Drugs for the Treatment of Attention Deficit Disorder
Attention-deficit/hyperactivity disorder (ADHD) is a developmental neurobehavioral disorder characterized by excessive inattentiveness, impulsivity, and hyperactivity. By definition, ADHD begins during childhood, with symptoms typically recognized before 7 years of age. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), criteria for inattention are met when an individual displays often six or more of the following symptoms: inattention to details/making careless mistakes, difficulty sustaining attention in tasks or play activities, seems not to listen to what is being said, does not follow through and fails to finish tasks, difficulty organizing tasks and activities, avoids or strongly dislikes tasks requiring sustained attention, loses things necessary for tasks and activities, easily distracted, and forgetful. Similarly, the impulsivity and hyperactivity criteria are met when an individual displays often six or more of the following: blurts out answer before question is finished, difficulty awaiting turn or waiting in lines, interrupts or intrudes on others, fidgets, unable to stay seated, inappropriate running or climbing, difficulty in engaging in leisure activities quietly, “on the go”/driven by a motor, and talks excessively. When the criteria are met for inattention but not impulsivity and hyperactivity, the diagnosis of ADHD predominantly inattentive type is made. On the other hand, when the criteria are met for impulsivity and hyperactivity but not inattention, the diagnosis of ADHD predominantly hyperactive/impulsive type is made. When the criteria are met for both, the diagnosis of ADHD combined type is made. ADHD is a disorder that significantly impacts school performance, occupational functioning, and family and social functioning. Untreated, children with ADHD often have poor outcomes, including poor academic outcomes, increased risk of substance use disorders (SUDs) and other psychiatric disorders, and even a greater risk of arrest.
EPIDEMIOLOGY
A current estimate of the prevalence of ADHD in school-aged children and adolescents is approximately 5% to 9%. The increased awareness and recognition of the predominantly inattentive type of ADHD is thought to be a major contributing factor to the recent increase in the rates of diagnosis and treatment of ADHD in children. In addition, differences in criteria between the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R), and the DSM-IV classifications, namely, that the DSM-III-R required 8 of 14 symptoms, whereas the DSM-IV requires only 6 symptoms in either category, may have also contributed to the increased prevalence. As a result of the increased recognition of ADHD, there has also been an increase in the number of children treated for this condition. In fact, a recent study has shown a 2.9-fold increase in the rate of children with ADHD prescribed medications. In community epidemiologic samples, the male-to-female ratio in younger populations is closer to 2:1, although in clinical samples boys tend to greatly outnumber girls. In adults, the prevalence is thought to be somewhat lower and hovers around 4%, with a gender ratio of approximately 1:1.
ETIOLOGY
ADHD is thought to have multiple possible etiologic factors, including genetic, environmental, and neurologic ones. There is a highly significant association
between maternal smoking during pregnancy and ADHD in the offspring (but it is unclear whether the smoking might be causal or a marker of maternal risk). Interestingly, adults with ADHD are more likely to smoke than the general population and their quit rate is significantly lower. Cerebral ischemia at birth may be a risk factor for ADHD, but it does not explain the vast majority of cases. It has also been postulated that abnormalities in dopaminergic, noradrenergic, and/or cholinergic neurotransmission may underlie ADHD, but the evidence is scant, and the nature of the putative abnormalities is unclear. All of these neurotransmitters are involved in higher cognitive function, with dopamine (DA) clearly playing important roles in executive function mediated by the prefrontal cortex. A more specific dopaminergic hypothesis states that cognitive impairments associated with ADHD result from a hypodopaminergic state in the prefrontal cortex, whereas hyperactivity and impulsivity result from a hyperdopaminergic state in the striatum, possibly secondary to the prefrontal hypodopaminergic state.
between maternal smoking during pregnancy and ADHD in the offspring (but it is unclear whether the smoking might be causal or a marker of maternal risk). Interestingly, adults with ADHD are more likely to smoke than the general population and their quit rate is significantly lower. Cerebral ischemia at birth may be a risk factor for ADHD, but it does not explain the vast majority of cases. It has also been postulated that abnormalities in dopaminergic, noradrenergic, and/or cholinergic neurotransmission may underlie ADHD, but the evidence is scant, and the nature of the putative abnormalities is unclear. All of these neurotransmitters are involved in higher cognitive function, with dopamine (DA) clearly playing important roles in executive function mediated by the prefrontal cortex. A more specific dopaminergic hypothesis states that cognitive impairments associated with ADHD result from a hypodopaminergic state in the prefrontal cortex, whereas hyperactivity and impulsivity result from a hyperdopaminergic state in the striatum, possibly secondary to the prefrontal hypodopaminergic state.
