Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and hyperactive behavior. Researchers first concluded that children would outgrow these symptoms as they reached adulthood. Yet today 4-5% of children and .5-2% of adults suffer from some form of ADHD (Buitelaar, 2002, as cited in Bakker et al., 2003). ADHD’s increasingly prevalent diagnosis in children and adults has led to a significant amount of research on the causes and treatment of the disorder. One goal of this research is to formulate a neurochemical mechanism that underlies the disorder. Once a mechanism of ADHD is identified, researchers can create treatments targeting neurochemical pathways and anatomical components.
A comprehensive understanding of the pharmacological perspective of stimulant and non-stimulant drug treatment is essential to formulate a neurochemical mechanism of ADHD. To form this pharmacological perspective, knowledge of the disorder’s etiology, genetic contribution, and symptomology and diagnostic techniques is required. Grasping these factors, researchers will be able to observe behavioral characteristics of ADHD through cognitive deficits and quantitative electroencephalography (QEEG).
Cognitive deficits in ADHD manifest in severe working memory (WM) problems. Baddely (1997) proposed that WM deals primarily with an individual’s ability to hold and manipulate information in thought. The executive functioning (EF) associated with WM includes deficits related to organization and information processing, the mobilization of attention, and the inhibition of inappropriate responding (Cornoldi et al., 1999). Researchers of cognitive deficits have supported two fundamental theories of behavior in individuals with ADHD: poor inhibitory control and delay aversion (Songua-Barkem, 2002). The similarities and difference of these theories allows researchers to identify possible neurochemical pathways and appropriate treatments. Also, the introduction of neural imaging via QEEG has aided researchers in further understanding the unique pattern of brain activity that causes the inattentiveness characteristic of the disorder. Researchers concluded that cognitive activity of individuals with ADHD is asymmetrical in the fronto-centro-temporal region of the right hemisphere compared to the left hemisphere (Crawford & Barabasz, 1996). Thus, the normal balance of electrical activity that exists between the left and right hemispheres of the brain is not evident in individuals with ADHD.
For more than 60 years, the treatment for ADHD has relied on stimulant drugs. Yet, researchers working on stimulant drug treatments observed that only 70% of individuals exhibit a decrease in symptoms. The other 30% suffer from severe side effects or do not respond well to stimulant drug treatments (Diamond et al., 1999, as cited in Turner, 2004). Side effects of stimulant drugs include decreased appetite, insomnia, motor tics, and a delayed growth rate. The two most common drugs are methylphenidate (MPH) and dexamphetamine. Currently, researchers are focusing on non-stimulant drug treatments that depend less on stimulant therapy, effectively relieve symptoms, and are safe for all individuals.
ADHD is a complex disorder that is the result of an interconnected network of factors. According to Barabasz and Barabasz (1996), the etiology of ADHD is biological. The first biological explanation deals with exposure to teratogens and complications during pregnancy and delivery. Barkely (1990, as cited in Barabasz & Barabasz, 1996) observed that teratogens such as smoking and alcohol consumption significantly increase the likelihood of children developing ADHD. These teratogens have a severe impact on normal prenatal development. Alcohol’s teratogenic effects are exhibited in children who suffer from fetal alcohol syndrome (FAS). FAS symptoms include memory problems, poor judgment, distractibility, impulsiveness, and hyperactivity, which are also characteristics evident in children with ADHD. Complications during pregnancy and delivery that lead to hypoxia are also likely to cause ADHD due to the lack of oxygen to the brain. Toxemia and eclampsia are examples of such complications that have been linked to predisposing children to ADHD (Faraone & Biederman, 1998).
The most popular etiologies of ADHD are dietary and nutritional factors. At one point, the media suggested that symptoms of ADHD could be cured by the elimination of food additives from an individual’s diet. Other theories claimed that the cause of ADHD symptoms was excessive sugar intake; therefore, decreasing or eliminating sugar in an individual’s diet would cure ADHD symptoms (Faraone & Biederman, 1998). The metabolism of glucose as well as deficiencies in tryptophan may affect serotonin levels and brain function. Currently, researchers are investigating the role of diet and serotonin in individuals with ADHD. Though a proper diet is essential in development, it was not found to alleviate ADHD symptoms.
