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Based on the following articles: Behav Brain Res 1998;94:127-52; J Clin Psychiatry 2006;67(suppl 8):32-7

Reviewed by: Robert D. Hunt, MD

Center for Attention and Brain Function Nashville, Tennessee

As research elucidates more of the mechanisms in the field of attention-deficit/hyperactivity disorder (ADHD), investigators are also learning to address the key neuropsychiatric mechanisms in treatments. Two key chemicals involved in the pathogenesis of ADHD, and therefore important to target in treatment, are the neurotransmitters dopamine and norepinephrine (Table 1).

Table 1.The Functions of Dopamine and Norepinephrine

THE ROLE OF NOREPINEPHRINE

One of the landmark papers in ADHD (Solanto MV. Behav Brain Res 1998;94:127-52) describes the interrelationship of these mechanisms in the condition’s pathogenesis.

There are different noradrenergic receptors with distinctive actions. The alpha-2 norepinephrine receptors are involved in two major components of ADHD: overall hyperactivity and executive function. Compounds used to regulate overall hyperactivity include clonidine and guanfacine. Both of these medications have a quieting effect on excessive arousal; however, both arousal and executive function need to be addressed.

The beta2 norepinephrine receptors regulate executive function which consists of thinking and reasoning. As Solanto describes the process, in healthy individuals, the new information induces an increased arousal that subsequently allows the individual to take the new information into account and respond to it in an effective manner by providing a burst of epinephrine. Recognizing that something is new and changed, and being able to respond to that change effectively, is a key area of difficulty in attention deficit disorder (ADD) and ADHD. Norepinephrine facilitates thinking and reasoning, it is critical to regulating arousal and enabling people to respond effectively to change.

THE ROLE OF DOPAMINE

Dopamine dysregulation is an important component of ADHD because this neurotransmitter aids our ability to attach and sustain attention. Solanto notes that dopamine also regulates motor output.

The component of dopamine that is most related to attention in humans is that which is regulated through the ventral tegmental area. This area of the brain facilitates attention. When an individual is focused on something that is important, and he or she is able to apply greater intensity to the task, that ability to focus is a dopamine effect.

The second aspect of dopamine that is relevant to attention is its ability to solve problems. These effects of dopamine are dose-dependent. In low doses, dopamine increases focus and can quiet hyperactive behaviour and movement. However, in excessive doses, it has the opposite effect and can cause stereotypic movement.

Therefore, the stimulants used to treat ADHD have a dose-dependent effect on locomotor activity. Higher doses cause more induction of stereotypic behaviour. However, lower doses allow patients to have more control over activity because low doses have an inhibitory effect. As Solanto noted, these different effects have been seen in animal studies. In clinical practice, we can safely use stimulants that have an effect on dopamine if the dopaminergic component is given in a low dose. Using this strategy, we derive the benefits of dopaminergic treatment without the unintentional movements associated with higher doses.

THE EFFECT ON REWARD PROCESSES

Stimulants have a particularly important effect on reward processes. According to Solanto, one core finding of neuroimaging studies is that the nucleus accumbens, the reward centre in the brain, is rich in dopamine receptors and is the area most affected by psychostimulants.

The purpose of stimulant treatment is to increase the reward-reinforcing properties of dopamine, which are mediated by D1 and D2 dopamine receptors. As humans, our ability to experience a sense of reward and pleasure in our efforts and to convert that reward into a sense of meaning and purpose is the mechanism for reinforcement in the academic setting. Stimulant medications can increase the potency of reward and the environment (salience) to the reward.

For ADHD and ADD patients, one of the challenges is to identify a meaningful reward. For children who live with either ADHD or ADD, parents and teachers have often been frustrated by the minimal impact that rewards such as allowance and privilege offer when the child is off medication. We are finding that stimulant medications increase the salience of rewards so that behaviour can be influenced.

