Nattawat Ngamsamut

Impact of Pharmacogenetic Markers of CYP2D6 and DRD2 on Prolactin Response in Risperidone-Treated Thai Children and Adolescents With Autism Spectrum Disorders.

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.

Hyperprolactinemia in Thai children and adolescents with autism spectrum disorder treated with risperidone.

Hyperprolactinemia is a common adverse effect observed in children with autism spectrum disorder (ASD) during pharmacotherapy with risperidone. The main aim of this study was to investigate important clinical factors influencing the prolactin response in risperidone-treated Thai ASD. A total of 147 children and adolescents (127 males and 20 females) aged 3–19 years with ASD received risperidone treatment (0.10–6.00 mg/day) for up to 158 weeks. Prolactin levels were measured by chemiluminescence immunoassay. The clinical data of patients collected from medical records – age, weight, height, body mass index, dose of risperidone, duration of treatment, and drug-use pattern – were recorded. Hyperprolactinemia was observed in 66 of 147 (44.90%) subjects. Median prolactin level at the high doses (24.00, interquartile range [IQR] 14.30–29.20) of risperidone was significantly found to be higher than at the recommended (16.20, IQR 10.65–22.30) and low (11.70, IQR 7.51–16.50) doses of risperidone. There was no relationship between prolactin levels and duration of risperidone treatment. Dose-dependence is identified as a main factor associated with hyperprolactinemia in Thai children and adolescents with ASD treated with risperidone. This study suggests that risperidone treatment causes prolactin elevations and the effects of risperidone on prolactin are probably dose-related in pediatric patients.

Development and Validation of Liquid Chromatography/Tandem Mass Spectrometry Analysis for Therapeutic Drug Monitoring of Risperidone and 9-Hydroxyrisperidone in Pediatric Patients with Autism Spectrum Disorders.

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.

Significant Association of HLA-B Alleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study

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.

Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects

Background: Atypical antipsychotics have been found to be associated with hyperuricemia. Risperidone, one of the atypical antipsychotics, might be related to the hyperuricemia among autism spectrum disorder (ASD) patients. The aims of this study were to determine the prevalence of hyperuricemia in ASD patients treated with risperidone and to determine associations between serum uric acid levels and risperidone dosage, treatment duration, and metabolic parameters. Methods: 127 children and adolescents with ASD treated with risperidone and 76 age-matched risperidone-naïve patients with ASD were recruited. The clinical data and laboratory data were analyzed. Hyperuricemia was defined as serum uric acid >5.5 mg/dl. Results: Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD and 57.50% of ASD patients treated with risperidone. The fasting uric acid levels were significantly higher in the risperidone group than in the risperidone-naïve group (5.70 vs. 5.35 mg/dl, P = 0.01). The increased uric acid concentrations were significantly associated with adolescent patients treated with risperidone. The higher dose of risperidone and/or the longer treatment time were associated with the increased uric acid levels. Uric acid levels significantly rose with body mass index (BMI), waist circumference (WC), triglyceride (TG) levels, triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C), insulin levels, homeostatic model assessment index (HOMA-IR), high-sensitivity CRP (hs-CRP) levels, and leptin levels. Conversely, the levels of HDL-C and adiponectin were negatively correlated with uric acid levels. In multiple regression analysis, there were age, BMI, TG/HDL-C ratio, and adiponectin levels remained significantly associated with uric acid levels. Conclusion: Hyperuricemia may play a role in metabolic adverse effect in children and adolescents with ASDs receiving the high dose and/or the long-term treatment with risperidone.

Clinically relevant genetic variants of drug-metabolizing enzyme and transporter genes detected in Thai children and adolescents with autism spectrum disorder.

Single-nucleotide polymorphisms (SNPs) among drug-metabolizing enzymes and transporters (DMETs) influence the pharmacokinetic profile of drugs and exhibit intra- and interethnic variations in drug response in terms of efficacy and safety profile. The main objective of this study was to assess the frequency of allelic variants of drug absorption, distribution, metabolism, and elimination-related genes in Thai children and adolescents with autism spectrum disorder. Blood samples were drawn from 119 patients, and DNA was extracted. Genotyping was performed using the DMET Plus microarray platform. The allele frequencies of the DMET markers were generated using the DMET Console software. Thereafter, the genetic variations of significant DMET genes were assessed. The frequencies of SNPs across the genes coding for DMETs were determined. After filtering the SNPs, 489 of the 1,931 SNPs passed quality control. Many clinically relevant SNPs, including CYP2C19*2, CYP2D6*10, CYP3A5*3, and SLCO1B1*5, were found to have frequencies similar to those in the Chinese population. These data are important for further research to investigate the interpatient variability in pharmacokinetics and pharmacodynamics of drugs in clinical practice.