Research on essential fatty acid metabolism has shown structural importance in cell membranes and biological pathways (Chen et al., 2004). The most recent research on dietary patterns investigated blood fatty acid composition in children in Taiwan with ADHD, which showed that children with ADHD have a higher intake of iron and vitamin C. The increase of vitamin C intake shows it may be involved in the hydroxylation of tryptophan used in synthesis of serotonin (Chen et al., 2004). Spivak et al. (1999, as cited in Chen et al., 2004) reported that individuals with ADHD have low serum levels of serotonin. When serotonin was administered to individuals with ADHD, a calming effect and alleviation of aggressive behavior was observed. The above theories have guided research in forming a more complete theory of ADHD’s etiology. Despite research, though, there is currently no known etiology of ADHD.
Not until modern molecular genetics and the Human Genome Project could one imagine a genetic contribution to the underlying causes of ADHD. Genetic researchers of twin studies have concluded that the heritability factor of ADHD is .80 (Faraone & Biederman, 1998; Pliszka, 2003). Thus, the genetic and environmental factors contributing to ADHD are 80% and 20% respectively. Researchers have further isolated the environmental contributions to non-shared characteristics of twins such as personal experiences, infections, and injuries (Pliszka, 2003).
Targeting dopaminergic pathways, stimulant drug treatment of ADHD has directed researchers to isolate the genes of dopamine receptors D3 and D4. High concentrations of D3 receptors have been observed in the nucleus accumbens, or the ventral striatum. Researchers have suggested that D3 receptors in these areas may play a role in the inhibition of locomotion and motor deficits. The most compelling evidence for D3 receptor’s role in ADHD comes from “knock-out” mouse studies. In the absence of the D3 receptor gene, the mice displayed a hyperdopaminergic phenotype characterized by increased locomotion (Faraone & Biederman, 1998; Muglia, Jain, & Kennedy, 2002). A transmission disequilibrium test used to determine an excess of transmission of D3 from heterozygous parents was performed. Researchers concluded from the results that there was no excess of transmission; thus, genes coding for D3 receptors do not have an impact on the inhibition of locomotion or motor deficits observed in ADHD (Muglia et al., 2002).
Although D3 receptor’s influence on ADHD genetics is not fully known, additional data has identified the importance of D4 receptors. D4 receptors have been labeled 7-repeat, given their unique amino acid configuration. Typically, the D4 allele repeats two or four times in individuals with normal behavior. However, reports of individuals with the 7-repeat D4 receptor describe themselves as impulsive, exploratory, and excitable, all traits common in individuals with ADHD (Pliszka, 2003). Faraone and Biederman (1998) suggest that D4 mRNA located in the brain acts on cognitive function and emotional behavior. With the numerous factors contributing to ADHD, it would be unwise to claim that D4 receptor dysfunction is the only genetic deficit. Therefore, this data should be used as a framework for further research to identify the role of dopamine receptors involved in ADHD.
Fisher et al. (2002) noted that the first whole genome scan of American affected sibling pairs did not identify any chromosomal regions that contained linkage for ADHD. The use of affected sibling pairs is advantageous because the mode of inheritance is not considered in the genes of interest. Recently, Bakker et al. (2003) performed a whole genome scan of 164 Dutch affected sibling pairs with ADHD and identified linkage regions on chromosomes 7p and 15q. In observing individuals with ADHD and autism, researchers have reported a degree of overlap existing between the symptoms of both disorders. Bailey et al. (1995, as cited in Bakker et al., 2003) suggest that ADHD and autistic-spectrum disorders may have a common genetic factor: chromosome 15q 11-13 has been identified as being prone to causing autistic-like symptoms. Individuals with ADHD have experienced social and communication problems, while individuals with autism display inattention, hyperactivity, and impulsivity (Clarke et al., 1999; Luteijn et al., 2000; Noterdaeme et al., 2001, as cited in Bakker et al., 2003). In general, genetic researchers are unable to provide enough conclusive data for an accurate replication of their study (Altmuller et al., 2001, as cited in Bakker et al., 2003). Any conclusions drawn from genetic research on ADHD should not be interpreted as fact but as necessary contributions to understanding the disorder.
