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Abstract

The purpose of the present paper was to review studies of two candidate genes for attention deficit–hyperactivity disorder (ADHD) and to separate aetiological from therapeutic effects. Genomic studies of ADHD were reviewed for candidate dopamine genes and studies selected to distinguish catechol-o-methyltransferase (COMT) and dopamine transporter (DAT-1) effects. Pharmacogenomic findings for the COMT gene were in agreement with the 1977 observations of Sprague and Sleator, who reported that at low psychostimulant doses, children with ADHD showed a remarkable improvement on a short-term memory test at all levels of task load, whereas at higher doses, there was a significant decrement in performance on the more difficult versions of the task, corresponding to an ‘inverted ‘U’ shaped curve’. Recent studies show that individuals with the homozygous COMT (valine/valine) genotype demonstrated improvement following psychostimulant treatment, because their tonic dopamine (DA) levels were low, whereas the homozygous COMT (methionine/methionine) individuals, who already have high initial prefrontal cortex (PFC) dopamine levels performed more poorly after medication, in tasks with high working memory load. On the other hand aetiological findings for DAT-1 gene were heterogenous, but more often positive than for COMT. Contrasting findings for COMT and DAT-1 may best be considered in terms of prediction of medication response in ADHD in the case of COMT, but in aetiological terms in the case of DAT-1, which is abundant in the striatum and possibly plays a greater role in determining hyperactivity and impulsivity, than working memory deficiencies.

Keywords

ADHD genes pharmacogenomic

Most theories of attention deficit–hyperactivity disorder (ADHD) have postulated a primary role for the prefrontal cortex (PFC) in ADHD. For example, Barkley in an influential theory postulated that ADHD represented a deficit in PFC inhibition, resulting in deficits in four subsidiary executive functions: verbal working memory, internalization of speech (verbal working memory, self- regulation of affect, and reconstitution) [1].

Subsequent theories such as that by Sonuga-Barke [2] and Sagvolden et al. have postulated deficits in dopaminergic PFC-subcortical systems, including mesocortical, mesolimbic and nigro-striatal circuits [2, 3]. Sagvolden et al. have argued that the main component of altered reinforcement processes in ADHD children is a steeper delay-of-reinforcement gradient, or shorter time interval between response and effective reinforcer, resulting in less effective reinforcement and also less effective extinction of previously established, responses. Recent developments including twin and molecular genetic studies may add a developmental component to ADHD theories. For example, Hay et al, utilizing data from the Australian Twin Study of ADHD, showed that additive genetic influences on Hyperactivity/Impulsivity varied from Time 1 to Time 2 of the study 3–4 years later, indicating specific and shared genetic influences at Time 1 but only shared influences at Time 2 [4]. Thus genetic influences may vary with age.

There has been considerable interest in candidate dopaminergic genes, including dopamine transporter-1 (DAT-1) and a number of dopamine receptors including the dopamine D4 receptor (DRD4) as well as DRD5, and D2 and D1 receptors [5]. Kirley et al. postulated a working hypothesis in relation to genotype and abnormalities of dopamine transmission in ADHD [6]. Their detailed review of genotypic evidence available at that time found that a definitive theory of dopamine neurotransmission was not yet possible. The candidate genes receiving most support were DAT-1, DRD4, DRD1 and DRD5, while dopamine β hydroxylase (DBH) and tyrosine hydroxylase (TH) received some support. The evidence for DAT-1 supported a theory of decreased dopamine neurotransmission in ADHD, but biochemical pathways were likely to be complicated with multiple feedback and protective pathways.

Volkow et al. showed that oral methylphenidate (MPH) at average therapeutic doses significantly increased extracellular dopamine (DA) in the brain, as evidenced by a significant reduction in dopamine D2 receptor availability in the striatum [7]. They postulated that the increase in DA caused by the blockade of DAT by MPH amplified weak DA signals and enhanced task-specific signalling. They also speculated that an age-associated decline in DAT could contribute to the decrease in symptomatology in most ADHD subjects as they grow older, and a failure to show DAT decline with age could account for persistence of symptomatology in subjects with ADHD.

