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

Abstract

Aim: About a third of patients with autism spectrum disorder (ASD) receive pharmacological treatment for comorbid symptoms. However, 30%-50% do not respond adequately and/or present severe and long-lasting side effects. Previous studies have reported the influence of variants in genes coding for drug targets on the efficacy and safety of pharmacological treatments, including genetic polymorphisms in dopaminergic and serotonergic systems. However, most studies have focused on the adult population, with relatively few studies in children and adolescents, and no clear biomarkers of response have been reported in these populations. The aim of our study was to identify genetic predictors of drug response in patients with ASD. This information may be used to personalise pharmacological treatment and improve the efficacy and safety of psychotropic drugs in patients with ASD. Methods: Genetic variants in dopaminergic and serotonergic drug targets ( SLC6A3 , DRD2 , DRDRD3 , DRD4 , HTR2A , and HTR2C ) and in other genes previously associated with treatment efficacy and/or induced side effects ( ANKK1 , BDNF , COMT , and HTR1A ) were investigated in 176 children and adolescents diagnosed with ASD and undergoing pharmacological treatment. Results: A SLC6A3 genetic variant was associated with response to methylphenidate in our ASD cohort, whereas HTR2A and HTR2C allele and haplotype distributions were associated with adverse reactions such as somnolence, mood alterations, and BMI. ANKK1 , COMT , and BDNF genetic variants were mainly associated with treatment side effects. Conclusion: If confirmed, these genetic variants may be used as predictors of clinical outcome and help to personalise pharmacological treatments in patients with ASD. previous study reported this polymorphism associated with insulin-resistance in patients with ASD treated with risperidone [25] . We did not find any significant association with the other dopaminergic variants investigated ( DRD2 rs18012028, DRD3 rs167771 & rs6280, and a 48bp repeat in DRD4 ), although DRD3 haplotype combinations were found nominally associated with shutdowns in the total sample ( P = 0.04) and with side effects in the methylphenidate subgroup ( P = 0.05). Previous studies reported association between the DRD3 rs6280 polymorphism and methylphenidate response in a group of 64 children with ASD [14] and risperidone response in a sample of 45 patients with ASD [15] . These findings require further investigation in larger samples to confirm the possible contribution of DRD3 variants to treatment response variability in ASD.