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Stimulant Medication Therapy in the Treatment of Children with Attention Deficit Hyperactivity Disorder
Clinical Phamacology
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Stimulant Medication Therapy in the Treatment of Children with Attention Deficit Hyperactivity Disorder
Richard D. Stevenson, MD, * and Mark L. Wolraich, MDt
Stimulant medications have been the major psychotropic agents employed in the management of childhood behavior problems for over 50 years. They have been widely used clinically and have been the focus of the most extensive research effort directed toward the use of any psychotropic medication in children. Despite this widespread clinical use and tremendous research effort, the use of stimulant medications in children has remained controversial. In the early 1970s in Omaha, Nebraska, the general public became alarmed on learning that an inordinate number of children were being medicated with methylphenidate to control their behavior. This issue was raised again in 1987 in Atlanta, Georgia. In 1988, Safer and Krager reported that from 1971 to 1987 the rate of medication treatment for hyperactive/inattentive students in Baltimore County, Maryland, doubled every 4 to 7 years 57 so that by 1987 nearly 6 per cent of all public elementary school students were under treatment. Why the concerns, and are stimulants being prescribed appropriately? The pediatric practitioner frequently is called on to prescribe stimulants to aid in the management of children with attention deficit hyperactivity disorder (ADHD). In light of the continued controversy, how is the practitioner to proceed? The present article will review what is known about the pharmacodynamics of stimulants, as well as their pharmacokinetics and side effects. It will focus on the three most commonly prescribed stimulants: methylphenidate (Ritalin), dextroamphetamine sulfate (Dexedrine), and pemoline (Cylert). The intent of this review is to summarize current knowledge regarding stimulant medications and their use to aid the practitioner in making important management decisions. *Assistant Professor, Department of Pediatrics, Kluge Children's Rehabilitation Center and Research Institute, University of Virginia, Charlottesville, Virginia t Professor of Pediatrics, Department of Pediatrics, Division of Developmental Disabilities, The University of Iowa, Iowa City, Iowa
Pediatric Clinics of North America-Vol. 36, No.5, October 1989
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HISTORY
Ever since 1937, when Bradley9 first reported the beneficial effects of Benzedrine on the behavior and school performance of 14 out of 30 children with behavior problems, stimulant medications have been the major psychotropic agents employed in the management of children's behavior. Initially used in children with various behavior disorders, it was not until after the hyperkinetic impulse syndrome was identified by Laufer et al. in 195740 that hyperactivity became the specific focus of stimulant medication use. Laufer identified the positive effects of stimulants as being most beneficial when used in children with the constellation of symptoms that include hyperactivity, short attention span, impulsivity, low frustration tolerance, poor school work, visual motor problems, writing and reading reversals, and poor handwriting. Laufer's report and the synthesis of methylphenidate in 1954 provided the initiative for what was to become the most extensive research effort into, and most extensive clinical use of, a psychotropic medication in children. A major issue in the use of stimulant medications has revolved around difficulties with the conceptualization of hyperactivity. Prior to Laufer's report, Strauss and Lehtinen68 identified the constellation of hyperactivity, disinhibition, and distractibility as being the result of brain damage. However, because it frequently was difficult to identify specific central nervous system injury, Clements 14 in 1966 popularized the concept of minimal brain dysfunction in children, manifested by hyperactivity, short attention span, impulsivity, and disinhibition; usually associated with specific learning and perceptual deficits; and identified on physical examination by developmentaily based "soft neurologic" signs. The categorization of these children as having neurologic deficits was fraught with problems because no specific neurologic abnormalities were identified consistently in this population. Therefore, in 1980, the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders (DSM-III)l redesignated the syndrome as "attention deficit disorder with or without hyperactivity." This recharacterization took the focus off the neurologic dysfunction and emphasized behavior as a basis for the diagnosis. It also changed the emphasis from hyperactivity to attention deficits and actually suggested that it is possible to find attentional problems in children without the presence of hyperactive behavior. Most recently in the revision to the DSM-III criteria (DSM-IIIR),2 hyperactivity was reintroduced as an essential component, and the syndrome has been renamed attention deficit hyperactivity disorder (ADHD). With all these changes in the categorization of the syndrome, it is not surprising that there is confusion about which children meet the diagnostic criteria and are therefore appropriate candidates for treatment with stimulant medications. . Adding to the difficulties is the fact that the symptoms of ADHD most frequently occur when the children are placed in situations that require them to focus their attention without much one-on-one contact. This means that many times the problems are most evident at school, and diagnosis depends on reports from the teacher rather than any objective tests or direct observation by the physician. Although several objective tests, such
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as the continuous performance test (CPT)47 and the paired associate learning (PAL) test,67 have been suggested as methods of assessment to determine treatment efficacy, it is unclear whether changes in these tests truly reflect changes in school behavior. 67 Additionally, Rapoport et al. 51 also were able to demonstrate in children what was already known in adults,39 that at least with dextroamphetamine the beneficial effects of stimulants observed in children with attention deficit disorder also are observed in normal children. Thus, confusion and difficulties with the diagnosis of ADHD, the importance of the child's environmental context, and the nonspecificity of the effects of stimulant medication create the potential for the overuse of the medications, and fuel the continued controversy.
CLINICAL PHARMACOLOGY A tremendous body of literature exists addressing the question of whether stimulant therapy is effective in the treatment of ADHD. Several comprehensive reviews of this literature have been published. 5, 33, 49, 84 The conclusions of all these reviews are the same: 1) for most children, the treatment of ADHD with stimulant medications is effective, and 2) dextroamphetamine, methylphenidate, and pemoline are equally effective in the treatment of ADHD, In general, the literature reflects consistent, positive drug effects on behavior, activity level, and attention. Variable and modest effects on academic performance and measures of cognition are reported. The authors of the more recent review articles5, 33 have used meta-analysis that has enabled them to examine the combined results of multiple controlled drug studies. The results obtained using this technique support the conclusions of the earlier reviews. The most commonly used measures of efficacy in stimulant drug trials have been changes in behavior, and this has been most commonly documented by employing behavior rating scales. Most behavior rating scales are designed to assess activity level, distractibility, impulsivity, and attention span. Behavior rating scales have been developed for teacher, as well as parent, use, and these scales have consistently been drug sensitive. 5, 33, 84 The most commonly used teacher rating scale has been the Conners Abbreviated Teacher Rating Scale (ATRS), 17 although recently some concerns have been raised about how specific it is for children with attention deficit disorder,73 The attention deficit disorder with hyperactivity (ADDH) Comprehensive Teacher Rating Scale (ACTeRS)14 is also sensitive to drug-placebo differences 71 and incorporates diagnostic criteria from DSMIII but has been used much less extensively. Useful parent questionnaires include the Conners Parent Rating Scale,17 the Pediatric Behavior Scale,42 and the Werry-Weiss-Peters Scale. 78 Other more objective measures of activity level and attention span have also been consistently drug sensitive.5, 33, 84 Measures of academic performance and intelligence have shown variable effects. Earlier reviews of the literature5, 7, 25, 84 reveal little or no drug effects, but meta-analysis 33 , 49 reveals modest, but definite, drug effects on academic performance and on intellectual measures. Recent reports have
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noted positive effects on language processing,4 information processing, 18 memory,22 and learning efficiency. 21 It remains unclear whether these specific effects are independent or mediated through the stimulant effects on attention. Further research in this area is needed. Finally, Schachar58 reported positive effects on family function and relationships in the families of drug responders, but not in the families of nonresponders. BarkleyB had previously reported more positive parental response with more frequent rewards to child-initiated behavior in methylphenidate-treated children. Schachar suggests that families of children who respond to stimulants may be more amenable to other forms of intervention that could affect long-term outcome. Studies that have used stimulants in combination with behavior modification suggest some additive effects. 83 Despite the overwhelming evidence for the short-term efficacy of stimulants in children with ADHD, long-term studies have not revealed consistent improvement. In part, this may be due to logistical problems associated with obtaining rigorous long-term study data,23 but the consistent lack of long-term drug effects in the literature argues against this being due solely to the "vicissitudes of follow-up studies. "23 In their reviews, Wolraich84 and Barkley5 both report little evidence for long-term efficacy. Hechtman,31 in a recent review of adolescent outcome of hyperactive children treated with stimulants, reaches the same conclusion but adds that some studies suggest that treatments combining stimulants with other multimodal interventions may result in more positive outcomes. Thus, although the literature does not document any long-term efficacy of stimulant medication use, it does provide some support for the suggestion that stimulants may help improve long-term outcome when used in the context of multimodal therapeutic strategies. Although stimulant medications are an effective treatment for most children with ADHD, as many as 25 per cent of children5 treated with stimulants remain unchanged or appear to worsen. 5. 45 It is not clear which children respond to stimulants and why some do not respond. Attempts to predict response to stimulants using history, physical examination, and other characteristics have been unsuccessful. 6. 45 This fact, together with the previously discussed difficulties of diagnosis, creates something of a dilemma for the clinician. First of all, diagnosis and response to treatment must rely largely on the observations of parents and teachers who are not necessarily impartial observers. Thus, the practitioner is frequently in the position of having to make diagnostic and therapeutic decisions based on secondhand information from parents who, in turn, have been told by teachers about their child's behavior in school. Perhaps more importantly, however, once the practitioners make the diagnosis of ADHD, they must then decide how treatment should proceed and who should receive stimulant medications. Several investigators have recently proposed a pragmatic approach to the medical treatment of children with ADHD'45' 72. 75 using individual single-blind placebo-controlled crossover trials with medication to more objectively assess treatment efficacy. These blinded, placebo-controlled drug trials are feasible in the office setting. The most important prerequisites