IMAGING STUDIES
Although neuroimaging techniques cannot be used to make a diagnosis of ADHD, they have revealed abnormalities in frontal lobe function and in cortical-subcortical circuits. A study has suggested abnormal morphology in the frontal cortices of patients with ADHD, with reduced regional brain size localized mainly to inferior portions of dorsal prefrontal cortices bilaterally and in anterior temporal cortices bilaterally. In another study, ADHD subjects demonstrated smaller total brain size, superior prefrontal, and right superior prefrontal volumes, as well as significantly smaller areas for cerebellar lobules I-V and VIII-X, total corpus callosum area, and splenium.
Dopamine transporter (DAT) densities seem to be particularly elevated in the brain of ADHD patients, particularly in the striatum, and tend to decrease after treatment with methylphenidate (MPH). A study examined DA D(2/3) receptor binding with positron emission tomography using [11C] raclopride as a tracer and found that high DA receptor availability was predicted by a history of low neonatal cerebral blood flow, supporting the hypothesis of cerebral ischemia at birth as a risk factor for ADHD.
Functional neuroimaging studies have evidenced deficits in striatal and prefrontal activation, as well as changes in activation in parietal areas, confirming the postulated importance of frontostriatal networks in ADHD, as deficits in this network have now been associated with a wide range of cognitive tasks. A recent study used diffusion tensor imaging to show that reduced frontostriatal activation during a go/no-go task was related to reduced white matter integrity in both children with ADHD and their affected parents.
GENETIC AND FAMILY STUDIES
Family studies have clearly shown an increase in the risk for ADHD in first-degree relatives of probands with ADHD compared with relatives of controls, and twin studies have demonstrated higher concordance among monozygotic twins rather than dizygotic twins. The heritability of ADHD tends to range between 0.6 and 0.9, depending on the study. ADHD families can include individuals with differing phenotypes, including both more inattentive and impulsive subtypes. Among the various genes investigated, the human thyroid receptor-β gene has been linked to an increased risk for ADHD. A fairly recent meta-analysis concluded that, to date, only seven candidate genes have risk alleles where the pooled odds ratio is significantly >1.0 and that are therefore overtransmitted in ADHD. These genes include five catecholamine genes [DA 4 (DRD4) and DA 5 (DRD5) receptors, dopamine transporter (DAT1), dopamine-β-hydroxylase (DBH), and synaptosomal-associated protein of 25 kDa (SNAP-25) genes] and two in the serotonin system [serotonin
transporter (5-HTT) and serotonin 1B-receptor (HTR1B) genes]. Results from studies using a mouse model of ADHD using a combination of genetic and pharmacologic approaches demonstrated that DR4R signaling is essential for the expression of juvenile hyperactivity and impaired behavioral inhibition. A study suggests that variation in the glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene may confer an increased risk for ADHD and that this, at least in part, might be responsible for the previously reported linkage results suggesting the presence of a susceptibility locus on chromosome 16p13.
transporter (5-HTT) and serotonin 1B-receptor (HTR1B) genes]. Results from studies using a mouse model of ADHD using a combination of genetic and pharmacologic approaches demonstrated that DR4R signaling is essential for the expression of juvenile hyperactivity and impaired behavioral inhibition. A study suggests that variation in the glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene may confer an increased risk for ADHD and that this, at least in part, might be responsible for the previously reported linkage results suggesting the presence of a susceptibility locus on chromosome 16p13.
COMORBIDITY
Comorbidity tends to be the rule more than the exception in ADHD, with approximately two thirds of patients with ADHD having comorbid psychiatric conditions. Conduct disorder and oppositional defiant disorder are often present in children with ADHD, as well as major depressive disorder, multiple anxiety disorders, and, to a lesser degree, bipolar disorder. The risk for developing substance use disorder (SUD) is higher in ADHD probands than controls, although pharmacologically treated ADHD probands have rates of SUD closer to controls. In fact, stimulant therapy does not increase but rather reduces the risk for cigarette smoking and SUDs in adolescents with ADHD. Furthermore, there is no evidence that stimulant treatment increases or decreases the risk for subsequent SUDs in children and adolescents with ADHD when they reach young adulthood. A significant proportion of children with ADHD have learning disabilities in the areas of spelling, mathematics, or reading (20% to 30%). Tourette’s syndrome is also not uncommon in patients with ADHD and, certainly, ADHD is common in patients with Tourette’s syndrome.
