Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by a symptomatology based on persistent inattention, hyperactivity, and impulsivity that has been considered a progressively ceaseless condition [
1]. The ADHD symptomatology interferes with subject function and development according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria [
2] impairing daily function [
3,
4]. Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.) [
5], and in adult age it is a risk factor for various mental disorders [
6,
7]. Therefore, ADHD is a significant burden for the affected youngsters, adults, their families and society everywhere.
The worldwide prevalence of ADHD is around 4–12% in children and 2.5–5% in adults [
8‐
11]. It is estimated that 15–50% of children diagnosed with ADHD carry its manifestations into adulthood, but ADHD symptoms are not as easily defined in adulthood as in childhood. Generally speaking, symptoms are likely to adapt when growing into adulthood. Hyperactivity and impulsivity in adults seem to be reduced, as hyperactivity is expressed as an inner tension, and impulsivity becomes more verbal than physical, while inattentiveness can be retained [
12,
13].
ADHD, as with other psychiatric disorders, is not easy to diagnose. In this sense, their diagnosis has been criticized because it is not based on a biological testing, and it has been considered subjective [
14]. There is no medical test that determines the presence of the condition. However, there are some manuals that establish its diagnosis criteria, the DSM-5 and the International Classification of Diseases 11th revision (ICD-11) being the most usual ones, which observe behaviour defects and study symptoms such as hyperactivity, inattentiveness and impulsivity [
15]. One of the reasons that hinder the diagnosis and treatment of this disorder is the lack of complete understanding of the underlying molecular pathology [
16]. However, the main features of the diagnosis are the presentation of developmentally inappropriate levels of hyperactive-impulsive and/or inattentive symptoms, or both combined, for at least 6 months and at different settings, with possible impairment of life tasks. The disorder can affect highly intelligent people, often co-occurring with other psychiatric disorders [
14].
Following a primary diagnosis of ADHD in a child, adolescent or adult, clinicians have at their disposal a wide range of non-pharmacological and pharmacological treatment options [
17] which are administered in combination with a multidisciplinary approach [
17,
18], as recommended by current treatment guidelines [
19].
Non-pharmacological therapy includes several procedures as behavioural interventions, such as training of parent behaviour and/or social skills [
20‐
22]; cognitive training, focused in reducing ADHD symptoms by improving performance in specific neuropsychological functions using electronic interfaces (computers, tablets, smartphones) or noncomputerized methods that allow performance reassessment so that training is adaptive [
23‐
25]; neurofeedback based on improving self-control over brain activity patterns (real-time electroencephalogram (EEG) data monitoring of, for example, theta (vigilance) and beta (concentration and neuronal excitability waves) [
26‐
28]; or coaching programs, focused on improving executive functions [
29‐
32].
Pharmacologic treatment is based on stimulants [amphetamines, such as the prodrug lisdexamfetamine dimesylate (LDX), and methylphenidate (MPH)] and nonstimulants (atomoxetine, guanfacine, clonidine, bupropion, modafinil) [
17]. Stimulants have generally been used as first-line pharmacologic treatment owing to a higher efficacy in symptomatology reduction compared to nonstimulant medications in all groups of age (children, adolescents and adults) [
17,
33,
34]. In this sense, a systematic review and network meta-analysis carried out in 2018 using 133 double-blind randomised controlled trials positioned MPH in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD [
34]. Nonstimulants are considered as second-line medication and are administered when stimulants are contraindicated or because of lack of response or intolerance [
35].
Despite stimulant medications for ADHD being among the most effective drugs in psychiatry [
36], there is a substantial placebo effect in subjects with ADHD [
37], which could be explained by a synergy between placebo effects that influence the parent of the patient with ADHD and those acting on the clinician when interviewing the parent. Moreover, a nocebo effect affecting patient tolerability is reported, and it is mainly translated into dropouts due to adverse events or any other reason, and weight loss [
37], indicating that explanation of potential adverse events due to medication must be expressed better to minimise nocebo effects.