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are a pharmacist willing to make up a supply of gelatin capsules, some containing active drug and some containing placebo, and teachers who are willing to participate. Efficacy of medication is determined by teachers using one of the standardized teacher rating scales, such as the ADD-H Comprehensive Teacher Rating Scale (ACTeRS).74 The teachers, parents, and the child are blinded as to whether the child is taking drug or placebo. The teacher rating scale is performed on a regular basis, usually weekly. McBride 45 suggests using a fixed dose of methylphenidate (0.3 mg per kg per dose given b. i. d.) for 2 weeks and placebo for 2 weeks in random order. Because the rate of absorption and response to medication is variable, as is discussed in the pharmacokinetics section, it may be better to begin with an open clinical trial of methylphenidate first, to adjust the dose to optimize any apparent effects and to identifY clinical drug responders. Nonresponders would need no further trial, but apparent responders could then proceed to a drug versus placebo trial. It is important to note that because this will only entail one patient at a time, a single-subject design 34 with multiple changeovers is the most appropriate. One reasonable possibility is a 6-week trial with the child on the active drug during weeks one, four, and six and on placebo during weeks two, three, and five so as not to create a repetitive pattern. This would minimize the possibility that apparent benefit may be due to chance or extraneous causes. Because the blinded trial begins with the same dose determined in the unblinded trial, any artifactual changes related to the assessment process itself can be detected in that first week. Even though developing the ability to conduct single-blind drugplacebo trials initially requires time on the clinician's part, as noted by Deuel,20 the use of such trials "leapfrogs many knotty unresolved conceptual issues and lands directly on the key question": Does stimulant medication benefit this child? This method helps to identifY the 18 to 30 per cent49 , 72 of placebo responders, it provides the parents with convincing evidence about the efficacy of the treatment, and it offers a followup method to record continued efficacy and thus guide dosage changes or discontinuation of treatment. This provides a better alternative than discontinuing the use of a safe and effective medication because of negative publicity stemming from overextensive use. Some studies69 , 80 have demonstrated that tolerance to the clinical effects of a stimulant may develop with chronic treatment. Regular followup, therefore, must include periodic determinations of efficacy. In addition to tolerance, changes in a child's classroom situation or improvement in a child's ability to attend because of maturation also may result in a child no longer requiring medication. Periodic trials off medication or reassessments with single-blind placebo trials can facilitate monitoring. In addition, weekend and vacation medication holidays may decrease the chance for tolerance to develop. PHARMACODYNAMICS The therapeutic effects of stimulants on the symptoms of ADHD are well documented, and stimulants have become the standard against which
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the efficacy of other medications and other forms of therapy, 85 such as the Feingold diet and behavior modification, are measured. To understand the possible mechanisms of action-the pharmacodynamics--of these medications, it is necessary to review what is known about the neurochemistry of ADHD. The earliest evidence suggesting a neurochemical abnormality as the basis for ADHD was derived from the symptoms of children with von Economo's encephalitis during the early part of this century. In contrast to adults, who developed Parkinson's disease following acute encephalitis, children developed characteristic attentional and motor problems. In light of the well-known relationship between dopamine deficiency and parkinsonism, Wender76 proposed that the behavioral problems exhibited by children also might be neurochemically based and related to dopamine deficiency. Much of the current understanding of the neurochemistry of ADHD stems from neuropharmacologic, neurochemical, and neuroanatomic studies in animals, coupled with clinical pharmacologic research in humans. Methylphenidate, dextroamphetamine, and pemoline all increase the release and inhibit the reuptake of dopamine and norepinephrine 24, 37 from neurons in the central nervous system. The catecholamines, norepinephrine and dopamine, serving as neurotransmitters, are probably involved at some level in the pathogenesis and treatment effects of ADHD. All drugs that have some efficacy in the treatment of ADHD also have some effect on catecholamine metabolism. This has led to much research examining the potential role each neurotransmitter may play in the pathophysiology of ADHD. Dopamine Much of the interest and support for the role of dopamine in the pathophysiology of ADHD has come from the animal model of Shaywitz.61 Following central dopamine depletion in newborn rats, the animals exhibited significantly more motor activity and learning deficits. These deficits could be reversed by stimulant medications. In addition, clinical trials in humans with specific dopamine agonists 38 as well as antagonists such as haloperidol 82 have proven modestly effective in the treatment of children with ADHD. However, a simple dopamine effect does not fully explain ADHD because the therapeutic effects of stimulants are far greater than those of the specific dopamine agonists and antagonists. 89 Additionally, many biochemical studies comparing dopamine and its metabolites in urine, blood, and cerebrospinal fluid of children with ADHD and normal controls have been completed, and most studies have not demonstrated Significant differences. 89 Interestingly, however, the therapeutic effects of dopamine antagonists seem to be additive with methylphenidate. 26 Thus, dopamine does appear to playa part in the pathophysiology of ADHD, but a simple dopamine effect does not fully explain ADHD nor the therapeutic effects of stimulants. Norepinephrine A specific noradrenergic effect in ADHD was first suggested by Kornetskf6 who posed the hypothesis that perhaps hyperactive children
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are "overaroused" and that amphetamines accomplish their therapeutic effect by competitively inhibiting postsynaptic noradrenergic neurotransmission. This hypothesis was not supported by subsequent research l2 ; however, there is evidence for a noradrenergic effect. Shekim,63 and Yucun and Yu-feng,86 have demonstrated decreased metabolites of norepinephrine in urine of patients with ADHD. In contrast, Khan and Dekirmenjian35 demonstrated increased urinary norepinephrine metabolites in patients with ADHD. These reports all support a role for norepinephrine in ADHD, but the apparently contradictory findings are perplexing. This issue has been addressed by Raskin,53 who suggests that perhaps ADHD is associated with a general failure of noradrenergic systems to function within certain limits rather than simply "too much or too little" norepinephrine. Interestingly, studies of norepinephrine metabolites in ADHD children who are taking stimulants report decreases in the metabolites from a baseline level. 10, 62. 63, 87 In addition, clinical trials using drugs that affect noradrenergic, but not dopaminergic, pathways (e.g., tricyclic antidepressants, clonidine) have demonstrated moderate clinical improvement. 89 Evidence against a simple noradrenergic effect includes early biochemical studies that show no difference between patients with ADHD and normal controls. 52, 77 The strongest evidence, however, is that the therapeutic effects of the more specific noradrenergic agents are not as great as the stimulants. Thus, norepinephrine appears to play only a partial role in the pathophysiology of ADHD. Serotonin Serotonin, another important neurotransmitter in the central nervous system, is probably not involved in the basic pathophysiology of ADHD because drugs that significantly influence serotonin metabolism have minimal efficacy on ADHD symptoms. 53, 89 Combined Catecholamines Although neither the dopamine nor the noradrenergic effects are sufficient to explain the physiology and treatment of ADHD, both neurotransmitter pathways appear to be important. In addition, another catecholamine, phenylethylamine, has been postulated to playa role in ADHD87 and in mental illness. 54 Further evidence in support of a combined catecholamine effect includes recent clinical trials with monoamine oxidase inhibiters. These agents affect norepinephrine, serotonin, phenylethylamine, and dopamine metabolism and are almost as effective as dextroamphetamine in controlling classroom behavior in children with ADHD. 88 The strongest support for this hypothesis is the superior clinical efficacy of the stimulants and their known effects on both norepinephrine and dopamine. Although all of the stimulants affect both norepinephrine and dopamine metabolism, it is becoming clear that they do so in different ways. For example, methylphenidate acts by facilitating the release of dopamine from a reserpine-sensitive storage pool,48 but dextroamphetamine facilitates the release of newly synthesized dopamine from a reserpine-resistant pool. 13 The results of these and other studies imply that although the stimulants are essentially equivalent in efficacy, they may exert their therapeutic
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effects via different mechanisms. This suggests that a child with ADHD who does not respond to one stimulant may respond to another, and thus it is possible that selective response to stimulants may help to distinguish subtypes of ADHD in what now is a very heterogeneous group of patients. This is an area in need of further research. To summarize, the neurochemical effects of stimulant medication appear to be related to the norepinephrine, dopamine, catecholamine axis. However, in spite of many years of active research and much progress in the understanding of the neurochemistry and pathophysiology of ADHD, much remains to be learned, and the precise mechanism of action of stimulant medications in the treatment of symptoms of ADHD is not yet fully understood. Currently, the most tenable hypothesis to explain how stimulants exert their clinical effects is the combined catecholamine hypothesis. PHARMACOKINETICS
Methylphenidate, dextroamphetamine, and pemoline are rapidly absorbed following oral administration. Methylphenidate serum concentrations usually peak within 1 to 2 hours; the drug's elimination half-life ranges from 2 to 4 hours after an oral dose. 81 Dextroamphetamine is a little slower in its absorption, peaking in 2 to 3 hours and displaying a half-life of 6.8 hours. 11 Pemoline is the slowest to be absorbed, with peak concentrations occurring at approximately 2.4 hours after an oral dose and an elimination half-life of about 7 to 7V2 hours. 15 All of these drugs are poorly bound to plasma proteins. Methylphenidate is metabolized primarily by de-esterification to ritalinic acid, which accounts for 75 to 91 per cent of the total methylphenidate identified in the urine. 81 A great deal of interindividual variability exists for all three drugs. Much variability also is found between plasma levels and behavioral responses in each child. 81 Therefore, it is important clinically (as stated earlier) to titrate the dose to determine the optimal response in any patient. Not only is there a great deal of interindividual variation, but there is also variation depending on what effect is monitored. For methylphenidate, positive effects on behavior measured with teacher rating scales have been found to continue, improving with increasing doses up to as high as 1.0 mg per kg, while the effects on performance on simple cognitive tasks were found to peak at a dose of 0.6 mg per kg. 66. 79 Both methylphenidate and dextroamphetamine also are produced in delayed or sustained release forms. These forms and pemoline were developed so that it would be possible to administer the medication without requiring the child to receive a dose at school, which for some children is an embarrassment or may be difficult. The methylphenidate sustainedrelease form is slower in onset and has a different time course than the standard form. It has also been found to be slightly less effective on some measures of social behavior. 50 Given these factors and the increased cost of the sustained form, it appears that there would need to be a compelling reason for not administering a dose at school before one should switch from
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the standard tablet, now available in generic form at considerably lower cost. The administration instructions for methylphenidate recommend that it be given 30 to 45 minutes before a meal, so that it is administered on an empty stomach; however, a study by Swanson et al. 70 found no difference in the behavioral, cognitive, or electrophysiologic effects of MPH whether it was given with or 30 minutes before breakfast. In sum, stimulant medications are fast-acting medications not readily bound to plasma protein. The pharmacokinetics exhibit a good deal of individual variation necessitating individual titration of the dose for each child, and the sustained release forms do not appear to provide any major advantage over the standard forms.