Symptomology and Diagnosis
ADHD’s etiology and genetics are used to predict the severity of symptoms in individuals and aid in the diagnosis of the disorder. ADHD is commonly diagnosed in adolescence. However, symptoms associated with ADHD may also occur in a normally developing adolescent. Due to the overlap between adolescence and ADHD symptoms, the fourth edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) outlined the symptoms of ADHD. According to the DSM-IV, the three types of ADHD are:
(1) predominately hyperactive-impulsive, (2) predominately inattentive, and (3) the combined type. Symptoms of the predominately hyperactive-impulsive type include the following: fidgeting with hands, excessive talking, and an inability to remain seated. Impulsive symptoms include interruption of others, inability to wait one’s turn, and speaking when not appropriate. Symptoms of the predominately inattentive type include making careless errors in schoolwork, being unable to follow through with a task (i.e. work, school, chores), and being easily distracted by unimportant stimuli. The combined type is a combination of the symptoms observed in the predominately hyperactive-impulsive and predominately inattentive types of the disorder. Approximately 80% of individuals diagnosed with ADHD have symptoms that occur across each type, resulting in a majority of combined type diagnoses (Buitelaar, 2002, as cited in Durston, 2003). While these symptoms may be useful in categorizing the disorder, they are not as beneficial in the diagnosis as are etiology and genetics (Durston, 2003).
An accurate diagnosis of ADHD must include an observation of six or more symptoms in one of the three types. These symptoms must be consistent and must occur for at least six months. The onset of symptoms and the diagnosis commonly occur at age 7. During this time, one is likely to observe many of the symptoms working together to contribute to more overt behavior. Recent data gathered by Barabasz and Barabasz (2000) has led to the use of QEEG in examining brain activity in individuals with ADHD (QEEG considerations are described in detail later). As a result, diagnosis of ADHD may be confirmed through deficits in areas of the brain already identified in attention and planning.
Since the DSM-IV criterion for diagnosing ADHD is stated in terms of adolescent symptoms, it is difficult to make an accurate diagnosis of adult ADHD. Edward Hallowell and John Ratey developed a list of symptoms that has been useful in diagnosing individuals with adult ADHD. Common symptoms include difficulty getting organized, chronic procrastination, search of and need for high stimulation, impatience, and a sense of insecurity (as cited in Restak, 2003). It is important that a diagnosis of adult ADHD can only be made by a physician after comprehensive psychological and observational tests.
Due to the increase in ADHD diagnoses, it is important for physicians to accurately consider the DSM-IV criteria, and if necessary, use brain-imaging techniques to make the most accurate diagnosis. Because symptoms of ADHD are also observed in individuals who do not have the disorder, diagnosing ADHD should be a collaborative effort on the part of the individual with ADHD, his or her parents, teachers, spouse, and the physician.
Cognitive deficits in EF comprise the most severe impairments in individuals with ADHD. EF is the processing and organizing of information, the mobilization of attention, and the inhibition of inappropriate responding. ADHD’s tendencies to prompt inappropriate responses or impulsive behaviors have received the most interest by cognitive researchers. It is reasonable to surmise that individuals with ADHD do not consider the consequences of their actions; thus, their impulsive acts are not intentionally disruptive.
However, according to Barkely (1997), individuals with ADHD do consider the consequences of their actions, but an inhibitory deficit in EF causes the individual to appear to act without thinking. According to Cornoldi, Barbierim, Gaiani, and Zocchi (2000), individuals with ADHD display problems with memorizing material that requires forming associations and being organized. These researchers also noted that individuals have the most difficulty when asked to complete tasks involving memorization while inhibiting old responses. Increased activity in the prefrontal cortex (PFC), the area of the brain containing EF, has been correlated with tasks involved in planning and strategic memory (Baddeley, 1986; Shallice, 1998, as cited in Cornoldi, 2000). Also, the failure of EF in individuals with ADHD is evidence that the main deficits occur in the prefrontal cortex (Grodzinsky & Diamon, 1992; Shue & Douglas, 1992, as cited in Cornoldi et al., 2000).
Theories of Behavior
One of the most debated issues on the subject of cognitive deficits in ADHD is concerned with either a deficit in inhibitory control or delay aversion. First, the inhibitory pathway is hypothesized to be associated with the inability to regulate the thoughts and actions of an individual. The second pathway, delay aversion, concerns a fundamental deficit in an individual’s reward mechanism (Sonuga-Barke, 2002). Much of the evidence that supports the role of inhibitory deficits as the cause for EF has come from stop-signal studies. These experiments test whether an individual with ADHD can inhibit a visual “go signal” when an auditory “stop signal” is presented at varying intervals. Individuals with ADHD are unable to inhibit wrong responses when faced with more than one option. Thus, more incorrect responses were recorded (Sonuga-Barke, 2002).
