Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

Sukasem, Chonlaphat; Vanwong, Natchaya; Srisawasdi, Pornpen; Ngamsamut, Nattawat; Nuntamool, Nopphadol; Hongkaew, Yaowaluck; Puangpetch, Apichaya; Chamkrachangpada, Bhunnada; Limsila, Penkhae

doi:10.1111/bcpt.12970

Cited by 29 publications

(15 citation statements)

References 66 publications

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“…However, the relation of ABCB1 1236C>T with overweight/obesity did not survive Bonferroni correction ( Table 6). The current study supports prior reports that did not find associations between ABCB1 1236C>T, 2677T>A, and 3435C>T polymorphisms with the risperidone response (Nuntamool et al, 2017), with metabolic abnormality/insulin resistance (Sukasem et al, 2018), or with steady-state plasma concentrations of risperidone or 9-hydroxyrisperidone (Yasui-Furukori et al, 2004). However, here further discrepancies are apparent in the literature, where the ABCB1 1236C>T polymorphism showed a significant association with response to risperidone (Xing et al, 2006) and an observed effect of the ABCB1 2677G>T and 3435C>T polymorphisms on risperidone-induced weight gain in patients with schizophrenia (Kuzman et al, 2008).…”

Section: Discussionsupporting

confidence: 92%

Risperidone-Induced Obesity in Children and Adolescents With Autism Spectrum Disorder: Genetic and Clinical Risk Factors

et al. 2020

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Aims: Obesity is a significant problem for patients taking atypical antipsychotics. There were two aims of our study. The first aim was to compare the prevalence of overweight and obesity between children and adolescents with autism spectrum disorder (ASD) treated with risperidone with the general pediatric population. The second aim was to investigate the association of the HTR2C-759C>T, ABCB1 1236C>T, ABCB1 2677G>T/A, and ABCB1 3435C>T polymorphisms with risperidone-induced overweight and obesity in children and adolescents with ASD. Methods: Body weight and height were measured in 134 subjects. Overweight and obesity in children and adolescents were classified using the International Obesity Task Force (IOTF) criteria. Genotyping was performed by TaqMan real-time polymerase chain reaction (PCR). Results: Our study found that the prevalence of overweight and obesity was significantly higher in children and adolescents with ASD treated with risperidone compared with healthy individuals (p 0.01 and p 0.002). The genetic polymorphisms of HTR2C-759C>T, ABCB1 1236C>T, ABCB1 2677G>T/A, and ABCB1 3435C>T were not associated with overweight/obesity in children and adolescents with ASD treated with risperidone after adjustment for multiple comparisons by the method of Bonferroni. Additionally, haplotype analysis revealed that there was no significant association between ABCB1 3435T-2677T/A-1236T haplotype and overweight/obesity. In multivariate logistic regression, after adjustment by the Bonferroni correction, there was only the duration of risperidone treatment that was significantly associated with overweight/obesity in children and adolescents with ASD. Conclusions: The findings suggest that children and adolescents with ASD treated with risperidone are at a higher risk of obesity, especially patients with extended treatment with risperidone. For the pharmacogenetic factors,-759C>T polymorphism of HTR2C gene

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Section: Discussionsupporting

confidence: 92%

Risperidone-Induced Obesity in Children and Adolescents With Autism Spectrum Disorder: Genetic and Clinical Risk Factors

et al. 2020

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“…After scanning the titles and abstracts, 62 articles relevant to present subject were identified for full-text scrutiny. Several studies were excluded as they did not have necessary data (11 studies) [20][21][22][23][24][25][26][27][28][29][30] ; lack of healthy controls (6 studies) [31][32][33][34][35][36] ; sample source is not peripheral blood (5 studies) 18,[37][38][39][40] ; samples derived from postmortem brain (3 studies) 10,11,41 ; participants were adults (3 study) 16,42,43 ; had patient samples that overlapped with another studies (1 study) 44 ; neurotrophic factors were studied in less than 3 articles (1 study) 19 and non-English publication (1 studies) 45 . Therefore, a total of 31 studies met the criteria were included for this meta-analysis ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Peripheral blood neurotrophic factor levels in children with autism spectrum disorder: a meta-analysis

