Chapter 150 Attention Deficit Hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) is defined by the Diagnostic and Statistical Manual, Fourth Edition as a condition characterized by developmentally appropriate inattention and impulsivity with or without hyperactivity. ADHD has three subtypes:
• The majority of symptoms (six or more) are in the inattention category and fewer than six symptoms of hyperactivity-impulsivity are present, although hyperactivity-impulsivity may still be present to some degree.
• Children with this subtype are less likely to act out or have difficulties getting along with other children. They may sit quietly, but they are not paying attention to what they are doing. Therefore, the child may be overlooked, and parents and teachers may not notice that he or she has ADHD.
ADHD characteristics are frequently associated with difficulties in school, both in learning and behavior. If not intensively managed, a child with ADHD will likely experience academic impairment, increased risk of injuries, and problems with self-esteem and socialization. Later in adolescence and adulthood, those with ADHD have a high risk of experiencing depression or anxiety, substance abuse and addictions, traffic accidents, financial problems, vocational underachievement, and social problems. Nevertheless, ADHD is a condition that can be transcended, because many with ADHD have achieved a high level of personal success.
Depending on the region and the investigator, ADHD has been found in 5% to 15% of school-aged children or about 10 million children in the United States. Clinical observation and epidemiologic surveys typically report a greater incidence in boys than girls (approximately 2:1). Over 5.5 million children in the United States take prescription drugs for ADHD every day. Onset is usually by 3 years of age, although the diagnosis is often not made until later when the child is in school.1
The behavioral and cognitive manifestations of ADHD arise from evidence associating this disorder with diminished function of polysynaptic dopaminergic circuits belonging to executive centers within the brain’s prefrontal cortex.2,3 These executive centers are largely inhibitory in nature and are responsible for impulse control and the ability to maintain sustained attention.4
Evidence from studies using magnetic resonance imaging, positron emission tomographic scanning, single-photon emission computed tomographic scan imaging, and electroencephalograms (EEGs) suggested that the brains of those with ADHD exhibit differences both morphologically and metabolically from normal controls, particularly with regard to the prefrontal executive centers.5,6 Various disturbances in dopaminergic activity within these brain centers have remained the primary molecular defects implicated in ADHD, although other neurotransmitters (particularly norepinephrine) have also been incriminated. Decreased sensitivity of the dopaminergic (D4) receptor and heightened dopamine reuptake by the presynaptic dopamine transporter were both suggested to result in diminished dopaminergic activity within executive centers. However, all of these defects are not necessarily permanent, because as children with ADHD grow up, the brain develops a normal level of dopamine activity, and their anatomic variations lessen. In addition, ADHD symptoms also tend to improve.7
Genetic factors may play a significant role in the etiology of ADHD.8 For example, studies identified differences in genes encoding for both the D2 and the D4 dopamine receptors in ADHD. Other studies associated ADHD with genetic polymorphisms associated with increased activity of the presynaptic dopamine transporter (which would result in increased uptake of dopamine). Other genetic factors contributing to ADHD may include inherited tendencies toward allergic states, decreased immune competence, and various genetic polymorphisms, resulting in diminished capacity to detoxify drugs, heavy metals, and xenobiotics. In other words, although there is little doubt that genetics are a predisposing factor, like most health conditions, environmental and dietary factors appear to play a significant role in how and whether these genetic factors manifest to produce ADHD in an individual.
The role of nutritional and environmental factors as the underlying cause of ADHD has been increasingly recognized. Despite significant advances in the use of nutritional therapies for ADHD, the prevailing conventional approach to the treatment of ADHD relies almost entirely on amphetamine drugs for purely symptomatic relief. These drugs, like Ritalin (methylphenidate), Adderall (amphetamine and dextroamphetamine), Concerta (methylphenidate), and Vyvanse (lisdexamfetamine dimesylate), improve ADHD symptoms primarily by potentiating the neurotransmitter dopamine within all brain regions, including those affected in ADHD. These medications reportedly improved behavior and cognitive functioning in approximately 75% of children in formal placebo-controlled trials. However, the success of treatment when studied in actual clinical practice might be significantly lower. Furthermore, follow-up studies failed to demonstrate long-term benefits with these stimulant medications. Additionally, these drugs are associated with a high prevalence of adverse effects, such as decreased appetite, sleep problems, anxiety, and irritability. Some of the long-term effects of these drugs could be extremely detrimental to both brain function and behavior.9–11
Nonstimulant drugs like atomoxetine (Strattera) have been promoted as a safe alternative to parents. However, the drug has its own set of problems, including studies that showed that children and teenagers who took atomoxetine were more likely to have suicidal thoughts than children and teenagers with ADHD who did not take it.12
One of the primary goals in many cases of ADHD treatment is to enhance cognitive function. Perhaps up to 50% of people with ADHD have definable learning disabilities, and most have measurable cognitive disturbances. Particularly disabling is the diminishment in nonverbal working memory exhibited by most ADHD patients.13,14 This feature of ADHD results in a diminished sense of time, as well as a decreased ability to hold events or tasks in the mind. Tardiness, missed appointments, procrastination, poor task planning, and failure to meet deadlines are all examples of how diminished working memory can result in serious consequences, particularly in adulthood.
