Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Abstract

Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G4A, DRD3 Ser9Gly, HTR2C c.995G4A and ABCB1 1236C4T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G4A, HTR2C c.68G4C (p.C33S), HTR6 c.7154-2542C4T and BDNF c.196G4A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G4C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

DRD3 Ser9Gly Polymorphism and Its Influence on Risperidone Response in Autistic Children

“…Among the GPCRs, the eminent role of DRD3 in etiology and therapeutic response of many of these disorders has been frequently reported (8,(30)(31)(32). However, except a few studies (8,33) not much has been conveyed regarding autism.…”

“…Some reports has previously suggested this variant to be a predictor for clinical improvement with risperidone therapy (33,48) and also a parameter associated with risperidone side effects (49). On the other side, some studies suggest no significant contribution of this variant to risperidone treatment (30,50).…”

The Autism Treatment Network and Autism Intervention Research Network on Physical Health: Future Directions

“…Clinicians increasingly report that results of chromosomal microarray influence the medical care they provide to their patients. 5 The systematic collection of microarray data as part of the patient registry can help answer questions that may impact health care, policy, and research.…”

“…5 Using this genetic information in the refinement of patient selection algorithms could help make personalized medicine a reality for individuals with ASD. Recent statements from key professional groups supporting the use of microarray data in the evaluation of children with unspecified causes of intellectual disability should help make this testing standard of care for children with autism.…”

The role of neurotrophic factors in autism

“…A recent study has shown the BDNF Val66Met polymorphism to be associated with prolactine elevation caused by risperidone treatment in autistic patients. 180 Thus, knowledge about the BDNF genotype might help to limit prolactine elevation-associated side effects.…”