INTRODUCTION: Pharmacogenomic testing in psychiatry is an emerging area with potential clinical application of guiding medication choice and dosing. Interest has been fanned by commercial pharmacogenomic providers who have commonly marketed combinatorial panels that are direct-to-consumer. However, this has not been adopted widely due to a combination of barriers that include a varying evidence base, clinician and patient familiarity and acceptance, uncertainty about cost-effectiveness, and regulatory requirements. This review aims to examine recent updates in this field and provide a contextualised summary and recom-mendations for Asian populations in order to guide healthcare professionals in psychiatric practice. METHOD: A review of recent literature about current evidence and guidelines surrounding pharmacoge-nomics in psychiatric practice was carried out with particular attention paid to literature evaluating Asian populations. The Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework was applied. Consensus meetings comprising workgroup psychiatrists from the public and private sectors were held prior to arriving at the key recommendations. RESULTS: Pharmacogenomic testing should be mainly limited to drug-gene pairs with established clinical evidence, such as antidepressants and CYP2C19/ CYP2D6. Direct-to-consumer pharmacogenomic panels that assay multiple genes and analyse them via proprietary algorithms, are not presently recommended in Singapore's psychiatric setting due to inconclusive evidence on clinical outcomes. CONCLUSION Pharmacogenomic testing in psychiatry is not recommended as standard clinical practice. Exceptions may include concerns about drug concentrations or potential severe adverse drug reactions. Studies investigating newly identified drug-gene associations, and clinical effectiveness and cost-effectiveness of utilising pharmacogenomic testing in psychiatry is encouraged.
Humans ; Psychiatry/methods* ; Pharmacogenetics ; Cytochrome P-450 CYP2C19/genetics* ; Asian People/genetics* ; Pharmacogenomic Testing/methods* ; Antidepressive Agents/therapeutic use* ; Cytochrome P-450 CYP2D6/genetics* ; Practice Guidelines as Topic ; Singapore ; Mental Disorders/genetics* ; Psychotropic Drugs/therapeutic use*

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.
Adult ; Child ; Humans ; Adrenergic Uptake Inhibitors/therapeutic use* ; Atomoxetine Hydrochloride/therapeutic use* ; Attention Deficit Disorder with Hyperactivity/genetics* ; Cytochrome P-450 CYP2D6/therapeutic use* ; Drug Monitoring ; Genetic Testing ; Propylamines/therapeutic use* ; Treatment Outcome

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.
Anticoagulants/therapeutic use ; Antidepressive Agents/therapeutic use ; Antimetabolites, Antineoplastic/therapeutic use ; Antitubercular Agents/therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Coronary Artery Disease/drug therapy/genetics ; Cytochrome P-450 CYP2C19/genetics ; Cytochrome P-450 CYP2C9/genetics ; Cytochrome P-450 CYP2D6/genetics ; Depressive Disorder/drug therapy/genetics ; Genotype ; Isoniazid/therapeutic use ; Laboratories, Hospital/standards ; Methyltransferases/genetics ; Pharmacogenomic Testing/*methods/standards ; Platelet Aggregation Inhibitors/therapeutic use ; Pulmonary Embolism/drug therapy/genetics ; Ticlopidine/analogs & derivatives/therapeutic use ; Tuberculosis/drug therapy/genetics ; Vitamin K Epoxide Reductases/genetics ; Warfarin/therapeutic use

CYP2D6 is primarily responsible for the metabolism of clomiphene citrate (CC). The purpose of the present study was to investigate the relationship between CYP2D6 genotypes, concentrations of CC and its major metabolites and drug response in infertility patients. We studied 42 patients with ovulatory dysfunction treated with only CC. Patients received a dose of 100 mg/day CC on days 3-7 of the menstrual cycle. CYP2D6 genotyping and measurement of CC and the major metabolite concentrations were performed. Patients were categorized into CC responders or non-responders according to one cycle response for the ovulation. Thirty-two patients were CC responders and 10 patients were non-responders with 1 cycle treatment. The CC concentrations were highly variable within the same group, but non-responders revealed significantly lower (E)-clomiphene concentration and a trend of decreased concentrations of active metabolites compared to the responders. Nine patients with intermediate metabolizer phenotype were all responders. We confirmed that the CC and the metabolite concentrations were different according to the ovulation status. However, our results do not provide evidence for the contribution of CYP2D6 polymorphism to either drug response or CC concentrations.
Adult ; Chromatography, High Pressure Liquid ; Clomiphene/blood/metabolism/*therapeutic use ; Cytochrome P-450 CYP2D6/*genetics ; Estrogen Antagonists/analysis/metabolism/therapeutic use ; Female ; Genotype ; Humans ; Infertility/*drug therapy/genetics ; Ovulation Induction ; Phenotype ; *Polymorphism, Genetic ; Republic of Korea ; Tandem Mass Spectrometry

