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Abstract

Objective:

To review literature relevant to a possible prediction of stimulant side effects in attention deficit hyperactivity disorder (ADHD), with implications for guidelines.

Method:

Recent literature on inverted-U effects of dopamine in the prefrontal cortex (PFC), default mode processing, and motor circuits relevant to stimulant side effects is reviewed.

Results:

The literature on inverted-U effects in the PFC suggests that catechol-O-methyltransferase (COMT) Met versus Val polymorphisms may predict excess dopaminergic effects, including headache and introversion in Met/Met subjects, but therapeutic effects in Val/Val subjects, while dopamine transporter polymorphisms may predict motor side effects. In particular, an understanding of ‘inverted-U’ effects helps to explain why some children may experience side effects while others show improvements at similar dose ranges.

Conclusion:

Genetic prediction of stimulant side effects should be investigated, particularly given recent controversies in relation to National Health and Medical Research Council guidelines for stimulant use. A better understanding of treatment-emergent effects will also provide a better understanding of therapeutic effects.

Keywords

ADHD CNS stimulants genetic inverted-U side effects default mode

Background

While a number of professional organisations such as the American Academy of Child and Adolescent Psychiatry (AACAP) (2007), the American Academy of Pediatrics (2001) and, more recently, the Australian National Health and Medical Research Council (NHMRC) (2012) have attempted to draw up comprehensive clinical guidelines for the use of stimulant medications for attention deficit hyperactivity disorder (ADHD), the issue of side effects has not been addressed in terms of possible underlying physiological mechanisms. For example, the AACAP practice parameters describe appetite decrease, weight loss, insomnia or headache as common side effects and tics and emotional lability and irritability as less common treatment-emergent effects. The guidelines advise assessment of severity and monitoring of side effects as they ‘may be transient in nature’. If the side effects persist, the physician is advised to lower the dose, but it is pointed out that the dose that does not produce a side effect may not be adequate to treat the ADHD, and an alternate medication is then advised. While the advice to monitor side effects and if necessary reduce dose levels is valid, the question should now be asked as to whether there are potential methods of predicting side effects or at least better investigating them when they occur? As an indication of the current confusion and ‘heat’ aroused by these issues, the Draft Guidelines will be soon be removed from the NHMRC website. However, NHMRC will continue to provide advice to health professionals on ADHD, and is currently developing Clinical Practice Points on the Diagnosis, Assessment and Management of ADHD in Children and Adolescents (the CPPs) (NHMRC 2012). Unfortunately, much of the discussion in relation to the guidelines has been politically rather than scientifically motivated, particularly in relation to the potential side effects of stimulants.

Despite a very large literature on the aetiology and treatment of ADHD, the genetic prediction of side effects of stimulant medications has not been investigated.

Inverted-U processes in neural circuits, as a function of optimal levels of arousal in both learning and psychopathology, were suggested for schizophrenia, parkinsonism and attention deficit disorder (Grossberg, 1999). Circuit sensitivity was thought to be optimal at moderate arousal levels (Golden Mean), but degraded when the circuit was either over-aroused or under-aroused.

Sprague and Sleator (1977) described an ‘inverted-U’ effect on cognitive short-term memory with increasing doses of Benzedrine. The investigators reported that at low-stimulant 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 decrease in performance on the more difficult versions of the task. On the other hand, behaviour ratings continued to improve despite this cognitive decrement, up to a dose of 1.0 mg per kg. This was referred to as an ‘inverted-U’ effect and was influential in suggesting that low-dose regimens were optimal for ADHD children (Swanson et al., 2011).

The apparent dual effect was postulated as a ‘dual pathway’ model of ADHD (Sonuga-Barke, 2002). This included executive function, related to cognitive control of behaviour, while motivational circuits were thought to be related to the inability of ADHD children to delay gratification for later reward. The executive circuit was believed to involve the prefrontal cortex (PFC), striatum and thalamus, with reciprocal connections back to the cortex, while the reward circuit was suggested as involving the ventral striatum and anterior cingulate. In both cases, dopamine (DA) was an important neuro-modulator. An important distinction here is that DA metabolism is predominantly via the DA transporter at subcortical levels, but via catechol-O-methyltransferase at the PFC (Floresco et al., 2003).

