Responsável: Astrid Vicente
Financiamento e data: Pharmacogenetics of risperidone therapy in autism spectrum disorders - Fundação Ciência e Tecnologia, POCTI/FCB/44706/2002 (2003-2007). 51.234€
Resumo: Autism is a behavioral syndrome characterized by deficiencies in social interaction, impaired communication, and restricted and stereotyped behaviors. A psychoeducational approach is the main intervention available for autism. Sometimes, however, pharmacological intervention is helpful in the control of the most disruptive behaviors associated with the disorder, in some cases effectively improving typical symptoms.
The atypical antipsychotic risperidone. is used to control disruptive behaviors associated with autism. It has been intensively tested in children with pervasive developmental disorders (PDD), proving to be relatively free of extrapyramidal effects and to be effective in treating aggressiveness, hyperactivity, irritability, stereotypies, social withdrawal and lack of interest. However, there is considerable individual variability in response to risperidone therapy and occurrence of side effects and little has been reported on the factors, genetic or other, that underlie this variability, particularly for autism.
This ongoing pharmacogenetic study aims at the identification of genetic factors underlying the variability in individual response to risperidone. For this purpose, autistic patients with clinical indication for risperidone therapy and initiating medication are recruited for this study. Individuals with autism are diagnosed using the ADI-R and ADOS, and are undergo an extensive assessment protocol at baseline. Drug response in terms of efficacy and tolerability is monitored at specific times after risperidone introduction, using an extensive evaluation protocol that includes the Autism Treatment Evaluation Checklist (ATEC), a number of behavioural and adaptive scales, cognitve and language assessment and measurement of specific biochemical parameters. Safety and tolerability measures include determination of prolactin levels, weight gain and extrapyramidal movements. In the 44 patients participating thus far, ATEC scores decreased very significantly during all time intervals, corresponding to an improvement that was more pronounced in the behavioural and sociability domains and generally during the first month of treatment, and significantly correlated with gender. Prolactin levels, weight, Body Mass Index (BMI) and waist circumference increased most significantly in the first month of treatment.
Risperidone is mainly metabolized by cytochrome P4502D6, while drug absorption and bioavailability are mediated by glycoprotein P, encoded by MDR1 gene. As an atypical antipsychotic, risperidone presents a high serotonin 5-HT2A/Dopamine D2 binding ratio. Genotyping of selected candidate genes known to be involved in risperidone pathways and metabolism is ongoing. Genetic data is tested for association with efficacy and tolerability, as measured by qualitative or quantitative behavioural, physiological and biochemical parameters assessed in the medicated patients. Because drug response is likely to be determined by a complex interplay of factors, a multiparametric approach will be used for the association analysis that takes into account age, gender, weight, ethnic background and other covariates.
The final aim of this project is to be able to predict individual drug response and side effects based on specific genotypic and phenotypic information. Such information will be extremely valuable in clinical settings for informed decision making regarding treatment protocols, leading to improved efficacy and minimal occurrence of side effects, and thus contributing to a better quality of life of autistic individuals
Institutional Partners: Instituto Gulbenkian de Ciência, Hospital Pediátrico de Coimbra