METABOLIC ADVERSE EFFECTS INDUCED BY SECOND GENERATION ANTIPSYCHOTIC DRUGS IN PEDIATRIC PATIENTS: PHARMACOGENETIC PROFILING AND MECHANISTIC ANALYSIS OF GENETIC VARIANTS EFFECT IN VITRO MODELS
type: CreativeWork
description: Second-generation antipsychotics (SGAs) are increasingly used in pediatric patients both in and offlabel. The rise in SGA prescription rates may be due to the perception of improved safety compared with first-generation antipsychotics. However, SGA use is often associated with rapid weight gain and metabolic syndrome as adverse drug reactions (ADRs). Interestingly, these side effects are not observed in all SGA-treated children, suggesting that some underlying genetic factors may predispose an individual to develop these adverse conditions. Recent studies have identified single nucleotide polymorphisms (SNPs) in genes encoding for enzymes involved in drug metabolism (CYP450) and SGA receptors in the central nervous system (CNS), which partly explain the inter-patient variability in ADR development. With this project, we intend to define the role of SNPs in genes related to the pharmacodynamics of SGA, expressed in peripheral tissues, to evaluate their involvement in the mechanisms responsible for weight change and metabolic ADRs. To this end in a cohort of 209 paediatric patients affected by disruptive behavioural disturbance who are prescribed SGAs (risperidone and aripiprazole), we have assessed the association of pharmacodynamics genetic variants with the occurrence of changes in body mass index (BMI) Zscore. This allows us to evaluate if the presence of specific variant alleles increases or decreases the risk of weight changes and metabolic adverse events. Tested SNPs will be selected from a comprehensive meta-analysis by Zhang e al (2016) of associated gene variants with antipsychotic-related weight gain. Between the 15 SNPs studied, the variants statistically significant associated with BMI changes are rs6318, rs3813929, rs5181147 in 5- Hydroxytryptamine Receptor 2C (HTR2C), rs1799732, rs6275, rs7131056 in D2 dopamine receptor (DRD2) and rs489693 in melanocortin-4-receptor (MCR4). We consider that the identification of these SNPs might provide useful input for…
abstract: Second-generation antipsychotics (SGAs) are increasingly used in pediatric patients both in and offlabel. The rise in SGA prescription rates may be due to the perception of improved safety compared with first-generation antipsychotics. However, SGA use is often associated with rapid weight gain and metabolic syndrome as adverse drug reactions (ADRs). Interestingly, these side effects are not observed in all SGA-treated children, suggesting that some underlying genetic factors may predispose an individual to develop these adverse conditions. Recent studies have identified single nucleotide polymorphisms (SNPs) in genes encoding for enzymes involved in drug metabolism (CYP450) and SGA receptors in the central nervous system (CNS), which partly explain the inter-patient variability in ADR development. With this project, we intend to define the role of SNPs in genes related to the pharmacodynamics of SGA, expressed in peripheral tissues, to evaluate their involvement in the mechanisms responsible for weight change and metabolic ADRs. To this end in a cohort of 209 paediatric patients affected by disruptive behavioural disturbance who are prescribed SGAs (risperidone and aripiprazole), we have assessed the association of pharmacodynamics genetic variants with the occurrence of changes in body mass index (BMI) Zscore. This allows us to evaluate if the presence of specific variant alleles increases or decreases the risk of weight changes and metabolic adverse events. Tested SNPs will be selected from a comprehensive meta-analysis by Zhang e al (2016) of associated gene variants with antipsychotic-related weight gain. Between the 15 SNPs studied, the variants statistically significant associated with BMI changes are rs6318, rs3813929, rs5181147 in 5- Hydroxytryptamine Receptor 2C (HTR2C), rs1799732, rs6275, rs7131056 in D2 dopamine receptor (DRD2) and rs489693 in melanocortin-4-receptor (MCR4). We consider that the identification of these SNPs might provide useful input for…
author: NAPOLI, ALESSANDRA
language: eng
keywords: second-generation antipsychotics, pediatric patients, weight gain, metabolic adverse drug reaction, pharmacogenetis, adipose tissue, Settore BIO/14 - Farmacologia
date published: 2023-04-04
date modified: 2026-07-27T20:18:58Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/961276

PropertyValue
property ID: DOI
value: 10.13130/napoli-alessandra_phd2023-04-04