Pharmacogenetic influences on the response to pharmacological treatment in autism spectrum disorders

Hervás, Amaia; Serra-LLovich, Alexandre; Rueda, Isabel; Targa, Irene; Guijarro, Silvina; Bigorra, Aitana; Cancino, Martha; Bote, Valentin; Cárcel, Maria; Amasi-Hartoonian, Nare; Hernández, Marta; Arranz, Maria

doi:10.20517/jtgg.2021.25

Cited by 4 publications

(5 citation statements)

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“…15 We combined the information obtained in this study with the information on the dopamine transporter SLC6A3 gene from a previous study to investigate possible synergistic effects. 34 However, we did not find any statistically significant association supporting a synergistic effect.…”

Section: Discussioncontrasting

confidence: 75%

“…The results of the genotyping of a SLC6A3 3UTR_VNTR variant from a previous study were included to analyze possible synergistic interactions between the three genes. 34 This sample has ≥70–85% statistical power to detect associations with ORs ≥3 with genetic variants with MAF=0.05–0.10, respectively (95% CI, two-sided, calculated with EpiInfo v. 7.2.5.0).…”

Section: Methodsmentioning

confidence: 99%

“…Pharmacogenomics and Personalized Medicine 2022:15 952 genes. 34 This sample has ≥70-85% statistical power to detect associations with ORs ≥3 with genetic variants with MAF=0.05-0.10, respectively (95% CI, two-sided, calculated with EpiInfo v. 7.2.5.0).…”

Section: Dovepressmentioning

confidence: 99%

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CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders

Hernández¹,

Bote²,

Serra-LLovich³

et al. 2022

PGPM

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Autistic spectrum disorders (ASD) children and adolescents usually present comorbidities, with 40-70% of them affected by attention deficit hyperactivity disorders (ADHD). The first option of pharmacological treatment for these patients is methylphenidate (MPH). ASD children present more side effects and poorer responses to MPH than ADHD children. The objective of our study is to identify genetic biomarkers of response to MPH in ASD children and adolescents to improve its efficacy and safety. Patients and Methods: A retrospective study with a total of 140 ASD children and adolescents on MPH treatment was included. Fifteen polymorphisms within genes coding for the MPH target NET1 (SLC6A2) and for its primary metabolic pathway (CES1) were genotyped. Multivariate analyses including response phenotypes (efficacy, side-effects, presence of somnolence, irritability, mood alterations, aggressivity, shutdown, other side-effects) were performed for every polymorphism and haplotype. Results: Single marker analyses considering gender, age, and dose as covariates showed association between CES1 variants and MPH-induced side effects (rs2244613-G (p=0.04), rs2302722-C (p=0.02), rs2307235-A (p=0.03), and rs8192950-T alleles (p=0.03)), and marginal association between the CES1 rs2302722-C allele and presence of somnolence (p=0.05) and the SLC6A2 rs36029-G allele and shutdown (p=0.05). A CES1 haplotype combination was associated with efficacy and side effects (p=0.02 and 0.03 respectively). SLC6A2 haplotype combination was associated with somnolence (p=0.05). Conclusion: CES1 genetic variants may influence the clinical outcome of MPH treatment in ASD comorbid with ADHD children and adolescents.

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Section: Discussioncontrasting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

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CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders

Hernández¹,

Bote²,

Serra-LLovich³

et al. 2022

PGPM

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“…The most common adverse effects include decreased appetite, sleep disturbances, increased blood pressure, and increased heart rate. The risk of serious adverse effects such as suicidal attempts is very low [74].…”

Section: Discussionmentioning

confidence: 99%

Influence of COMT (rs4680) and DRD2 (rs1076560, rs1800497) Gene Polymorphisms on Safety and Efficacy of Methylphenidate Treatment in Children with Fetal Alcohol Spectrum Disorders

Śmiarowska

Brzuchalski

Grzywacz

et al. 2022

IJERPH

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Fetal alcohol spectrum disorders (FASD) in a course of high prenatal alcohol exposure (hPAE) are among the most common causes of developmental disorders. The main reason for pharmacological treatment of FASD children is attention deficit hyperactivity disorder (ADHD), and methylphenidate (MPH) is the drug of choice. The aim of the study was to assess whether children born of hPAE with ADHD, with or without morphological FASD, differ in terms of catechol-O-methyltransferase (COMT) and dopamine receptor D2 (DRD2) gene polymorphisms, and if genetic predisposition affects response and safety of MPH treatment. The polymorphisms of COMT (rs4680) and DRD2 (rs1076560, rs1800497) were analyzed in DNA samples. A borderline significance was found for the correlation between MPH side effects and the G allele of COMT (rs4680) (p = 0.04994) in all ADHD children. No effect of COMT (rs4680) and DRD2 (rs1076560, rs1800497) polymorphisms and the treatment efficacy was observed. The analyzed DRD2 and COMT gene polymorphisms seem to play no role in MPH efficacy in ADHD children with hPAE, while low-activity COMT (Met158) variant carriers may be more intolerant to MPH. The MPH treatment is effective in ADHD independent of FASD, although the ADHD-FASD variant requires higher doses to be successful. These results may help in optimization and individualization in child psychiatry.

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“…[14][15][16] Less evidence exists for the application of pharmacodynamic genetic results, but investigations continue evaluating associations with dopaminergic and serotonergic variants. 17 The application of pharmacogenetic information is included on Food and Drug Administration (FDA) labels for some drugs, and multidisciplinary pharmacogenetic guidelines are available for some selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics; however, this guidance is not specific to ASD and is commonly based on studies of neurotypical adults. 18 Some research has demonstrated the benefits of pharmacogenetic testing in children with epilepsy, which may have relevance for youth with ASD given the elevated rates of epilepsy in this population.…”

mentioning

confidence: 99%

Pharmacogenetic Testing in Patients with Autism Spectrum Disorder Evaluated in a Precision Medicine Clinic

Goodson,

Wagner,

Sandritter

et al. 2023

J Dev Behav Pediatr

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Objective: This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results. Methods: Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital's precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients' co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories. Results: Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status. Conclusion: In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.

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Pharmacogenetic influences on the response to pharmacological treatment in autism spectrum disorders

Cited by 4 publications

References 0 publications

CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders

CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders

Influence of COMT (rs4680) and DRD2 (rs1076560, rs1800497) Gene Polymorphisms on Safety and Efficacy of Methylphenidate Treatment in Children with Fetal Alcohol Spectrum Disorders

Pharmacogenetic Testing in Patients with Autism Spectrum Disorder Evaluated in a Precision Medicine Clinic

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