Methylphenidate (MPH) has benefit in reducing hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASD), however individuals vary widely in response and tolerability.
Objectives:
We hypothesized that variants in key monoaminergic genes may moderate the clinical effects of MPH in ASD associated with hyperactivity and contribute to individual differences in their response.
Methods:
Sixty-six children ages 5 - 14 years (mean age 6.9 years) with DSM-IV Autistic Disorder, Asperger’s Disorder, and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) were randomized to varying sequences of placebo and three different doses of MPH during a 4-week blinded, crossover study. MPH doses used approximated 0.125, 0.25, and 0.5 mg/kg/dose twice daily with an additional afternoon half-doses. Primary outcome measures utilized include the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-Hyperactivity Index). Subjects were genotyped for common functional and tag single nucleotide polymorphism (SNP) variants in the genes encoding the dopamine receptor subtypes 1-5 (DRD1-DRD5), the alpha adrenergic 2A receptor subtype (ADRA2A), the serotonin transporter protein (SLC6A4), and the enzymes monoamine oxidase A and B (MAOA and MAOB). Functional variants in the dopamine transporter (SLC6A3) and catechol-o-methyl-transferase (COMT) genes were also assayed.
Results:
MPH was associated with significant improvement on hyperactive-impulsive symptoms (p<0.001), with 49% of the sample meeting responder criteria of CGI-I "much" or "very much improved" and a decrease of >25% of ABC-Hyperactivity subscale scores from baseline. Significant differences by SLC6A4 STin2 (p<0.04), ADRA2A rs1800544 (p<0.02), COMT val/met (p<0.05), DRD1 rs5326 (p=0.007) and rs 4867798 (p<0.05), DRD3 ser9gly (p<0.04) and DRD4 rs11246226 (p<0.05)genotype were found for responders versus non-responders. Dimensional analyses of symptom severity for dose by genotype interaction showed associations with DRD4 and SLC6A4.
Conclusions:
Individual differences in MPH’s efficacy in reducing common ADHD symptoms in children with ASD may be moderated by genetic effects on dopaminergic and noradrenergic systems. Results are interpreted in relation to known expression and regulatory effects of associated variants and identified dopamine system differences in presynaptic dopamine uptake, DAT1 binding, and CSF HVA in ASD studies. Larger replication studies and tests of the clinical significance of the observed associations are warranted.
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