SIDE EFFECTS The most commonly reported side effects of stimulant medications are insomnia, anorexia, stomach pains, and weight loss. These recently have been reviewed29 and evidence indicates that these effects are transient and diminish as treatment continues in most patients. Pemoline has been found to cause liver dysfunction in some children, so liver function needs to be monitored during treatment when pemoline is used. Dextroamphetamine and methylphenidate have significant sympathicomimetic effects, so blood pressure should be monitored at regular intervals in all patients, but especially in those with underlying hypertension. Clinicians have long been taught that methylphenidate lowers seizure threshold; however, this caveat has recently been refuted. 45, 46 The effects of stimulant medications on growth and the relationship between stimulant use and motor tics have been of major concern and deserve further mention. Growth Effects In 1972, Safer and colleagues56 first suggested a growth suppressant effect of all doses of dextroamphetamine and high doses of methylphenidate. Subsequent studies revealed conflicting results. In 1979, the Pediatric Subcommittee of the FDA Psychopharmacologic Drugs Advisory Committee, working in conjunction with outside experts, reviewed and synthesized all relevant literature and published their results. 55 They concluded that, although evidence clearly indicates a temporary decrease in the rate of weight gain and suggests a temporary decrease in linear growth, there was no evidence that this significantly affected adult stature and weight. The temporary effects seemed related to drug dosage and the presence or absence of drug holidays, but no conclusions could be reached about the relative effects of each of the stimulants used. 30, 55 Research has not demonstrated any alterations in the hypothalamic, pituitary, or somatomedin axis associated with methylphenidate use. 59 A recent study demonstrated no growth suppression with doses of methylphenidate up to 0.8 mg per kg per day over a 2-year period. 32 A larger study found a statistically significant but small growth suppressant effect in prepubertal children in which methylphenidate dosage accounted for only 2 per cent of variance in final
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height. 44 These authors suggest careful monitoring of growth and dosage reduction in individual cases in which growth suppression occurs. A recent statement by the American Academy of Pediatrics Committee on Drugs and Children with Disabilities 16 implies that the' risk of growth suppression with stimulant use is no longer felt to be significant. In conclusion, although short-term effects of stimulants on weight gain and growth have been reported for all doses of dextroamphetamine and high doses of methylphenidate, other studies have demonstrated contradictory results. There is no evidence that stimulants have any effect on ultimate adult stature. Use of lower doses of methylphenidate (3 mg per kg) and drug holidays on weekends and vacation periods have been suggested to minimize the effects on growth. This is a reasonable practice for most children; however, use of stimulants on weekends and holidays for selected patients is not contraindicated and can be considered safely. Tics In 1974, Golden 27 reported the case of a 9-year-old boy who had a sudden onset of Tourette's syndrome following the use of methylphenidate for the treatment of ADHD. Since then methylphenidate, dextroamphetamine, and pemoline have all been reported to either precipitate or exacerbate tic disorders.3. 43, 65 The relationship between stimulant medications and tics recently has been reviewed.28 Although some dissenting views have been expressed, 60 the literature supports the observation that some children may experience worsening of preexisting tics or the appearance of new motor tics during or sometime after treatment with stimulants. Overall, the risk of a child with ADHD developing transient motor tics after treatment with stimulants has been reported to be 1. 3 per cent. 19 In a child with a family history of TOl1rette's syndrome or other tic syndromes, however, the risk may be substantially higher. Because Qf the reported relationship between stimulants and motor tics, practical guidelines for clinical use of stimulant medications in children with ADHD have been published. 28, 43 Generally, in patients with both ADHD and tics, the use of stimulant medications should be avoided if at all possible. These childr~n pose a therapeutic dilemma and management can be quite challenging. If stimulants are used in these patients, their tics must be monitored carefully, and the medication discontinued if the tics worsen. Some investigators have recommended the use of clonidine in children with tics and' ADHD. 41,64 Children with ADHD who do not have tics need to be monitored carefully so that the medication can be discontinued if tics develop. .
SUMMARY Despite the tremendous research advances that have increased our knowledge regarding the pharmacodynamics, clinical pharmacology, pharmacokinetics, and adverse effects of stimulant medications in the treatment of children with ADHD, our knowledge is yet incomplete. Perhaps the most central unresolved issue concerns our underst;mding of the pathogen-
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esis, pathophysiology, and diagnosis of AOHO. This review has touched briefly on the controversy and confusion surrounding this issue. Although our understanding of the use of stimulant medications in this disorder is similarly incomplete, a review of the literature does allow certain conclusions to be made that are helpful to the practitioner. 1. Stimulant medications are an effective treatment modality for most children with ADHD. Short-term efficacy is well documented, and long-term outcome may be improved when stimulants are used with other therapeutic strategies. Stimulants in and of themselves are not a panacea. 2. It is impossible to predict which children will have a favorable response to stimulant medications and which children may have a placebo response. The use of individual single-blind medication trials is a practical solution to this problem and should be considered for all children who are candidates for stimulant therapy as a means for preventing overuse or inappropriate use of these medications. 3. The precise mechanism of action of stimulants is not yet completely understood, but stimulants appear to exert their therapeutic effects through their influence on multiple neurotransmitters in the catecholamine, dopamine, norepinephrine axis in the central nervous system. 4. The three major stimulants-methylphenidate, dextroamphetamine, and pemoline-appear to be equally efficacious, although methylphenidate has emerged as the most commonly used and most studied drug. Because of its potential for causing liver toxicity, pemoline has remained a second-line medication. 5. The three major stimulants appear to have somewhat different mechanisms of action so that failure of a patient to respond to one medication does not mean that he or she will not respond to another. 6. The recommended starting doses for the stimulants are 0.3 mg per kg of methylphenidate, 0.15 mg per kg of dextroamphetamine, and 37.5 mg of pemoline. There is a great deal of individual variability in dose response, so doses must be titrated for optimal effects in each child. Sustained release preparations are much more expensive than regular preparations and may be less effective. 7. There is no evidence that stimulants have any effect on ultimate adult height. 8. Although relatively uncommon, motor tics have been observed in children on stimulants, and all children on stimulants need to be carefully monitored for the development of tics.
Primary care practitioners have the unique opportunity to educate and update children, parents, and teachers about the diagnosis and management of children with attentional problems. Although they work in concert with other professionals in managing children with AOHO, physicians are responsible for providing medications. They must guard against becoming "surrogate prescribers" (0-1) and strive to become informed managers of treatment modalities that employ stimulant medications, so that they may not only optimally serve their patients but also educate the public. Continued research and education still are needed if we are to resolve the controversy that has long surrounded the use of stimulants in children with AOHO.
REFERENCES 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-III). Washington, DC, American Psychiatric Association, 1980
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2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental DisordersRevised (DSM-III-R). Washington, DC, American Psychiatric Association, 1987 3. Bachman DS: Pemoline-induced Tourette's disorder: A case report. Am J Psychiatry 138:1116, 1981 4. Ballinger CT, Varley CK, Nolen PA: Effects of methylphenidate on reading in children with attention deficit disorder. Am J Psychiatry 141:1590, 1984 5. Barkley RA: A review of stimulant drug research with hyperactive children. J Child Pschol Psychiat 18:137, 1977 6. Barkley RA: Predicting the response of hyperkinetic children to stimulant drugs: A review. J Abnorm Child Psychol 4:327, 1974 7. Barkley RA, Cunningham CEo Do stimulant drugs improve the academic performance of hyperkinetic children? A review of outcome research. Clin Pediatr 17:85, 1978 8. Barkley RA, Cunningham CEo The effects of methylphenidate on the mother-child interactions of hyperactive children. Arch Gen Psychiatry 36:201, 1979 9. Bradley C: The behavior of children receiving Benzedrine. Am J Psychiatry 94:577, 1937 10. Brown GL, Ebert MH, Hunt RD, et al: Urinary 3-methoxy-4-hydroxyphenylglycol and homovanillic acid response to d-amphetamine in hyperactive children. Bioi Psychiatry 16:779, 1981 11. Brown GL, Hunt RD, Ebert MH, et al: Plasma levels of D-amphetamine in hyperactive children. Psychopharmacology 62:133, 1979 12. Callaway E, Holliday R, Naylor H: Hyperactive children's event-related potentials fail to support underarousal and maturational-lag theories. Arch Gen Psychiatry 11:1243, 1983 13. Clemens JA, Fuller RW: Differences in the effects of amphetamine and methylphenidate on brain dopamine turnover and serum prolactin concentration in reserpine-treated rats. Life Sciences 24:2077, 1979 14. Clements SD: Minimal brain dysfunction in children: Terminology and identification. Washington, DC, US Department of Health, Education, and Welfare, 1966 15. Collier CP, Soldin SJ, Swanson JM, et al: Pemoline pharmacokinetics and long term therapy in children with attention deficit disorder and hyperactivity. Clin Pharmacokinet 10:269, 1985 16. Committee on Children with Disabilities, Committee on Drugs: Medication for children with an attention deficit disorder. Pediatrics 80:758, 1987 17. Conners CK: Rating scales for use in drug studies with children. Psychopharmacol Bull (Special Issue):24, 1973 18. Coons HW, Klorman R, Borgstedt AD: Effects of methylphenidate on adolescents with a childhood history of attention deficit disorder: II. Information processing. J Am Acad Child Adolesc Psychiatry 26:368, 1987 19. Denckla MB, Bemporad JR, MacKay MC: Tics following methylphenidate administration. JAMA 235:1349, 1976 20. Deuel RK: Treatment of attention problems with stimulant medication. J Pediatr 113:68, 1988 21. Douglas VI, Barr RG, O'Neill, et al: Short-term effects of methylphenidate on the cognitive learning and academic performance of children with attention deficit disorder in the laboratory and classroom. J Child Psychol Psychiatry 27:191, 1986 22. Evans RW, Gualtieri CT, Amara 1: Methylphenidate and memory: Dissociated effects in hyperactive children. Psychopharmacology 90:211, 1986 23. Firestone P, Crowe D, Goodman JT, et al: Vicissitudes of follow-up studies: Differential effects of parent training and stimulant medication with hyperactives. Am J Orthopsychiatry 56:184, 1986 24. Fuller RW, Perry KW, Bymaster FP, et al: Comparative effects of pemoline, amfoelic acid, and amphetamine on dopamine uptake and release in vitro on brain 3, 4dihydroxyphenylacetic acid concentration on spiperone-treated rats. J Pharm Pharmacol 30:197, 1978 25. Gadow KD: Effects of stimulant drugs on academic performance in hyperactive and learning disabled children. J Learn Disabil16:127, 1983 26. Gittelman R, Klein D, Kartz S, et al: Comparative effects of methylphenidate and thioridazine in hyperkinetic children. Arch Gen Psychiatry 33:1217, 1976 27. Golden GS: Gilles de la Tourette's syndrome following methylphenidate administration. Dev Med Child Neurol 16:76, 1974
