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

• Published in: Molecular psychiatry Vol. 12; no. 8; pp. 707 - 747
• Main Authors: ARRANZ, M. J, DE LEON, J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.08.2007
• Subjects: Adult and adolescent clinical studies; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Antipsychotic drugs; Antipsychotics; Biological and medical sciences; Bipolar disorder; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Clinical medicine; Complications and side effects; CYP2D6 protein; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Dopamine; Dopamine D2 receptors; Dopamine D3 receptors; Dosage and administration; Drug dosages; Drug Interactions - genetics; Drug therapy; Dyskinesia; Epigenetics; Genetic aspects; Genetic screening; Genetic testing; Genotyping; Hematologic and hematopoietic diseases; Humans; Medical sciences; Mental disorders; Metabolic rate; Metabolism; Movement disorders; Neuropharmacology; Neurotransmitter Agents - metabolism; Other diseases. Hematologic involvement in other diseases; Patients; Pharmacogenetics; Pharmacogenomics; Pharmacology. Drug treatments; Phenotypes; Polymorphism; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Psychosis; Psychotropic drugs; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - genetics; Schizophrenia - metabolism; Serotonin S2 receptors; Siblings; Side effects; Tardive dyskinesia; Twins; United Kingdom; United Kingdom > UK; Leukopenia; Neuroleptic; Psychotropic; Agranulocytosis; Schizophrenia; Hemopathy; Review; Weight gain; Psychosis; TD; Chemotherapy; Treatment; NMS; antipsychotics; Antipsychotic; pharmacogenetics and pharmacogenomics; Neutropenia
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4002009

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.