COURSE
Although ADHD may remit in childhood or adolescence, approximately 40% to 80% of patients diagnosed with ADHD will continue to exhibit symptoms during young adulthood. ADHD may persist as a disorder or as residual symptoms. Residual symptoms of ADHD in adulthood are an increasingly recognized condition, offering challenges both diagnostically and therapeutically. The diagnosis requires an established diagnosis of ADHD in childhood, with residual inattention and impulsiveness in adulthood. The difficulty in diagnosing and studying this condition reflects, in part, the difficulty of making a retrospective diagnosis of childhood ADHD based on the memories of the patient, the patient’s parents, and teachers. Although adults with ADHD are generally reliable reporters of their past symptoms, they may tend to underreport compared with reports from their parents. Another difficulty with this diagnosis is that adults with residual symptoms of ADHD frequently suffer from one or more comorbid psychiatric disorders, most frequently mood disorders and SUDs, that may have significant symptom overlap with ADHD.
By themselves, the typical adult residual symptoms of ADHD are nonspecific, including restlessness, difficulty in concentrating, excitability, impulsiveness, and irritability. These symptoms are often associated with poor job or academic performance, anxiety, temper outbursts, antisocial behavior, and substance abuse. When untreated, ADHD is often accompanied by significant academic, familial, and social dysfunction at all ages, and may put those who suffer at risk for SUD. Although those treating children may be focused on conflicts with peers, poor academic performance, and oppositional behavior at school and at home, those treating adults tend to be focused on job and school difficulties.
DIAGNOSIS
ADHD is typically diagnosed clinically, on the basis of reported symptomatology and associated impairments. Collateral informants are very important to the diagnosis, in both children and adolescents. Diagnostic criteria described earlier
require that symptoms be pervasive and have persisted for at least 6 months to a degree that is maladaptive and inconsistent with the developmental level, manifested before age 7 years, and cause significant academic and/or social impairment. Several scales are used to support the clinical diagnosis of ADHD: the ADD-H Comprehensive Teacher Rating Scale, the Barkley Home Situations Questionnaire and School Situations Questionnaire, the parent-completed Child Behavior Checklist, the Teacher Report Form of the Child Behavioral Checklist, the Conners’ Parent and Teacher Rating Scales, and the ADHD Rating Scale. Although these scales can be useful clinically in supporting the diagnosis, they are not used in the real world as frequently as one would expect.
require that symptoms be pervasive and have persisted for at least 6 months to a degree that is maladaptive and inconsistent with the developmental level, manifested before age 7 years, and cause significant academic and/or social impairment. Several scales are used to support the clinical diagnosis of ADHD: the ADD-H Comprehensive Teacher Rating Scale, the Barkley Home Situations Questionnaire and School Situations Questionnaire, the parent-completed Child Behavior Checklist, the Teacher Report Form of the Child Behavioral Checklist, the Conners’ Parent and Teacher Rating Scales, and the ADHD Rating Scale. Although these scales can be useful clinically in supporting the diagnosis, they are not used in the real world as frequently as one would expect.
When the diagnosis of ADHD is made in an adult or an adolescent, the clinician needs to assess current symptoms and must also obtain a childhood history of ADHD. Self-report rating scales, such as the Brown Attention Deficit Disorder Scale, can be used to help assess whether ADHD was present during childhood, as well as the Conners’ Adults ADHD Rating Scale. School records and report cards can also be used to support the diagnosis, as well as collateral informants. The clinician-rated ADHD rating scale and the Adult ADHD Self-Report Scale Symptom Checklist are often used in clinical trials to track the effects of treatment.
A number of conditions can mimic or complicate ADHD, including head injury, substance abuse, learning disabilities, Asperger’s syndrome, autism, mood disorders, hearing or visual impairment, and mental retardation. It is important to be aware of these differential diagnoses when assessing patients for ADHD.
