Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder that typically begins in childhood and often persists into adulthood. Up to 7% of children between the ages of 4 and 17 years are affected by the disorder, with approximately 2/3 of those diagnosed currently taking medication to help manage the symptoms. ADHD symptoms include abnormal levels of inattention, hyperactivity, and/or impulsivity. The most common treatment modality for ADHD is stimulant-type medications that work to regulate dopamine and norepinephrine levels in the brain. Exercise has also been shown to help control ADHD symptoms through the regulation of dopamine and norepinephrine. This article briefly compares the pharmacological mechanisms of ADHD medications with the physiological mechanisms of exercise relative to ADHD. Recommendations for the concomitant use of both treatment modalities are also provided.
‘Therefore, modulating dopamine and norepinephrine availability in individuals with ADHD may improve executive functioning and effectively regulate arousal.’
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder that typically begins in childhood and often persists into adulthood. ADHD is characterized by developmentally inappropriate levels of inattention and hyperactivity, resulting in functional impairment in academic, family, and social settings. 1 ADHD is the most commonly diagnosed neurobehavioral disorder of childhood. It is estimated that the cost of illness for ADHD is between $36 and $52 billion per year. 2
The Centers for Disease Control and Prevention (CDC) reports that in 2007, the national estimates of the number of children reported by their parents to have ever been diagnosed with ADHD among children aged 4 to17 years was 9.5%, representing 5.4 million children. 1 Of those with a history of ADHD, 78% (4.1 million, or 7.2% of all children aged 4-17 years) were reported to currently have the condition. Of those who had ever been diagnosed with ADHD, boys were more than twice as likely to have ADHD than girls (13.2% vs 5.6%). 1 Among children with current ADHD, 66.3% are taking medication for the disorder. In total, 4.8% of all children aged 4 to 17 years (2.7 million) are taking medication for ADHD. 1
Studies published over the past few years suggest that the symptoms of ADHD in children may be improved with exercise.3,4 The purpose of this article is to briefly show the relationship between the pharmacological actions of medications used to treat ADHD symptoms and the physiological actions of exercise relative to ADHD symptoms in children.
Pathophysiology of ADHD
ADHD is a clinical diagnosis with multiple reported causes that involve both genetic and nongenetic factors. 5 No definitive pathophysiological markers have been indentified for ADHD. However, smaller prefrontal cortex, basal ganglia, and caudate volumes have been reported in those with the disorder. 5 The prefrontal cortex in the cerebellum part of the brain is the center for thinking and executive function. The basal ganglia help sort the attention resources as the cortex demands. Dopamine, a catecholamine neurotransmitter, is necessary in this portion of the brain to control executive function and thinking and to allow for attentiveness to important stimuli while ignoring unimportant stimuli when necessary. 3 Norepinephrine, a catecholamine neurotransmitter in the locus coeruleus portion of the brain stem, is necessary for adequate control of the arousal center of the brain. Individuals with ADHD have unbalanced and dysregulated levels of dopamine and norepinephrine. As a result, children with ADHD are unable to be attentive on a consistent basis, control their behavior, resist distraction, and discern an awareness of space and time. 5 Additional research has reported that individuals with ADHD are more likely to have a defective DRD4 dopamine receptor gene, causing a deficiency in translating dopaminergic signals, of which norepinephrine and epinephrine are agonists. 5 Therefore, modulating dopamine and norepinephrine availability in individuals with ADHD may improve executive functioning and effectively regulate arousal.
Pharmacology of ADHD Medications
There are 2 main classes of medications used to treat the symptoms of ADHD: stimulants (first-line therapy) and nonstimulants. It should be noted that a positive clinical response associated with ADHD medications, especially stimulants, is not diagnostic for ADHD. Individuals diagnosed with ADHD as well as those without ADHD have both shown improvements in attentiveness and decreased motor activity when taking these medications.
Stimulants
Medications in this class act as stimulants on the brain stem arousal system and cortex of the central nervous system. 5 The mode of therapeutic action for ADHD is not completely understood. However, these medications are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron, thereby increasing concentrations in the extraneural space. Although specific to each individual medication, the onset of action can be as early as 1 hour after administration. Immediate release formulations can produce a therapeutic effect for 3 to 5 hours, with sustained- and extended-release formulations lasting up to 12 hours. 5 These medications have the potential for abuse and are, therefore, listed as controlled substances. They have frequently occurring side effects such as reduced appetite, insomnia, headache, and irritability. 5
Examples of medications in this class include methylphenidate (Ritalin, LA, SR; Concerta; Daytrana; Metadate CD, ER; Methylin, ER), dexmethylphenidate (Focalin, XR), dextroamphetamine and amphetamine mixed salts (Adderall, XR), and lisdexamfetamine (Vyvanse).
