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

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 À141-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 (À759ÀT/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.

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

“…We therefore propose to direct more research toward (i) understanding how some of the existing antipsychotic drugs could act on the myelination level or synaptic function in the brain, (ii) identifying genetic or anatomical (e.g. on MRI scans) markers that may determine subgroups of patients that should benefit the most from these treatment 61 and (iii) establishing genetic tests and clinical interventions to handle patients with higher risks of antipsychotic induced metabolic adverse effect. [61][62][63] …”

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses

“…Part of this variability may be explained by differences in drug metabolism between different individuals. 6,7 Most antipsychotic agents are highly lipophilic and undergo extensive metabolism, in particular by the cytochrome P450 (CYP450) enzymes CYP2D6, CYP1A2 and CYP3A4 8 (Table 1). Most of the work to date has focused on the role of CYP2D6 polymorphisms in determining variability in drug levels and thereby in the response to antipsychotics.…”

Candidate-gene association analysis of response to risperidone in African-American and white patients with schizophrenia

“…By one estimate, currently available medications are effective for about 50% of patients. 1 The ability to predict response to a given medication is desirable for many reasons. 2,3 First among them is the desire to stabilize the patient as quickly as possible.…”

“…The association between response to antipsychotic medications and polymorphisms in genes believed to confer susceptibility to schizophrenia or to influence antipsychotic response (e.g., genes encoding drug receptors, transporters and metabolizing enzymes) has been examined in over 70 studies. 1 However, identifying polymorphisms that consistently predict response has been difficult. Some polymorphisms have been examined in only a single study and, for those that have been examined more than once, results frequently conflict.…”