Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by persistent inattention, hyperactivity and impulsivity. Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.). The ADHD symptomatology interferes with subject function and development. The treatment of ADHD requires a multidisciplinary approach based on a combination of non-pharmacological and pharmacological treatments with the aim of ameliorating the symptomatology; among first-line pharmacological treatments are stimulants [such as methylphenidate (MPH) and lisdexamfetamine dimesylate (LDX)]. In this review we explored recent ADHD- and stimulants-related literature, with the aim of compiling available descriptions of molecular pathways altered in ADHD, and molecular mechanisms of current first-line stimulants MPH and LDX. While conducting the narrative review, we applied structured search strategies covering PubMed/MEDLINE database and performed handsearching of reference lists on the results of those searches. The aetiology and pathophysiology of ADHD are incompletely understood; both genetic and environmental factors have been associated with the disorder and its grade of burden, and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications. The lack of comprehensive understanding of the underlying molecular pathology makes both the diagnosis and treatment difficult. Few published studies evaluating molecular data on the mechanism of action (MoA) of MPH and LDX on ADHD are available and most of them are based on animal models. Further studies are necessary to improve the knowledge of ADHD pathophysiology and how the MoAs of MPH and LDX differentially modulate ADHD pathophysiology and control ADHD symptomatology.

Methylphenidate-Associated Ecchymosis in a Young Patient With Poststroke Attention Deficit

“…13 Psychostimulants, including methylphenidate, increase the extracellular level of DA and NE by blocking the DA and NE reuptake, thereby ameliorating ADHD symptoms. 13,14 Dopamine has been demonstrated to induce platelet aggregation and enhance adenosine diphosphate-induced platelet aggregation at the micromolar and nanomolar ranges. 15,16 Similar observation was also seen in an animal study involving NE.…”

“…The etiology of ADHD is complex, involving several cellular and molecular processes. Neurotransmitter imbalance, particularly catecholamines dopamine (DA) and norepinephrine (NE) deficiencies, which are pivotal in modulating attention, memory, and behavior, underlies the pathophysiology of ADHD 13 . Psychostimulants, including methylphenidate, increase the extracellular level of DA and NE by blocking the DA and NE reuptake, thereby ameliorating ADHD symptoms 13,14 .…”

“…Neurotransmitter imbalance, particularly catecholamines dopamine (DA) and norepinephrine (NE) deficiencies, which are pivotal in modulating attention, memory, and behavior, underlies the pathophysiology of ADHD 13 . Psychostimulants, including methylphenidate, increase the extracellular level of DA and NE by blocking the DA and NE reuptake, thereby ameliorating ADHD symptoms 13,14 . Dopamine has been demonstrated to induce platelet aggregation and enhance adenosine diphosphate-induced platelet aggregation at the micromolar and nanomolar ranges 15,16 .…”

“…However, recent evidence suggests that methylphenidate does not affect serotonin reuptake. 13,14 Furthermore, methylphenidate has also been linked to blood dyscrasia such as thrombocytopenia and neutropenia. 18,19 It is postulated that peripheral platelet destruction may underlie the reversible thrombocytopenia observed in some cases of methylphenidate use, although this assertion lacks empirical substantiation.…”

From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

“…Despite its well-known clinical efficacy, the exact molecular mechanisms responsible for the beneficial effects of MPH in ADHD remain elusive ( Yde Ohki et al, 2020 ). The effects of MPH are usually attributed to its ability to block the reuptake of dopamine, noradrenaline, and (in low affinity) serotonin to potentiate the effects of monoamines in the synaptic cleft ( Quintero et al, 2022 ). Nevertheless, accumulating evidence suggests that the ability of MPH to stimulate cortical maturation [responsible for its long-term effects ( Shaw et al, 2009 ; Walhovd et al, 2020 )] may be mediated by a separate mechanism not related to the inhibition of monoamine transporters ( Bartl et al, 2010 , 2013b , 2017 ; Grünblatt et al, 2018 ; Yde Ohki et al, 2020 ).…”