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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...
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... Pearson's χ 2 test or Fisher's exact test of each parameter between two groups, the results showed that there was a statistically significant relationships between the presence of hyperprolactinemia and sex (P=0.001) and risperidone-dose group (P=0.004). However, there was no significant relationship in age-group and type of drug use found between patients with and without hyperprolactinemia, as summarized in Table 2. ...
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Citations
... All subjects were recruited from the Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Samut Prakan, Thailand. Some of the samples used in this investigation were taken from a prior study conducted by our organization (Hongkaew et al., 2015). Drug substrates, inhibitors and inducers of CYP2D6 enzyme were excluded from this study. ...
... The current study's multivariate analysis discovered a significant relationship between high risperidone dose and high prolactin levels. This is similar to another study which investigated the influence of clinical factors on the prolactin level in risperidone treated patients and reported a significant association between higher doses and hyperprolactinemia, but no significant association was found with duration of risperidone treatment (Hongkaew et al., 2015). ...
Abstract
Background
Risperidone causes hyperprolactinemia by blocking D2 receptors on lactotrophs anterior pituitary, which prevents prolactin secretion inhibition. Risperidone is converted to 9-hydroxyrisperidone by the CYP2D6 enzyme. Polymorphisms in CYP2D6 may affect serum prolactin and could be a predictor of hyperprolactinemia. The goal of this study was to see if there was an association between CYP2D6 variants, risperidone dose, clinical data and serum prolactin levels in Thai children and adolescents with autism spectrum disorder (ASD).
Method
In 107 Thai ASD patients on risperidone, allele-specific primer extension and multiplex PCR platforms were used to genotype the CYP2D6 gene. The chemiluminescence immunoassay (CLIA) technique was used to measure fasting serum prolactin levels.
Results
The median serum prolactin level was 16.25 ng/mL (IQR; 10.43-22.18), and patients with CYP2D6*1/*5 (6.54%) had substantially lower prolactin levels than those with CYP2D6*1/*1 [median; 11.2 ng/mL (IQR; 3.95-21.10) vs. 21.3 (IQR; 14.43-32.18), p=0.032]. CYP2D6*1/*10, *10/*10, and *10/*41 produced less prolactin than *1/*1 (wild type). Furthermore, gender and risperidone dose were associated with significantly different prolactin levels with p-value 0.02 and 0.006, respectively. Multivariate analysis showed a significant association of serum prolactin level with body mass index and risperidone dose (p<0.05).
Conclusions
Our study showed that CYP2D6 carriers of absent and decreased functional alleles had lower serum prolactin levels in Thai ASD patients treated with risperidone treatment; this is important to clinicians, indicating that they should consider about CYP2D6 genotyping before beginning risperidone in ASD patients. CYP2D6 genotypes might be a predictor for levels of prolactin in clinical treatment.
... BUN, Cr, and Ccr are indicators of renal function, which are also included in the prediction model according to our results. It is proven in a long-term study that risperidone treatment induced PRL increase and hyperprolactinemia (27). Serum concentration of 9-hydroxyrisperidone was predominantly related to increased PRL levels, especially in autistic patients with hyperprolactinemia during risperidone treatment (28). ...