Environmental factors that contribute to the development of ADHD may begin at or even before conception. Maternal-to-fetal transport of various neurotoxins can occur readily during pregnancy. A woman who has an ongoing exposure to or a significant body burden of neurotoxic substances (e.g., heavy metals like lead and mercury, solvents, pesticides, polychlorinated biphenyls [PCBs], alcohol, or other drugs of abuse) may herself exhibit features consistent with ADHD and give birth to a child who presents with symptoms of ADHD. In such cases, it might be assumed that ADHD is inherited when it is actually acquired. Children remain susceptible to neurotoxins after birth, and some of these agents have been shown to be common among children in North America.15,16
Maternal tobacco and drug use has been associated with a higher risk of ADHD.17–19 One study suggested that up to 25% of all behavioral disorders in children can be attributed to exposure to cigarette smoking during pregnancy.17 In addition, long-term, low-level lead intoxication in North American children was reported to exist in an alarmingly high incidence.16,20
The Centers for Disease Control and Prevention estimated that about 2% of American children younger than age 6 currently meet the criteria for lead toxicity at a level that has been associated with cognitive deficits and behavioral disturbances (more than 10 mg/dL whole blood lead).20 Low-level lead intoxication has also been associated with addictive behaviors and impulsivity, suggesting neurologic changes consistent with the reward deficiency syndrome, as described earlier.21 In keeping with these data, pilot studies demonstrated improvement in ADHD behaviors in some children with moderate elevations in blood lead levels who were treated with intravenous ethylenediaminetetraacetic acid chelation.22
In addition to lead, other heavy metals, such as mercury, cadmium, and aluminum, as well as pesticides and PCBs, are nearly ubiquitous contaminants arising from dental amalgams, food, air, and drinking water, and these agents may act synergistically to impair neurologic function and development in susceptible children. The Consumer’s Union of the United States recently conducted the largest study to date looking at the level of human exposure to a wide range of pesticides in the U.S. food supply. In this startling report, it was demonstrated that human exposure to pesticides is far greater than ever previously estimated, and that children are at particularly high risk for neurotoxic effects from regular inadvertent pesticide exposure from common foods.23
The hypothesis that food additives can cause hyperactivity in children stemmed from the research of Benjamin Feingold, MD, and is commonly referred to as the “Feingold Hypothesis.” According to Feingold, many hyperactive children, perhaps 40% to 50%, are sensitive to artificial food colors, flavors, and preservatives.24
Feingold’s claims were based on his experience with over 1200 cases in which food additives were linked to learning and behavior disorders. Since Feingold’s presentation to the American Medical Association in 1973, the role of food additives as a contributing cause of hyperactivity has been hotly debated in the scientific literature. In actuality, however, researchers focused on only 10 food dyes versus the 3000 food additives with which Feingold was concerned.
At first glance, it appears that the majority of the double-blind studies designed to test the hypothesis showed essentially negative results. However, upon closer examination of these studies and further investigation into the literature, it becomes evident that food additives do play a major role in hyperactivity.25–27 Overwhelming evidence was produced in several of these studies.
In the most recent study, 153 3-year-old and 144 8- to 9-year-old children from the general population (in other words, the study was not conducted on children with the specific diagnosis of ADHD) were challenged with either a drink that contained sodium benzoate and an artificial food coloring mix or a placebo mix. The main outcome measure was a global hyperactivity aggregate, based on observed behaviors and ratings by teachers and parents, plus, for the 8- to 9-year-old children, a computerized test of attention. The results showed that the children given the artificial food coloring agents definitely had a statistically significant adverse reaction on hyperactivity and behavior. The results were so clear that the authors concluded that “Artificial colours or a sodium benzoate preservative (or both) in the diet result in increased hyperactivity in 3-year-old and 8/9-year-old children in the general population.”28
It is interesting to note that, although the U.S. studies were largely negative, the reports from the United Kingdom, Australia, and Canada were more supportive. Feingold contended that there is a conflict of interest on the part of the Nutrition Foundation, an organization supported by the major food manufacturers—Coca Cola, Nabisco, General Foods, and so forth. It appears significant that the Nutrition Foundation financed most of the negative studies. The conflict of interest arises because these companies would suffer economically if food additives were found to be harmful. Other countries have significantly restricted the use of artificial food additives because of the possible harmful effects.
In looking at all of the data on the role of food additives in ADHD, the following conclusions can be made: virtually every study (both negative and positive) demonstrated that some hyperactive children consistently react with behavioral problems when challenged by specific food additives. Critics of the hypothesis ignore the significance of the clear (reproducible under double-blind conditions) individual results. The bottom line is that some children definitely react quite strongly to food additives, warranting the exclusion of these compounds for at least 10 days to judge their significance in all cases of ADHD.
In addition to eliminating food additives, there appears to be an interrelationship between sugar consumption and artificial food dyes. One study demonstrated that destructive-aggressive and restless behavior significantly correlated with the amount of sugar consumed.29 The higher the sugar intake, the worse the behavior. In another study, researchers performed 5-hour oral glucose tolerance tests on 261 hyperactive children, with the result that 74% displayed abnormal glucose tolerance or hypoglycemia.30
Numerous studies have shown that children with ADHD have a measurable reduction in tissue levels of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with age-matched controls. Omega-3 (EPA+DHA) supplementation in ADHD has been studied extensively and is considered a sensible intervention even by many mainstream physicians. Of particular importance is the recognition that omega-3 fatty acid supplementation improves many symptoms of ADHD, including impulsive-oppositional behavior, a symptom not typically helped by the pharmaceutical treatment of ADHD.31
Because these omega-3 fatty acids are critical in the structure and function of brain cells, it is thought that low levels play a key role in ADHD. The nerve endings in the areas of the brain affected in ADHD should be rich in DHA, because they are highly fluid and should be composed of approximately 80% DHA. DHA deficiency has also been shown to result in increased permeability of the blood–brain barrier in animal studies, and is thought to play a critical role in protecting the brain from an influx of neurotoxic compounds.32,33
Human breast milk is also rich in DHA, and several studies suggested that children who are formula fed are at twice the risk of developing ADHD as those who are breastfed.34 The role of DHA in brain development, intelligence, and possible protection against ADHD finally led to its inclusion in many infant formulas and other foods.