Although the effects of stimulant medications are similar, they show different specific mechanisms of action (MoAs). Both MPH and amphetamines act by blocking presynaptic dopamine (DA) and norepinephrine (NE) transporters, thus increasing catecholamine transmission; however, amphetamines additionally increase the presynaptic efflux of DA [
38]. In the case of LDX, the exact MoA in ADHD is not fully understood [
39,
40]. It is presumed that is likely related to a blockage of the reuptake of NE and DA into the presynaptic neuron and an increase in the release of these monoamines into the extraneuronal space [
39]. Despite this, the molecular mechanisms of stimulant medications are not fully understood. These mechanisms, or how patients respond to these drugs, can be further complicated by their interaction with patients’ genotypes; in this sense, pharmacogenomics research seeks to explain how some drugs are more effective and or better tolerated for specific genotypes in improving patient outcomes [
41]. Most of the pharmacogenomic markers for psychiatric drugs compiled by regulatory agencies to date are related to drug metabolism rather than to the mechanism of action [
42]. Some stimulants, such as amphetamines, and non-stimulants, such as atomoxetine, have been reported to be substrates of cytochrome P450s, and their performance has been linked to CYP2D6 genotype [
41,
42]. While MPH’s US Food and Drug Administration (FDA) label does not contain pharmacogenomic biomarkers, a lot of research has been performed on the impact of genotype on MPH efficacy, and several biological pathways have been suggested to potentially affect MPH mechanisms through patient genotype, mostly concerning monoamine pathways [
43‐
48]. Although the research in this field has been increasing in recent years, and has the potential to affect prescription and possibly improve the outcomes of patients with ADHD [
49], no clear guidelines have been developed and there is still much to understand in this regard [
50]. Our review will not cover this issue further, as this aspect has been extensively reviewed by other authors [
41,
51‐
53].
The purpose of this review is to summarize the molecular evidence around the mechanisms of stimulant drugs on the molecular pathophysiology of ADHD in children and adults.
Methodology
While it is not a formal systematic review, we applied structured search strategies covering PubMed/MEDLINE database. In addition, we performed handsearching of reference lists in the articles identified through the structured searches.
To describe ADHD at the molecular level, we first explored the landscape of available molecular information on ADHD to obtain a picture of the pathophysiological processes involved. We reviewed indexed literature reviews in PubMed database, using the following search string (January 2020): (“Attention deficit hyperactivity disorder” [Title] OR “ADHD” [Title] OR “Attention-Deficit/Hyperactivity Disorder” [Title]) AND (“pathogenesis” [[Title/Abstract] OR “pathophysiology” [Title/Abstract] OR “molecular” [Title/Abstract]) AND Review [ptyp]; we explored these results full-length, and reviewed their list of references as well as PubMed “related articles” to completely cover all published molecular pathophysiological knowledge.
Then, we explored the molecular information around first-line stimulant drugs, to identify described direct protein targets and drug-induced molecular changes. Thus, we performed a literature search in PubMed database considering the drugs’ generic and commercial names and the following search string (April 2020): (“molecular” [Title/Abstract] OR “mechanism” [Title/Abstract] OR “pathophysiology” [Title/Abstract] OR “pathogenesis” [Title/Abstract] OR “mode” [Title/Abstract] OR “action” [Title/Abstract] OR “signalling” [Title/Abstract] OR “signalling ”[Title/Abstract] OR “expression” [Title/Abstract] OR “activation” [Title/Abstract] OR “inhibition” [Title/Abstract] OR “activity” [Title/Abstract]). Again, we explored these results full-length, and reviewed their list of references as well as PubMed “related articles” to identify relevant leads.
