Pharmacogenetics of Second-Generation Antipsychotics

Abstract

This review considers pharmacogenetics of the so called 'second-generation' antipsychotics. Findings for polymorphisms replicating in more than one study are emphasized and compared and contrasted with larger-scale candidate gene studies and genome-wide association study analyses. Variants in three types of genes are discussed: pharmacokinetic genes associated with drug metabolism and disposition, pharmacodynamic genes encoding drug targets, and pharmacotypic genes impacting disease presentation and subtype. Among pharmacokinetic markers, CYP2D6 metabolizer phenotype has clear clinical significance, as it impacts dosing considerations for aripiprazole, iloperidone and risperidone, and variants of the ABCB1 gene hold promise as biomarkers for dosing for olanzapine and clozapine. Among pharmacodynamic variants, the TaqIA1 allele of the DRD2 gene, the DRD3 (Ser9Gly) polymorphism, and the HTR2C -759C/T polymorphism have emerged as potential biomarkers for response and/or side effects. However, large-scale candidate gene studies and genome-wide association studies indicate that pharmacotypic genes may ultimately prove to be the richest source of biomarkers for response and side effect profiles for second-generation antipsychotics.

Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population

“…4 At present, there is only a few variant that is well replicated and holds promise as clinical biomarkers, such as CYP2D6 and ABCB1. 8 In recent years, genome-wide association study, which has the potential to discover new molecular markers of drug actions, had been applied to antipsychotic response and drug-induced side effect studies. However, these studies were also mainly performed in relatively small samples, which has the low power to uncover the significant variants, and sometimes genome-wide association study results are not replicated across studies or population.…”

“…[9][10][11] There has been an increasing awareness that larger sample size is important for future studies to discover the reliable genomic variants with treatment response. 8 Furthermore, the drug response of antipsychotic drugs involves the process of absorption, distribution, metabolism, target response and excretion. Also, genes do not work in isolation, instead, complex molecular networks and pathways are often involved in drug response.…”

The impact of aripiprazole on INR in a psychotic patient during warfarin therapy

“…Aripiprazole, which is approximately 99% protein bound, may have displaced warfarin from plasma proteins, resulting in higher free concentration of warfarin. Therefore, increase in free plasma concentration of warfarin which is highly bound (99%) to plasma proteins may have led to an increase in INR levels and tendency to bleeding [5,10]. Therefore, it is evident from this case that aripiprazole which is highly protein bound should be used with caution in patients under warfarin therapy.…”

“…Both warfarin and aripiprazole metabolized via CYP 3A4, therefore competitive inhibition of CYP 3A4 by aripiprazole could cause increase in plasma warfarin levels and elevation of INR [5,10]. The second explanation may be protein binding.…”

Serotonin 7 Receptor Variants Are Not Associated with Response to Second-Generation Antipsychotics in Japanese Schizophrenia Patients

“…The study of polymorphisms in candidate genes of specific interest is a widely used approach to the investigation of genetic factors that modulate drug response in schizophrenia and other diseases [35], under the prospective of personalized medicine. HTR7 is located on chromosome 10q21-q24, is about 117,000 bp long, and has four exons [36,37].…”