A ‘developmental dynamic theory of ADHD’ described three parallel cortico–striatal–thalamic prefrontal loops (based on Alexander et al., 1986) (prefrontal, limbic and motor loops) believed to be modulated by dopamine:

The Dorsolateral prefrontal loop is involved in functions such as planning, short-term memory and attention.

The Limbic loop is involved in reinforcement and extinction of behaviour.

The Motor loop is involved in timing and the starting and stopping of motor behaviour. (Sagvolden et al., 2005)

More recently, an alternate neurobiological hypothesis for ADHD and other psychopathological conditions of childhood, which does not rely on ‘executive’ control, postulated that spontaneous patterns of low-frequency coherence, or a default mode network (DMN) ‘may intrude into periods of active task-specific processing’ (Castellanos et al., 2005, 2008; Sonuga-Barke and Castellanos, 2007). Central to the hypothesis is the notion of ‘anti-correlation of “task-positive” and “task-negative” activity’. Sonuga-Barke and Castellanos (2007) suggested a number of possible mechanisms, which might determine suppression of the DMN, but in general they described a threshold ‘under which persisting task-negative low frequency oscillations will not impinge on task-related attention, but over which periodic attention lapses will occur’. Excessive intrusion was described as being associated with greater reaction time (RT) variability during task performance, with exponentially prolonged latencies on occasional trials. Furthermore, affinity to the default mode versus affinity to a goal-directed state is thought to be reflected in intrinsic versus extrinsic motivation (i.e. introspection versus goal direction). However, physiological control of DMN suppression remains to be investigated.

In the present context, it is useful to return to the Sprague and Sleator (1977) findings of ‘inverted-U’ effects on cognitive performance, namely cognitive deterioration in some children at higher stimulant dose levels, with an apparent behavioural improvement at higher dosage. Clinical descriptions of side effects of stimulant medication in some children include excess introspection and tearfulness, while in other children there is an increase in cognitive rigidity or a ‘zombie’ effect. This dose-related effect has been demonstrated in animal studies where methylphenidate at dose levels of 1.0–2.0 mg/kg produced perseverative errors (Arnsten and Dudley, 2005). Interestingly, the advantageous effects of methylphenidate were blocked by administration of either the alpha-2 adrenoreceptor antagonist indoxan, or the dopamine D1 antagonist SCH23390 (Arnsten and Dudley, 2005). Arnsten et al. (1998) described how the PFC is highly sensitive to its neurochemical environment, and how dopamine and noradrenalin act synchronously at the D1 and alpha-2A receptors to promote working memory at low to moderate methylphenidate doses, whereas high doses disrupt PFC functions (Levy, 2009). Could these effects represent opposite poles of DMN intrusion?

COMT polymorphisms and inverted-U

The importance of D1 receptors in the prefrontal cortex (PFC) suggested a critical role in PFC-mediated working memory deficits (Goldman-Rakic, 1987; Sawaguchi and Goldman-Rakic 1994). In humans, the COMT gene contains a common variation in its coding sequence, which translates valine (Val) to methionine (Met). At room temperature the Met allele has one-fourth of the enzyme activity of the Val allele. Thus, the Val allele, associated with high-activity COMT and more rapid metabolism of DA, decreases DA concentrations in the PFC (Bellgrove et al., 2005; Levy 2009; Meyer-Lindenberg et al., 2005) more rapidly than does the Met allele.

It can be proposed that where COMT is important for DA metabolism, particularly in the PFC, the effect of increasing DA concentrations by stimulant medications may result in adverse effects such as cognitive rigidity and headache, when DA concentrations are already relatively high (as in Met/Met children), but result in both cognitive and behavioural improvement when DA levels in the PFC are low (as in Val/Val) children. Variation in degree of ‘introspection’ versus ‘exteroception’, as a consequence of excessive stimulant activity at the PFC D1 receptor, can also be postulated as a mechanism for the excess teariness and introspection clinically described in some children on too high (for them) doses of a stimulant. The likelihood of excess DA in this case is increased in children who show the Met/Met allele of the COMT gene as they already have less COMT activity and thus higher dopamine levels in the PFC, while children having the Val/Val allele may benefit from similar stimulant dose levels.