Emphasizing a motivational basis of ADHD, the delay aversion hypothesis has gained some interest given its complete divorce from the inhibitory data. This hypothesis suggests that behaviors are the result of a varying motivational style, with impulsivity and inattentiveness being the result of one’s choices (Sonuga-Barke, 2002). Researchers observed that individuals with ADHD display an unwillingness to wait for delayed rewards and often choose a lesser reward if it provides an immediate response (Sonuga-Barke, 2002). After a much-anticipated “head to head” experiment between the two hypothesized pathways, a comprehensive analysis determined that the pathways are unrelated to each other. Researchers observed that the cognitive deficits in ADHD are due to two distinct pathways: the disruption of thought and action pathway and the motivational style pathway (Sonuga-Barke, 2002).
Quantitative Electroencephalography (QEEG) Analysis
Researchers observed deficits in neurophysioclogical regulation, citing that 90% of individuals with ADHD showed abnormalities in QEEG scans (Sterman, 2000). The complex analysis of brain activity from QEEG data has greatly aided stimulant research of ADHD. Sterman (2000) offers an overview of past literature in which QEEG recordings were used to identify five distinct qualities of individuals with ADHD. First, an increased theta activity of about 4-8 Hz was observed in the prefrontal, frontal, and sensorimoter cortex. Second, a global excess of theta or slow alpha activity was observed in all cortical areas. Third, an excess of normal alpha activity occurred in the anterior cortical areas. Fourth, there was a general reduction from the normal activity of the sensorimotor area to an increase in activity speed. Fifth, asymmetrical activity was observed in the left and right posterior, temporal, and parietal regions. These criteria were used by Chabot and Serfontein (1996) to measure the brain activity of individuals with ADHD. They successfully identified 88% of children with ADHD from controls using QEEGs. Therefore, the use of QEEG recordings can serve as a dependable biological marker for ADHD. A promising use of QEEG markers, suggested by Chabot et al. (1999), is to select the most effective stimulant treatment based on the individual’s brain activity (as cited in Sterman, 2000).
QEEG researchers have proposed three patterns of brain activity outlining a possible etiology for ADHD. The first pattern is non-localized slowing of QEEG rhythms in all states of attention. This type of brain activity is found in 30% of individuals with ADHD. The defining characteristic is slower QEEG activity compared to non-ADHD controls. Slowed QEEG activity may be due to a delay in maturation of neural pathways and attentional pathways, namely neurotransmitter systems. The second pattern is concerned with abnormally slow activity in the prefrontal and frontal lobes of the brain. The dopamine (DA) and gamma-amino-butyric acid pathways of the basal ganglia often influence frontal QEEG activity in the anterior thalamic nuclei projecting to the anterior cortex. Therefore, this pattern of brain activity in ADHD is caused by a disruption in the cortical-striatal-thalamic pathway of the basal ganglia, a structure involved in the initiation of movement. Researchers observing the third pattern noted an increase in alpha activity in the central and parietal areas of the brain. In ADHD, elevated alpha activity may block the transfer of sensory information from the thalamus to the cortex, causing periods of increased inattentiveness (Sterman, 2000).
Early QEEG analysis in individuals with ADHD revealed many noteworthy findings, which were later used to identify how stimulant drugs work to relieve symptoms. Due to the involvement in EF, researchers are interested in frontal and cerebral regions of the brain, particularly FP1, FP2, F3, F4, C3, and C4. A study conducted by Crawford and Barabasz (1996) supports the fact that frontal and cerebral regions of the brain display an abnormal activity in ADHD. Yet, tests of parietal and occipital regions did not show the same QEEG differences reported in frontal and cerebral regions. The researchers concluded that the frontal sites (FP1, FP2, F7, and F8) had a decrease in alpha activity when subjects were asked to listen to a story with their eyes closed. Alpha wave deficits also occurred in the cerebral sites (C3 and C4) during tasks that involved completing mathematical problems (Crawford & Barabasz, 1996).
The use of QEEG is a necessary supplement to diagnosing individuals with ADHD. QEEG use can clarify the presence of ADHD in individuals who have been “diagnosed” by their parents but do not display all the necessary symptoms. Currently, researchers have focused on correlations between brain activity and treatment methods. If successful, individuals with ADHD could be given a treatment regimen to specific areas of the brain containing the least amount of activity. If implemented as a diagnostic tool, QEEG scans could limit the number of false diagnoses by providing a physiological basis for ADHD.
