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Is There Sexual Dimorphism of Hyperserotonemia in Autism Spectrum Disorder?
Objectives: Few studies have examined the effect of sex differences on hyperserotonemia within ASD. Based upon previous work suggesting that hyperserotonemia is more common prior to puberty, we focused our analysis on pre-pubertal children with ASD.
Methods: 292 participants with a diagnosis of Autistic Disorder, Asperger’s Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) were recruited based on the DSM-IV-TR criteria. ASD classification was confirmed using the Autism Diagnostic Observation Schedule (Lord et al. 2000) and the ADI-R (Lord et al. 1994). Participants who were taking medications that could affect 5-HT, such as serotonin reuptake inhibitors, stimulants, and atypical antipsychotic medications were excluded from analysis. Whole blood 5-HT was measured by high-performance liquid chromatography.
Results: We relied upon published norms to define the hyperserotonemia range as whole blood 5-HT levels above 270 mg/mL (Anderson, Freedman, et al., 1987; Anderson, Hertzig, & McBride, 2012). In the current study, 41% of pre-pubertal participants were in the hyperserotonemia range. Among 182 pre-pubertal children with ASD, the overall distribution of whole blood 5-HT levels showed a rightward shift from a normal distribution. Kolmogorov-Smirnov tests of normality indicated that whole blood 5-HT levels for pre- and post-pubertal females did not deviate significantly from normal (D(23)=0.15, p=.16; D(14)=0.13, p=.20); whereas distributions for pre- and post-pubertal males were abnormally distributed (D(157)=0.08, p=.005; D(70)=0.14, p=.001, respectively). The mean whole blood 5-HT levels were not significantly different for the male and female pre-pubertal populations (t(180) = 1.29, p = 0.19); however males were significantly more likely to have hyperserotonemia compared to females (x2 = 4.338, p = 0.03).
Conclusions: This represents the largest sample of subjects with ASD for whom whole blood 5-HT levels have been reported. Similar to previous studies, we found that a substantial subset of children with ASD had whole blood 5-HT levels in the hyperserotonemia range (Gabriele et al. 2014). In the pre-pubertal sample, we found that males with ASD are more likely to have hyperserotonemia than females. This may be consistent with the genetic literature identifying linkage to the 17q11 and 17q21 gene regions, containing SLC6A4 and ITGB3, respectively, in families with multiple affected males with ASD but not in families with affected females (Stone et al. 2004; Cantor et al. 2005; Sutcliffe et al. 2005), along with data showing association between these two genes and 5-HT levels in males within a large founder population (Weiss et al., 2005). More work will be needed to replicate this intriguing finding and to understand whether it relates to differences in patterns of ASD risk between males and females.