Contents

1 Tobacco Use in ADHD subjects

There is emerging evidence that cholinergic dysregulation (in particular, of nicotinic cholinergic systems) may play a role in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) [9]. Both clinical and epidemiological experiments indicate that ADHD is associated with an increased risk and earlier age of cigarette smoking [2, 7, 8]. A higher risk of smoking correlates directly with more ADHD symptoms [2]. Furthermore, maternal smoking during pregnancy increases the risk for ADHD in the offspring (independent of ADHD in mother) [6].

2 Use of Nicotinic Receptor Agonists in Treatment of ADHD

Activating the cholinergic system can improve a host of cognitive processes (reviewed by Levin et al. [4]) including learning, spatial and working memory, processing speed and ability, inhibition, selective accuracy, detection, and overall attention. In general, using the preclinical paradigms, the effects of nicotine appear to persist with chronic administration [4]. Cholinergic pathways originating in the basal forebrain project diffusely to the cerebral cortex [1]. acetylcholine (ACh) is particularly important for normal cognitive function, including processes mediated by the prefrontal cortex that are affected in ADHD, such as attention, working memory, and executive function. Additionally, nicotinic acetylcholine receptor (nAChR) stimulation can modulate dopaminergic neurotransmision [5, 10]. In animal experiments, nicotine produces a concentration dependent release of dopamine (DA) from slices of rat striatum [10], and nicotine has been shown to have effects on striatal presynaptic dopamine transporters (DATs) in adults with ADHD [3]. However, not all neuronal nAChR agonists reproduce the effects of nicotine on dopamine release.

Longitudinal data continue to highlight the chronicity and clinical and public health importance of ADHD and its treatment throughout the lifespan [11]. Unfortunately, many of the treatments for ADHD result in residual cognitive symptoms. Hence, treatment strategies that include adequate treatment of the general ADHD triad, and more specifically the attentional-based and executive function symptoms of ADHD are needed [11]. Nicotinic cholinergic neurotransmission plays an important role in attention and exectuve function processes, and nicotine has demontrated procognitive effects in a number of animal studies, and pilot data indicates some degree of efficacy in small proof-of-concept adult ADHD trails [11]. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel α4β2 nAChR agonists with improved safety/tolerability profiles have been discovered [11].

Acronyms

ACh

acetylcholine

ADHD

attention-deficit/hyperactivity disorder

DAT

dopamine transporter

DA

dopamine

nAChR

nicotinic acetylcholine receptor

References

Contents

1 Pharmacokinetics of Methylphenidate

Age at the time of drug treatment and pharmacokinetic differences in absorption, distribution and metabolism could influence both the acute and chronic effects of psychostimulants [28]. For a 10 mg dose in a 30 kg child, the maximum serum concentration occurs about 1.5 to 2 hours afterward and leads to concentrations of approximately 10 ng/mL in plasma after administration, dropping by 50 % about 2 hours later [4]. However, the optimal therapeutic dose varies considerably across individuals [9]. There is great variability among subjects and among dosing regimens in the rate of absorption of methylphenidate (MPH) and the rate of decay of MPH from plasma. This led to a 3.5-fold difference in blood levels between subjects taking the same dose in the most extreme case [21]. The therapeutic effects parallel the serum concentration of immediate-release MPH, with a maximum reduction in attention-deficit/hyperactivity disorder (ADHD) symptoms about 1.5 to 2 hours after dosing followed by a decline that is sufficient to require another dose about 4 hours after the first to reestablish full efficacy [23].

Oral MPH in normal adults has a half-life of about 2.1 h, the time to peak plasma concentration is about 2.2 h. Ritalinic acid (major metabolite) reaches peak plasma concentration at approximately the same time as MPH except that levels were several-fold those of MPH [27]. Oral MPH in ADHD children isn’t too different: half-life 2.4 h; time to peak 1.5 h [27].