MANAGEMENT
The first step in the management of patients with ADHD involves psychoeducation. When the subject diagnosed as having ADHD is a child, most of the educational effort typically focuses on the parents, although the child may benefit greatly from an age-appropriate explanation of what ADHD is and how it can be helped. When the subject diagnosed as having ADHD is an adolescent or an adult, clinicians typically discuss with the patient some of the basic aspects of ADHD, including symptoms, nature, course of the illness, and available treatments. It is also helpful to provide both patients and their families with written materials such as brochures or review articles, so that they have the opportunity of supplementing the information derived from their interaction with the clinician. There are several Web sites that can be used for this purpose (e.g., www.chadd.org and www.add.org). Treatment usually involves education, psychosocial interventions, and pharmacologic treatments.
Psychosocial Approaches
Most of the psychosocial treatment studies in ADHD have focused primarily on behavioral and cognitive-behavioral therapies. Behavioral therapies are typically considered the initial treatment of choice for preschoolers with ADHD, and they can be effectively delivered by parents and teachers. However, they require high motivation on the part of those involved in their administration, and they require training in the use of contingency management, such as point/token economy reward systems. A large, randomized study has shown that carefully delivered medication management alone was superior to behavioral treatment and that there was only a modest benefit of adding intensive behavioral treatment to medications alone. Despite these findings, many clinicians favor the combination approach, and there is some evidence that such combined approach may allow for the administration of lower doses of stimulants. As far as ADHD in adults is concerned, a recent review of the literature concludes that the available data support the use of structured, skillsbased psychosocial interventions as a viable treatment for adults with residual symptoms of ADHD. Common elements across the various treatment packages include psychoeducation, training in concrete skills (e.g., organization and planning
strategies), and emphasis on outside practice and maintenance of these strategies in daily life.
strategies), and emphasis on outside practice and maintenance of these strategies in daily life.
Pharmacologic Treatments
Psychostimulants and atomoxetine (Strattera) are typically considered the firstline pharmacologic agents for the treatment of ADHD. Bupropion, tricyclic antidepressants (TCAs), and modafinil (Provigil) are considered off-label, second-line agents, and a number of other classes of psychotropic drugs may have potential use in this condition.
PSYCHOSTIMULANTS
A wide variety of compounds (e.g., caffeine and strychnine) can produce central nervous system stimulation. However, the stimulant drugs that have found use in ADHD are sympathomimetic amines, of which the prototype is amphetamine. Amphetamine was first used as a bronchodilator, respiratory stimulant, and analeptic during the 1930s. Psychostimulants were then used in the treatment of depression until they were supplanted by TCAs and monoamine oxidase inhibitors (MAOIs) in the 1960s.
The clinical utility of stimulants had been limited by the perception of their risk to cause tolerance and psychological dependence and by their abuse potential. In 1970, the U.S. Food and Drug Administration (FDA) reclassified these drugs as schedule II, the most restrictive classification for drugs that are medically useful. They are currently approved only for the treatment of ADHD and narcolepsy. Their efficacy in ADHD has been demonstrated in all age groups, and the extensive experience with stimulant use in children, adolescents, and adults with ADHD has reassured the field about the safety of these agents when prescribed in a thoughtful way for those without a prior history of active substance misuse or abuse. In addition, the availability of extended-delivery preparations has reduced the risk of misuse of stimulants, although diversion remains a concern. Indeed, as mentioned earlier, meta-analytic data of children with ADHD followed from childhood, through adolescence and into adulthood show that longitudinal treatment with stimulants may reduce the risk of substance abuse, with greater protection conferred through adolescence than adulthood. Stimulants are currently the most frequently prescribed psychotropic agents in pediatric psychopharmacology, and they are increasingly prescribed to adults with ADHD as well. They also have several off-label uses in psychiatric practice (Table 9.1). Stimulants are the first-line choice for pharmacologic therapy of ADHD. Those psychostimulants that are most widely used in clinical practice are MPH, mixed amphetamine salts, and dextroamphetamine (DEX).
TABLE 9.1 Indications for Stimulants | ||||||||||||||||
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Chemistry
Amphetamine is a racemic compound, with DEX being the D-isomer, which is three to four times more potent than the L-isomer as a central nervous system stimulant. MPH is a piperidine derivative that is structurally similar to amphetamine, while dexmethylphenidate hydrochloride is the D-threo enantiomer of racemic MPH hydrochloride. Adderall is an amphetamine mixture containing equal parts of DEX sulfate, D,L-amphetamine sulfate, D,L-amphetamine aspartate, and DEX saccharate. Lisdexamfetamine is a prodrug of DEX. After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and converted to DEX, which is responsible for the drug’s activity.