Faraone et al. commented that there are several reasons why the dopamine transporter gene (DAT, SLC6A3) has been considered a suitable candidate gene for ADHD [5]. Primarily the therapeutic effects of psychostimulant medications, which block the dopamine transporter, suggest a candidate aetiological or pharmacogenomic role for DAT (in addition to knockout mouse studies). From an aetiological point of view, Cook et al. first reported an association between ADHD and the 10-repeat allele of a tandem repeat polymorphism located in the 3′ untranslated region of SLC6A3[8]. According to Faraone et al., a number of subsequent studies have found heterogenous results. A meta-analysis by Curran et al. found a small positive odds ratio (OR) [9]. Faraone et al. found that when results from family-based studies were pooled the OR was small (1.13, 95%CI = 1.03–1.24) [5].

The ‘tonic/phasic model’ proposed by Bilder et al. postulates that high-amplitude phasic DA released by behaviourally driven bursts of action potentials is regulated by fast re-uptake via the DAT [10–13]. Within subcortical systems, low levels of DA, which are not subject to the fast re-uptake process, will escape the synaptic cleft and contribute to the tonic extracellular pool of DA. Increases in tonic DA serve to suppress phasic DA activity via action on autoreceptors on the DA terminal. At the subcortical level DAT and monoaminoxidase (MAO) offer effective routes for DA metabolism. This system may be dramatically affected at both cortical and subcortical levels by taking a psychostimulant medication.

Bilder et al. point out that there are substantially fewer dopamine transporters on DA terminals in the PFC, which probably accounts for the higher proportion of DA in the extracellular space in the PFC compared to the striatum [10]. It has been proposed that most DA in the PFC is removed via re-uptake into noradrenergic terminals, requiring DA to diffuse long distances before inactivation via this route. This allows action on D1 receptors located at extrasynaptic sites. The metabolism of extrasynaptic DA is thought to be by catechol-O-methyltransferase (COMT), which has been found to have two possible nucleotide polymorphisms: methionine (Met) and valine (Val) at codon 158 of the COMT gene. At room temperature the Met allele is associated with low enzymatic activity, whereas the Val allele is associated with high activity. This has occasioned great interest in PFC functioning in schizophrenia research, but it is also believed that phenotypic expression of this polymorphism affects a broad range of neuropsychiatric syndromes and behaviour.

Bilder et al. proposed the following [10].

The Val allele associated with high-activity COMT increases phasic and reduces tonic DA transmission subcortically and decreases DA concentrations cortically. This leads to an increase in D₂ and a decrease in D₁ transmission; as a result there is decreased stability of neural networks, underlying working memory representations, including those that are responsible for the maintenance of behavioural programming (executive) functions, but there is also facilitation of the switching or transition to alternate network states mediating the resetting of working memory traces and flexibility in behavioural programmes (State 1).

The Met allele associated with low-activity COMT decreases phasic and increases tonic DA transmission subcortically, and increases DA concentrations cortically: this is associated with increased D1 and decreased D2 transmission in the PFC. This increases the stability of networks mediating sustained working memory representations, but makes it more difficult to switch or update the currently active networks that represent sustained working memory representations or ongoing behavioural programmes, (State 2).

Seamans and Yang [14]have reviewed principles of DA functional mechanisms at the PFC, identifying key features of DA modulation of PFC neurons [11]. These include a distinct bell-shaped dose–response profile of post-synaptic DA effects, and biphasic bi-directional modulation of N-methyl-D-aspartate (NMDA) receptors by D1 stimulation, with implications for the cellular aspects of working memory. In contrast, data obtained from striatal neurons suggest that DA acts via D1 receptors to depolarize gamma-amino-butyric acid (GABA) interneurons directly, yet acts pre-synaptically via D2 receptors to inhibit GABA release onto dorsal and ventral spiny output neurons. The authors describe the predominant role of COMT in the PFC as terminating DA's action. In normal individuals who have Val/Val COMT polymorphisms (and lower basal DA levels) administration of psychostimulants artificially increases DA levels, and this allows increased cortical efficiency.

Seamans and Yang describe two hypothesized neural states [14]. State 1 involves hypofunction of the DA system in the PFC, giving rise to premature termination of information in working memory and allowing ‘contamination’ by weak stimuli that are normally ignored, resulting in distractibility and tangential or intrusive thought patterns. They predict that a strong State 1 situation should be brought under control by blocking D2 receptors (e.g. by an antipsychotic medication) forcing the system into State 2.

State 2 is described as a situation in which the PFC is uncoupled from inputs about the external world by supra-optimal D1 receptor stimulation, and persistent activity becomes extremely and virtually impossible to disrupt, resulting in stereotypic thoughts or actions. Whereas in State 1 the predominant receptor is hypothesized to be D2, where there is easy access to working memory by an open gate, in State 2 the predominant receptor is D1, when the PFC gate is closed and only the strongest representations affect action, resulting in stereotyped or obsessive thoughts or actions.