MPH undergoes extensive and stereospecific presystemic metabolism [1] to form predominantly the inactive hydrolysis product, ritalinic acid, resulting in a low absolute oral bioavailability. The bioavailability of oral MPH measured in rat is 0.19, in monkey 0.22, with considerable intersubject variability: ranging from 0.08 to 0.44 in both species [27]. Animal studies have suggested that MPH is subject to substantial first-pass and presystemic metabolism, the primary action of presystemic metabolism is deesterification in the gut and/or intestinal wall [1, 27]. Interestingly, the rate and extent of d-MPH absorption were similar when administered with or without food [22]. MPH is metabolized extensively in the rat; less than 1 % unchanged MPH was found in the 48 h urine [7].

Intravenous administration of 1 mg/kg of MPH in rats shows rapid accumulation of MPH in the brain, the peak brain concentration within the first minute after injection [13]. Transfer of MPH from plasma to tissues is rapid and distribution is extensive [7]. During the first 30 min after MPH administration, there was an average of 8-fold greater MPH concentration in brain vs. plasma [13]. Peak serum and brain concentrations after oral administration of 1 mg/kg of MPH occurred at 10 min after dosing. At 45 min after dosing, the brain/serum ratios were approximately equal for both i.v. and oral routes of administration [13]. The half-life of MPH in the rat is 24.8 min [7]. MPH is ionized at physiological pH to a lesser extent than dextroamphetamine (D-AMPH) and is considerably more lipid soluble, which will induce quicker rise times to the brain [7].

After oral administration of [¹¹C]d-threo-MPH, the radiolabeled d-MPH was distributed stereoselectively in the rat brain, especially in the striatum. Further, it was shown that the d-isomer binds specifically to dopamine (DA) uptake sites in the striatum [2]. [¹¹C]l-threo-MPH had an homogeneous distribution throughout the brain (after i.v. administration) [26]. The rate of uptake in the brain for the two enantiomers was eqivalent but the clearance was significantly slower for [¹¹C]d-threo-MPH than for the l-isomer. The therapeutic and safety profile of d-MPH is similar to that of racemic d,l-MPH [15]. However, l-MPH offers anxiolytic and antipsychotic activity, serves as an antidote for stimulant overdose [3], reduces cocaine induced locomotor sensitization [6], and pretreatment with l-MPH attenuates the motor activity response to d-MPH [5].

The median effective dose (ED₅₀) for dopamine transporter (DAT) blockade was calculated to be 0.25 mg/kg oral MPH [24] and 0.075 mg/kg i.v. MPH [25]; the half maximal inhibitory concentration (IC₅₀) of MPH at DAT: 84 nm [8]. The ED₅₀ estimate for global norepinephrine transporter (NET) was 0.14 mg/kg ± 0.02 mg/kg MPH, although the local ED₅₀ did vary by brain region [10]; the IC₅₀ of MPH at NET: 510 nm [8] If occupancy = [10], then the average efficacious maintenance doses of MPH used in children and adults occupy 70 % to 80 % of NET but only 60 % to 70 % of DAT, based on the estimated ED₅₀ value of 0.14 mg/kg for NET and 0.25 mg/kg for DAT [24]. Interestingly, NET has greater affinity for DA than for norepinephrine (NE) [12], and whether DAT or NET is the predominant protein clearing DA depends on the abundance of the two transporters in a given region [11].

1.1 Sustained-release preparations of MPH

In recent years, new drug delivery methods have been developed to enhance the duration of action [21]. Through these efforts to develop effective long-acting MPH preparations, valuable new information has become available on the relationship between dosing regimens, blood levels, and therapeutic response. Efficacy of MPH declined in an administration regimen designed to provide consistent stable blood levels, presumably due to acute tolerance due to an adaptation response at the synaptic level in response to blockade of the DAT [18, 20]. This confirmed and extended findings of rapid tolerance previously observed by Srinivas et al. [16] in an acute administration paradigm. This lead to the discovery that there are two alterative strategies for providing sustained efficacy: Pulsatile delivery or escalating blood levels [17]. With pulsatile delivery, there is a drop in blood levels that enables the system to retain or regain sensitivity. With escalating delivery, the increasing blood levels presumably help to overcome emerging tolerance and waning sensitivity [19].