Nonstimulants
Although not considered first-line therapy, several medications have been used to treat ADHD symptoms for those who are unresponsive to or unable to tolerate stimulants. Most of the nonstimulant medications have indications for other ailments. Medications in this class have a slower onset of action compared with stimulants but do not have the potential for abuse and are, therefore, not in a controlled substance class.
The first nonstimulant drug approved for ADHD was atomoxetine (Strattera). Atomoxetine is a selective norepinephrine reuptake inhibitor that has been shown to produce therapeutic effects in patients with ADHD. The exact mechanism of how selective inhibition of presynaptic norepinephrine exerts effects in ADHD is yet to be determined, however. The onset of therapeutic effect for atomoxetine is 2 to 4 weeks. 5
Other FDA approved nonstimulants include guanfacine (Intuniv) and clonidine (Kapvay). 5 Both these medications were originally developed as antihypertensives but have shown a positive therapeutic effect when treating the symptoms of ADHD. However, the pharmacological mechanism of action for ADHD is unknown for both these medications. Several other medications used to treat depression and psychoses have been used as alternative or adjunct therapy to stimulants. The mechanism of action for ADHD in these medications is likewise, unknown. 5
Exercise Physiology and ADHD Symptoms
It has been known since the 1970s that physical movement produced increases in both dopamine and norepinephrine. 6 Since that time, it has been discovered that increases in these catecholamine neurotransmitters occur almost immediately with the onset of exercise to effectively regulate levels in the prefrontal cortex, basal ganglia, locus coeruleus, and amygdala (primary role of processing and memory of emotional reactions).3,4 Exercise has also been shown to grow new receptors for both dopamine and norepinephrine. As a result, aerobic exercise can improve the symptoms of ADHD because of increased releases and adequate regulation of both dopamine and norepinephrine. The onset of action appears to be immediate, with anecdotal evidence suggesting a therapeutic effect that lasts for approximately 60 to 90 minutes. 3
An additional important connection to make with regard to exercise and ADHD symptoms is that the motor cortex (which controls our movements) is located in the cerebellum part of the brain along with the prefrontal cortex. 3 Exercise appears to have an effect on both the thinking center and movement center of the brain simultaneously. Early models in rats have shown that more epinephrine and brain-derived neurotrophic factor are released when complex movements are performed that require both an aerobic component and a concentration component compared with aerobic movements alone.3,4,7 This suggests growth in the cerebellum and may be an important area of study for ADHD.
Conclusions
A comparison of the pharmacological and pathophysiological similarities between medications and exercise with regard to ADHD shows that they both work to more adequately regulate dopamine and norepinephrine levels in the brain. Medications are commonly used to treat the symptoms of ADHD, and have a therapeutic effect that can last for up to 12 hours; but they produce unwanted side effects and have the potential for abuse. Exercise has been shown to be effective in controlling ADHD symptoms, has essentially no side effects, but is largely understudied in this population. It should be noted that a major difference in the 2 treatment modalities is that medications have a defined effect on ADHD symptoms alone, whereas exercise produces physical, mental, and emotional advantages that are far reaching and more complex.
Research on exercise and ADHD has yet to quantify a dose-response relationship or the length of time that exercise will spike dopamine and norepinephrine levels. The type of exercise that is most effective to manage ADHD symptoms is still unknown. Evidence and theories by experts, however, have suggested that more complex exercises that involve both aerobic activity and concentration (eg, martial arts, figure skating, dance, and rock climbing) may be more effective for those with ADHD. 3
For several reasons, exercise may be an excellent tool to be used in conjunction with medications to effectively manage the symptoms of ADHD. Exercising in the morning and then taking ADHD medications approximately 60 minutes after the exercise is completed may be a reasonable treatment regimen, with an additional bout of exercise in the early afternoon. 3 It is important to note that everyone has different levels of attention deficit, and girls and boys may respond to treatment differently. Treatment regimens for ADHD should be individualized and tested in a systematic manner.