In terms of pharmacogenomic predictions, lower D1 activity in the PFC (Val allele) should respond to a psychostimulant medication that increases extrasynaptic DA, and hence D1 stimulation, and allows increased working memory capacity, whereas higher D1 activity (Met allele) should result in narrowed or stereotypic cognitive activity.

Pharmacogenomic studies of ADHD

McGough has reviewed genetic prediction of psychostimulant response, or pharmacogenomic studies of ADHD [12]. He concluded that the most frequently studied DAT-1–10 repeat polymorphism predicted both increased and decreased symptom reduction in various reports. Other dopamine candidate genes including dopamine receptors and COMT were limited by small sample sizes, inconsistent research designs, retrospective reports and a focus on symptom response. A study by Winsberg and Comings found that homozygosity of the 10-repeat allele of the DAT gene was characteristic of non-response to MPH, measured by the Conners’ Abbreviated Rating Scale, suggesting a possible direction for pharmacogenomic prediction of stimulant response [13]. A similar study by Roman et al. in Brazilian youth of European descent also found a decreased MPH response on the Clinical Global Assessment Scale, in individuals homozygous for the 10-repeat DAT-1 polymorphism [14].

In contrast, Kirley et al. applied the transmission disequilibrium test (TDT), which examined homo versus heterozygosity of particular DAT-1 alleles in ‘good’ responders, ‘mediocre’ responders and ‘non-responders’ [15]. They found an improved response in patients homozygous for the DAT-1 10-repeat allele, compared with those having a mediocre or no response. McGough [11] also reported other ‘in press’ or unpublished data showing either an improved response or no association of the DAT-1 10 repeat allele with MPH response. One of these studies by Hamarman et al. did not report significant DAT-1 associations, but found that the MPH dose required for normalization of behaviour on the Conners’ Global Index was 1.5 times greater in subjects with the 7-repeat allele of the DRD4 dopamine receptor gene [16].

Madras et al. have reviewed the role of the DAT in ADHD [17]. They point out that effective neuronal communication in the brain requires precise and dynamic regulation of neurotransmitter concentrations, which are regulated by monoamine transporters, which sequester them into neurons. While DAT is expressed selectively in all DA neurons, DAT and dopamine receptor densities are not consistent in all brain regions. The authors describe DAT as the major contributor to DA signalling in the nucleus accumbens, caudate-putamen, and substantia nigra. The ratio of DAT to dopamine receptor expression levels in the PFC is lower, and DA is also metabolized by the noradrenergic transporter (NET). The authors point out that atomoxetine, a noradrenergic re-uptake inhibitor, raises the level of DA in the frontal cortex, but not in the striatum. They describe a number of possible biochemical scenarios, which might be necessary or sufficient to alleviate ADHD symptoms. These may be (i) increased extracellular DA levels in the frontal cortex, with superfluous norepinephrine (NE) levels; (ii) increased NE levels with superfluous DA levels in the frontal cortex; (iii) essential elevation of both DA and NE levels; and (iv) reorganization of DA distribution in the frontal cortex and other regions.

Thus a systematic study of the effects of ADHD medications on extracellular monoamine levels in multiple brain regions remains to be completed. However, it is useful to differentiate pharmacogenomic or treatment predictions from genetic influences involved in aetiology (similarly beneficial and adverse therapeutic effects may be mediated through the same or through different transmitter pathways). The possible variations in DA/NE relationships described by Madras et al. [17] may be important in explaining therapeutic effects.

COMT effects

Interestingly, most studies of the COMT gene, despite some early suggestive findings [18], have subsequently yielded negative aetiological findings, despite the apparent role of COMT in DA metabolism [5]. In humans, the COMT gene contains a common variation in its coding sequence, which translates Val to Met. At room temperature the Met allele has one-fourth the enzyme activity of the Val allele. It is believed that COMT is important in the metabolism of DA in the PFC whereas DAT is more important in the striatum.

As reviewed by Faraone et al., there have been seven family-based studies, which have examined the Val/Met polymorphisms in ADHD [5]. Five of these found no significant association (Barr et al. [19]; Hawi et al. [20]; Manor et al. [21]; Payton et al. [22]; Tahir et al. [23]). Two studies reported significant associations, although one study subsequently corrected their report to show less over-transmission of the Val allele than originally reported [18], while the other study in Han Chinese was significant only when limited to male cases [24]. Thus the pooled analyses showed no evidence of an aetiological association between ADHD and COMT.

