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Page 279 Hervas et al. J Transl Genet Genom 2021;5:278-87 https://dx.doi.org/10.20517/jtgg.2021.25

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.

Keywords: Autism, pharmacogenetics, methylphenidate, antipsychotic, antidepressant, dopamine, serotonin

INTRODUCTION
Autistic spectrum disorders (ASD) are severe neurodevelopmental alterations characterised by deficits in
social communications and repetitive and restricted behaviours. Although there is no specific
pharmacological treatment for ASD, about a third of patients receive pharmacological treatment for
comorbid symptoms. Stimulant, antipsychotic, and antidepressant drugs are used for the treatment of
conduct, anxiety, and mood disorders observed in patients with ASD. Pharmacotherapy with
methylphenidate is the preferred treatment for attention deficit hyperactivity disorder (ADHD) comorbid
symptoms, as well as antipsychotics and selective serotonin reuptake inhibitors antidepressants for the
treatment of aggression and mood disorders. However, there is significant individual variability in the
response to pharmacological treatment. Not all ASD subjects respond to treatment, with 30%-50% not
responding and/or presenting with severe and long-lasting side effects, including increased irritability,
[1]
aggressiveness, and somnolence . Furthermore, children and adolescents are more susceptible to drug-
[2]
induced side effects than adults . Treatment failure and side effects have a negative effect on patients with
ASD, and predictors of response for the personalisation of pharmacological treatment are required.
There is strong evidence of the influence of genetic factors on the clinical outcome of pharmacological
treatments. Previous studies have reported the influence of variants in genes coding for targets of
psychotropic drugs on the efficacy and safety of pharmacological treatments. The dopaminergic and
serotonergic systems, both major targets for psychotropic drugs, have been implicated in the modulation of
treatment outcome [1,3,4] . Enzymes involved in the metabolism of catecholamines and proteins involved in
stress and mood alterations have also been implicated in the modulation of treatment response [3,5,6] .
However, relatively few pharmacogenetic studies have been performed on drug treated ASD subjects.

The clinical outcome of psychotropic drugs varies between children and adults . Most studies have focused
[7]
on the adult population, with relatively few studies in children and adolescents. Several studies have
associated genetic variants in the gene coding for the dopamine transporter (SLC6A3), a direct target of
[7,8]
methylphenidate in children and adolescents affected by ADHD . Variants in genes coding for
dopaminergic receptors type 2, 3, and 4 (DRD2, DRDRD3, and DRD4, respectively) have also been
associated with response to methylphenidate in young ADHD subjects [6,9,10] . Findings of association between
polymorphisms in genes coding for the adrenergic receptor 2A (ADRA2A), brain derived neurotrophic
factor (BDNF), catechol-O-methyltransferase (COMT), serotonin receptor 2A (HTR2A), serotonin
transporter (SLC6A4), norepinephrine transporter (SLC6A2), and methylphenidate clinical outcome in
young ADHD subjects have been reported in independent studies [7,11,12] . However, these findings have not
[7]
[13]
been universally replicated or showed inconsistent results . A meta-analysis by Bonvicini et al. did not
support an association of a polymorphism in the 3’-untranslated region (UTR) in the dopamine transporter
(SLC6A3) with response to methylphenidate. Significant associations between variants in dopamine
receptors 1, 3, and 4 (DRD1, DRD3, and DRD4), ADRA2A, COMT, SLC6A3, and SLCA4 genes and response