Stimulants increase the ability to use reinforcement by acting through the dopaminergic mechanism. The treatment with stimulants is one key reason that, when children with ADHD are treated, parents and educators are able to document improvements in their academic performance, particularly regarding spelling and math.

As physicians, we know that ADHD stimulant medications help patients stay on task, but we must also ascertain that they help patients to care about the task, their performance and results. The key is a balance in the dose. We find that there is a U-shaped curve regarding avoidance in task performance. When patients get too low a dose, treatment has little if any effect. When they get too high a dose, then their performance is driven by a level of anxiety that is too high to be functional.

AMPHETAMINES IN ADHD MANAGEMENT

With amphetamines, the effect is both dopaminergic and noradrenergic. One of the key formulations used is mixed amphetamine salts (MAS) which are typically given as a once-daily treatment. Amphetamines predominantly inhibit dopamine and norepinephrine reuptake. Therefore, by increasing the amount of dopamine and norepinephrine available, its key benefits are to help patients maintain and regulate arousal in response to change.

In the academic setting, this effect allows patients to stay focused and on task, and to improve executive function. Consequently, individuals taking MAS can make effective decisions in response to stimuli.

It is important to know that amphetamines and methylphenidate are not equivalent medications, as they exert different effects on both norepinephrine and dopamine. Amphetamines block dopamine reuptake but have two additional effects of increased production of dopamine and norepinephrine. Another way to view the role of amphetamines is that they have more effect on norepinephrine than does methylphenidate. Although we are just recently understanding the key role that norepinephrine plays in ADHD, we possess greater knowledge of its interaction with MAS agents.

Norepinephrine receptors are concentrated primarily in the prefrontal cortex of the brain, which governs attention, alertness, and vigilance. Norepinephrine facilitates working memory and inhibits the response to stimuli that are not relevant. By inhibiting the reuptake of norepinephrine and increasing its availability, MAS helps individuals to be less distracted and to make more effective decisions in response to relevant stimuli so that they can perform more effectively in academic and occupational settings.

METHYLPHENIDATE IN ADHD MANAGEMENT

Methylphenidate's primary effects are dopaminergic, so that it affects attention, hyperactivity, and the rewards system.

The positive effects of methylphenidate on attention are that it helps the patient allocate attention and discriminate and control his or her behaviour, to decide effectively whether to move or not move, whether to touch a button or not. Furthermore, there exist several types and multiple versions of ADD. Patients can vary by the degree of hyperactivity, attention deficit, and deficits in information processing. Patients can have trouble in learning situations because they are unable to sit down and be still; unable to focus or to integrate the information to which they have been exposed. Norepinephrine affects the latter deficit.

There is no one single optimal approach for all patients (Wilens TE. J Clin Psychiatry 2006;67(suppl 8): 32-8). No two patients are alike and therefore, treatment strategies need to be targeted to the individual. When deciding on a treatment for a patient, a thorough history from the parents is helpful, as well as input from the teacher. The physician can then identify the patient’s key symptoms and issues and tailor an appropriate treatment. Consequently, one effective approach is to give each patient a fair trial of more dopaminergic medication such as methylphenidate and then a trial of MAS which have a strong effect on both dopamine and norepinephrine.

THE CROSSOVER APPROACH

Often the best way to identify an optimal treatment is through a crossover approach, in which the patient takes first one medication, typically methylphenidate, and then switches to MAS two weeks later. The physician will then treat the patient with the medication that addressed his or her symptoms most effectively. In my practice, we try both medications on every patient and see which is associated with the best outcomes regarding the patient’s attention and comfort, including side effects.

It is important to try patients on both and carry out a crossover comparison in every patient. The crossover comparison is well worth the time involved. Patients with ADHD come to our clinics with a chronic problem that has typically persisted for some time and will not be quickly resolved. Understanding different effects of various neurotransmitters is important. As we continue to investigate the pathogenesis of ADHD, it may be that we find that norepinephrine is more important than dopamine in attention. Clinically, we try compounds in both categories.