Pharmacology
Absorption and Metabolism
Amphetamine and DEX are well absorbed after oral administration. Immediate-release amphetamines (i.e., DEX and mixed amphetamine salts tablets) have a short half-life (3 to 6 hours); thus, they are usually administered two to three times daily. DEX and mixed amphetamine salts are available in extended-delivery preparations, which are usually administered once and sometimes twice daily. They cross the blood-brain barrier easily and develop high concentrations in the brain. Amphetamine and DEX are partly metabolized in the liver and primarily (80%) excreted unchanged in the urine. Their excretion is hastened by acidification of the urine.
As it was originally formulated in 1954, MPH was produced as an equal mixture of D,L-threo-MPH and D,L-erythro-MPH. Soon afterwards, it was found that the erythro form of MPH produced the cardiovascular side effects of the original formulation, and thus MPH is now manufactured as an equal mixture of D,L-threo-MPH. Studies have indicated that the primarily active form of MPH is the D-threo isomer. Therefore, the makers of brand name MPH (Ritalin) now produce the isomer of D,L-threo-MPH called Focalin (D-threo-MPH or dexmethylphenidate). Clinicians should note that, in terms of potency, 10 mg of D,L-threo-MPH (Ritalin) is biologically equivalent to 5 mg of D-threo-MPH (Focalin). Oral administration of immediate-release D,L-threo-MPH (available in generic MPH, Ritalin, Metadate ER, Methylin) results in a variable peak plasma concentration within 1 to 2 hours, with a half-life of 2 to 3 hours. Behavioral effects of immediate-release MPH peak 1 to 2 hours after administration and tend to subside within 3 to 5 hours.
Although generic MPH has a similar pharmacokinetic profile to Ritalin, it may be more rapidly absorbed and may peak sooner. Oral administration of immediate-release D-threo-MPH (dexmethylphenidate, available as Focalin) results in peak plasma concentrations at about 1 to 1.5 hours postdose, with a half-life of approximately 2.2 hours. Behavioral effects of dexmethylphenidate peak 1 to 2 hours after administration and tend to subside within 3 to 5 hours.
Plasma levels of the sustained-release (SR) preparation of MPH (Ritalin SR) peak in 1 to 4 hours with a half-life of 2 to 6 hours. Clinicians observe significant variability in the absorption of the SR preparation and tend to use it less now that several alternative extended-delivery systems are available. Peak behavioral effects of this preparation occur 2 hours after ingestion and last up to 8 hours. Because of the wax-matrix preparation, absorption is clinically observed to be variable. Recently, several novel methods of delivering MPH and amphetamine have become available, with the goal of extending the clinical effectiveness of the stimulants. Although these medications all deliver stimulants, their pharmacokinetic profiles differ. Oros-MPH (Concerta), the first of these novel delivery systems, has been available since August 2000. Concerta uses the osmotic-controlled release oral delivery system technology to deliver a 50:50 racemic mixture of D,L-threo-MPH. An 18-mg caplet of Concerta delivers the equivalent of 15 mg of MPH (5 mg of MPH three
times a day) providing 12-hour coverage. Initially, the 18-mg caplet provides 4 mg of MPH and delivers the additional MPH in an ascending profile over a total of 12 hours. Concerta is recommended to be dosed between 18 and 72 mg daily. If Concerta is cut or crushed, its delivery system is compromised. Metadate CD, available as 10-, 20- and 30-mg capsules, which may be sprinkled, contains two types of beads containing D,L-threo-MPH. The 20-mg Metadate CD capsule delivers 30% or 6 mg of D,L-threo-MPH initially and 70% or 14 mg in an ascending profile designed to simulate dosing MPH in the morning and again 4 hours later to provide 8 hours of coverage. Ritalin LA, available in capsules of 20, 30, and 40 mg that may be sprinkled, delivers 50% of its D,L-threo-MPH initially and another bolus approximately 3 to 4 hours later, thus providing approximately 8 hours of coverage. Recently, an MPH patch (Daytrana) was approved by the FDA. All these MPH preparations easily pass to the brain. Their concentrations in the brain appear to be higher than those in the blood. MPH is metabolized by plasma-based esterases.