Risperidone is an efficacious second-generation antipsychotic (SGA) to treat a wide spectrum of psychiatric diseases, whereas its active moiety (risperidone and 9-hydroxyrisperidone) concentration without a therapeutic reference range may increase the risk of adverse drug reactions. We aimed to establish a prediction model of risperidone active moiety concentration in the next therapeutic drug monitoring (TDM) based on the initial TDM information using machine learning methods. A total of 983 patients treated with risperidone between May 2017 and May 2018 in Beijing Anding Hospital were collected as the data set. Sixteen predictors (the initial TDM value, dosage, age, WBC, PLT, BUN, weight, BMI, prolactin, ALT, MECT, Cr, AST, Ccr, TDM interval, and RBC) were screened from 26 variables through univariate analysis (p < 0.05) and XGBoost (importance score >0). Ten algorithms (XGBoost, LightGBM, CatBoost, AdaBoost, Random Forest, support vector machine, lasso regression, ridge regression, linear regression, and k-nearest neighbor) compared the model performance, and ultimately, XGBoost was chosen to establish the prediction model. A cohort of 210 patients treated with risperidone between March 1, 2019, and May 31, 2019, in Beijing Anding Hospital was used to validate the model. Finally, the prediction model was evaluated, obtaining R² (0.512 in test cohort; 0.374 in validation cohort), MAE (10.97 in test cohort; 12.07 in validation cohort), MSE (198.55 in test cohort; 324.15 in validation cohort), RMSE (14.09 in test cohort; 18.00 in validation cohort), and accuracy of the predicted TDM within ±30% of the actual TDM (54.82% in test cohort; 60.95% in validation cohort). The prediction model has promising performance to facilitate rational risperidone regimen on an individualized level and provide reference for other antipsychotic drugs' risk prediction.
... In our study, 44.35% (55 of 124) of patients had high prolactin levels, which is a concern for adverse drug reactions in children and adolescents treated with risperidone. The reported prevalence of hyperprolactinemia in patients on risperidone ranges between 44 and 61% (Hongkaew et al., 2015;An et al., 2016;Bonete Llacer et al., 2019), and abnormal prolactin levels occur in about 27% of patients taking risperidone (Lally et al., 2017). Hypothalamic dopamine inhibits prolactin secretion by acting on dopamine D2 receptors, which inhibits lactotroph cells (Ben-Jonathan and Hnasko, 2001). ...
We investigated the association between genetic variations in pharmacodynamic genes and risperidone-induced increased prolactin levels in children and adolescents with autism spectrum disorder (ASD). In a retrospective study, variants of pharmacodynamic genes were analyzed in 124 ASD patients treated with a risperidone regimen for at least 3 months. To simplify genotype interpretation, we created an algorithm to calculate the dopamine D2 receptor (DRD2) gene genetic risk score. There was no relationship between prolactin levels and single SNPs. However, the H1/H3 diplotype (A2/A2-Cin/Cin-A/G) of DRD2/ankyrin repeat and kinase domain containing 1 (ANKK1) Taq1A, DRD2 -141C indel, and DRD2 -141A>G, which had a genetic risk score of 5.5, was associated with the highest median prolactin levels (23 ng/ml). As the dose-corrected plasma levels of risperidone, 9-OH-risperidone, and the active moiety increased, prolactin levels in patients carrying the H1/H3 diplotype were significantly higher than those of the other diplotypes. DRD2 diplotypes showed significantly high prolactin levels as plasma risperidone levels increased. Lower levels of prolactin were detected in patients who responded to risperidone. This is the first system for describing DRD2 haplotypes using genetic risk scores based on their protein expression. Clinicians should consider using pharmacogenetic-based decision-making in clinical practice to prevent prolactin increase.
... Um estudo revelou que os níveis séricos de prolactina no grupo crianças e adolescentes com TEA que usavam doses altas da risperidona foi significativamente maior do que nos grupos que usavam doses recomendadas e baixas de risperidona e verificou que quanto mais alta a dose de risperidona, maior é o aumento no nível médio de prolactina sérica. Entretanto, mesmo com o uso de doses recomendadas pelo Food and Drug Administration (FDA) para pacientes pediátricos, o tratamento com risperidona pode causar hiperprolactinemia (39). ...