Pharmacological Perspective of ADHD
For the past decade the treatment of ADHD has relied primarily on the use of the stimulant drugs MPH (Concerta, Metadate CD, Metadate ER, Methylin, and Ritalin) and dexamphetamine (Dexedrine). Seventy percent of individuals with ADHD have reported benefits from stimulant drugs. However, a growing percentage of individuals, approximately 30%, reported having no beneficial effects or unmanageable side effects from stimulant drugs (Swason et al., 1998; Jensen et al., 1999, as cited in Clarke, Barry, McCarthy, & Selikowitz, 2002). MPH pharmacology, cognitive effects, and QEEG scans are necessary to observe how and why stimulant drugs work in ADHD. The success of the stimulant drug MPH in reducing ADHD symptoms has been the focus of stimulant drug research.
Methylphenidate. MPH has been reported to have a more desirable effect than dexamphetamine, as individuals with ADHD currently taking dexamphetamine reported having more side effects than individuals taking MPH (Enfron et al., 1997) An individual’s response to a particular stimulant drug does not guarantee a response to another (Chabot et al., 1996, as cited in Clarke et al., 2002). The pharmacology of MPH was thoroughly examined by using two drugs that mimic MPH’s effects on neurotransmitter systems, desipramine and L-dopa. MPH targets DA and noradrenaline (NE) neurotransmitter systems located in the synaptic cleft (Overtoom, Verbaten, Kemner, Kenemans, Van England, & Buitelaar et al., 2003). MPH affects NE by blocking re-uptake sites, so desipramine was used given its similar mechanism in noradrenergic neurons. MPH also acts to increase DA by blocking re-uptake sites. Therefore, L-dopa, a DA agonist, was used to mimic the effects of MPH. Although L-dopa does not have the same mechanism as MPH, the overall effect is an increase in DA. Researchers attempted to isolate whether a noradrenergic or a dopaminergic effect resulted in MPH’s ability to relieve symptoms of ADHD.
Overtoom et al. (2003) observed that individuals with ADHD taking a .46mg/kg dose of MPH had an increase in attention span. However, no attention span improvements were reported when individuals were given comparable doses of either desipramine or L-dopa. The researchers suggested that the effects of MPH in enhancing attention are due to an increase in both NE and DA.
Researchers have also shown that MPH is effective in decreasing an individual’s impulsive behavior. However, Overtoom et al. (2003) reported that a .46mg/kg dose of MPH did not decrease the level of impulsivity in individuals with ADHD. A reason for this discrepancy is that this study defined impulsivity as the inability to stop unwanted behavior. Yet, Sunohara et al. (1999) defined impulsivity as the number of false alarms recorded on the continuous performance task. Moreover, they observed a decrease in impulsive behavior in individuals with ADHD taking a MPH. Further explanation concluded that the dosage of MPH contributed to its varying effectiveness. Tannock et al. (1989) observed that a dosage of 1mg/kg of MPH decreased impulsive behavior in individuals with ADHD (as cited in Overtoom et al., 2003).
The data obtained from Overtoom et al. (2003) offers a different perspective on how MPH should be used in the treatment of attentional and impulsive symptoms of ADHD. Researchers mimicking MPH’s pharmacology by increasing either NE or DA using desipramine or L-dopa did not observe an increase in attention span in individuals with ADHD. However, an increase in both NE and DA increased attentiveness and relieved other ADHD symptoms. The different definitions of impulsive behavior used between studies suggest the possibility of multiple neural pathways of impulsivity. Researchers also observed that a dosage dependency of MPH with at least 1mg/kg was more effective in relieving impulsivity while lower amounts of .3-.5mg/kg were more effective in enhancing attention.
Cognitive effects. Researchers have identified the area of the brain most affected by ADHD and stimulant drugs as the PFC. Animal studies have shown PFC function, WM, and EF as being directly influenced by catecholaminergic pathways (Goldman-Rakic, 1991; 1994, as cited in Schweitzer et al., in press). Much of the research on stimulant drugs in individuals with ADHD has focused on the effect of MPH in relieving EF problems. Schweitzer et al. (in press) investigates MPH treatment on EF using the Paced Auditory Serial Addition Task which focuses on WM, attention, response inhibition, and speed of information processing. The researchers proposed four lines of evidence that link the function of the PFC to ADHD: (a) smaller PFC volumes, (b) altered PFC functioning in QEEG imaging, (c) decrease fluorodopa uptake by the catecholamine neurons in adult PFC, and (d) positive effects of stimulants in PFC contribute to EF improvement. They concluded that MPH is beneficial in improving EF in ADHD. However, the long-term effects of MPH on EF in adults have not been studied (Schweitzer et al., in press).
