Several studies seemed to show that non-responders to MPH among children with ADHD have a low primary striatal DAT availability, whereas patients with a better response to MPH treatment have a higher DAT concentration. The positive correlation between DAT and inattention could reflect lower and shorter DA signaling in subjects presenting a higher DAT concentration ( 17). One study showed a positive correlation between DAT availability in the striatum and inattention in patients with ADHD compared to healthy children ( 17). Studies in animal models, genetic research, and human neuroimaging reports have suggested an altered availability or function of DAT in ADHD ( 16). The three most common alleles are represented by the 10/10 genotype, 9/10 genotype, and 9/9 genotype, and each has been reported with differential gene expression, influencing DAT availability ( 14, 15). MPH is the most commonly prescribed psychostimulant in the pharmacological therapy of patients with ADHD ( 11) and its efficacy is complemented by behavioral strategies ( 12, 13).Ī variable number of tandem repeats (VNTR) in the DAT 3’-untranslated region (3’UTR) has been the most investigated polymorphism of this gene. Moreover, the dopamine (DA) transporter gene (SLC6A3) encodes the DAT protein, which controls the DA concentration at the synaptic level through its reuptake and influences the susceptibility to ADHD as well as response variability to methylphenidate (MPH) in subjects with ADHD ( 9, 10). Since the 1990s, neuroimaging studies ( 5, 6) and genetic research ( 7, 8) have revealed that dopaminergic and frontostriatal system dysfunction represent neurobiological substrates of ADHD. Over a lifetime, ADHD symptoms cause global dysfunctions with socio-economic impact with a significant effect in various areas, including education, employment, and quality of life ( 4). According to a recent meta-analysis, ADHD prevalence in pediatric population is 5.9%–7.1% and in adults is 5% ( 3). ADHD is diagnosed on the basis of persistent inattention, hyperactivity, and impulsivity lasting more than 6 months and interfering with subject function and development ( 2). Its effectiveness can vary based on DAT polymorphisms and can act as a modulator of HERV-H gene expression, pointing to targets for a precision medicine approach.Īttention-deficit/hyperactivity disorder (ADHD) represents one of the most common neurodevelopmental disorders with onset in early childhood, high heritability and documented brain abnormalities ( 1). In conclusion, there is a confirmed role for MPH as an elective drug in the therapy of ADHD alone or in association with behavioral therapy. In particular, several studies have revealed that ADHD is associated with HERV-H over-expression and that MPH administration results in decreased expression levels of this retroviral family and a reduction in the main symptoms of the disorder. Innovative lines of research have suggested that ADHD etiopathogenesis and its neuropsychological phenotypes also depend on the expression levels of human endogenous retrovirus (HERV). MPH efficacy may be influenced by polymorphisms in the DAT, and better responses to treatment were associated with the 10/10 genotype. Marked improvements in attentional and executive dysfunction have been observed in children with ADHD during treatment with MPH, as well as reductions in neurological soft signs. Literature analysis showed that MPH, the most commonly used psychostimulant in the therapy of ADHD, acts on multiple components of the disorder. It addressed the following aspects: 1) MPH effects on attention and executive functions in ADHD 2) the relation between MPH efficacy and dopamine transporter gene (DAT) polymorphism and 3) the role of MPH as an epigenetic modulator in ADHD. This narrative review describes an overview of the multiple effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD) and its potential neurobiological targets. 3Paediatric Clinic, Pietro Barilla Children’s Hospital, Department of Medicine and Surgery, Università of Parma, Parma, Italy.2Department of Child Neuropsychiatry, USL Umbria 2, Terni, Italy.1Division of Child Neuropsychiatry, Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy.Maria Bernarda Pitzianti 1,2 Simonetta Spiridigliozzi 1 Elisa Bartolucci 2 Susanna Esposito 3* Augusto Pasini 1,2
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