O transtorno do espectro autista (TEA) é um distúrbio de desenvolvimento neurológico, apresentando comprometimentos de ordem sócio, comunicativa e comportamental. A risperidona é um medicamento antipsicótico que tem sido usado para alívio dos sintomas e melhoria comportamental do TEA, no entanto,
vários efeitos adversos foram identificados. O objetivo deste trabalho foi realizar uma revisão da literatura sobre os efeitos adversos da risperidona especificamente em indivíduos com TEA. Foram realizadas buscas abrangentes nas bases de dados MedLine, PsycInfo e Science Direct, utilizando os descritores: “Autism Spectrum Disorder”, “Risperidone” e “Drug Related Side Effects and Adverse Reactions”. Por meio desta busca foram selecionados 29 artigos, publicados entre 2000 e 2019. Os resultados mostraram uma heterogeneidade de reações adversas, sendo as mais prevalentes: aumento de apetite e ganho de peso, sonolência, hiperprolactinemia, sintomas gastrointestinais, taquicardia e efeitos extrapiramidais. A maioria delas apresenta grau leve ou moderado e bem gerenciável. Entretanto, estudos mais recentes indicam que existem características do autismo que podem influenciar a resposta à risperidona e elevar o risco de surgimento de reações adversas, principalmente ligadas aos polimorfismos genéticos, ao compartilhamento de condições médicas concomitantes, às interações medicamentosas, entre outros. Dessa forma, considerando a complexidade do TEA e a vulnerabilidade de crianças e jovens autistas, esse medicamento deve ser usado com cautela nessa população, com prévia triagem, acompanhamento dos fatores de risco e monitoramento do uso, em especial quando for necessário uso prolongado.
... The reports on PRL levels in children and adolescent patients have shown that these populations present elevated HPRL, which has been reported in 44.9% of autism spectrum disorder (ASD) patients as unrelated to the duration of risperidone treatment (0.25-5 mg/kg, 1.03-158.03 months) (127). Still, there is evidence exposing the possible relation between plasma metabolite levels of risperidone and elevated PRL concentrations (128). ...
Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders.
... For observational studies, eight studies were judged as having a low risk of bias [33,[67][68][69][70][71][72][73], and six fell under the moderate risk of bias category [31,32,[74][75][76][77]. Agreement between the two reviewers for the quality assessment of the included papers was good (kappa value 0.63; 95% CI − 0.025 to 1.000). ...
Background
Antipsychotic medication is a commonly prescribed drug class in individuals with autism spectrum disorder (ASD). However, the safety of these agents has not been fully assessed.
Objective
Our objective was to investigate the safety and tolerability profile of antipsychotics in individuals with ASD.
Methods
The Cochrane Library, MEDLINE, Embase and PsycINFO databases were searched up to January 2018. We included studies that reported adverse events (AEs) in participants with ASD taking first- or second-generation antipsychotic medication. The studies included in the analysis were randomized controlled trials (RCTs) and observational studies that were comparative or noncomparative and published as full text in the English language. The primary outcome of this review was AEs of any severity reported with antipsychotic use at any dose. Meta-analysis was performed on studies with child and adolescent participants to estimate the pooled prevalence of the overall AEs and the relative risk (RR) of AEs associated with antipsychotic use using a random-effects model. The Cochrane Collaboration tool and the modified Newcastle–Ottawa Scale (NOS) were used to assess the risk of bias of the included RCTs and observational studies, respectively.
Results
In total, 54 citations fulfilled the inclusion criteria, of which 40 were RCTs and 14 were observational studies; eight RCTs were included in the meta-analysis to estimate the RR of AEs associated with antipsychotic use and seven observational studies were included to estimate the pooled prevalence of AEs. The RR of AEs with antipsychotic treatment was 22% higher than with placebo (RR 1.22; 95% confidence interval [CI] 1.11–1.34; I² = 30.6%; p = 0.184). The estimated pooled prevalence of AEs was 50.5% (95% CI 33–67). The most commonly reported AEs were increased appetite and weight gain, which were associated with discontinuation in many participants.
Conclusion
Antipsychotic-related AEs were common among patients with ASD. Further studies to investigate the implications of antipsychotic-related AEs on health and medication adherence are warranted. PROSPERO registration number: (CRD42018083632)
... Several studies have demonstrated the efficacy and safety of risperidone in improving behavioral problems associated with ASD [3][4][5]. However, evidences suggest the link between risperidone treatment and serum prolactin level elevations among ASD children [6][7][8][9]. The clinical manifestations of hyperprolactinemia are menstrual disturbances, amenorrhea, infertility, and galactorrhea in women and gynecomastia, decreased libido, and impotence in men. ...