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28. Golden, GS: The relationship between stimulant medication and tics. Pediatr Ann 17:405, 1988 29. Golinko, BE: Side effects of dextroamphetamine and methylphenidate in hyperactive children: A brief review. Prog Neuropsychopharmacol Bioi Psychiatry 8:1, 1984 30. Greenhill LL, Puig-Antich J, Halpern F: Growth disturbances in hyperkinetic children. Pediatrics 66:152, 1980 31. Hechtman L: Adolescent outcome of hyperactive children treated with stimulants in childhood: A review. Psychopharmacol Bull 21:178, 1985 32. Kalachnik JE, Sprague RL, Sleator EK, et al: Effect of methylphenidate hydrochloride on stature of hyperactive children. Dev Med Child Neurol 24:586, 1982 33. Kavale K: The efficacy of stimulant drug treatment for hyperactivity: A meta-analysis. J Learn Dis 15:280, 1982 34. Kazdin AE: Single-Case Research Designs: Methods for Clinical and Applied Settings. New York, Oxford University Press, 1982 35. Khan AU, DeKirmenjian H: Urinary excretion of catecholamine metabolites in hyperkinetic child syndrome. Am J Psychiatry 138:108, 1981 36. Kornetsky C: Psychoactive drugs in the immature organism. Psychopharmacologia 17:105, 1970 37. Kuczenski R: Biochemical actions of amphetamines and other stimulants. In Crease I (ed): Stimulants: Neurochemical, Behavior and Clinical Perspectives. New York, Raven Press, 1983, p 31 38. Langer DH, Rapoport JL, Brown GL, et al: Behavioral effects of carbidopallevodopa in hyperactive boys. JAm Acad Child Adolesc Psychiatry 21:10, 1982 39. Laties VG, Weiss B: Performance enhancement by the amphetamines: A new appraisal. In Brill H, Cole JO, Deniker P, et al (eds): Neuropsychopharmacology. Amsterdam, Excerpta Medica Foundation, 1967, p 800 40. Laufer MW, Denhoff E: Hyperkinetic behavior syndrome in children. J Pediatr 50:463, 1957 41. Leckman JF, Detlor J, Harcherik DF, et al: Short- and long-term treatment of Tourette's syndrome with clonidine: A clinical perspective. Neurology 35:343, 1985 42. Lindgren SD, Koeppl GK: Assessing child behavior problems in a medical setting: Development of the Pediatric Behavior Scale. In Prinz RJ (ed): Advances in Behavioral Assessment of Children and Families. Greenwich, CT, JAI Press, 1987, p 57 43. Lowe TL, Cohen DJ, Detlor J, et al: Stimulant medications precipitate Tourette's syndrome. JAMA 247:1729, 1982 44. Mattes JA, Gittelman R: Growth of hyperactive children on maintenance regimen of methylphenidate. Arch Gen Psychiatry 40:317, 1983 45. McBride MC: An individual double-blind crossover trial for assessing methylphenidate response in children with attention deficit disorder. J Pediatr 113:137, 1988 46. McBride MC, Wang DA, Torres CF: Methylphenidate in therapeutic doses does not lower seizure threshold. Ann Neurol 20:248, 1986 47. Mirsky AF, Rosvold HE: Behavioral and physiological studies in impaired attention. In Votava Z, Horvath M, Vinar 0 (eds): Psychopharmacological Methods: Proceedings of a Symposium on the Effects of Psychotropic Drugs on Higher Nervous Activity. Oxford, England, Pergamon Press, 1963, p 302 48. Moore KE, Chiueh CC, Zeldes G: Release of neurotransmitters from the brain in vivo by amphetamine, methylphenidate, and cocaine. In Ellinwood EH, Kilbey MM (eds): Cocaine and Other Stimulants. New York, Plenum Press, 1977, p 143 49. Ottenbacher KJ, Cooper HM: Drug treatment of hyperactivity in children. Dev Med Child Neurol 25:358, 1983 50. Pelham WE, Sturges J, Hoza J, et al: Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Pediatrics 80:491, 1987 51. Rapoport JL, Buchsbaum MS, Weingartner H, et al: Dextroamphetamine: Its cognitive and behavioral effects in normal and hyperactive boys and normal men. Arch Gen Psychiatry 37:933, 1980 52. Rapoport JL, Mikkelsen EJ, Ebert MH, et al: Urinary catecholamine and amphetamine excretion in hyperactive and normal boys. J Nerv Ment Dis 66:731, 1978 53. Raskin LA, Shaywitz SE, Shaywitz BA, et al: Neurochemical correlates of attention deficit disorder. Pediatr Clin North Am 31:387, 1984
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54. Reynolds GP: Phenylethylamine--a role in mental illness? TINS, October 1-3, 1979 55. Roche AF, Lipman RS, Overall JE, et al: The effects of stimulant medication on the growth of hyperkinetic children. Pediatrics 63:847, 1979 56. Safer D1. Allen RP: Factors influencing the suppressant effects of two stimulant drugs on the growth of hyperactive children. Pediatrics 51:660, 1973 57. Safer DJ, Krager JM: A survey of medication treatment for hyperactive/inattentive students. JAMA 260:2256, 1988 58. Schachar R, Taylor E, Wieselberg M, et al: Changes in family function and relationships in children who respond to methylphenidate. J Am Acad Child Adolesc Psychiatry 26:728, 1987 59. Schultz FR, Hayford JT, Wolraich ML, et al: Methylphenidate treatment of hyperactive children: Effects on the hypothalamic-pituitary-somatomedin axis. Pediatrics 70:987, 1982 60. Shapiro AK, Shapiro E: Do stimulants provoke, cause, or exacerbate tics and Tourette syndrome? Compr Psychiatry 22:265, 1981 61. Shaywitz BA, Yager RD, Klopper JH: Selective brain dopamine depletion in developing rats: An experimental model of minimal brain dysfunction. Science 191:305, 1976 62. Shekim WO, Dekirmenjian H, Chapel JL: Urinary catecholamine metabolites in hyperkinetic boys treated with D-amphetamine. Am J Psychiatry 134:1276, 1977 63. Shekim WO, Dekirmenjian H, Chapel JL: Urinary MHPG excretion in minimal brain dysfunction and its modification by D-amphetamine. Am J Psychiatry 136:667, 1979 64. Singer HS, Gammon K, Quaskey S: Haloperidol, fluphenagine and clonidine in Tourette syndrome: Controversies in treatment. Pediatr Neurosci 12:71, 1985-1986 65. Sleator EK: Deleterious effects of drugs used for hyperactivity on patients with Gilles de la Tourette syndrome. Clin Pediatr 19:453, 1980 66. Sleator EK, Sprague RL: Dose effects of stimulants in hyperkinetic children. Psychopharmacol Bull 10:29, 1974 67. Solanto MV: Neuropharmacological basis of stimulant drug action in attention deficit disorder with hyperactivity: A review and synthesis. Psychol Bull 95:387, 1984 68. Strauss AA, Lehtinen LE: Psychopathology and Education of the Brain-Injured Child. New York, Grune & Stratton, 1947, p 84 69. Swanson JM, Lerner M, Cantwell D: Blood levels and tolerance to stimulants in ADDH children. Clin Neuropharmacol (Suppl) 9:523, 1986 70. Swanson JM, Sandman CA, Deutsch C, et al: Methylphenidate hydrocloride given with or before breakfast. I. Behavioral, cognitive, and electrophysiologic effects. Pediatrics 72:49, 1983 71. Ullmann RK: ACTeRS useful in screening learning disabled from attention deficit disordered (ADD-H) children. Psychopharmacol Bull 21:339, 1985 72. Ullmann RK, Sleator EK: Responders, nonresponders, and placebo responders among children with attention deficit disorders: Importance of a blinded placebo evaluation. Clin Pediatr 25:594, 1986 73. Ullmann RK, Sleator EK, Sprague RL: A change of mind: The Conners Abbreviated Rating Scales reconsidered. J Abnorm Child Psychol 13:553, 1985 74. Ullmann RK, Sleator EK, Sprague RL: A new rating scale for diagnosis and monitoring of ADD children. Psychopharmacol Bull 20:160, 1984 75. Varley C, Trupin E: Double-blind assessment of stimulant medication for attention deficit disorder: A model for clinical application. Am J Orthopsychiatry 53:542, 1983 76. Wender PH: Minimal Brain Dysfunction in Children. New York, John Wiley & Sons, 1971 77. Wender PH, Epstein RS, Kopin IJ: Urinary monoamine metabolites in children with minimal brain dysfunction. Am J Psychiatry 127:1411, 1971 78. Werry JS: Studies on the hyperactive child. IV. An empirical analysis of the minimal brain dysfunction syndrome. Arch Gen Psychiatry 19:9, 1968 79. Werry JS, Sprague RL: Methylphenidate in children: Effect of dosage. Aust N Z J Psychiatry 60:512, 1977 80. Winsberg B, Matinsky S, Kupietz S: Is there dose-dependent tolerance associated with chronic methylphenidate therapy in hyperactive children: Oral dose and plasma considerations. Psychopharmacol Bull 23:107, 1987 81. Winsberg BG, Kupietz SS, Sverd 1. et al: Methylphenidate oral dose plasma concentrations and behavioral response in children. Psychopharmacology 76:329, 1982
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82. Winsberg BC, Yepes LE: Antipsychotics (major tranquilizers, neuroleptics). In Werry JS (ed): Pediatric Psychopharmacology: The Use of Behavior Modifying Drugs in Children. New York, Brunner/Mazel, 1978, p 234 83. Wolraich ML: Behavior modification therapy in hyperactive children. Clin Pediatr 18:563, 1979 84. Wolraich ML: Stimulant drug therapy in hyperactive children: Research and clinical implications. Pediatrics 60:512, 1977 85. Wolraich ML, Copeland L: Disorders of behavioral development: Attention deficit disorder-hyperactivity. In Wolraich ML: The Practical Assessment and Management of Children with Disorders of Development and Learning. Chicago, Year Book Medical Publishers, 1987, p 269 86. Yu-cun A, Yu-feng W: Urinary 3-methoxy-4-hydroxyphenylglycol sulfate excretion in seventy-three school children with minimal brain dysfunction syndrome. BioI Psychiatry 19:861, 1984 87. Zametkin AJ, Rapoport JL: Neurobiology of attention deficit disorder with hyperactivity: Where have we come in 50 years? J Am Acad Child Adolesc Psychiatry 26:676, 1987 88. Zametkin AJ, Karoum F, Rapoport JL: Phenylethylamine excretion in attention deficit disorder. J Am Acad Child Adolesc Psychiatry 23:310, 1984 89. Zametkin AJ, Karoum F, Rapoport JL, et al: Treatment of hyperactive children with monoamine oxidase inhibitors: I. Clinical efficacy. Arch Cen Psychiatry 42:962, 1985 Kluge Children's Rehabilitation Center and Research Institute 2270 Ivy Road Charlottesville, VA 22901
0031-3955/89 $0.00
+ .20
Stimulant Medication Therapy in the Treatment of Children with Attention Deficit Hyperactivity Disorder
Richard D. Stevenson, MD, * and Mark L. Wolraich, MDt
Stimulant medications have been the major psychotropic agents employed in the management of childhood behavior problems for over 50 years. They have been widely used clinically and have been the focus of the most extensive research effort directed toward the use of any psychotropic medication in children. Despite this widespread clinical use and tremendous research effort, the use of stimulant medications in children has remained controversial. In the early 1970s in Omaha, Nebraska, the general public became alarmed on learning that an inordinate number of children were being medicated with methylphenidate to control their behavior. This issue was raised again in 1987 in Atlanta, Georgia. In 1988, Safer and Krager reported that from 1971 to 1987 the rate of medication treatment for hyperactive/inattentive students in Baltimore County, Maryland, doubled every 4 to 7 years 57 so that by 1987 nearly 6 per cent of all public elementary school students were under treatment. Why the concerns, and are stimulants being prescribed appropriately? The pediatric practitioner frequently is called on to prescribe stimulants to aid in the management of children with attention deficit hyperactivity disorder (ADHD). In light of the continued controversy, how is the practitioner to proceed? The present article will review what is known about the pharmacodynamics of stimulants, as well as their pharmacokinetics and side effects. It will focus on the three most commonly prescribed stimulants: methylphenidate (Ritalin), dextroamphetamine sulfate (Dexedrine), and pemoline (Cylert). The intent of this review is to summarize current knowledge regarding stimulant medications and their use to aid the practitioner in making important management decisions. *Assistant Professor, Department of Pediatrics, Kluge Children's Rehabilitation Center and Research Institute, University of Virginia, Charlottesville, Virginia t Professor of Pediatrics, Department of Pediatrics, Division of Developmental Disabilities, The University of Iowa, Iowa City, Iowa
