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.

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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 (χ = 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.

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.

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 (r s = 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.Risperidone is the most used pharmacotherapy for irritability in autism spectrum disorder (ASD) and is currently approved by the US Food and Drug Administration (FDA) [1,2]. Moreover, risperidone has been demonstrated to have moderate and clinically significant benefits [3] in treatment of behavioural disturbances, including attention deficit hyperactivity disorder, anxiety disorders and obsessive-compulsive disorder [4].Primarily, risperidone is metabolized in the liver by the CYP2D6 enzyme. The main metabolite of risperidone, 9-hydroxyrisperidone, has similar pharmacological activity as its parent compound, and the serum concentration of the active moiety is thus the sum of the serum concentrations of risperidone and 9-hydroxyrisperidone [5]. Risperidone has high susceptibility to elevate prolactin levels compared with other atypical antipsychotic therapies [6] because these medications are known to have a potent antagonistic activity against serotonin 5HT2, but mild dopamine D2 antagonistic activity [7,8]. Elevation of prolactin concentration corresponds to dopamine D2 receptor blockade [9,10]. Most studies report that children and adolescents treated with risperidone have 38-50% incidence of hyperprolactinaemia [4,[11][12][13][14][15][16].Early studies reported adverse effects associated with prolactin elevation because hyperprolactinaemia is one of the most common endocrinological disorders of the hypothalamic-...

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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.

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.