Taerk et al. have examined PFC and COMT associations in 118 children aged 6–12 years meeting DSM-IV criteria for ADHD, utilizing the Wisconsin Card Sorting Test (WCST), which measures set-shifting ability and has differentiated ADHD children from controls, Tower of London, which measures planning ability, and the Self Ordered Pointing Task, a measure of working memory, also found capable of differentiating ADHD children from controls [25]. The investigators reported no association of the Val^108/158 Met polymorphism with these tasks.

In contrast, Diamond et al., in a study of healthy children, examined the Dots-Mixed task, which requires that participants remember two rules and inhibit the tendency to respond on the same side as the stimulus on one-half of the trials [26]. It is poorly performed by primates and by children with phenylketonuria, who have low prefrontal DA, and showed that approximately 26% of the variance was shared with COMT genotypes, while the Self-Ordered Pointing task, where children are shown six blocks of trials with line drawings and abstract designs presented in a rectangular grid and asked to point only once to each stimulus, (thought insensitive to DA levels), was not associated. The authors claimed a high level of specificity, in that the COMT polymorphism was linked only to tasks sensitive to the level of DA, and is consistent with the Taerk et al. [25] negative result.

Taerk et al. argued that the absence of an association between the COMT polymorphism and their measures of executive function could be related to the relatively young age of their sample, and that the functional importance of COMT in the PFC may be observable only in adults [25]. They quote animal studies indicating a positive relationship between aging and COMT. Certainly in humans COMT is likely to become more important with age, and further studies are needed to determine the phenotypic implications of DAT and COMT relationships in both normal development and ADHD.

Mattay et al. investigated the effect of dexamphetamine (AMP) on an N-back working memory task, with increasing levels of task load of 1-back, 2-back, and 3-back in healthy adult volunteers, typed for the COMT gene, as well as conducting a functional MRI during the task [27]. They found significant main effects of the COMT genotype and AMP on the distributed cortical activation patterns associated with a working memory task, with prominent locales of activation in prefrontal and parietal cortices. A significant genotype × drug interaction was restricted to the PFC. This result was observed when data from all subjects were analysed, as well as when they were restricted to the subsample of subjects who were more precisely matched for IQ, age, and gender across genotypes. At all levels of working memory load, subjects with the Val/Val genotype had a more efficient prefrontal activation response. This response was associated with a significant improvement in reaction time. N-back performance was dependent on genotype and drug condition. AMP caused a significant decrease in performance on the 3-back task in Met/Met individuals.

Theoretical inverted U model

To see how the two gene versions affect the living human brain, Meyer-Lindenberg et al. scanned 24 healthy young adults twice using positron emission tomography, which uses radioactive tracers to visualize brain function [28]. Frontal cortex activity increased as midbrain DA activity increased in subjects with Val, but decreased in those who had inherited two copies of the met COMT gene. This trait-like characteristic of the COMT gene type was thought to fit a model in which the PFC functions optimally when DA activity is neither too low nor too high, corresponding to the top of an upside-down U. The findings suggested that DA tunes prefrontal neurons to achieve an optimal signal-to-noise ratio, much like a fine-tuning dial on a radio. ‘For the clearest signal, the dial must be turned in opposite directions, depending on which version of the COMT gene one inherits: up with Val, down with Met’ [29]. ‘When baseline DA signalling was suboptimal, there was an improvement in the efficiency of PFC information processing in Val/Val individuals after AMP, presumably because of a shift of DA signalling from the lower end of the normal range to a higher level on the putative inverted U-shaped curve’ [28]. The effect was observed at all levels of task load. Also consistent with evidence that supranormal stimulation of DA D1 receptors can have detrimental effects on PFC function, there was a decrement in the efficiency of PFC information processing in Met/Met individuals on AMP at high load. The authors suggested that a load-dependent effect of COMT in Met/Met individuals may indicate that despite their relative position near the peak of the DA response curve, supra-optimal DA levels do not disrupt neuronal information processing until a critical threshold of DA signalling and associative processing load are exceeded. The combined effects on DA levels of AMP and high working memory load would push individuals with the Met/Met genotype beyond the critical threshold at which compensation can be made.