Pharmacogenomic Study Reveals New Variants of Drug Metabolizing Enzyme and Transporter Genes Associated with Steady-State Plasma Concentrations of Risperidone and 9-Hydroxyrisperidone in Thai Autism Spectrum Disorder Patients

The present study sought to investigate the genetic variants in drug metabolizing enzyme and transporter (DMET) genes associated with steady-state plasma concentrations of risperidone among Thai autism spectrum disorder (ASD) patients. ASD patients taking risperidone for at least 1 month were enrolled for this pharmacogenomic study. Genotyping profile was obtained using Affymetrix DMET Plus array interrogating 1931 variants in 231 genes. Steady-state plasma risperidone and 9-hydroxyrisperidone were measured using liquid chromatography/tandem mass spectrometry assay. The final analysis included 483 markers for 167 genes. Six variants, ABCB11 (c.3084A > G, c.∗420A > G, c.∗368G > A, and c.∗236G > A) and ADH7 (c.690G > A and c.-5360G > A), were found to be associated with plasma concentrations of risperidone. 9-Hydroxyrisperidone and the total active-moiety levels were associated with six gene variants, SCLO1B1 (c.-11187G > A and c.521T > C), SLCO1B3 (c.334G > T, c.699A > G, and c.1557G > A), and SLC7A5 c.∗438C > G. Polymorphisms in UGT2B4 c.∗448A > G and CYP2D6 (c.1661G > C, c.4180G > C, and c.-2178G > A) showed considerable but not significant associations with metabolic ratio. This pharmacogenomic study identifies new genetic variants of DMET genes in monitoring risperidone therapy.

Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders

OBJECTIVE To evaluate the influence of dose and duration of risperidone treatment on cardiovascular and diabetes risk biomarkers in children and adolescents with autistic spectrum disorders (ASDs). DESIGN AND METHODS In this cross-sectional analysis, a total of 168 ASDs patients (89% male) treated with a risperidone-based regimen for ≥12months were included. Blood samples were analyzed for glucose and lipid metabolic markers, adiponectin, leptin, prolactin, cortisol and high sensitive C-reactive protein. RESULTS The mean concentrations of glucose, insulin, prolactin and leptin and HOMA-IR significantly rose with risperidone dosage (all P<0.025), but those of adiponectin and cortisol did not. Using regression analysis, insulin, leptin, prolactin and glucose concentrations and HOMA-IR show significant association with dosage. None of the markers except adiponectin showed dependence on duration of treatment. However, insulin and leptin concentrations and HOMA-IR clearly increased with increasing both dosage and duration. Dosage and duration of treatment had minimal effect on standard lipid profile and lipoprotein subclasses. CONCLUSIONS Risperidone treatment disturbed glucose homeostasis and endocrine regulation (particularly leptin) in children and adolescents with ASDs, in a dose- and duration-dependent manner, being suggestive of leptin and insulin resistance mechanisms. Metabolic adverse effects, especially development of type 2 diabetes mellitus should be closely monitored, particularly in individuals receiving high doses and/or long-term risperidone treatment.

Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai Autistic Children and Adolescents

The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcome in autistic children and adolescents who were treated with risperidone for long periods. Eighty‐two autistic subjects diagnosed with DSM‐IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI‐I, aggressive, overactivity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), overactivity (71.95%), repetitive (70.89%) behaviour and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI‐I score. Patients in the non‐stable symptom group had DRD2 Taq1A non‐wild‐type (TT and CT) frequencies higher than the clinically stable group (p = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non‐stable clinical outcome (χ2 = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcome. On the other hand, risperidone dose, 9‐OH risperidone levels and prolactin levels were significantly higher in the non‐stable compared to the stable symptom group (p = 0.013, p = 0.044, p = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body‐weight, whereas it was not significantly associated with genetic variations and non‐genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long‐term treatment. However, Taq1A T – carrier of dopamine 2 receptor gene – is associated with non‐stable response in risperidone‐treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents.

Association between HLA-B*1502 allele and aromatic antiepileptic drugs-induced hypersensitivity syndrome reactions and the HLA-B*15:02 pharmacogenetics screening in autistic spectrum disorder

Some autistic children also have symptoms of depression, anxiety or obsessive-compulsive disorder (OCD). Aromatic anti-epileptic drugs (AEDs) may be used as a mood-stabilizing medication to treat these symptoms, including carbamazepine (CBZ), oxcarbazepine (OX-CBZ), and lamotrigene (LMG). Moreover, one in every four autistic spectrum disorder children have seizures, the use of AED becomes imperative in managing symptoms. Previous studies found a strong association between HLA-B*1502 and carbamazepine (CBZ)-induced cutaneous adverse reactions in Thai epileptic patients. This study aimed to identify whether HLA-B*1502 is associated with AEDs-induced hypersensitivity syndrome (HSS) reactions and also determine the frequency of HLA-B*15:02 in autistic spectrum disorder (ASD) in Thailand. In this study, patients that developed fever and cutaneous eruptions in the presence or absence of organ involvement with exposure to carbamazepine (CBZ), phenytoin (PHY), or lamotrigine (LTG) were enrolled. HLA-B* 15:02 was then determined in 21 patients with AED-induced HSS (6 with CBZ-HSS, 4 PHY-HSS patients and 11 LTG-HSS patients and 292 children with ASD. HLA-B genotyping using PCR-SSOP methods was performed. HLA-B*15:02 was observed with HSS-induced by AEDs, which included carbamazepine (n=4; 66.7%), phenytoin (n=2; 50%), and lamotrigine (n=3; 27%). In addition, the allele frequencies of HLA-B*15:02 in ASD was 14.72% (43/292). HSS-induced by CBZ, PHY and LMG is strongly, moderately and slightly associated with HLA-B*15:02 in Thai patients, respectively. Our findings suggest that HLA-B*15:02 testing before AED therapy would be effective at risk of hypersensitivity and applicable to ASD populations providing hope for prevention in the future.