AGNP guidelines suggest therapy individualisation with therapeutic drug monitoring of plasma concentrations and pharmacogenetic testing. We present the retrospective analysis of the last 5 years’ data collected in real life settings as indirect evidence of the applications of the AGNP guidelines in the routine clinical management of psychiatric patients requiring pharmacologic treatments. Methods Plasma concentrations were quantified using a liquid chromatography/tandem mass spectrometry method. Genomic DNA was isolated using an automatic DNA extraction system. All genotypes were determined by Real-Time PCR. Results We collected a total of 4582 requests for TDM and 212 requests for pharmacogenetic analysis. A wide distribution in the trough concentrations was observed for most drugs indicating a high interpatient variability. Nearly 45% of the samples had trough levels below the minimum effective drug concentrations set by the AGNP guidelines; only 8% of the samples had high concentrations. For pharmacogenetics analysis, among antipsychotics, clozapine, haloperidol and aripiprazole were the most requested (78%); while for antidepressants SSRIs were the most frequently prescribed. Conclusions These data suggest that physicians are becoming more confident with the laboratory pharmacologic tools to optimise treatments and/or that the pharmacological treatment of patients with psychiatric disorders is becoming more challenging. TDM and PGx might significantly contribute to the rational selection of the best drug and best dose in individual cases.

Peculiarities of the Effect of Antipsychotics: Pharmacogenetic Studies

Currently, antipsychotics are the only type of drugs for the treatment of schizophrenia. The efficacy of antipsychotics in the treatment of schizophrenia is unsatisfactory. Specifically, more than 20% of schizophrenia patients are antipsychotic-resistant patients not sensitive to at least two antipsychotics. A combination of factors affecting the drug metabolism (pharmacokinetics) and the drug action (pharmacodynamics) underlies the differences in the response to the same antipsychotic agent. There is an obvious genetic contribution to the variability of response to psychotropic agents. Moreover, it is known that side effects caused by administration of these drugs may have an even stronger genetic component. This review presents the results of the most recent world research in the field of pharmacogenetics of antipsychotics.

Pharmacogenetics of antipsychotics: focus on the glutamatergic system

A major drawback of the therapy with antipsychotics is the lack of efficacy and the occurrence of extrapyramidal symptoms in some patients that can limit therapy and compliance. Thus, the availability of a predictive tool for response to antipsychotics is desirable. The glutamatergic system may be relevant to the pathophysiology of psychosis and the effects of antipsychotic treatments. We analyzed a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol in a sample of 101 acutely ill psychotic patients. Antipsychotic effect was investigated using PANSS and motor side effects using ESRS. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures ANOVA, p = 0.0002), followed by a subsequent fast adaptation. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher ESRS scores (overall p = 0.01, haplotype p = 0.000001). We replicated this finding in two independent samples (n = 71 and n = 118) of schizophrenic patients treated with antipsychotics. This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment.

Pharmacogenetic of response efficacy to antipsychotics in schizophrenia: pharmacodynamic aspects. Review and implications for clinical research

Pharmacogenetics constitutes a new and growing therapeutic approach in the identification of the predictive factors of the response to antipsychotic treatment. This review aims to summarize recent finding into pharmacodynamic approach of pharmacogenetics of antipsychotics and particularly second generation. Studies were identified in the MEDLINE database from 1993 to July 2008 by combining the following Medical Subject Heading search terms: genetic, polymorphism, single nucleotide polymorphism, pharmacogenetics, antipsychotics, and response to treatment as well as individual antipsychotics names. Only pharmacodynamics studies were analyzed and we focused on efficacy studies. We also reviewed the references of ll identified articles. Most studies follow a polymorphism-by-polymorphism approach, and concern polymorphisms of genes coding for dopamine and serotonin receptors. Haplotypic approach has been considered in some studies. Few have studied the combinations of polymorphisms of several genes as a predictive factor of the response to antipsychotics. We present this gene-by-gene approach while detailing the features of the polymorphisms being studied (functionality, linkage disequilibrium) and the features of the studies (studied treatment(s), prospective/retrospective study, pharmacological dosage). We discuss the heterogeneity of the results and their potential clinical implications and extract methodological suggestions for the future concerning phenotype characterization, genotypes variants studied and methodological and statistical approach.

P03-74 - Individual genetic variation and response to antipsychotic medications

Schizophrenia is a severe mental disorder with relatively high occurrence in general population (around 1%). Classical genetic studies (Family, twin and adoption) undoubtedly prove its genetic etiology. On the other hand genetics studies are important in exploration of innate mechanisms responsible for specific response to antipsychotic medications. Significant differences in therapeutic responses to antipsychotic agents in patients suffering from schizophrenia were observed and therefore pharmacogenetics of antipsychotics represents main focus in current psychiatric genetics studies.This is particularly observed at polymorphisms in dopamine and serotonin receptor genes, but also some other biomolecules involved in signal transduction mechanism such are regulators of G-protein signalling in brain (RGS4). In order to test this hypothesis, association between certain variants of RGS4 linked polymorhic marker and responsiveness status towards antypsychotics was evaluated within the group of 52 psychiatric patients under antipsychotics treatment. No association between specific allele or genotype for RGS4 linked loci and therapeutical response using Fisher´s Exact Test was found (P>0.05).

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and -141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (-759-T/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

Pharmacogenetics of antipsychoatics.

Although a number of antipsychotics have been introduced for the treatment of schizophrenia, inter-individual differences of in antipsychotic response and the number of refractory schizophrenic patients have become two of the most challenging problems in clinical psychiatry. Thus, the pharmacogenetics of antipsychotics have been aimed at providing genetic components of this inter-individual variability in antipsychotic response in order to establish an individually-based pharmacotherapy for schizophrenia and to elucidate the mechanism of antipsychotic response so as to solve the refractoriness of schizophrenia. Pharmacogenetics, which is defined as the science of pharmacological response and its modification by hereditary influence can be divided into two categories: the genetic background of pharmacokinetics, i.e. the absorption, distribution, tissue localization, biotransformation and excretion of drugs, and pharmacodynamics, i.e. the biochemical and physiological consequences of a drug and its mechanism of action. Pharmacokinetics of antipsychotics has been focused mainly on the association between genetic polymorphisms in CYP genes, including CYP2D6, and the metabolism of these drugs. Polymorphism in CYP2D6 enables a division of individuals within a given population into at least two groups, i.e. poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) of certain drugs. PMs have higher plasma concentrations of and more adverse effects from antipsychotics. UMs could be one of the important factors that induce treatment-refractoriness to antipsychotics. Genetic polymorphisms in serotonin and dopamine receptors that have a high affinity for antipsychotics have so far been extensively investigated in the pharmacodynamics of this type of drug. Not just one gene but multiple genes play a role in complex phenotypes, including the clinical response to medication. Thus, a multiple candidate genes approach has recently been adopted in the pharmacogenetics of antipsychotics. The new field of pharmacogenomics using DNA microarray analysis, which focuses on the genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually-tailored antipsychotics.