Finally, we used keywords from the ADHD pathophysiology description to identify published data relating these processes to the drugs and drug-related molecular changes. Equivalent searches and evaluation of the results were performed for both drugs. All the results were contextualised considering the potential clinical implications of these mechanisms as per the known role of the molecular mechanisms in behaviour regulation.
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Conclusions
Based on the literature published, the MoAs of both LDX and MPH (current first-line pharmacological treatments) have an effect in the network of the specific molecules involved in the described pathophysiological motives of ADHD.
Regarding NT imbalance, LDX and MPH are related to the increase of central DA and NE activity in brain regions promoting the downregulation of DAT and NET at presynaptic level. Activation of DRD and ADRA by LDX and MPH at postsynaptic level is involved in DA and NE transmission. LDX regulates more receptors (TAAR1, VMAT2, SERT, MAOA and MAOB) than MPH in neurotransmission, and minimal differences, such as ERK2 phosphorylation and the action on locus coeruleus neurons by LDX, could differentiate efficacy between both drugs. The regulation of TAAR1 is also related to MAPK3 activation, crucial in the downstream modulation of the neuroinflammation inducing the expression of some anti-inflammatory cytokines (e.g. IL-2, IL-10). In this regard, neuroinflammation and defective immunoregulation have been observed in ADHD. Long-term use of stimulant medication could cause loss of DA transmission and, therefore, efficacy. The studies published show MPH as a drug with a pro-inflammatory profile mainly due to its activation of cytokines TNFα and IL-1β. LDX promotes the activation of pro-inflammatory cytokines such as TNFα and IL-6, although it also promotes the expression of the anti-inflammatory cytokines IL-4 and IL-10 in the frontal cortex, striatum and serum. On the contrary, TNFα promotes astrocyte activation reducing glutamate on the synaptic cleft, which could improve the synaptic signalling. More studies are necessary to understand the effect of both drugs on TNF in ADHD. Also, altered neural viability and neurodegeneration have been observed in ADHD. Mechanisms of neuron survival and oxidative stress are involved in neurodegeneration. It has been shown that MPH could have an effect on neurodegeneration and oxidative stress modulation through several mechanisms. Apoptotic enzymes have been related to MPH although its MoA in that regard remains unclear. Moreover, MPH has been shown to promote ROS via RAC1and CAMK4 activation, although the evidence regarding whether MPH use indeed induces or reduces oxidative stress is not clear. The relationship between LDX and neurodegeneration has only been shown through increasing oxidative stress by downregulating the level of antioxidant enzymes CAT, GSH-Px and SOD. Lastly, circadian system dysfunction is also observed in ADHD. In this regard, the mechanisms of action of MPH involved in the circadian rhythm are unknown, although it has been shown that the use of MPH in children with ADHD normalizes serotonin and melatonin levels to those of non-ADHD population. Nevertheless, no evidence has been found on the effect of LDX on the circadian rhythm in ADHD.
Both LDX and MPH have improve the neuronal signalling that leads to an increase of DA and NE levels in the prefrontal cortex, by acting on DAT and NET and improving attentional deficit and cognitive functions. However, LDX acts on more targets than MPH. Regarding neuroinflammation and defective immunoregulation control, it seems that LDX has a greater effect related to its interaction with TAAR1 and MAOA, and its promotion of anti-inflammatory cytokines such as IL-10. MPH, as well as LDX, promotes the activation of IL-1 and TNF but the role of TNF must be studied in more depth. Regarding neural viability and neurodegeneration, it seems that both drugs have a deleterious effect resulting in increased oxidative enzyme levels. Lastly, MPH shows more evidence as a potential option for treating circadian clock impairments in patients with ADHD.
Despite the studies published on the effect of MPH and LDX on pathophysiological processes and their specific molecules involved in ADHD, there are few data published on the subject and some are based on investigations run in animal models. Further studies are necessary to improve the knowledge of the ADHD pathophysiology and to identify how the MoAs of the MPH and LDX, as current first-line pharmacological treatments, control ADHD symptomatology.