1.2 Placebo effects of MPH

Subjects receiving placebo showed no significant degree of benefit and on average were slightly worse following placebo administration than when they first arrived at the laboratory in an unmedicated state [21]. ADHD does not appear to be a placebo-responsive disorder when evaluated using objective measures. Instead, after placebo administration, a clear pattern of deterioration across the day emerges, in contrast to the pattern of improvement with MPH [18]. Improvement of ADHD children on placebo in studies using observer ratings is probably due in large part to a halo effect, in which teachers or parents score children differently if they believe that they have been medicated [21]. Also, when MPH is given therapeutically and produces large improvements in the classroom, children with ADHD do not attribute this ‘success’ to the drug [14]. This indicates that expectancy does not play a prominent role in MPH’s therapeutic effects.

Acronyms

ADHD

attention-deficit/hyperactivity disorder

D-AMPH

dextroamphetamine

DAT

dopamine transporter

DA

dopamine

ED₅₀

median effective dose

IC₅₀

half maximal inhibitory concentration

MPH

methylphenidate

NET

norepinephrine transporter

NE

norepinephrine

References

Contents

1 Epidemiology and Risk Factors

The etiology of attention-deficit/hyperactivity disorder (ADHD) is unclear. However, it is well accepted that ADHD has both genetic and environmental risk factors [3, 13]. ADHD is likely not a single pathophysiological entity, which suggests complex and multiple etiologies. Multiple genetic and environmental factors may act in concert, which gives rise to a spectrum of neurobiological liability [10] which manifests as a set of ADHD symptoms. Estimates of heritability from many familial and twin studies range from 0.5 to 0.9, average 0.75; which, taken together with a five-fold increased risk in first-degree relatives, strongly implies a genetic component [3, 8, 10, 13, 30]. Environmental risk factors such as obstetric complications, family conflict, and lead exposure have also shown positive, yet small, increases in risk for ADHD.

2 Genetic Risk Factors

No single gene abnormality reliably predicts ADHD, but consistent association between several genes regulating dopamine (DA) transport and signaling have been implicated (these have been the genes most studied by candidate gene association studies because of prevalent DA hypotheses concerning the pathophysiology of ADHD [19, 37] and the mechanisms of the most popular drugs used to treat ADHD [32, 34–36] ). Genome-wide association studies have failed to report any associations that are significant after correction for multiple testing [10]. Cortese et al. [8] estimates that a genome-wide association study would have to use sample sizes between 10,000 to 20,000 subjects in order to accurately detect novel genes involved in ADHD with risk factors similar to those seen in candidate gene association studies. Candidate gene association studies have shown positive, but small correlations with the dopamine receptor D4 gene (DRD4), dopamine receptor D5 gene (DRD5), dopamine transporter gene (SLC6A3), dopamine β-hydroxylase (DβH), synaptosomal-associated protein of 25 kDa gene (SNAP25), serotonin transporter gene (SLC6A4), and the serotonin 1B receptor gene (HTR1B) [3], which is in line with the multifactorial polygenic model in which a plethora of genes each confer a small but real risk to the disorder [8]. It is easy to imagine that combinations of risk alleles impacting dopaminergic signaling could produce an extreme hypodopaminergic state that would lead to poor cognitive function [30].

The SLC6A3 and DRD4 genes show variation amongst the population based on a variable number of tandem repeats where the nucleotide or base pair sequence is repeated a different number of times in different alleles of the gene. A 40 base pair variable tandem nucleotide repeat in the 3′ untranslated region of the human DAT1 gene (SLC6A3 [7]) and a 48 base pair DA D4 receptor 7-repeat allele [17] have both been implicated in ADHD, and have been the most consistently positive across multiple candidate gene association studies [13, 14, 20, 29], which is not always common [6, 9].