An association between the COMT valine (Val) 108/158 methionine (Met) polymorphism and the response to treatment with methylphenidate in children with ADHD was reported by Cheon et al. (2008). They found that 62.5% of the patients showing a good response to methylphenidate treatment had the Val/Val genotype, while 41.7% and 11.7%, respectively, of patients showing a poor response had the Val/Met and Met/Met genotypes. In adults, inverted-U effects on working memory, as a function of COMT genotype, were shown by Mattay et al. (2003). While this suggested a central role for the D1 receptor in attention, visuo-spatial memory and dorso-lateral prefrontal functions, the question of noradrenergic functions has remained unanswered.

In investigations of animal and human studies of the ‘inverted-U’ effect, monkeys performed a working memory task after administration of a wide range of methylphenidate (MPH) or atomoxetine (ATM) doses (Gamo et al., 2010). Optimal doses were challenged with the alpha-2A adrenoreceptor antagonist idoxan or the D1 DA receptor antagonist SCH 23390. The results indicated that both MPH and ATM generally produced inverted-U dose–response curves, with improvements at moderate doses, but not at higher doses, and these effects were shown to be blocked by indoxan or SCH 23390, respectively. These effects were consistent with previous studies of the effects of selective alpha-2A and/or D1 receptor agonists on PFC function (Arnsten and Dudley 2005; Arnsten et al., 1998; Del Campo et al., 2011).

Default network

The ‘default-mode interference’ hypothesis of Sonuga-Barke and Castellanos (2007) suggested that the characteristic increase in RT variability in ADHD might be due to intrusions by the default attention network into goal-directed activity. Namely, the normally adaptive state of periodically attending to potential novel events in the environment (subserved by the default attention network) would become maladaptive when this interfered with ongoing task processes (Fassbender et al., 2009). Recent studies on ‘resting brain’ activity have provided complementary information to data produced using cognitive activation paradigms. A few studies have focused on ‘deactivations’ or decreases in regional cerebral blood flow (rCBF) or functional Magnetic Resonance Imaging (fMRI) signal during a task of interest relative to a control task (Bush, 2010). Bush described three separable networks of brain support: (1) cognitive or focused, goal-directed behaviour; (2) internal state monitoring; and (3) vigilance for salient external stimuli. Gusnard and Raichle (2001) and Gusnard et al. (2001) noted that some cortical areas such as posterior cingulate cortex (PCC), retrosplenial cortex and precuneus, and other posterolateral parietal areas near the angular gyrus are thought to be tonically active during unstructured rest periods, to support environmental vigilance and monitoring of the internal milieu.

Dopamine transporter (DAT) and tic disorders

Alternatively, the activity of differing DAT alleles at subcortical levels (currently less well understood) may predict a liability to the development of tic disorders seen in a number of ADHD children. At subcortical levels, DA uptake via DAT provides the primary mechanism through which DA is metabolised. Linear dose by gene related improvements in a heterogeneous ADHD sample of children lacking the DAT-10 repeat allele (Froelich et al., 2011). They showed greater improvements in symptoms with increasing dose compared with DAT-10 carriers. This again drew attention to a gene by dose effect.

An investigation of 103 Tourette syndrome (TS) patients and their parents for different DA-related polymorphisms, including DRD4, DAT1 and the Val 58 Met polymorphism of the COMT gene, used a dimensional approach. The DAT1 40bp VNTR showed an association with peak tic severity as measured by the Yale Global Tic Severity Scale, suggesting a dopaminergic/DAT component in motor tics (Tarnok et al., 2007). According to Singer and Minzer (2003), dopamine from the substantia nigra pars compacta can have either an excitatory or inhibitory effect, depending on receptor subtype. D1 receptors stimulate adenylate cyclase and enhance activity, whereas D2 receptors inhibit adenylate cyclase and decrease activity. According to the authors, the basic tenet of most hypotheses is that tonically active inhibitory GPi/SNPr (pars reticulata) acts as a brake on excitatory thalamic nuclei, that in turn influence motor pattern generation in the cortex or brainstem. In ADHD, DAT genes may be important in determining the dose level at which motor side effects of stimulants become evident, via effects on niagro/striatal D2 receptors. Thus, DAT variants may be candidate genes for vulnerability to motor tic side effects of stimulants via the D2 receptor.