Individuals with ADHD may be unable to process and hold information in WM, showing deficits in EF. Schweitzer et al. (in press) observed an increase in DA in the PFC and a shift in usage from EF structures to structures associated with motor preparation. A reduction in EF activity in the PFC was observed by investigators using positron emission tomography scans. These scans showed that individuals with ADHD had a regional decrease in cerebral blood flow. This reduction was due to a release of DA in the PFC acting on D1 and D2 receptors. The effect of DA on synaptic inhibition was thought to enhance resistance to distracters in WM, increasing EF ability. Therefore, MPH’s effectiveness in EF is due to an increase in interneuron response related to filtering out distracters.
Moreover, areas of cognitive processing in normal controls were not observed in individuals with ADHD taking MPH. Normal controls relied on the anterior cingulate and PFC to handle given tasks. Individuals with ADHD however, relied more on areas of the basal ganglia. Additionally, the caudate and putamen were reported as having increases in activity related to EF tasks (Schweitzer et al., in press). Understanding EF and WM deficits, dopamine receptors in the PFC, and the increased dependency on motor areas of the brain has allowed researchers to apply this knowledge to stimulant research.
QEEG analysis. Princep and John (1990) and Chabot et al. (1996), examined QEEG scans of individuals with ADHD with different stimulant treatment, either MPH or dexamphetamine, and differences between good and poor responders to each stimulant drug (as cited in Clarke, Barry, McCarthy, & Selikowitz, 2002). Princep and John (1990) successfully used a function analysis of QEEG data that was 82% accurate in determining a positive response to MPH. Additionally, Chabot et al. (1996), using a more in-depth six point QEEG measure, correctly identified 75.6% of individuals as good MPH responders and 75.8% as good dexamphetamine responders. However, the results of Chabot et al.’s experiment were too complex and deterred clinicians from using their technique in diagnosis.
Clarke et al. (2002) further investigated the relationship between QEEG analysis and stimulant drug preference. QEEG literature states that individuals with ADHD commonly have increased theta and posterior delta activity, decreased alpha and beta activity, and increased theta/alpha and theta/beta ratios. Clarke et al. (2002) observed QEEG differences in individuals on either MPH or dexamphetamine, and between good responders of both stimulants. First, good responders had consistently higher total power compared to poor responders. This data agrees with good MPH responders having increased power in the delta and theta bands. Rowe, Robinson, & Gordon (in press) observed that increased inhibitory activity of the thalamic reticular nucleus was responsible for generating the characteristic ADHD delta and theta activity seen in QEEG scans. Second, good responders to dexamphetamine contained less alpha and beta activity. Researchers reported a greater total power and less absolute and relative alpha activity in good dexamphetamine responders. Third, Clark et al. (2002), comparing responders from both studies, observed that good MPH responders had a greater number of QEEG abnormalities. Good MPH responders also had increased theta/beta ratios and a greater total posterior power. These findings show that good responders to MPH are more cortically hyperaroused, meaning more brain activity is observed in QEEG scan. Thus, two types of ADHD exist in which either MPH or dexamphetamine is considered a better treatment for a particular individual. This study offers a concrete line of evidence supporting the need for a more thorough diagnosis of individuals with ADHD.
There is no theory as to why 30% of individuals are unaffected by or have unmanageable side effects to stimulant drugs (Clarke et al., 2002). The increasing number of ADHD diagnoses, along with the added concern of long-term effects of stimulant treatment, has led to a search for stimulant alternatives. It is important to consider whether non-stimulant drugs will treat ADHD symptoms as effectively as stimulant drugs. Currently, the importance placed on research of non-stimulant treatments has led to a better understanding of the neurochemical mechanism of ADHD. The following non-stimulant treatments—buspirone, inositol, selegiline, modafinil, and zinc sulfate—vary in their effectiveness in treating ADHD, but all have contributed to a better understanding of the pharmacology of the disorder.