times a day) providing 12-hour coverage. Initially, the 18-mg caplet provides 4 mg of MPH and delivers the additional MPH in an ascending profile over a total of 12 hours. Concerta is recommended to be dosed between 18 and 72 mg daily. If Concerta is cut or crushed, its delivery system is compromised. Metadate CD, available as 10-, 20- and 30-mg capsules, which may be sprinkled, contains two types of beads containing D,L-threo-MPH. The 20-mg Metadate CD capsule delivers 30% or 6 mg of D,L-threo-MPH initially and 70% or 14 mg in an ascending profile designed to simulate dosing MPH in the morning and again 4 hours later to provide 8 hours of coverage. Ritalin LA, available in capsules of 20, 30, and 40 mg that may be sprinkled, delivers 50% of its D,L-threo-MPH initially and another bolus approximately 3 to 4 hours later, thus providing approximately 8 hours of coverage. Recently, an MPH patch (Daytrana) was approved by the FDA. All these MPH preparations easily pass to the brain. Their concentrations in the brain appear to be higher than those in the blood. MPH is metabolized by plasma-based esterases.
Adderall, as mentioned earlier, is the brand name for a single-entity amphetamine product combining salts of DEX and amphetamine. It is available in two preparations—immediate-release and extended-release. It has a short half-life (8 to 12 hours) and is usually administered one or two times daily.
The Tmax of DEX is approximately 3.5 hours following single-dose oral administration of 30, 50, or 70 mg lisdexamfetamine (Vyvanse) after an 8-hour overnight fast, whereas the Tmax of lisdexamfetamine is approximately 1 hour. After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract. Lisdexamfetamine is converted to DEX and L-lysine, which is believed to occur by first-pass intestinal and/or hepatic metabolism. The plasma elimination half-life of lisdexamfetamine typically averaged less than 1 hour in studies of lisdexamfetamine dimesylate in volunteers.
Although data from the late 1960s suggest potential for drug interactions, the MAOIs remain the only contraindicated medication and usually the stimulants do not cause clinically significant medication interactions. It should be noted that when stimulants are administered with other sympathomimetics, patients may experience significant side effects. Tolerance to the sympathomimetic effects and to the drug-induced euphoria of amphetamine and MPH develops rapidly. Thus, chronic abusers often take very large doses that would be extremely toxic if taken by a nontolerant individual.
Mechanism of Action
Amphetamine and the similarly acting MPH are often termed indirectly acting amines. This is because they are thought to act primarily by causing release of amines. In particular, amphetamine increases extracellular norepinephrine, DA, and serotonin. Amphetamine enters different types of monoamine neurons via the DAT, norepinephrine transporter, and serotonin transporter, respectively. Acting on the vesicular transporter shared by all monoamine neurons [vesicular monoamine transporter (VMAT)], amphetamine causes monoamine neurotransmitters to exit their storage vesicles and to be released into the synapse via the uptake transporter. In other words, amphetamine-like drugs cause the DAT, norepinephrine transporter, and serotonin transporter to act in reverse. (In contrast, cocaine blocks these transporters, allowing already released monoamines to build up in the synapse.) Amphetamine-like drugs also have modest and reversible inhibitory effects on monoamine oxidase A. The main effect of amphetamines is thought to be through the dopaminerguic system: amphetamines inhibit DA transport by the DAT, stimulate DAT to move DA in the reverse direction, increase the rate of DA synthesis, inhibit monoamine oxidase, and redistribute DA from vesicles into the cytosol. MPH chiefly affects the prefrontal cortex and striatum by modulating
catecholaminergic tone. MPH treatment produces an increase in DA signaling through multiple actions, including blockade of the DA reuptake transporter, disinhibition of DA D2 autoreceptors, and activation of DA D1 receptors on the postsynaptic neuron. The actions of MPH may also be mediated by stimulation of the noradrenergic α2 receptor and DA D1 receptor in the cortex. Therefore, the effects on DA are thought to be most important to the mechanism of action of both MPH and amphetamine in ADHD, since, when used at the high doses that characterize abuse rather than therapeutic use, the release of DA is the action that produces rewarding and reinforcing effects.
catecholaminergic tone. MPH treatment produces an increase in DA signaling through multiple actions, including blockade of the DA reuptake transporter, disinhibition of DA D2 autoreceptors, and activation of DA D1 receptors on the postsynaptic neuron. The actions of MPH may also be mediated by stimulation of the noradrenergic α2 receptor and DA D1 receptor in the cortex. Therefore, the effects on DA are thought to be most important to the mechanism of action of both MPH and amphetamine in ADHD, since, when used at the high doses that characterize abuse rather than therapeutic use, the release of DA is the action that produces rewarding and reinforcing effects.
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