Abstract
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.
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Acknowledgements
In the past 2 years, Dr Jose de Leon has been on the advisory board of the Bristol-Myers Squibb and Roche Molecular Systems, Incs. He received investigator-initiated grants from Roche Molecular Systems, Inc., and Eli Lilly Research Foundation. Dr de Leon has lectured once supported by Eli Lilly, once supported by Bristol-Myers Squibb, twice supported by Janssen and six times by Roche Molecular Systems, Inc.
Dr Maria J Arranz is a consultant for the company TheraGenetics (UK), and actively collaborates with the company LGC (UK) in the development of genetic tests, including a test for the prediction of clozapine response. Dr Arranz has received consultancy money from LGC and has royalty rights over the clozapine response test.
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Arranz, M., de Leon, J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 12, 707–747 (2007). https://doi.org/10.1038/sj.mp.4002009
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DOI: https://doi.org/10.1038/sj.mp.4002009
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