When performing a crossover comparison to determine the best fit for each patient, we need to briefly and objectively rate two domains of response: firstly, efficacy; or the impact of each medication on attention, task performance, organization and any side effects produced. Secondly, the duration of action of each medication in relation to the patients activities and tasks throughout the day. For a child in the classroom the structure of activities is relatively predictable. For an adult, we need to individualize measure of response in relation to the specific tasks of their life throughout the day.

MEDICATION OPTIMIZATION STRATEGY

We developed and presented at the 2004 American Psychiatry Association, a validated tracking system (the Hunt-medication Efficacy and Duration System) that allows simple measures of medication response throughout the day prompted by cue every two hours from the patient’s handheld PDA. These measures, combined with a weekly Conners Adult ADD rating scale provide objective measures of comparative medication response using a crossover trial. We have also developed a brief Medication Preference Scale that enables patients to score their reasons for preference between psychostimulants. These reasons not only encompass medication efficacy and side effects, but often reflect responses to questions comparing medications in areas of subjectivity, social and task performance.

Medications like clonidine also decrease hyperactivity but in a different manner from stimulants; this agent can also be used in combination with stimulants. They can work in synergy with methylphenidate to reduce the dose of methylphenidate needed to focus attention. Amphetamines have a vertical inhibitory effect. On the higher levels of the central nervous system (CNS) by calming down the lower part, or the motor component.

In younger patients, medications that work on noradrenergic arousal are often helpful in improving academic performance. The main task with young patients is to increase the inhibitory effect, and therefore reduce hyperactivity and impulsivity. The MAS XR approach can help by inhibiting excessive movement and also by improving arousal. This agent is more noradrenergic in its effects than methylphenidate. Therefore, physicians can tell parents that the key symptoms in which they will probably see improvements are in staying focused and on-task with schoolwork assignments, and in decision-making with school assignments. Spelling and math are typical school subjects in which patients who are treated with MAS XR experience improvement.

NEUROIMAGING FINDINGS AND FUTURE RESEARCH DIRECTIONS

The advances in neuroimaging have helped us understand the role of dopamine and norepinephrine neurotransmitters in ADHD. For example, it is now possible to radio-label dopamine receptors. The brain imaging study that is ordered can then be ligand-specific for dopamine. It would be interesting to observe the actual dopamine receptor activities across the specific ADHD subtypes. We are now able to see the effect of treatment with methylphenidate or MAS XR.

Some investigators are now making progress in identifying the genetic variants that may play a role in promoting ADHD. We now have identified seven genes that are active in the dopaminergic and noradrenergic pathways. In the future, clinical trials may require a molecular genetics analysis of participating patients, and they may also require brain imaging so that a treatment’s specific effects on dopaminergic binding can be seen. However, at present, no noradrenergic ligand has been identified.

We look forward to more advances regarding the genetic variants that could be influencing the development of ADHD. Knowing the specific genetic issues in individual patients could help us deliver therapies that are targeted to individual patients and therefore improve outcomes.

SUMMARY

The dopamine and norepinephrine neurotransmitters are both critical to learning and decision-making, and both are affected in people with ADD or ADHD. In ADHD, the individual experiences excessive reuptake of both of these neurotransmitters, so that less of each is available to his or her system. These deficits give ADHD the hallmark characteristics of inattentiveness, inability to remain focused on a task, impulsivity and hyperactivity. The key stimulants used to treat ADD and ADHD are amphetamines and methylphenidate. Alteration in dopaminergic and noradrenergic functions seem necessary for clinical efficacy of these stimulants. Methylphenidate acts primarily on dopamine receptors; so that it affects attention, hyperactivity, and the rewards system. Amphetamine acts on both dopamine and norepinephrine, so that its key benefits are to help patients stay focused and on task, and to improve executive function, so that individuals can make effective decisions in response to stimuli.