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Ever since 1937, when Bradley9 first reported the beneficial effects of Benzedrine on the behavior and school performance of 14 out of 30 children with behavior problems, stimulant medications have been the major psychotropic agents employed in the management of children's behavior. Initially used in children with various behavior disorders, it was not until after the hyperkinetic impulse syndrome was identified by Laufer et al. in 195740 that hyperactivity became the specific focus of stimulant medication use. Laufer identified the positive effects of stimulants as being most beneficial when used in children with the constellation of symptoms that include hyperactivity, short attention span, impulsivity, low frustration tolerance, poor school work, visual motor problems, writing and reading reversals, and poor handwriting. Laufer's report and the synthesis of methylphenidate in 1954 provided the initiative for what was to become the most extensive research effort into, and most extensive clinical use of, a psychotropic medication in children. A major issue in the use of stimulant medications has revolved around difficulties with the conceptualization of hyperactivity. Prior to Laufer's report, Strauss and Lehtinen68 identified the constellation of hyperactivity, disinhibition, and distractibility as being the result of brain damage. However, because it frequently was difficult to identify specific central nervous system injury, Clements 14 in 1966 popularized the concept of minimal brain dysfunction in children, manifested by hyperactivity, short attention span, impulsivity, and disinhibition; usually associated with specific learning and perceptual deficits; and identified on physical examination by developmentaily based "soft neurologic" signs. The categorization of these children as having neurologic deficits was fraught with problems because no specific neurologic abnormalities were identified consistently in this population. Therefore, in 1980, the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders (DSM-III)l redesignated the syndrome as "attention deficit disorder with or without hyperactivity." This recharacterization took the focus off the neurologic dysfunction and emphasized behavior as a basis for the diagnosis. It also changed the emphasis from hyperactivity to attention deficits and actually suggested that it is possible to find attentional problems in children without the presence of hyperactive behavior. Most recently in the revision to the DSM-III criteria (DSM-IIIR),2 hyperactivity was reintroduced as an essential component, and the syndrome has been renamed attention deficit hyperactivity disorder (ADHD). With all these changes in the categorization of the syndrome, it is not surprising that there is confusion about which children meet the diagnostic criteria and are therefore appropriate candidates for treatment with stimulant medications. . Adding to the difficulties is the fact that the symptoms of ADHD most frequently occur when the children are placed in situations that require them to focus their attention without much one-on-one contact. This means that many times the problems are most evident at school, and diagnosis depends on reports from the teacher rather than any objective tests or direct observation by the physician. Although several objective tests, such
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as the continuous performance test (CPT)47 and the paired associate learning (PAL) test,67 have been suggested as methods of assessment to determine treatment efficacy, it is unclear whether changes in these tests truly reflect changes in school behavior. 67 Additionally, Rapoport et al. 51 also were able to demonstrate in children what was already known in adults,39 that at least with dextroamphetamine the beneficial effects of stimulants observed in children with attention deficit disorder also are observed in normal children. Thus, confusion and difficulties with the diagnosis of ADHD, the importance of the child's environmental context, and the nonspecificity of the effects of stimulant medication create the potential for the overuse of the medications, and fuel the continued controversy.
CLINICAL PHARMACOLOGY A tremendous body of literature exists addressing the question of whether stimulant therapy is effective in the treatment of ADHD. Several comprehensive reviews of this literature have been published. 5, 33, 49, 84 The conclusions of all these reviews are the same: 1) for most children, the treatment of ADHD with stimulant medications is effective, and 2) dextroamphetamine, methylphenidate, and pemoline are equally effective in the treatment of ADHD, In general, the literature reflects consistent, positive drug effects on behavior, activity level, and attention. Variable and modest effects on academic performance and measures of cognition are reported. The authors of the more recent review articles5, 33 have used meta-analysis that has enabled them to examine the combined results of multiple controlled drug studies. The results obtained using this technique support the conclusions of the earlier reviews. The most commonly used measures of efficacy in stimulant drug trials have been changes in behavior, and this has been most commonly documented by employing behavior rating scales. Most behavior rating scales are designed to assess activity level, distractibility, impulsivity, and attention span. Behavior rating scales have been developed for teacher, as well as parent, use, and these scales have consistently been drug sensitive. 5, 33, 84 The most commonly used teacher rating scale has been the Conners Abbreviated Teacher Rating Scale (ATRS), 17 although recently some concerns have been raised about how specific it is for children with attention deficit disorder,73 The attention deficit disorder with hyperactivity (ADDH) Comprehensive Teacher Rating Scale (ACTeRS)14 is also sensitive to drug-placebo differences 71 and incorporates diagnostic criteria from DSMIII but has been used much less extensively. Useful parent questionnaires include the Conners Parent Rating Scale,17 the Pediatric Behavior Scale,42 and the Werry-Weiss-Peters Scale. 78 Other more objective measures of activity level and attention span have also been consistently drug sensitive.5, 33, 84 Measures of academic performance and intelligence have shown variable effects. Earlier reviews of the literature5, 7, 25, 84 reveal little or no drug effects, but meta-analysis 33 , 49 reveals modest, but definite, drug effects on academic performance and on intellectual measures. Recent reports have
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noted positive effects on language processing,4 information processing, 18 memory,22 and learning efficiency. 21 It remains unclear whether these specific effects are independent or mediated through the stimulant effects on attention. Further research in this area is needed. Finally, Schachar58 reported positive effects on family function and relationships in the families of drug responders, but not in the families of nonresponders. BarkleyB had previously reported more positive parental response with more frequent rewards to child-initiated behavior in methylphenidate-treated children. Schachar suggests that families of children who respond to stimulants may be more amenable to other forms of intervention that could affect long-term outcome. Studies that have used stimulants in combination with behavior modification suggest some additive effects. 83 Despite the overwhelming evidence for the short-term efficacy of stimulants in children with ADHD, long-term studies have not revealed consistent improvement. In part, this may be due to logistical problems associated with obtaining rigorous long-term study data,23 but the consistent lack of long-term drug effects in the literature argues against this being due solely to the "vicissitudes of follow-up studies. "23 In their reviews, Wolraich84 and Barkley5 both report little evidence for long-term efficacy. Hechtman,31 in a recent review of adolescent outcome of hyperactive children treated with stimulants, reaches the same conclusion but adds that some studies suggest that treatments combining stimulants with other multimodal interventions may result in more positive outcomes. Thus, although the literature does not document any long-term efficacy of stimulant medication use, it does provide some support for the suggestion that stimulants may help improve long-term outcome when used in the context of multimodal therapeutic strategies. Although stimulant medications are an effective treatment for most children with ADHD, as many as 25 per cent of children5 treated with stimulants remain unchanged or appear to worsen. 5. 45 It is not clear which children respond to stimulants and why some do not respond. Attempts to predict response to stimulants using history, physical examination, and other characteristics have been unsuccessful. 6. 45 This fact, together with the previously discussed difficulties of diagnosis, creates something of a dilemma for the clinician. First of all, diagnosis and response to treatment must rely largely on the observations of parents and teachers who are not necessarily impartial observers. Thus, the practitioner is frequently in the position of having to make diagnostic and therapeutic decisions based on secondhand information from parents who, in turn, have been told by teachers about their child's behavior in school. Perhaps more importantly, however, once the practitioners make the diagnosis of ADHD, they must then decide how treatment should proceed and who should receive stimulant medications. Several investigators have recently proposed a pragmatic approach to the medical treatment of children with ADHD'45' 72. 75 using individual single-blind placebo-controlled crossover trials with medication to more objectively assess treatment efficacy. These blinded, placebo-controlled drug trials are feasible in the office setting. The most important prerequisites
