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Frontiers of Medicine

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Front Med    2013, Vol. 7 Issue (2) : 180-190    https://doi.org/10.1007/s11684-013-0249-3
REVIEW
Pharmacogenomics can improve antipsychotic treatment in schizophrenia
Qingqing Xu1,2, Xi Wu1,2, Yuyu Xiong1,2, Qinghe Xing3, Lin He1,2,3(), Shengying Qin1,2()
1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; 2. Shanghai Genome Pilot Institutes for Genomics and Human Health, Shanghai 200030, China; 3. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Abstract

Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that about 30% of the patients exhibit little or no improvements associated with antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications.
Keywords pharmacogenomics      epigenetics      schizophrenia      antipsychotics     
Corresponding Author(s): He Lin,Email:helin@bio-x.cn; Qin Shengying,Email:chinsir@sjtu.edu.cn   
Issue Date: 05 June 2013
 Cite this article:   
Qingqing Xu,Xi Wu,Yuyu Xiong, et al. Pharmacogenomics can improve antipsychotic treatment in schizophrenia[J]. Front Med, 2013, 7(2): 180-190.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0249-3
https://academic.hep.com.cn/fmd/EN/Y2013/V7/I2/180
FGAsSGAs
Main contentButyrophenones, phenothiazines thioxanthenesClozapine, olanzapine, risperidone, quetiapine, ziprasidone, etc.
Calming effectPowerfulWeaker (except clozapine)
Receptor targetsNarrow, mainly D2 receptorsMultitarget, D2 receptors and serotonin receptors
High prolactinCommonLess common(except risperidone)
EfficacyGood [13]Equivalent or superior [14,15]
Positive symptomsGood efficacyGood efficacy
Negative symptomsWeaker efficacyBetter efficacy
Cognitive symptomsWeaker efficacyBetter efficacy
Extrapyramidal symptomsSeriousLight
Tardive dyskinesiaCommonRare
Effective doseLarge dosageGenerally small
ComplianceBadBetter
Weight gainObviousMore obvious(except ziprasidone)
Metabolic syndromeCommon, higher risk [16]Rare, lower risk
Tab.1  A summary of the first-generation antipsychotic medications (FGAs) and second-generation antipsychotic medications (SGAs) [-]
GenePolymorphismSample sizePAssociationReference
ABCB11236C/T130 Chinese patientsP = 0.021Patients with the TT genotype showed greater improvement [45]
3435T116 patientsNo reportPatients on olanzapine homozygous for ABCB1 3435T had more significant social and clinical needs [46]
3435T/2677T/1236T46 white patientsP = 0.026Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower dose-corrected plasma concentrations of 9-hydroxyrisperidone [22]
3435T/2677T/1236T46 white patientsP = 0.028Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly active moiety [22]
c.3435CC40 men and 20 women-Require higher clozapine doses to achieve the same plasma concentrations as CT or TT patients [47]
3435 T allele and 2667 T-3435 T haplotype83 drug-naive patients-More frequent among subjects without extrapyramidal syndromes [24]
1236T/2677T/3435T haplotype37 white outpatients (10 smokers and 27 nonsmokers)P = 0.018Had higher serum and cerebrospinal fluid olanzapine concentrations [48]
2677T101 previously non-medicated female patientsP<0.001Significantly associated with greater increase in fasting glucose level in blood after olanzapine/ risperidone treatment [49]
3435T101 previously non-medicated female patientsP = 0.028Significantly associated with greater increase in fasting glucose level in blood after olanzapine/ risperidone treatment [49]
2677G/A23 healthy Chinese subjects-May play a role in risperidone pharmacokinetics, needs further studies [50]
5-HT2C-759T101 previously non-medicated female patientsP = 0.03, P = 0.046 and P = 0.045, respectivelyGreater increase in waist circumference, fasting glucose level and triglyceride level in blood after olanzapine/ risperidone treatment [49]
UGT1A4142T/G121 patients-Predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient not carrying the variants compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T / G SNP [51]
Tab.2  Associations of genetic variants with response to antipsychotics
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