paliperidone-palmitate and Autism-Spectrum-Disorder

Paliperidone is FDA-approved for schizophrenia aged 12-17. However, the pharmacologic portfolio, extrapolation from adult studies, and the long track record of the parent drug, risperidone in child/adolescent psychiatric (CAP) population might expand its therapeutic potential.. EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant studies of using paliperidone in child psychiatry up to date of February 2019.. Sound evidence base supports its use in early-onset schizophrenia, juvenile bipolar, and autism spectrum disorder. A modicum of evidence supports its use in Tourette syndrome and as adjuventia in attention-deficit/hyperactivity disorder (ADHD).. Paliperidone has some dynamic and kinetic superiority to the parent drug risperidone. Nonetheless, larger rigorous studies would define the real place of the atypical antipsychotic paliperidone in child and adolescent psychiatry. Until then, risperidone with its long track record in CAP population would remain a first option though.

Topics: Adolescent; Antipsychotic Agents; Attention Deficit and Disruptive Behavior Disorders; Autism Spectrum Disorder; Basal Ganglia Diseases; Bipolar Disorder; Child; Child Psychiatry; Humans; Long QT Syndrome; Off-Label Use; Paliperidone Palmitate; Schizophrenia; Tourette Syndrome; Treatment Outcome

Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness.. Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models.. A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01).. Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.

Topics: Adolescent; Antipsychotic Agents; Autism Spectrum Disorder; Child; Cytochrome P-450 CYP2D6; Humans; Male; Paliperidone Palmitate; Risperidone

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).. 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).. 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.. 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.

Topics: Alleles; Antipsychotic Agents; Autism Spectrum Disorder; Child; Chromatography, Liquid; Cytochrome P-450 CYP2D6; Female; Genotype; Humans; Male; Paliperidone Palmitate; Polymorphism, Genetic; Real-Time Polymerase Chain Reaction; Risperidone; Tandem Mass Spectrometry; Thailand

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.

Topics: Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Hyperprolactinemia; Linear Models; Male; Multivariate Analysis; Paliperidone Palmitate; Prolactin; Risperidone; Thailand; Young Adult

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.. 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.. 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.. The determination of RIS in individual patients might be clinically useful for monitoring and prediction of treatment response.

Topics: Antipsychotic Agents; Autism Spectrum Disorder; Chromatography, Liquid; Drug Monitoring; Female; Humans; Male; Paliperidone Palmitate; Risperidone; Statistics as Topic; Statistics, Nonparametric; Tandem Mass Spectrometry