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The aim of this study was to investigate the association of drug-metabolizing enzyme and transporter (DMET) polymorphisms with the risperidone-induced prolactin response using an overlapping gene model between serum prolactin level and hyperprolactinemia in autism spectrum disorder (ASD) patients. Eighty-four ASD patients who were receiving risperidone for at least 1 month were recruited and then assigned to either the normal prolactin group or the hyperprolactinemia group based on their serum prolactin level. The genotype profile of 1936 (1931 single nucleotide polymorphisms (SNPs) and 5 copy number variation (CNVs) drug metabolism markers was obtained using the Affymetrix DMET Plus GeneChip microarray platform. Genotypes of SNPs used to test the accuracy of DMET genotype profiling were determined using TaqMan SNP Genotyping Assay kits. Eighty-four patients were selected for the allelic association study after microarray analyses (51 in the normal prolactin group, and 33 in the hyperprolactinemia group). An overlapping allelic association analysis of both analyses discovered five DMET SNPs with a suggestive association (P < 0.05) with risperidone-induced prolactin response. Three UGT1A1 SNPs (UGT1A1*80c.-364C > T, UGT1A1*93 c.-3156G > A, and UGT1A1 c.-2950A > G, showed a suggestive association with the risperidone-induced prolactin response and found to be in complete linkage disequilibrium (D' value of 1). In this DMET microarray platform, we found three UGT1A1 variants with suggestive evidences of association with the risperidone-induced prolactin response both measured by hyperprolactinemia and by prolactin level. However, due to the lack of validation studies confirmation and further exploration are needed in future pharmacogenomic studies.

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body-weight and height. Genotyping was performed by TaqMan real-time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP-binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag-SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) -2548G>A (rs7799039), ghrelin gene (GHRL) -604G>A (rs27647) and brain-derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: The purpose of this study was to investigate the influence of CYP2D6 gene polymorphisms on plasma concentrations of risperidone and its metabolite in Thai children and adolescents with autism spectrum disorder (ASD)., Methods: All 97 autism spectrum disorder patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by real-time polymerase chain reaction (PCR)-based allelic discrimination for CYP2D6*4, *10, and *41 alleles. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: Among the 97 patients, the most important nonfunctional alleles (CYP2D6*4 and *5) were detected, whereas the most common allele was CYP2D6*10 (55.9%). CYP2D6 genotyping revealed 90 (92.78%) patients to be extensive metabolizers (EM) and 7 (7.22%) to be intermediate metabolizers (IM). Plasma levels of risperidone were significantly higher in individuals with CYP2D6*5/*10 (p = 0.02), CYP2D6*10/*10 (p = 0.04), and CYP2D6*10/*41 (p = 0.04). Additionally, the plasma concentration of risperidone/9-OH risperidone ratio in patients with a CYP2D6 activity score of 0.5 were significantly higher than those with a CYP2D6 activity score of 2 (p = 0.04). Conversely, no significant influence was found among CYP2D6 polymorphisms, plasma concentrations of 9-hydroxyrisperidone, and the total active moiety., Conclusions: This is the first study to investigate the effects of CYP2D6 genetic polymorphisms on the plasma concentrations of risperidone in Thai children with ASD. The findings indicate that CYP2D6 polymorphisms affect the plasma concentrations of risperidone and the risperidone/9-hydroxyrisperidone ratio. Genetic screening for CYP2D6 polymorphisms could help to predict unexpected adverse events caused by the higher plasma concentration of risperidone.

Background: Risperidone (RIS) is a widely used atypical antipsychotic drug. We developed and validated a sensitive and accurate LC-MS/MS method, which requires a small-volume of plasma and small-volume injection for measurement of RIS levels in ASD pediatric patients. We also investigated the relationship between RIS levels and RIS dosages, including prolactin levels., Method: Blood samples were processed by protein precipitation extraction. Only 1 μl of sample was injected. Plasma samples were separated on a C18 column (4.6 cm × 50 mm; 1.8 μm particle size). Detection was by MS-MS with an analytical run time of 6 min., Results: The inter-day accuracy of RIS was 101.33-107.68% and 95.24-103.67% for 9-OH-RIS. The inter-day precision of RIS was ≤7.27% CV and ≤7.41% CV for 9-OH-RIS. The extraction recovery of RIS and 9-OH-RIS were 95.01 ± 7.31-112.62 ± 7.50% and 90.27 ± 11.15-114.00 ± 10.35%, respectively. This method was applied in the therapeutic drug monitoring of ASD pediatric patients. Higher RIS dosage has a tendency to produce higher RIS plasma levels. The high RIS plasma levels have a tendency to produce hyperprolactinemia., Conclusion: The determination of RIS in individual patients might be clinically useful for monitoring and prediction of treatment response., (© 2016 Wiley Periodicals, Inc.)