Dopamine receptor genes linked to ADHD The DA D4 receptor is prevalently expressed in frontal and subcortical networks that are implicated in the pathophysiology of ADHD [3]. DRD4 association studies have assayed a variant known as the exon-III 7-repeat allele (16 amino acid repeat in the 3rd intracellular loop of the receptor that couples the receptor to pre- or post-synaptic G-protein effectors [30]), which while it shows a positive association with ADHD, may paradoxically be protective, as the DRD4 7-repeat allele produces an in vitro blunted response to dopamine, but subjects with the DRD4 7-repeat allele and ADHD tend to have better clinical and academic outcomes than those with ADHD and the DRD4 4-repeat allele more common in the general population [3, 17, 30]. Candidate gene studies of the DA D5 receptor, which is expressed in the hippocampus, and especially the dentate gyrus [16], have shown positive correlation with ADHD with a repeated sequence near the transcription start site [3].

Although DA D1 and D2 receptors are thought to be the major effectors of stimulant-induced alterations in impulsive, addictive, and compulsive behavior [33], it is unsettled as to whether variants of these full-length genes are associated with ADHD [27].

Dopamine transporter gene linked to ADHD When pooled in meta-analysis, studies of the SLC6A3 10-repeat sequence in the 3′ untranslated region (the 3′ untranslated region of mRNA often contains regulatory sequences that can influence post-transcriptional gene expression) estimate an increased odds ratio of 1.13 for ADHD [3, 7]. It may be possible that different variants of the dopamine transporter (DAT) have an altered sensitivity to endogenous DA. At present, no such variations in the coding sequence of the DAT are known, nor are they separable pharmacologically [27].

Norepinephrine synthesis linked to ADHD Dopamine β-hydroxylase is the main enzyme and rate-limiting step in converting DA to norepinephrine (NE). Meta-analysis of multiple family studies suggest a significant association with ADHD and the 5′ Taq1 polymorphism of the DβH gene [3].

Serotonin signaling linked to ADHD Both the serotonin transporter gene (SLC6A4) and the serotonin 1B receptor gene (HTR1B) have been implicated in ADHD. A functional variant of the SLC6A4 has a meta-analysis adjusted odds ratio of 1.31 for ADHD. Many studies of the HTR1B have also been positive, with a non-functional marker showing an odds ratio of 1.44 [3].

Synaptic transmission linked to ADHD SNAP25 is a neuron-specific protein involved in synaptic vesicle transport, fusion, and release. A meta-analysis of several studies assessing the association between the gene and ADHD found an odds ratio of 1.19. SNAP25 knockout mice also show spontaneous hyperactivity which can be reduced with stimulant drugs [3].

Negative candidate gene results Candidate gene association studies have also been done on several genes that have provided negative or equivocal results. Two genes involved in monoamine degredation, catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO), have shown negative results, as well as the norepinephrine transporter gene (SLC6A2) and the norepinephrine 1C, 2A, and 2C receptors [3].

3 Environmental Risk Factors

Environmental factors play a critical role in the etiology of ADHD. One of the best evidences supporting this point comes from the genetic twin studies, which show that the risk of ADHD in monozygotic twins is much lower than 100 % [8]. Many studies have indicated that complications during pregnancy and delivery could be associated with childhood ADHD. The complications that are associated with later ADHD tend to include chronic exposures to the fetus, and complications that lead to hypoxia rather than acute events [3].

Prenatal risk factors Maternal alcohol use during pregnancy leads to behavioral, cognitive, and learning problems that could present as ADHD. Prenatal alcohol exposure is known to induce brain structural anomalies, and children exposed to prenatal alcohol are more hyperactive, disruptive, impulsive, and are at increased risk of a range of psychiatric disorders [10]. Studies of ADHD children show an increased likelihood of having been exposed to alcohol as a fetus [3].