Buspirone. Early pharmacology studies in ADHD observed that a combination of MPH and clonidine, an alpha2 noradrenergic agonist, was effective in reducing hyperactivity and aggression (Hunt, 1988, as cited in Nederhofer, 2003). However, side effects such as hypotension and sedation were also reported. Garattini et al. (1982) suggested that buspirone, a serotonin agonist, would affect the DA system in a way similar to clonidine without its sedative or addictive effects. Buspirone treatment considerably reduced hyperactivity, increased frustration tolerance, and affected modulation. Buspirone showed a more specific action on activity, frustration tolerance, and anxiety compared to MPH. Moreover, the side effects were minimal. Like clonidine, buspirone was suggested to be used in combination treatment with MPH (Nederhofer, 2003). More research is needed to identify any long-term effects and combination treatments with dexamphetamine.
Inositol. Biederman et al. (1989) observed that children with ADHD benefit from antidepressant therapy. They later suggested inositol, a simple isomer of glucose, positively affected mood, insomnia, anxiety, and agitation (as cited in Levine, Ring, Barak, Elizur, & Belmarker, 1995). Furthermore, inositol acts as a second messenger for NE and serotonin in the phosphatidylinositol cycle (Levine et al., 1995). Subjects were given 200mg/kg of inositol twice a day dissolved in juice. The control group received 200mg/kg of glucose administered the same way. According to the Conners Parent Teacher Rating Scale and compared to the placebo, inositol worsened the symptoms of ADHD. Six out of the nine subjects showed improvement taking the placebo while only three out of the nine subjects showed improvement taking inositol. Due to inositol’s negative effects in relieving ADHD symptoms, a diet low in inositol may be beneficial.
Selegiline. Stimulant drugs have been successful because of their ability to block the re-uptake of DA and NE. Also, stimulants have been shown to increase the inhibitory influences of frontal cortical activity. Selegiline is a type B monoamine oxidase inhibitor that is metabolized to amphetamine and methamphetamine. Akhondzadeh, Amini, Davari-Ashtiani, Arabgol, and Tavakolian (2003) proposed that selegiline would inhibit the breakdown of DA and increase DA in the synapses. Long-term studies of selegiline in animal models of ADHD have shown reduced hyperactivity and increased sustained attention (Bix et al., 1998, as cited in Akhondzadeh et al., 2003). Researchers concluded that compared to MPH, selegiline offered a more effective treatment of ADHD. They reported that selegiline was safer and had more tolerable side effects than MPH. These results offer an effective alternative to MPH.
Modafinil. Early studies have observed modafinil, a wake-promoting agent, is effective in reducing hyperactivity, inattention, and impulsivity in individuals with ADHD. Although the biochemical pathway has not been fully defined, researchers suggest modafinil may be acting via orexin-A and orexin-B neuropeptides released from histaminergic pathways (Chemelli et al., 1999, as cited in Turner, Clark, Dowson, Robbins, & Sahakian, 2004). Research on the benefits of modafinil in children with ADHD compared to adults with ADHD is primarily concerned with response inhibition and cognition. Modafinil is associated with a pattern of cognitive enhancement similar to healthy controls (Tuner, 2004). According to Ferraro et al. (1996), modafinil’s psychomotor action is not mediated by catecholamine pathways, which explains its reduced side effects and low abuse rate. The action of modafinil appears to produce arousal effects through nondopaminergic pathways and does not bind to adrenergic receptors or to NE receptors. Recent finding’s in animals showed that modafinil was integral in the release of histamine from the anterior hypothalamus (Ishizuka et al., 2003, as cited in Turner et al., 2004). Further research is needed to observe modafinil’s long-term effects. If accepted, modafinil may be considered in treating ADHD symptoms because it has fewer adverse side effects than the previous stimulant drugs.