PURPOSE: Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs. MATERIALS AND METHODS: Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations. RESULTS: Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively. CONCLUSIONS: Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.
Adolescent ; Adult ; Aged ; Body Mass Index ; Cytochrome P-450 CYP2D6/genetics ; Humans ; Leptin/blood ; Male ; Middle Aged ; Mutation ; Paroxetine/*administration & dosage/blood ; Polymorphism, Genetic ; Premature Ejaculation/*drug therapy/genetics ; Receptor, Serotonin, 5-HT1A/genetics ; Risk Factors ; Serotonin Uptake Inhibitors/*administration & dosage ; Time Factors ; Treatment Outcome ; Young Adult

PURPOSE: Nonresponse to any selective serotonin reuptake inhibitor (SSRI) treatment is rare. In this study, we aimed to investigate ejaculation delay nonresponse to paroxetine treatment in men with lifelong premature ejaculation (PE) who were also known to be nonresponders to other SSRIs. MATERIALS AND METHODS: Five males with lifelong PE who were known nonresponders to paroxetine and other serotonergic antidepressants and eight males with lifelong PE who were specifically recruited were included. Blood sampling occurred 1 month and 1 day before the start of treatment and at the end of three consecutive series of 4 weeks of daily treatment with 10-, 20-, and 30-mg paroxetine, respectively. Blood samples for measurement of leptin and paroxetine were taken at 8:30 AM, 9:30 AM, 10:30 AM, and 11:30 AM, respectively. At 9:00 AM, one tablet of 10-, 20-, or 30-mg paroxetine was taken during the first, second, and third month, respectively. Intravaginal ejaculatory latency time (IELT) was measured with a stopwatch. The main outcome measures were the fold increase in the geometric mean IELT, serum leptin and paroxetine concentrations, body mass index (BMI), 5-HT1A receptor C-1019G polymorphism, and CYP2D6 mutations. RESULTS: Between the 7 paroxetine responders and 6 nonresponders, the fold increase in the geometric mean IELT was significantly different after daily 10-mg (p=0.003), 20-mg (p=0.002), and 30-mg paroxetine (p=0.026) and ranged from 2.0 to 8.8 and from 1.1 to 1.7, respectively. BMI at baseline and at the end of the study was not significantly different between responders and nonresponders. Serum leptin levels at baseline were similar in responders and nonresponders and did not change during treatment. The serum paroxetine concentration increased with increasing dosage and was not significantly different between responders and nonresponders. There was no association between the fold increase in the geometric mean IELT and serum paroxetine levels during the three treatment periods nor between leptin levels during the treatment periods and serum paroxetine levels. For the 5-HT1A receptor C-1019G variation, all responders had the CC genotype and all nonresponders had the GC genotype, respectively. CONCLUSIONS: Complete absence of paroxetine-induced ejaculation delay is presumably related to pharmacodynamic factors and perhaps to 5-HT1A receptor gene polymorphism.
Adolescent ; Adult ; Aged ; Body Mass Index ; Cytochrome P-450 CYP2D6/genetics ; Humans ; Leptin/blood ; Male ; Middle Aged ; Mutation ; Paroxetine/*administration & dosage/blood ; Polymorphism, Genetic ; Premature Ejaculation/*drug therapy/genetics ; Receptor, Serotonin, 5-HT1A/genetics ; Risk Factors ; Serotonin Uptake Inhibitors/*administration & dosage ; Time Factors ; Treatment Outcome ; Young Adult