Discussion

The withdrawal of the ‘Draft Australian NHMRC Guidelines on Attention Deficit Hyperactivity Disorder’ (2009) in response to political and anti-psychiatry pressures, and subsequent replacement by an invited committee with varying interests and experience, is unfortunate in a number of respects. In particular, it is important to point out that the above AACAP guideline in relation to titration of appropriate stimulant dose levels is often assisted by teacher ratings of medication response, but since the withdrawal of the NHMRC 2009 draft guidelines, some teachers have become reluctant to take this responsibility. Second, the important ethical and scientific issues involved in the use of stimulant medications (which have been in use since 1937) have become clouded in an atmosphere of moral panic, rather than scientific debate, leaving the rest of the world to investigate the issues raised in the present paper, while Australian parents and clinicians struggle at the coalface (Levy, 2012).

While routine genetic testing is ethically and economically a long way off, genetic understandings of PFC functions may help illuminate the present controversies. It is suggested that the COMT alleles (Met/Met or possibly Met/Val) may be candidate genes for the prediction of excessive cognitive rigidity as a response to excessively high doses of stimulant medications in such children, when dose levels are above the ‘golden mean’ of the ‘inverted-U’. Clear demonstration of this effect may have been masked in the past by heterogeneous samples of children, including Met/Met and Val/Val genotypes, where the latter show increasing benefits of medication in the clinical dose range, and may not enter the downward slope of the inverted-U, whereas the former show cognitive and/or emotional side effects.

The development or tendency to development of tics may reflect insufficient activity of the DAT-10 allele at niagrostriatal levels, resulting in excessive availability of DA, while differential effects on D2 and/or D1 receptors may also be important. The dissociated effects of D1 at cortical levels and D2 at subcortical levels may be important in understanding the capacity of TS patients to temporarily suppress tic behaviours. As tics are not limited to stimulant side effects, it is of general importance to understand these mechanisms.

Finally, new data and insights into the activity of the default network should be considered. The relevance of the DMN is not clear, but certainly more introversion is sometimes demonstrated by some children on higher stimulant dose levels. It has long been described clinically that some children can become excessively introspective and tearful when prescribed stimulant medications. It is possible that this phenomenon represents insufficient inhibition of the DMN. While speculative at this stage, further work is needed to determine whether the effect can be predicted by COMT or DAT status or reflects other local mechanisms. The association of reaction time variability with DMN intrusion, while speculative, provides a measurable method for further investigation of D1/alpha-2A effects of stimulants on the PFC, and requires further investigation linking genetic status, reaction time variability, clinical status and medication response.

Thus, the key issues for further investigation include: inverted-U effects of stimulants at cortical levels, as reflected in individual differences in development of cognitive side effects versus improvement at similar dose ranges; individual differences in effects of stimulants on the DMN, as possibly reflected by increased introspection and tearfulness; the importance of D1 and alpha-2A receptor synergy in the PFC; subcortical effects of DAT at the D2 receptor, as may be reflected in tic vulnerability and impulsivity; and individual differences in the DMN (default mode network), as reflected in reaction time variability.

These issues are of clear public health importance, especially given the rhetoric surrounding discussions of the ‘Draft Australian NHMRC Guidelines on Attention Deficit Hyperactivity Disorder’ (2009). A better understanding of stimulant side effects should provide a better understanding of PFC functions in relation to both therapeutic and treatment-emergent effects, and possibly child development in general.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Stimulant side effects and inverted-U: Implications for ADHD guidelines

Abstract

Objective:

Method:

Results:

Conclusion:

Keywords

Background

COMT polymorphisms and inverted-U

Default network

Dopamine transporter (DAT) and tic disorders

Discussion

Footnotes

Funding

Declaration of interest

References