Liu

Xiao

Fan

et al. 2021

Sci Rep

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Increasing evidence suggests that abnormal regulation of neurotrophic factors is involved in the etiology and pathogenesis of Autism Spectrum Disorder (ASD). However, clinical data on neurotrophic factor levels in children with ASD were inconsistent. Therefore, we performed a systematic review of peripheral blood neurotrophic factors levels in children with ASD, and quantitatively summarized the clinical data of peripheral blood neurotrophic factors in ASD children and healthy controls. A systematic search of PubMed and Web of Science identified 31 studies with 2627 ASD children and 4418 healthy controls to be included in the meta-analysis. The results of random effect meta-analysis showed that the peripheral blood levels of brain-derived neurotrophic factor (Hedges’ g = 0.302; 95% CI = 0.014 to 0.591; P = 0.040) , nerve growth factor (Hedges’ g = 0.395; 95% CI = 0.104 to 0.686; P = 0.008) and vascular endothelial growth factor (VEGF) (Hedges’ g = 0.097; 95% CI = 0.018 to 0.175; P = 0.016) in children with ASD were significantly higher than that of healthy controls, whereas blood neurotrophin-3 (Hedges’ g = − 0.795; 95% CI = − 1.723 to 0.134; P = 0.093) and neurotrophin-4 (Hedges’ g = 0.182; 95% CI = − 0.285 to 0.650; P = 0.445) levels did not show significant differences between cases and controls. Taken together, these results clarified circulating neurotrophic factor profile in children with ASD, strengthening clinical evidence of neurotrophic factor aberrations in children with ASD.

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“…Leptin acts by directly regulating pancreatic β cells and insulin-sensitive tissues, independent of its effects on adiposity 39. In our previous study on children and adolescents with autistic spectrum disorders, we demonstrated that risperidone therapy directly and adversely affects glucose homeostasis by inhibiting the actions of leptin and insulin 40,41. Studies on mice conducted by Cheng et al revealed that palmitic acid and arachidonic acid can inhibit leptin signaling in the paraventricular nucleus of the hypothalamus, attenuating the central leptin regulation of glucose homeostasis 42,43.…”

Section: Discussionmentioning

confidence: 95%

Association between polymorphisms of LEP, LEPR, DRD2, HTR2A and HTR2C genes and risperidone- or clozapine-induced hyperglycemia

Puangpetch

Srisawasdi

Unaharassamee

et al. 2019

PGPM

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Objective To determine whether genetic polymorphisms related to pharmacodynamics with metabolic adverse effects, namely leptin promoter ( LEP ) rs7799039, leptin receptor rs1137101, dopamine D2 rs4436578, serotonin 5-HT2A rs6313, and serotonin 5-HT2C rs518147 and rs12836771, are associated with hyperglycemia induced by risperidone or clozapine in adult Thai patients with psychosis. Methods A total of 180 patients treated with risperidone-based ( n =130) or clozapine-based ( n =50) regimens were included in this study. Blood samples were analyzed for genotyping of the candidate genes and biochemical testing. Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis. Results The prevalence of hyperglycemia was higher in patients receiving clozapine (64.0%) than in those receiving risperidone (30.8%). Among the candidate genes, only the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia (χ 2 =9.879, P =0.008) in patients treated with risperidone; patients with the AA genotype had the highest risk (41.1%), followed by those with AG (20.8%) and GG (0%) genotypes. Using the recessive genetic model (AA vs AG + GG), the odds ratio and 95% CI were 3.28 and 1.44 −7.50, respectively. None of the genes were associated with hyperglycemia in patients treated with clozapine. A binary logistic regression revealed that the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia, independent of body-mass index (BMI) in patients receiving risperidone; the odds ratio (95% CI) was 3.188 (1.399–7.262), P =0.006. By contrast, none of the pharmacodynamic genetic factors, except for BMI, were significantly associated with hyperglycemia in patients receiving clozapine. Conclusion The risk of type 2 diabetes mellitus is associated with the LEP rs7799039 polymorphism in Thai adults receiving risperidone but not in those receiving clozapine. Clarifying underlying mechanisms and risk of hyperglycemia provides an opportunity to prevent impaired glucose metabolism in patients receiving risperidone or clozapine.

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Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

Cited by 29 publications

References 66 publications

Risperidone-Induced Obesity in Children and Adolescents With Autism Spectrum Disorder: Genetic and Clinical Risk Factors

Risperidone-Induced Obesity in Children and Adolescents With Autism Spectrum Disorder: Genetic and Clinical Risk Factors

Peripheral blood neurotrophic factor levels in children with autism spectrum disorder: a meta-analysis

<p>Association between polymorphisms of <em>LEP</em>,<em> LEPR</em>, <em>DRD2</em>, <em>HTR2A</em> and<em> HTR2C</em> genes and risperidone- or clozapine-induced hyperglycemia</p>

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