<p>BACKGROUNDMany studies indicated the human cytochrome P450 2D6 (CYP2D6) gene polymorphism was associated with acute leukemia (AL) susceptibility, however, the results were inconsistent. So we performed this meta-analysis to evaluate the relationship between CYP2D6*3 or CYP2D6*4 polymorphism and AL susceptibility.p><p>METHODSWe searched PubMed database up to February 20, 2013, and finally yielded 9 case-control studies including 1343 cases and 1843 controls which tested the association between CYP2D6*3 or *4 polymorphism and AL. After data extraction, we conducted a meta-analysis using the Comprehensive Meta Analysis software.p><p>RESULTSOverall, no significant association between CYP2D6*3 or *4 polymorphism and AL risk was found in this metaanalysis (+ vs. -: OR = 1.13, 95% CI = 0.79-1.63; +/+ vs. -/-: OR = 1.73, 95% CI = 0.99-3.02; -/+ vs. -/-: OR = 1.03, 95% CI = 0.68-1.56; (-/+ and +/+) vs. -/-: OR = 1.08, 95% CI = 0.72-1.63; +/+ vs. (-/+ and -/-): OR = 1.76, 95% CI = 0.98-3.17). Similar results were also been found in stratified subgroup analysis. There was no publication bias.p><p>CONCLUSIONCYP2D6*3 or *4 polymorphism might not be associated with AL susceptibility. However, the results need to be further confirmed by well-designed and high quality randomized controlled trials with larger sample sizes.p>
Acute Disease ; Cytochrome P-450 CYP2D6 ; genetics ; Genetic Predisposition to Disease ; Humans ; Leukemia ; etiology ; genetics ; Polymorphism, Genetic ; Risk

<p>OBJECTIVETo explore the association of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning (CBP) comprehensively by case-control design.p><p>METHODS152 CBP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. 30 single nucleotide polymorphisms (SNPs) in 13 genes such as CYP2E1 were tested by PCR-RFLP, sequencing approaches. Logistic regression model was used to detect main effects and 2-order interaction effects of gene and/or environment. Multifactor dimensionality reduction (MDR) was used to detect high-order gene-gene or gene-environment interactions.p><p>RESULTSBased on logistic regression, the main effects of GSTP1 rs947894, EPHX1 rs1051740, CYP1A1 rs4646903, CYP2D6 rs1065852 and rs1135840 were found to be significant (P < 0.05) while the confounding factors of sex, cigarette smoking, alcohol consumption and the intensity of benzene exposure were controlled. EPHX1 rs1051740 might be associated with CBP (P = 0.06). There existed 3 types of interactions were as followed: interactions of GSTP1 rs947894 with alcohol consumption, CYP2E1 rs3813867 with EPHX1 rs3738047, EPHX1 rs3738047 with alcohol consumption(P < 0.05), while the main effects of CYP2E1 rs3813867 and EPHX1 rs3738047 were not significant (P > 0.05). The other SNPs did not show any significant associations with CBP. According to MDR, a 3-order interaction with the strongest combined effect was found, i.e. the 3-factor combination of CYP1A1 rs4646903, CYP2D6 rs1065852 and CYP2D6 rs1135840.p><p>CONCLUSIONGene-gene, gene-environment interactions are important mechanism to genetic susceptibility of CBP.p>
Adult ; Benzene ; poisoning ; Case-Control Studies ; Cytochrome P-450 CYP1A1 ; genetics ; Cytochrome P-450 CYP2D6 ; genetics ; Cytochrome P-450 CYP2E1 ; genetics ; Epoxide Hydrolases ; genetics ; Female ; Gene-Environment Interaction ; Genetic Predisposition to Disease ; Genotype ; Humans ; Logistic Models ; Male ; Middle Aged ; Multifactor Dimensionality Reduction ; Occupational Exposure ; Polymorphism, Single Nucleotide ; Young Adult