There is also a well documented, almost 3-fold increased risk for the disorder in children whose mothers smoked during pregnancy [3, 24]. Exposure of the fetus to nicotine can damage the development of the brain at critical time points as nicotinic receptors modulate dopaminergic activity [11, 12, 31], and animal studies have also shown a correlation between chronic nicotine exposure of pregnant dams and hyperactive offspring [3].

Perinatal risk factors Low birthweight (< 2500g) and premature birth (< 37weeks gestation) increase the risk for ADHD [2, 3, 18, 22]. Very low birthweight children show a 2-fold increase in the proportion of those with ADHD vs. average birthweight counterparts [10]. Interestingly, prenatal tobacco exposure can result in both low birthweight and preterm birth [15]. In a huge study from the Danish longitudinal birth registers, Linnet et al. [21] found a rate ratio for hyperkinetic disorder (the International Statistical Classification of Diseases and Related Health Problems (ICD) analogue of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)’s ADHD) of 1.7 for 34 to 37 weeks gestation and rate ratio 2.7 for less than 34 weeks gestation. Likewise, low birth weight for children born at term gave a rate ratio of 1.9 for birthweight of 1500 g to 2499 g and 1.5 for birthweight 2500 g to 2999 g [21]. In a similar study, Mick et al. [23] reported that ADHD cases were 3.1 times more likely than controls to be born under 2500 g.

Postnatal and childhood risk factors Malnutrition and dietary deficiency have been proposed, and iron deficiency has been implicated in some cases of ADHD, however further evidence is necessary to firmly establish a role [10].

Lead exposure Lead exposure has been implicated in the pathophysiology of ADHD, although most children with ADHD do not show lead contamination and many children with high lead exposure do not become affected with the disorder [3]. Nigg et al. [26] suggests that low-level lead exposure, below the US Environmental Protection Agency (EPA) limits, may represent a hidden major effect on ADHD incidence. A population sample, Braun et al. [4] reported that very low levels of lead were associated with ADHD, even with lead exposures below 5 μg/dL, which highlights the importance of a gene–environment interaction model, as these levels of lead exposure are common in the US population [5].

4 Gene–Environment Interactions

Molecular genetics supports the association of ADHD with several DA signaling related genes, and environmental effects suggests increased risks for ADHD related to maternal smoking, exposure to low levels of lead, premature birth or low birth weight, and other factors that alter fetal development with lasting or possibly permanent effects on attention and behavior [30]. It is noteworthy that individual genes or environmental risk factors carry quite modest risk, and also that some of the environmental risk factors associated with ADHD (e.g. low lead exposure) are quite common in the general population [30]. More complex models of the etiology of ADHD which incorporate gene–environment interactions are being studied. However, the multitude of possible etiologies of gene–environment combinations add complexity, and would require enormous sample sizes for adequate evaluation [30]. Neuman et al. [25] demonstrated that smoking during pregnancy is associated with the ADHD combined subtype in children with the ‘susceptible’ DRD4 and dopamine transporter gene (SLC6A3) gene variants. Also, a significant interaction between SLC6A3 genotype and prenatal smoke exposure was found in males: Men with prenatal smoke exposure and homozygous for the SLC6A3 10-repeat allele had higher hyperactivity/impulsivity than males from all other groups [1]. Through unknown mechanisms, abnormal DAT density is a common feature among subjects with ADHD [28].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

CDC

Center for Disease Control and Prevention

COMT

catechol-O-methyl-transferase

DAT

dopamine transporter

DA

dopamine

DbH

dopamine β-hydroxylase

DRD4

dopamine receptor D4 gene

DRD5

dopamine receptor D5 gene

DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

EPA

US Environmental Protection Agency

HTR1B

serotonin 1B receptor gene

ICD

International Statistical Classification of Diseases and Related Health Problems

MAO

monoamine oxidase

NE

norepinephrine

SLC6A2

norepinephrine transporter gene

SLC6A3

dopamine transporter gene

SLC6A4

serotonin transporter gene

SNAP25

synaptosomal-associated protein of 25 kDa gene

References