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are a pharmacist willing to make up a supply of gelatin capsules, some containing active drug and some containing placebo, and teachers who are willing to participate. Efficacy of medication is determined by teachers using one of the standardized teacher rating scales, such as the ADD-H Comprehensive Teacher Rating Scale (ACTeRS).74 The teachers, parents, and the child are blinded as to whether the child is taking drug or placebo. The teacher rating scale is performed on a regular basis, usually weekly. McBride 45 suggests using a fixed dose of methylphenidate (0.3 mg per kg per dose given b. i. d.) for 2 weeks and placebo for 2 weeks in random order. Because the rate of absorption and response to medication is variable, as is discussed in the pharmacokinetics section, it may be better to begin with an open clinical trial of methylphenidate first, to adjust the dose to optimize any apparent effects and to identifY clinical drug responders. Nonresponders would need no further trial, but apparent responders could then proceed to a drug versus placebo trial. It is important to note that because this will only entail one patient at a time, a single-subject design 34 with multiple changeovers is the most appropriate. One reasonable possibility is a 6-week trial with the child on the active drug during weeks one, four, and six and on placebo during weeks two, three, and five so as not to create a repetitive pattern. This would minimize the possibility that apparent benefit may be due to chance or extraneous causes. Because the blinded trial begins with the same dose determined in the unblinded trial, any artifactual changes related to the assessment process itself can be detected in that first week. Even though developing the ability to conduct single-blind drugplacebo trials initially requires time on the clinician's part, as noted by Deuel,20 the use of such trials "leapfrogs many knotty unresolved conceptual issues and lands directly on the key question": Does stimulant medication benefit this child? This method helps to identifY the 18 to 30 per cent49 , 72 of placebo responders, it provides the parents with convincing evidence about the efficacy of the treatment, and it offers a followup method to record continued efficacy and thus guide dosage changes or discontinuation of treatment. This provides a better alternative than discontinuing the use of a safe and effective medication because of negative publicity stemming from overextensive use. Some studies69 , 80 have demonstrated that tolerance to the clinical effects of a stimulant may develop with chronic treatment. Regular followup, therefore, must include periodic determinations of efficacy. In addition to tolerance, changes in a child's classroom situation or improvement in a child's ability to attend because of maturation also may result in a child no longer requiring medication. Periodic trials off medication or reassessments with single-blind placebo trials can facilitate monitoring. In addition, weekend and vacation medication holidays may decrease the chance for tolerance to develop. PHARMACODYNAMICS The therapeutic effects of stimulants on the symptoms of ADHD are well documented, and stimulants have become the standard against which
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the efficacy of other medications and other forms of therapy, 85 such as the Feingold diet and behavior modification, are measured. To understand the possible mechanisms of action-the pharmacodynamics--of these medications, it is necessary to review what is known about the neurochemistry of ADHD. The earliest evidence suggesting a neurochemical abnormality as the basis for ADHD was derived from the symptoms of children with von Economo's encephalitis during the early part of this century. In contrast to adults, who developed Parkinson's disease following acute encephalitis, children developed characteristic attentional and motor problems. In light of the well-known relationship between dopamine deficiency and parkinsonism, Wender76 proposed that the behavioral problems exhibited by children also might be neurochemically based and related to dopamine deficiency. Much of the current understanding of the neurochemistry of ADHD stems from neuropharmacologic, neurochemical, and neuroanatomic studies in animals, coupled with clinical pharmacologic research in humans. Methylphenidate, dextroamphetamine, and pemoline all increase the release and inhibit the reuptake of dopamine and norepinephrine 24, 37 from neurons in the central nervous system. The catecholamines, norepinephrine and dopamine, serving as neurotransmitters, are probably involved at some level in the pathogenesis and treatment effects of ADHD. All drugs that have some efficacy in the treatment of ADHD also have some effect on catecholamine metabolism. This has led to much research examining the potential role each neurotransmitter may play in the pathophysiology of ADHD. Dopamine Much of the interest and support for the role of dopamine in the pathophysiology of ADHD has come from the animal model of Shaywitz.61 Following central dopamine depletion in newborn rats, the animals exhibited significantly more motor activity and learning deficits. These deficits could be reversed by stimulant medications. In addition, clinical trials in humans with specific dopamine agonists 38 as well as antagonists such as haloperidol 82 have proven modestly effective in the treatment of children with ADHD. However, a simple dopamine effect does not fully explain ADHD because the therapeutic effects of stimulants are far greater than those of the specific dopamine agonists and antagonists. 89 Additionally, many biochemical studies comparing dopamine and its metabolites in urine, blood, and cerebrospinal fluid of children with ADHD and normal controls have been completed, and most studies have not demonstrated Significant differences. 89 Interestingly, however, the therapeutic effects of dopamine antagonists seem to be additive with methylphenidate. 26 Thus, dopamine does appear to playa part in the pathophysiology of ADHD, but a simple dopamine effect does not fully explain ADHD nor the therapeutic effects of stimulants. Norepinephrine A specific noradrenergic effect in ADHD was first suggested by Kornetskf6 who posed the hypothesis that perhaps hyperactive children
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are "overaroused" and that amphetamines accomplish their therapeutic effect by competitively inhibiting postsynaptic noradrenergic neurotransmission. This hypothesis was not supported by subsequent research l2 ; however, there is evidence for a noradrenergic effect. Shekim,63 and Yucun and Yu-feng,86 have demonstrated decreased metabolites of norepinephrine in urine of patients with ADHD. In contrast, Khan and Dekirmenjian35 demonstrated increased urinary norepinephrine metabolites in patients with ADHD. These reports all support a role for norepinephrine in ADHD, but the apparently contradictory findings are perplexing. This issue has been addressed by Raskin,53 who suggests that perhaps ADHD is associated with a general failure of noradrenergic systems to function within certain limits rather than simply "too much or too little" norepinephrine. Interestingly, studies of norepinephrine metabolites in ADHD children who are taking stimulants report decreases in the metabolites from a baseline level. 10, 62. 63, 87 In addition, clinical trials using drugs that affect noradrenergic, but not dopaminergic, pathways (e.g., tricyclic antidepressants, clonidine) have demonstrated moderate clinical improvement. 89 Evidence against a simple noradrenergic effect includes early biochemical studies that show no difference between patients with ADHD and normal controls. 52, 77 The strongest evidence, however, is that the therapeutic effects of the more specific noradrenergic agents are not as great as the stimulants. Thus, norepinephrine appears to play only a partial role in the pathophysiology of ADHD. Serotonin Serotonin, another important neurotransmitter in the central nervous system, is probably not involved in the basic pathophysiology of ADHD because drugs that significantly influence serotonin metabolism have minimal efficacy on ADHD symptoms. 53, 89 Combined Catecholamines Although neither the dopamine nor the noradrenergic effects are sufficient to explain the physiology and treatment of ADHD, both neurotransmitter pathways appear to be important. In addition, another catecholamine, phenylethylamine, has been postulated to playa role in ADHD87 and in mental illness. 54 Further evidence in support of a combined catecholamine effect includes recent clinical trials with monoamine oxidase inhibiters. These agents affect norepinephrine, serotonin, phenylethylamine, and dopamine metabolism and are almost as effective as dextroamphetamine in controlling classroom behavior in children with ADHD. 88 The strongest support for this hypothesis is the superior clinical efficacy of the stimulants and their known effects on both norepinephrine and dopamine. Although all of the stimulants affect both norepinephrine and dopamine metabolism, it is becoming clear that they do so in different ways. For example, methylphenidate acts by facilitating the release of dopamine from a reserpine-sensitive storage pool,48 but dextroamphetamine facilitates the release of newly synthesized dopamine from a reserpine-resistant pool. 13 The results of these and other studies imply that although the stimulants are essentially equivalent in efficacy, they may exert their therapeutic
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effects via different mechanisms. This suggests that a child with ADHD who does not respond to one stimulant may respond to another, and thus it is possible that selective response to stimulants may help to distinguish subtypes of ADHD in what now is a very heterogeneous group of patients. This is an area in need of further research. To summarize, the neurochemical effects of stimulant medication appear to be related to the norepinephrine, dopamine, catecholamine axis. However, in spite of many years of active research and much progress in the understanding of the neurochemistry and pathophysiology of ADHD, much remains to be learned, and the precise mechanism of action of stimulant medications in the treatment of symptoms of ADHD is not yet fully understood. Currently, the most tenable hypothesis to explain how stimulants exert their clinical effects is the combined catecholamine hypothesis. PHARMACOKINETICS
Methylphenidate, dextroamphetamine, and pemoline are rapidly absorbed following oral administration. Methylphenidate serum concentrations usually peak within 1 to 2 hours; the drug's elimination half-life ranges from 2 to 4 hours after an oral dose. 81 Dextroamphetamine is a little slower in its absorption, peaking in 2 to 3 hours and displaying a half-life of 6.8 hours. 11 Pemoline is the slowest to be absorbed, with peak concentrations occurring at approximately 2.4 hours after an oral dose and an elimination half-life of about 7 to 7V2 hours. 15 All of these drugs are poorly bound to plasma proteins. Methylphenidate is metabolized primarily by de-esterification to ritalinic acid, which accounts for 75 to 91 per cent of the total methylphenidate identified in the urine. 81 A great deal of interindividual variability exists for all three drugs. Much variability also is found between plasma levels and behavioral responses in each child. 81 Therefore, it is important clinically (as stated earlier) to titrate the dose to determine the optimal response in any patient. Not only is there a great deal of interindividual variation, but there is also variation depending on what effect is monitored. For methylphenidate, positive effects on behavior measured with teacher rating scales have been found to continue, improving with increasing doses up to as high as 1.0 mg per kg, while the effects on performance on simple cognitive tasks were found to peak at a dose of 0.6 mg per kg. 66. 79 Both methylphenidate and dextroamphetamine also are produced in delayed or sustained release forms. These forms and pemoline were developed so that it would be possible to administer the medication without requiring the child to receive a dose at school, which for some children is an embarrassment or may be difficult. The methylphenidate sustainedrelease form is slower in onset and has a different time course than the standard form. It has also been found to be slightly less effective on some measures of social behavior. 50 Given these factors and the increased cost of the sustained form, it appears that there would need to be a compelling reason for not administering a dose at school before one should switch from
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the standard tablet, now available in generic form at considerably lower cost. The administration instructions for methylphenidate recommend that it be given 30 to 45 minutes before a meal, so that it is administered on an empty stomach; however, a study by Swanson et al. 70 found no difference in the behavioral, cognitive, or electrophysiologic effects of MPH whether it was given with or 30 minutes before breakfast. In sum, stimulant medications are fast-acting medications not readily bound to plasma protein. The pharmacokinetics exhibit a good deal of individual variation necessitating individual titration of the dose for each child, and the sustained release forms do not appear to provide any major advantage over the standard forms.
