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

Pasini, Augusto; Sinibaldi, Lorenzo; Paloscia, Claudio; Douzgou, Sofia; Pitzianti, Mariabernarda; Romeo, Elena; Curatolo, Paolo; Pizzuti, Antonio

doi:10.1016/j.ejpn.2013.02.002

Cited by 26 publications

(31 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…If a drug can induce opposite cognitive effects at the same dose and in the same tests in mice carrying different mutations, it is also possible that similar divergent effects may also occur in humans. This underscores the need for studies of drug-gene interaction to develop better cognition enhancing agents and personalized treatments for cognitive symptoms in people with gene polymorphisms affecting monoamine-mediated neurotransmission (Baehne et al, 2009;Pasini et al, 2013;Serretti et al, 2011). Furthermore, the distinct cognitive profiles of DAT-KO and Tph2-KI mice observed in the H-maze denotes the needs to develop strategies to further study the specific impact of such polymorphisms on behavior by coupling the use of animals carrying specific human variants with new technical approaches like the H-maze.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Del’Guidice

Lemay

Lemasson

et al. 2013

Neuropsychopharmacol

View full text Add to dashboard Cite

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. The 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-HT 2C 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-HT 2 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Del’Guidice

Lemay

Lemasson

et al. 2013

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Froehlich et al (2011) 58 reported that 10R carriers vs. non-carriers are poorer responders to methylphenidate, with an effect size of 0.59–0.64 (though n=89). Pasini et al (2013) 59 compared responses of 108 drug-naïve patients to methylphenidate treatment across a 24-week period. The sample was stratified into 9R/9R, 9R/10R, and 10R/10R sub-cohorts, with various outcomes (response inhibition, working memory, planning) assessed longitudinally.…”

Section: Presentmentioning

confidence: 99%

Attention-Deficit Hyperactivity Disorder and Pharmacotherapy—Past, Present, and Future: A Review of the Changing Landscape of Drug Therapy

Connolly

Glessner

Kao

et al. 2015

Ther Innov Regul Sci

View full text Add to dashboard Cite

Attention deficit hyperactivity disorder (ADHD) is the most common neurobiological disorder in children, with a prevalence of ~6-7% 1,2 that has remained stable for decades 2 . The social and economic burden associated with patients 3 , families, and broader systems (healthcare/educational) is substantial, with the annual economic impact of ADHD exceed $30 billion in the US alone 4 . Efficacy of pharmacotherapy in treating ADHD symptoms has generally been considerable with at least ¾ of individuals benefitting from pharmacotherapy, typically in the form of stimulants 5 . In this review, we begin by briefly reviewing the history of pharmacotherapy in relation to ADHD, before focusing (primarily) on the state-of-the-field on themes such as biophysiology, pharmacokinetics, and pharmacogenomics. We conclude with a summary of emerging clinical and research studies, particularly the potential role for precision therapy in matching ADHD patients and drug types. KeywordsADHD; pharmacotherapy; pharmacology; drug; medication; adverse events PASTThe most common and effective medications are methylphenidates and amphetamines. Atomoxetine and the a-adrenergic agonists are also widely-used, while tricyclics such as modafinil and Wellbutrin are less common and typically less effective 6 .First synthesized in 1887, amphetamine (alpha-methylphenethylamine) was not studied clinically until 1927, initially as an artificial replacement for epinephrine 7 . For several years,

show abstract

“…Several studies have also observed association between core components of ADHD and variation in the DAT gene, including spatial working memory function (Brehmer et al, 2009; Li et al, 2012; Shang and Gau, 2013), attentional asymmetry (Bellgrove et al, 2005; Newman et al, 2012), impulsivity (Costa et al, 2013a; Forbes et al, 2009; Paloyelis et al, 2010), response inhibition (Cornish et al, 2005; Cummins et al, 2012), and reward-related striatal responsivity (Hahn et al, 2011; Hoogmann et al, 2013; Wittmann et al, 2013). In addition, DAT genotype is linked to how well a patient responds to psychostimulant treatment (Costa et al, 2013b; Gilbert et al, 2006; Kambeitz et al, 2013; Pasini et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: On the path to an animal model of attention-deficit hyperactivity disorder

Mergy

Gowrishankar

Davis

et al. 2014

Neurochemistry International

View full text Add to dashboard Cite

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 the creation of a mouse model derived from a functional nonsynonymous variant 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.

show abstract

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

Cited by 26 publications

References 45 publications

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Attention-Deficit Hyperactivity Disorder and Pharmacotherapy—Past, Present, and Future: A Review of the Changing Landscape of Drug Therapy

Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: On the path to an animal model of attention-deficit hyperactivity disorder

Contact Info

Product

Resources

About