This study is to compare the influence of CYP2D6 *3 and *4 genotypes and phenotypes on the metabolic activity of CYP2D6 in Chinese Han, Uygur and Kazakh ethnic groups. Allele specific amplification (ASA) was used to determine the CYP2D6*3 and CYP2D6*4 genotypes. Phenotypes of CYP2D6 in all subjects were determined using dextromethorphan as probe drug by HPLC methods. Among the 132 Han subjects, one subject (0.76%) exhibited the *1/*3 combination, and one (0.76%) exhibited the *1/*4. Among the 136 Uygur subjects, 4 subjects (2.94%) showed the *1/*3 combination, 12 (8.82%) showed *1/*4, 4 (2.94%) showed *4/*4, and one (0.74%) showed *3/*4. Among the 116 Kazakh subjects, 2 (1.72%) exhibited the *1/*3 combination, 7 (6.03%) exhibited *1/1*4, and one (0.86%) showed *4/*4. This research revealed significant differences in the occurrence frequencies of the CYP2D6 genotype between Han and Uygur ethnic groups, as well as between Uygur and Kazakh populations. However, no difference was found between Han and Kazakh populations. In addition, the prevalence of PMs of the Uygur is comparable to that of the Caucasians. However, the molecular mechanism underlying the poor metabolism is different in these two populations.
Adolescent ; Adult ; Asian Continental Ancestry Group ; classification ; genetics ; China ; ethnology ; Chromatography, High Pressure Liquid ; methods ; Cytochrome P-450 CYP2D6 ; genetics ; Dextromethorphan ; pharmacokinetics ; Female ; Gene Frequency ; Genotype ; Humans ; Male ; Minority Groups ; Phenotype ; Young Adult

CYP2D6 is an important drug-metabolizing enzyme. The polymorphism of CYP2D6 leads to metabolism difference and the different reactions of drugs in the individuals and different races are normal phenomenon in clinical medication. CYP2D6*10 is an important subtype in Asian people and 51.3% Chinese are classified with this subtype. To obtain recombinant active CYP2D6*1/CYP2D6*10 in baculovirus system by optimizing coexpression with CYPOR, and detect their activity to catalyze dextromethorphan, three recombinants pFastBac-CYP2D6*1, pFastBac-CYP2D6*10 and pFastBac-CYPOR were constructed and transformed into DH10Bac cell to obtain the recombinant Bacmid-CYPOR, Bacmid-CYP2D6*1 and Bacmid-CYP2D6*10. And then the recombinant CYP2D6*1 and CYP2D6*10 virus were obtained by transfecting Sf9. Then homogenate protein activity was determined with dextromethorphan as substrate. The multiple of infection (MOI) and its ratio of recombinant CYP2D6 virus to CYPOR virus were adjusted by detecting the activity of the homogenate protein. The Km and Vmax are 26.67 +/- 2.71 micromol x L(-1) (n=3) and 666.7 +/- 56.78 pmol x nmol(-1) (CYP2D6) x min(-1) (n=3) for CYP2D6*1 to catalyze dextromethaphan. The Km and Vmax are 111.36 +/- 10.89 micromol x L(-1) (n=3) and 222.2 +/- 20.12 pmol x nmol(-1) (CYP2D6) x min(-1) (n=3) for CYP2D6*10 to catalyze dextromethorphan. There is significant difference between CYP2D6*1 and CYP2D6*10 for Vmax and Km (P < 0.01). The clearance ratio of CYP2D6*1 is 25.0 and the clearance ratio of CYP2D6*10 is 2.0. The expressed CYP2D6*1 and CYP2D6*10 are useful tools to screen the metabolism profile of many xenobiotics and endobiotics in vitro, which are benefit to understand individual metabolism difference.
Animals ; Baculoviridae ; enzymology ; genetics ; Catalysis ; Cells, Cultured ; Chromatography, High Pressure Liquid ; methods ; Cytochrome P-450 CYP2D6 ; genetics ; metabolism ; Dextromethorphan ; metabolism ; Isoenzymes ; metabolism ; NADPH-Ferrihemoprotein Reductase ; genetics ; metabolism ; Plasmids ; Recombinant Proteins ; genetics ; metabolism ; Spectrometry, Mass, Electrospray Ionization ; Spodoptera ; cytology ; virology ; Transfection