SIDE EFFECTS The most commonly reported side effects of stimulant medications are insomnia, anorexia, stomach pains, and weight loss. These recently have been reviewed29 and evidence indicates that these effects are transient and diminish as treatment continues in most patients. Pemoline has been found to cause liver dysfunction in some children, so liver function needs to be monitored during treatment when pemoline is used. Dextroamphetamine and methylphenidate have significant sympathicomimetic effects, so blood pressure should be monitored at regular intervals in all patients, but especially in those with underlying hypertension. Clinicians have long been taught that methylphenidate lowers seizure threshold; however, this caveat has recently been refuted. 45, 46 The effects of stimulant medications on growth and the relationship between stimulant use and motor tics have been of major concern and deserve further mention. Growth Effects In 1972, Safer and colleagues56 first suggested a growth suppressant effect of all doses of dextroamphetamine and high doses of methylphenidate. Subsequent studies revealed conflicting results. In 1979, the Pediatric Subcommittee of the FDA Psychopharmacologic Drugs Advisory Committee, working in conjunction with outside experts, reviewed and synthesized all relevant literature and published their results. 55 They concluded that, although evidence clearly indicates a temporary decrease in the rate of weight gain and suggests a temporary decrease in linear growth, there was no evidence that this significantly affected adult stature and weight. The temporary effects seemed related to drug dosage and the presence or absence of drug holidays, but no conclusions could be reached about the relative effects of each of the stimulants used. 30, 55 Research has not demonstrated any alterations in the hypothalamic, pituitary, or somatomedin axis associated with methylphenidate use. 59 A recent study demonstrated no growth suppression with doses of methylphenidate up to 0.8 mg per kg per day over a 2-year period. 32 A larger study found a statistically significant but small growth suppressant effect in prepubertal children in which methylphenidate dosage accounted for only 2 per cent of variance in final
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height. 44 These authors suggest careful monitoring of growth and dosage reduction in individual cases in which growth suppression occurs. A recent statement by the American Academy of Pediatrics Committee on Drugs and Children with Disabilities 16 implies that the' risk of growth suppression with stimulant use is no longer felt to be significant. In conclusion, although short-term effects of stimulants on weight gain and growth have been reported for all doses of dextroamphetamine and high doses of methylphenidate, other studies have demonstrated contradictory results. There is no evidence that stimulants have any effect on ultimate adult stature. Use of lower doses of methylphenidate (3 mg per kg) and drug holidays on weekends and vacation periods have been suggested to minimize the effects on growth. This is a reasonable practice for most children; however, use of stimulants on weekends and holidays for selected patients is not contraindicated and can be considered safely. Tics In 1974, Golden 27 reported the case of a 9-year-old boy who had a sudden onset of Tourette's syndrome following the use of methylphenidate for the treatment of ADHD. Since then methylphenidate, dextroamphetamine, and pemoline have all been reported to either precipitate or exacerbate tic disorders.3. 43, 65 The relationship between stimulant medications and tics recently has been reviewed.28 Although some dissenting views have been expressed, 60 the literature supports the observation that some children may experience worsening of preexisting tics or the appearance of new motor tics during or sometime after treatment with stimulants. Overall, the risk of a child with ADHD developing transient motor tics after treatment with stimulants has been reported to be 1. 3 per cent. 19 In a child with a family history of TOl1rette's syndrome or other tic syndromes, however, the risk may be substantially higher. Because Qf the reported relationship between stimulants and motor tics, practical guidelines for clinical use of stimulant medications in children with ADHD have been published. 28, 43 Generally, in patients with both ADHD and tics, the use of stimulant medications should be avoided if at all possible. These childr~n pose a therapeutic dilemma and management can be quite challenging. If stimulants are used in these patients, their tics must be monitored carefully, and the medication discontinued if the tics worsen. Some investigators have recommended the use of clonidine in children with tics and' ADHD. 41,64 Children with ADHD who do not have tics need to be monitored carefully so that the medication can be discontinued if tics develop. .
SUMMARY Despite the tremendous research advances that have increased our knowledge regarding the pharmacodynamics, clinical pharmacology, pharmacokinetics, and adverse effects of stimulant medications in the treatment of children with ADHD, our knowledge is yet incomplete. Perhaps the most central unresolved issue concerns our underst;mding of the pathogen-
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esis, pathophysiology, and diagnosis of AOHO. This review has touched briefly on the controversy and confusion surrounding this issue. Although our understanding of the use of stimulant medications in this disorder is similarly incomplete, a review of the literature does allow certain conclusions to be made that are helpful to the practitioner. 1. Stimulant medications are an effective treatment modality for most children with ADHD. Short-term efficacy is well documented, and long-term outcome may be improved when stimulants are used with other therapeutic strategies. Stimulants in and of themselves are not a panacea. 2. It is impossible to predict which children will have a favorable response to stimulant medications and which children may have a placebo response. The use of individual single-blind medication trials is a practical solution to this problem and should be considered for all children who are candidates for stimulant therapy as a means for preventing overuse or inappropriate use of these medications. 3. The precise mechanism of action of stimulants is not yet completely understood, but stimulants appear to exert their therapeutic effects through their influence on multiple neurotransmitters in the catecholamine, dopamine, norepinephrine axis in the central nervous system. 4. The three major stimulants-methylphenidate, dextroamphetamine, and pemoline-appear to be equally efficacious, although methylphenidate has emerged as the most commonly used and most studied drug. Because of its potential for causing liver toxicity, pemoline has remained a second-line medication. 5. The three major stimulants appear to have somewhat different mechanisms of action so that failure of a patient to respond to one medication does not mean that he or she will not respond to another. 6. The recommended starting doses for the stimulants are 0.3 mg per kg of methylphenidate, 0.15 mg per kg of dextroamphetamine, and 37.5 mg of pemoline. There is a great deal of individual variability in dose response, so doses must be titrated for optimal effects in each child. Sustained release preparations are much more expensive than regular preparations and may be less effective. 7. There is no evidence that stimulants have any effect on ultimate adult height. 8. Although relatively uncommon, motor tics have been observed in children on stimulants, and all children on stimulants need to be carefully monitored for the development of tics.
Primary care practitioners have the unique opportunity to educate and update children, parents, and teachers about the diagnosis and management of children with attentional problems. Although they work in concert with other professionals in managing children with AOHO, physicians are responsible for providing medications. They must guard against becoming "surrogate prescribers" (0-1) and strive to become informed managers of treatment modalities that employ stimulant medications, so that they may not only optimally serve their patients but also educate the public. Continued research and education still are needed if we are to resolve the controversy that has long surrounded the use of stimulants in children with AOHO.
