Article

Neurocognitive effects of methylphenidate on ADHD children with different DAT genotypes: A longitudinal open label trial.

Division of Child Neuropsychiatry, Department of Neuroscience, University of Rome "Tor Vergata", Via Alberico 2 n.35, 00193 Rome, Italy. Electronic address: .
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society (Impact Factor: 1.93). 03/2013; DOI: 10.1016/j.ejpn.2013.02.002
Source: PubMed

ABSTRACT The variable number of tandem repeat polymorphism in the 3'-untranslated region of the dopamine transporter gene (DAT) may influence the variability of the therapeutic response to methylphenidate (MPH) in Attention Deficit/Hyperactivity Disorder (ADHD). For this reason we evaluated the neuropsychological functioning after a prolonged period of MPH treatment and after a specific time from MPH suspension. Relationship between DAT VNTR genotypes and neurocognitive response to MPH was analyzed in a sample of 108 drug-naive ADHD patients. The performance of children with ADHD on measures of working memory, inhibition and planning was assessed at 4, 8 and 24 weeks and at 8 weeks after MPH withdrawal. Patients with 9/9 genotype evidenced an improvement in response inhibition and working memory only at 4 weeks of treatment, in planning at 24 weeks of therapy and after 8 weeks of MPH suspension. Patients with 9/10 showed an improvement in response inhibition at 4, 8 and 24 weeks of treatment, in planning at 24 weeks and after 8 weeks of MPH suspension. Patients with 10/10 evidenced an improvement in response inhibition and working memory at 4, 8 and 24 weeks of treatment and in planning at 4, 8 and 24 weeks of treatment and after 8 weeks of suspension. These results indicate that the 9/9 ADHD genotype has a different response at 24 weeks treatment with MPH. 10/10 DAT allele seems to be associated with an increased expression level of the dopamine transporter and seems to mediate the MPH treatment response in ADHD patients.

Download full-text

Full-text

Available from: Lorenzo Sinibaldi, Jul 03, 2015
1 Follower
 · 
81 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity. To remedy this situation, we have pursued an effort to create a mouse model derived from functional nonsynonymous variation in the DAT gene (SLC6A3) of ADHD probands. We trace our path from the identification of these variants to in vitro biochemical and physiological studies to the production of the DAT Val559 mouse model. We discuss our initial findings with these animals and their promise in the context of existing rodent models of ADHD.
    Neurochemistry International 12/2013; 73. DOI:10.1016/j.neuint.2013.11.009 · 2.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Prescription stimulant medication, the most frequently recommended treatment for college students with attention deficit/hyperactivity disorder (ADHD), has become increasingly available on college campuses. Research investigating prescription stimulant misuse among college students indicates that significant numbers of students without ADHD are taking prescription stimulants to enhance their cognitive performance. This article systematically reviews studies concerning misuse of prescription stimulants among college students with and without ADHD as well as the cognitive and morphological brain changes associated with prescription stimulants in humans and other animals. Whether these morphological changes are accompanied by improved cognitive performance remains equivocal. Implications of this body of literature are discussed and suggestions for future research are advanced. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
    Experimental and Clinical Psychopharmacology 10/2013; 21(5):385-407. DOI:10.1037/a0034013 · 2.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task and a delayed reversal task. Possible contribution of locomotion, reward and sensory perception were also investigated. Expression of loss of function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT2C receptor agonist CP809.101, reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT2 receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.Neuropsychopharmacology accepted article preview online, 7 November 2013; doi:10.1038/npp.2013.313.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2013; DOI:10.1038/npp.2013.313 · 7.83 Impact Factor