Zinc sulfate. Current research on ADHD drug therapy has shown that zinc sulfate is a powerful substitute for stimulant drugs. According to Golub et al. (1996), animal and human studies showed that zinc sulfate plays an important role in regulating hyperactive behavior (as cited in Bilici et al., 2004). A zinc sulfate deficiency is often characterized by concentration impairments and jitters. Also, zinc sulfate was found to be deficient in individuals with ADHD compared to controls. A previous study examining individuals with ADHD with a severe deficiency in serum zinc sulfate showed they also had low free fatty acid levels. Possible combination therapy using zinc sulfate and fatty acids may provide an alternative to current stimulant treatment. The Attention Deficit Hyperactivity Disorder Scale showed that compared to a placebo, zinc sulfate administration could possibly lead to a greater reduction of ADHD symptoms. Zinc sulfate treatment in ADHD significantly improved an individual’s hyperactivity, impulsivity, and socialization scores on the Attention-Deficit/Hyperactivity Scale. However, the results show that there was no positive effect on the attention deficiency scores. There are two possible reasons why zinc sulfate showed a marked improvement in hyperactivity but not in attention. First, zinc sulfate is essential for converting dietary pyridoxine to its active form, pyridoxal phosphate, which is subsequently used to convert tryptophan to serotonin. Studies of individuals with ADHD who had low levels of serotonin in their blood that showed symptoms were effectively treated using serotonin re-uptake inhibitors, which are used primarily in treating depression. (Arnold & Jensen, 1998, as cited in Bilici et al., 2004). Zinc sulfate’s effectiveness on impulsivity control in individuals with ADHD may be due to increases in serotonergic activity. Second, zinc sulfate’s function in the production and modulation of melatonin is essential in the regulation of DA (Chen et al., 1999, as cited in Bilici et al., 2004). Zinc sulfate may also play a vital role in the formation of free fatty acid lipids by means of desaturase enzymes. Therefore, zinc sulfate is essential in the production of serotonin, DA, and free fatty acid. Further research is needed to determine the proper dosage of zinc sulfate and extended use as a treatment for ADHD.
An Underlying Mechanism of ADHD
Research on the underlying mechanism of ADHD has focused on the role that stimulant drugs play in relieving ADHD symptoms. One reason why a stimulant drug mechanism is more appropriate is because little is known about non-stimulants. Stimulant drugs have proven effective by treating 70% of individuals with ADHD (Diamond et al., 1999, as cited in Turner, 2004). Researchers have concluded that these factors of stimulant drug function are important in forming a theory for an underlying mechanism of ADHD.
A possible mechanism of ADHD proposed by Anthony Grace (2000) distinguishes between phasic and tonic releases of DA. A phasic release of DA is a transient firing of action potentials in response to a prolonged stimulus. A tonic release of DA is sustained activity in response to an ongoing stimulation. A tonic release can occur when DA is not taken up by transporters or when heteroreceptors, glutamate receptors on the DA nerve terminal, stimulate the release of DA. An effective tonic release of DA should stimulate DA autoreceptors causing a decrease in the phasic release. Grace (2000) concluded that individuals with ADHD have high levels of DA due to an inability to stimulate DA autoreceptors during tonic releases. According to Grace (2000), when stimulants are administered they increase the already high phasic response to a maximum level. Therefore, stimulants work by increasing tonic releases of DA, which influences DA autoreceptors. As a result, phasic releases contain less DA, and researchers have stated that low DA levels are consistent with effective ADHD treatment (as cited in Pliszka, 2003).
Rowe, Robinson and Gordon (in press) identified a biophysical model of ADHD consisting of three fundamental aspects. This study is the first to identify a mechanism of ADHD using QEEG results to examine changes in neurophysiology during stimulant treatment. The aspects of their model present a distinct relationship between anatomical components and their function in overt behavior. First, stimulant drugs are known to reduce the activity of the locus coeruleus, causing stimulation of the thalamic reticular nucleus. As a result, the intrathalamic activity in the thalamic reticular nucleus will be reduced. Second, stimulant drugs will decrease the excitatory activity of cortical neurons by increasing cortical NE levels and activating noradrenergic receptors. Finally, stimulant drugs will decrease dendritic activity. This decrease is expected given the reduced activity in inhibitory neurons and improved arousal (Rowe et al., in press). This model depicts a new way of integrating stimulant treatment results and QEEG to form a more comprehensive underlying mechanism of ADHD.
The growing number of adults and children with ADHD brings an increasing demand for a more effective and less harmful method of treatment for all affected individuals. Due to the early use of stimulant drugs and their effectiveness in 70% of individuals with ADHD, research has not focused on the possible long-term effects of prolonged use. In addition, it is important that the 30% of individuals who report having adverse side effects or an ineffectiveness to stimulants be treated with medication that is as effective as stimulants. Today, research is concentrated on looking for a non-stimulant treatment of ADHD using mechanisms proposed by cognitive deficits, QEEG scans, and stimulant drug treatments. This interdisciplinary approach to ADHD is essential to form an underlying neurochemical mechanism, which will lead to a more accurate diagnosis and effective treatment.
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