The aforementioned authors believe that their findings and the model are in agreement with the classical observations of Sprague and Sleator, who reported that at low psychostimulant doses, children with ADHD showed a remarkable improvement on a short-term memory test at all levels of task load, whereas at higher doses, there was a significant decrement in performance on the more difficult versions of the task [29]. In contrast, behaviour ratings continued to improve despite this decrement, up to a dose of 1.0 mg kg⁻¹. This was referred to as an ‘inverted U-shaped curve’, and for a time was very influential in suggesting that low-dose regimens were optimal for ADHD children. However, a number of studies such as that by Evans and Pelham, and Douglas et al., queried this result [30, 31]. Douglas et al. reviewed the question of whether high doses of psychostimulants impaired flexible thinking in ADHD. They reported a positive linear dose–response pattern on a number of cognitive tasks, based on the WCST, Trail making and verbal fluency tests, up to 0.9 mg kg⁻¹. These reports sometimes resulted in the clinical use of much higher dose ranges, at times well beyond 1.0 mg kg⁻¹ per day.

But suspicions remained that subgroups of ADHD children might show adverse reactions to high-dose psychostimulants. For example, Solanto and Wender, and Tannock and Schachar, reported the presence of subgroups within their samples, which manifested adverse responses, so the issue has remained largely unresolved [32, 33].

Discussion

The aforementioned inverted U-response studies were carried out in adults, but Sprague and Sleator described a similar effect in children [29]. If it is assumed that children and particularly ADHD children have an immaturely functioning DA system, the clinical features of distractibility and impulsivity most resemble State 1, where ‘any internally or externally derived representation can guide action’. At an early age behaviour is more likely to be controlled at subcortical levels and thus etiological studies may show an association with DAT-1. In contrast, studies of the therapeutic response to psychostimulant medication should reflect a tendency to drive the response to State 2 or ‘better behaviour’. Thus pharmacogenomic studies of ADHD would be predicted to show over-transmission of the Val allele in children who respond well to medication, and over-transmission of the Met allele in children who show stereotypic responses to medication, a hypothesis not tested in the studies described here. In contrast, aetiological studies might show heterogenous associations depending on the maturity of the child and the variety of genetic and environmental influences on subcortical DA functions.

The present review suggests that pharmacogenetic studies of ADHD might benefit from the separation of putative etiological candidate genes from genetic findings in relation to medication response. This distinction is based on the differential DA metabolic pathways at cortical and subcortical levels described by Madras et al. [17] and Bilder et al. [10]. As described by Madras et al., therapeutic response may be more dependent on prefrontal monoamine levels while aetiology may be more complex. According to Floresco et al., ‘., the DA system is compartmentalized consisting of a synaptic (and potentially peri-synaptic) compartment and a tonically maintained extrasynaptic compartment, each of which is differentially affected by uptake processes’ [34]. Thus the tonic/phasic model would predict that synaptic DA could have quite different genetic influences from extrasynaptic DA, the latter more likely to be affected by COMT and the former subject to a number of dopaminergic genetic influences.

In the present context the varied DAT-1 10- repeat findings may reflect heterogenous or multiple genetic involvement in the aetiology of ADHD. In contrast, the negative findings for COMT and ADHD suggest a secondary role for COMT in aetiology, while the striking medication response in relation to COMT described by Mattay et al. and Meyer-Lindenberg et al. suggests a primary role for COMT in medication response [27, 28]. The absence of demonstrated aetiological associations between COMT and ADHD, at least in childhood samples, suggests that the symptoms of ADHD in childhood may relate more to subcortical factors, where DAT metabolism is of greater importance. However, the demonstrated response of ADHD children to stimulant medications, and the ‘inverted U-shaped curve’ of Sprague and Sleator suggest that the response to psychostimulant medications may resemble adult COMT effects via extrasynaptic DA effects on the PFC even in childhood, and as a result medication effects would be predicted by Val/Met transmission patterns [29].

Conclusions

The contrasting genomic findings for the DAT-1 10-repeat allele and COMT in ADHD may be explained by separation of aetiological and therapeutic mechanisms. Aetiology may be heterogenous at a genetic level. In contrast, homozygosity of the COMT Val allele in medication responders, and homozygosity of the Met allele in adverse responders, could provide a test for prediction of those likely to have severe side-effects to stimulant medications. While the findings in adults in relation to COMT go some way to solving the Sprague and Sleator puzzle, questions remain about the age at which the COMT effect is manifest, and also await further experimental findings of the relationship between DAT and COMT genotypes in the prediction of medication response, which may be affected by underdevelopment of large frontal pyramidal neurons, particularly where there is atypical development.

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