Abstract
We investigated the association between genetic variations in pharmacodynamic genes and risperidone-induced increased prolactin levels in children and adolescents with autism spectrum disorder (ASD). In a retrospective study, variants of pharmacodynamic genes were analyzed in 124 ASD patients treated with a risperidone regimen for at least 3 months. To simplify genotype interpretation, we created an algorithm to calculate the dopamine D2 receptor (DRD2) gene genetic risk score. There was no relationship between prolactin levels and single SNPs. However, the H1/H3 diplotype (A2/A2-Cin/Cin-A/G) of DRD2/ankyrin repeat and kinase domain containing 1 (ANKK1) Taq1A, DRD2 -141C indel, and DRD2 -141A>G, which had a genetic risk score of 5.5, was associated with the highest median prolactin levels (23 ng/ml). As the dose-corrected plasma levels of risperidone, 9-OH-risperidone, and the active moiety increased, prolactin levels in patients carrying the H1/H3 diplotype were significantly higher than those of the other diplotypes. DRD2 diplotypes showed significantly high prolactin levels as plasma risperidone levels increased. Lower levels of prolactin were detected in patients who responded to risperidone. This is the first system for describing DRD2 haplotypes using genetic risk scores based on their protein expression. Clinicians should consider using pharmacogenetic-based decision-making in clinical practice to prevent prolactin increase.
Highlights
Risperidone is an atypical antipsychotic used to treat autism spectrum disorder (ASD)
We suggest that clinicians should perform DNA analysis of the three SNPs of the DRD2 haplotype as pre-emptive genetic testing, and prolactin levels should be monitored before and after 3 months to prevent hyperprolactinemia, especially in patients with the H1/H3 diplotype
Other studies have found that prolactin levels are inconsistently associated with efficacy (Wang et al, 2007; Lostia et al, 2009), our study revealed that prolactin levels may induce changes in neurogenesis, potentially affecting aberrant behaviors in ASD, consistent with several other studies (Zhang et al, 2002; Lee and Kim, 2006; Ates et al, 2015)
Summary
Risperidone is an atypical antipsychotic used to treat autism spectrum disorder (ASD). Risperidone has a more favorable safety and efficacy profile than typical antipsychotic drugs (Peuskens et al, 2014). Two clinical trials (McCracken et al, 2002; Shea et al, 2004) established the efficacy and tolerability of risperidone in patients with ASD and showed that risperidone significantly attenuated disruptive behaviors compared with the placebo over 8 weeks, as measured by a reduction in the irritability subscale of the aberrant behavior checklist (ABC) scores. The improvement in the risperidone treatment group was higher (56.9–64.0%) compared with that in the placebo group (14.1–31.0%) (McCracken et al, 2002; Shea et al, 2004)
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