... The sample size was calculated according to the equation n = [(Z α/2 ) 2 (p)(1−p)]/d 2 where Z α/2 represents the value for a 95% confidence interval = 1.96, p represents the prevalence of risperidone-induced hyperprolactinemia in Thailand [7] = 0.45, and d represents the allowed error of the test = 0.15. According to the calculation, at least 43 samples should be collected for statistical validity. ...
... Hyperprolactinemia was defined as a serum prolactin level greater than the 97.5th percentile value of age-and sex-matched control subjects [22]. The cutoff points for the 97.5th percentile values by patient age and sex for prolactin levels were: 14 4-6, 7-8, 9-10, 11, 12, 13, 14, 15, 16, 17, and 18-19 years old, respectively according to Elmlinger et al. [7,8,18,22]. ...
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.
... For example, patients prescribed SGA drugs often show greater improvement in negative and cognitive symptoms, higher functional capacity, and have better quality of life with lower risks of extrapyramidal side effects (EPS) and tardive dyskinesia (TD) [3]. However, some concerns exist about treatment with risperidone as it may induce side effects such as hyperprolactinaemia [4][5][6], hyperuricaemia [7], weight gain [8] and dyslipidaemia [9]. Additionally, risperidone could increase the risk of type 2 diabetes [10]. ...
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 five percent of the patients presented with hyperglycaemia. Insulin resistance was detected in 16 percent of the patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (P=0.01 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.
... Prolactin that binds to its receptors in the hypothalamus might be related to the control of aggression in human beings [36]. Risperidone dose and DRD2 variation were found to be associated with high prolactin levels in previous studies [23,37]. On the other hand, prolactin levels in this study showed only an association with HTR2A polymorphism but not with DRD2 polymorphisms. ...
The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcomes 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, over-activity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), over-activity (71.95%), repetitive (70.89%) behavior 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-wildtype (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(2) = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcomes. 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 dopamine2 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 article is protected by copyright. All rights reserved.
... In our view, increase in prolactin merits particular attention. First, increase in prolactin levels under RISP has been observed repeatedly (Hongkaew et al., 2015;Maayan and Correll, 2011;Park and Park, 2015;Peuskens et al., 2014). Second, in children and adolescents, hyperprolactinemia might result in galactorrhea, amenorrhea, gynecomastia, and maturational delay with growth failure (Fideleff and Boquete, 2009). ...
Children with ADHD often show symptoms of oppositional defiant disorders (ODD). We investigated the impact
of adjuvant risperidone (RISP) to a standard treatment with methylphenidate (MPH) in children with ADHD
and symptoms of ODD. Eighty-four children with ADHD and ODD (age: M=8.55; range: 7.28–9.95 years;
73.8% males) took part in a double-blind, randomized, placebo-controlled, clinical trial lasting eight weeks.
Participants were randomly assigned either to the MPH+RISP (1 mg/kg/d+0.5 mg/d) or to the MPH+PLCO
(1 mg/kg/d+placebo) condition. Symptoms of ADHD, weight, height, and blood pressure were assessed at
baseline, and at weeks 2, 4, 6 and 8. Symptoms of ADHD decreased over time, but more so in the MPH+RISP
than in the MPH only condition. In the MPH+RISP condition weight, waist circumference and prolactine levels
increased over time. Data suggest that adjuvant RISP improved symptoms in children with ADHD and ODD,
but weight gain and higher prolactine levels were also observed, which are two alarming side effects. This may
become an issue, once children become adolescents, a period of life in which body shape and body self-image are closely linked to self-confidence and peer acceptance. Health care professionals should carefully balance the short-term and long-term costs and benefits of administration of RISP.