Although our previous study revealed an association between prolactin level and risperidone dosage, data regarding the plasma concentration of risperidone are lacking. Therefore, this study aimed to investigate the association between plasma drug concentrations of risperidone, 9-hydroxyrisperidone and serum prolactin level in Thai children and adolescents with autism spectrum disorder (ASD). The individuals for this study were 103 children and adolescents with ASD (90 males and 13 females). In the 12th hour after the last risperidone dose, blood samples were collected for analysis. Serum prolactin, plasma risperidone and 9-hydroxyrisperidone levels were measured. Patients' clinical data were collected from medical records - age, weight, height, body mass index, dose of risperidone and duration of treatment. Serum prolactin level was significantly positively correlated with plasma 9-hydroxyrisperidone level (rs = 0.355, p < 0.001). The median concentration of 9-hydroxyrisperidone in individuals with hyperprolactinaemia (7.59 ng/ml; IQR 4.86-15.55) was significantly higher than non-hyperprolactinaemic individuals (5.18 ng/ml; IQR 2.10-8.99) after risperidone treatment (p = 0.006). By multivariate analysis, high prolactin level was correlated to high 9-hydroxyrisperidone level (p = 0.010). The results of this study showed that serum prolactin levels, especially in autistic individuals with hyperprolactinaemia during risperidone treatment, were significantly correlated with the level of 9-hydroxyrisperidone. These results suggest that hyperprolactinaemia may develop during risperidone treatment., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: The aim of the study was to identify the impact of pharmacogenetic markers associated with prolactin concentration in risperidone-treated children and adolescents with autism spectrum disorders., Methods: One hundred forty-seven children and adolescents with autism, aged 3 to 19 years, received risperidone. The clinical data of patients were recorded from medical records. Prolactin levels were measured by chemiluminescence immunoassay. Three CYP2D6 single nucleotide polymorphisms, CYP2D6*4 (1846G>A), *10 (100C>T), and *41 (2988G>A), 1 gene deletion (*5), and DRD2 Taq1A (rs1800497) polymorphism were genotyped by TaqMan real-time polymerase chain reaction., Results: The 3 common allelic frequencies were CYP2D6*10 (55.10%), *1 (32.65%), and *5 (6.12%), respectively. Patients were grouped according to their CYP2D6 genotypes. There was no significant correlation between the concentrations of prolactin among the CYP2D6 genotypes. In addition, there were no statistical differences in the prolactin response among the CYP2D6-predicted phenotypes of extensive metabolizer and intermediate metabolizer. The DRD2 genotype frequencies were Taq1A A2A2 (38.77%), A1A2 (41.50%), and A1A1 (19.73%), respectively. There were statistically significant differences in prolactin level of patients among the 3 groups (P = 0.033). The median prolactin level in patients with DRD2 Taq1A A2A2 (17.80 ng/mL) was significantly higher than A1A2 (17.10 ng/mL) and A1A1 (12.70 ng/mL)., Conclusions: DRD2 Taq1A A2A2 polymorphisms may play a significant role in the hyperprolactinemia- associated with risperidone treatment in children and adolescent with autism spectrum disorder. Many drugs used chronically in psychiatric diseases exert their effects mainly through the dopamine D2 receptor. It is therefore possible that these drugs could alter the expression of any dopamine receptor, thus affecting the pharmacodynamics characteristics and toxicity of drug substrates during pharmacotherapy.

CYP2D6 is involved in the biotransformation of a large number of drugs, including risperidone. This study was designed to detect CYP2D6 polymorphisms with a Luminex assay, including assessment the relationship of CYP2D6 polymorphisms and risperidone plasma concentration in autism spectrum disorder children (ASD) treated with risperidone. All 84 ASD patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by Luminex assay. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Among the 84 patients, there were 46 (55.42%) classified as EM, 33 (39.76%) as IM, and 4(4.82%) as UM. The plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients were significant differences among the CYP2D6 predicted phenotype group (P = 0.001 and P < 0.0001 respectively). Moreover, the plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients with CYP2D6 activity score 0.5 were significantly higher than those with the CYP2D6 activity score 2.0 (P = 0.004 and P = 0.002 respectively). These findings suggested that the determination of the accurate CYP2D6 genotype-predicted phenotype is essential in the clinical setting and individualization of drug therapy. The use of the Luminex assay for detection of CYP2D6 polymorphisms could help us more accurately identify an individual's CYP2D6 phenotype., (Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Autism is a severe neurodevelopmental disorder. Many susceptible causative genes have been identified. Most of the previous reports showed the relationship between the Human Leukocyte Antigen (HLA) gene and etiology of autism. In order to identify HLA-B alleles associated with autism in Thai population, we compared the frequency of HLA-B allele in 364 autistic subjects with 952 normal subjects by using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP) method based on flow-cytometry technology. HLA-B (⁎) 13:02 (P = 0.019, OR = 2.229), HLA-B (⁎) 38:02 (P = 0.049, OR = 1.628), HLA-B (⁎) 44:03 (P = 0.016, OR = 1.645), and HLA-B (⁎) 56:01 (P = 1.78 × 10(-4), OR = 4.927) alleles were significantly increased in autistic subjects compared with normal subjects. Moreover, we found that the HLA-B (⁎) 18:02 (P = 0.016, OR = 0.375) and HLA-B (⁎) 46:12 (P = 0.008, OR = 0.147) alleles were negatively associated with autism when compared to normal controls. Both alleles might have a protective role in disease development. In addition, four HLA-B genotypes of autistic patients had statistically significant relationship with control groups, consisting of HLA-B (⁎) 3905/(⁎) 5801 (P = 0.032, OR = 24.697), HLA-B (⁎) 2704/(⁎) 5801 (P = 0.022, OR = 6.872), HLA-B (⁎) 3501/(⁎) 4403 (P = 0.021, OR = 30.269), and HLA-B (⁎) 1801/(⁎) 4402 (P = 0.017, OR = 13.757). This is the first report on HLA-B associated with Thai autism and may serve as a marker for genetic susceptibility to autism in Thai population.