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2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental DisordersRevised (DSM-III-R). Washington, DC, American Psychiatric Association, 1987 3. Bachman DS: Pemoline-induced Tourette's disorder: A case report. Am J Psychiatry 138:1116, 1981 4. Ballinger CT, Varley CK, Nolen PA: Effects of methylphenidate on reading in children with attention deficit disorder. Am J Psychiatry 141:1590, 1984 5. Barkley RA: A review of stimulant drug research with hyperactive children. J Child Pschol Psychiat 18:137, 1977 6. Barkley RA: Predicting the response of hyperkinetic children to stimulant drugs: A review. J Abnorm Child Psychol 4:327, 1974 7. Barkley RA, Cunningham CEo Do stimulant drugs improve the academic performance of hyperkinetic children? A review of outcome research. Clin Pediatr 17:85, 1978 8. Barkley RA, Cunningham CEo The effects of methylphenidate on the mother-child interactions of hyperactive children. Arch Gen Psychiatry 36:201, 1979 9. Bradley C: The behavior of children receiving Benzedrine. Am J Psychiatry 94:577, 1937 10. Brown GL, Ebert MH, Hunt RD, et al: Urinary 3-methoxy-4-hydroxyphenylglycol and homovanillic acid response to d-amphetamine in hyperactive children. Bioi Psychiatry 16:779, 1981 11. Brown GL, Hunt RD, Ebert MH, et al: Plasma levels of D-amphetamine in hyperactive children. Psychopharmacology 62:133, 1979 12. Callaway E, Holliday R, Naylor H: Hyperactive children's event-related potentials fail to support underarousal and maturational-lag theories. Arch Gen Psychiatry 11:1243, 1983 13. Clemens JA, Fuller RW: Differences in the effects of amphetamine and methylphenidate on brain dopamine turnover and serum prolactin concentration in reserpine-treated rats. Life Sciences 24:2077, 1979 14. Clements SD: Minimal brain dysfunction in children: Terminology and identification. Washington, DC, US Department of Health, Education, and Welfare, 1966 15. Collier CP, Soldin SJ, Swanson JM, et al: Pemoline pharmacokinetics and long term therapy in children with attention deficit disorder and hyperactivity. Clin Pharmacokinet 10:269, 1985 16. Committee on Children with Disabilities, Committee on Drugs: Medication for children with an attention deficit disorder. Pediatrics 80:758, 1987 17. Conners CK: Rating scales for use in drug studies with children. Psychopharmacol Bull (Special Issue):24, 1973 18. Coons HW, Klorman R, Borgstedt AD: Effects of methylphenidate on adolescents with a childhood history of attention deficit disorder: II. Information processing. J Am Acad Child Adolesc Psychiatry 26:368, 1987 19. Denckla MB, Bemporad JR, MacKay MC: Tics following methylphenidate administration. JAMA 235:1349, 1976 20. Deuel RK: Treatment of attention problems with stimulant medication. J Pediatr 113:68, 1988 21. Douglas VI, Barr RG, O'Neill, et al: Short-term effects of methylphenidate on the cognitive learning and academic performance of children with attention deficit disorder in the laboratory and classroom. J Child Psychol Psychiatry 27:191, 1986 22. Evans RW, Gualtieri CT, Amara 1: Methylphenidate and memory: Dissociated effects in hyperactive children. Psychopharmacology 90:211, 1986 23. Firestone P, Crowe D, Goodman JT, et al: Vicissitudes of follow-up studies: Differential effects of parent training and stimulant medication with hyperactives. Am J Orthopsychiatry 56:184, 1986 24. Fuller RW, Perry KW, Bymaster FP, et al: Comparative effects of pemoline, amfoelic acid, and amphetamine on dopamine uptake and release in vitro on brain 3, 4dihydroxyphenylacetic acid concentration on spiperone-treated rats. J Pharm Pharmacol 30:197, 1978 25. Gadow KD: Effects of stimulant drugs on academic performance in hyperactive and learning disabled children. J Learn Disabil16:127, 1983 26. Gittelman R, Klein D, Kartz S, et al: Comparative effects of methylphenidate and thioridazine in hyperkinetic children. Arch Gen Psychiatry 33:1217, 1976 27. Golden GS: Gilles de la Tourette's syndrome following methylphenidate administration. Dev Med Child Neurol 16:76, 1974
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28. Golden, GS: The relationship between stimulant medication and tics. Pediatr Ann 17:405, 1988 29. Golinko, BE: Side effects of dextroamphetamine and methylphenidate in hyperactive children: A brief review. Prog Neuropsychopharmacol Bioi Psychiatry 8:1, 1984 30. Greenhill LL, Puig-Antich J, Halpern F: Growth disturbances in hyperkinetic children. Pediatrics 66:152, 1980 31. Hechtman L: Adolescent outcome of hyperactive children treated with stimulants in childhood: A review. Psychopharmacol Bull 21:178, 1985 32. Kalachnik JE, Sprague RL, Sleator EK, et al: Effect of methylphenidate hydrochloride on stature of hyperactive children. Dev Med Child Neurol 24:586, 1982 33. Kavale K: The efficacy of stimulant drug treatment for hyperactivity: A meta-analysis. J Learn Dis 15:280, 1982 34. Kazdin AE: Single-Case Research Designs: Methods for Clinical and Applied Settings. New York, Oxford University Press, 1982 35. Khan AU, DeKirmenjian H: Urinary excretion of catecholamine metabolites in hyperkinetic child syndrome. Am J Psychiatry 138:108, 1981 36. Kornetsky C: Psychoactive drugs in the immature organism. Psychopharmacologia 17:105, 1970 37. Kuczenski R: Biochemical actions of amphetamines and other stimulants. In Crease I (ed): Stimulants: Neurochemical, Behavior and Clinical Perspectives. New York, Raven Press, 1983, p 31 38. Langer DH, Rapoport JL, Brown GL, et al: Behavioral effects of carbidopallevodopa in hyperactive boys. JAm Acad Child Adolesc Psychiatry 21:10, 1982 39. Laties VG, Weiss B: Performance enhancement by the amphetamines: A new appraisal. In Brill H, Cole JO, Deniker P, et al (eds): Neuropsychopharmacology. Amsterdam, Excerpta Medica Foundation, 1967, p 800 40. Laufer MW, Denhoff E: Hyperkinetic behavior syndrome in children. J Pediatr 50:463, 1957 41. Leckman JF, Detlor J, Harcherik DF, et al: Short- and long-term treatment of Tourette's syndrome with clonidine: A clinical perspective. Neurology 35:343, 1985 42. Lindgren SD, Koeppl GK: Assessing child behavior problems in a medical setting: Development of the Pediatric Behavior Scale. In Prinz RJ (ed): Advances in Behavioral Assessment of Children and Families. Greenwich, CT, JAI Press, 1987, p 57 43. Lowe TL, Cohen DJ, Detlor J, et al: Stimulant medications precipitate Tourette's syndrome. JAMA 247:1729, 1982 44. Mattes JA, Gittelman R: Growth of hyperactive children on maintenance regimen of methylphenidate. Arch Gen Psychiatry 40:317, 1983 45. McBride MC: An individual double-blind crossover trial for assessing methylphenidate response in children with attention deficit disorder. J Pediatr 113:137, 1988 46. McBride MC, Wang DA, Torres CF: Methylphenidate in therapeutic doses does not lower seizure threshold. Ann Neurol 20:248, 1986 47. Mirsky AF, Rosvold HE: Behavioral and physiological studies in impaired attention. In Votava Z, Horvath M, Vinar 0 (eds): Psychopharmacological Methods: Proceedings of a Symposium on the Effects of Psychotropic Drugs on Higher Nervous Activity. Oxford, England, Pergamon Press, 1963, p 302 48. Moore KE, Chiueh CC, Zeldes G: Release of neurotransmitters from the brain in vivo by amphetamine, methylphenidate, and cocaine. In Ellinwood EH, Kilbey MM (eds): Cocaine and Other Stimulants. New York, Plenum Press, 1977, p 143 49. Ottenbacher KJ, Cooper HM: Drug treatment of hyperactivity in children. Dev Med Child Neurol 25:358, 1983 50. Pelham WE, Sturges J, Hoza J, et al: Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder. Pediatrics 80:491, 1987 51. Rapoport JL, Buchsbaum MS, Weingartner H, et al: Dextroamphetamine: Its cognitive and behavioral effects in normal and hyperactive boys and normal men. Arch Gen Psychiatry 37:933, 1980 52. Rapoport JL, Mikkelsen EJ, Ebert MH, et al: Urinary catecholamine and amphetamine excretion in hyperactive and normal boys. J Nerv Ment Dis 66:731, 1978 53. Raskin LA, Shaywitz SE, Shaywitz BA, et al: Neurochemical correlates of attention deficit disorder. Pediatr Clin North Am 31:387, 1984
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54. Reynolds GP: Phenylethylamine--a role in mental illness? TINS, October 1-3, 1979 55. Roche AF, Lipman RS, Overall JE, et al: The effects of stimulant medication on the growth of hyperkinetic children. Pediatrics 63:847, 1979 56. Safer D1. Allen RP: Factors influencing the suppressant effects of two stimulant drugs on the growth of hyperactive children. Pediatrics 51:660, 1973 57. Safer DJ, Krager JM: A survey of medication treatment for hyperactive/inattentive students. JAMA 260:2256, 1988 58. Schachar R, Taylor E, Wieselberg M, et al: Changes in family function and relationships in children who respond to methylphenidate. J Am Acad Child Adolesc Psychiatry 26:728, 1987 59. Schultz FR, Hayford JT, Wolraich ML, et al: Methylphenidate treatment of hyperactive children: Effects on the hypothalamic-pituitary-somatomedin axis. Pediatrics 70:987, 1982 60. Shapiro AK, Shapiro E: Do stimulants provoke, cause, or exacerbate tics and Tourette syndrome? Compr Psychiatry 22:265, 1981 61. Shaywitz BA, Yager RD, Klopper JH: Selective brain dopamine depletion in developing rats: An experimental model of minimal brain dysfunction. Science 191:305, 1976 62. Shekim WO, Dekirmenjian H, Chapel JL: Urinary catecholamine metabolites in hyperkinetic boys treated with D-amphetamine. Am J Psychiatry 134:1276, 1977 63. Shekim WO, Dekirmenjian H, Chapel JL: Urinary MHPG excretion in minimal brain dysfunction and its modification by D-amphetamine. Am J Psychiatry 136:667, 1979 64. Singer HS, Gammon K, Quaskey S: Haloperidol, fluphenagine and clonidine in Tourette syndrome: Controversies in treatment. Pediatr Neurosci 12:71, 1985-1986 65. Sleator EK: Deleterious effects of drugs used for hyperactivity on patients with Gilles de la Tourette syndrome. Clin Pediatr 19:453, 1980 66. Sleator EK, Sprague RL: Dose effects of stimulants in hyperkinetic children. Psychopharmacol Bull 10:29, 1974 67. Solanto MV: Neuropharmacological basis of stimulant drug action in attention deficit disorder with hyperactivity: A review and synthesis. Psychol Bull 95:387, 1984 68. Strauss AA, Lehtinen LE: Psychopathology and Education of the Brain-Injured Child. New York, Grune & Stratton, 1947, p 84 69. Swanson JM, Lerner M, Cantwell D: Blood levels and tolerance to stimulants in ADDH children. Clin Neuropharmacol (Suppl) 9:523, 1986 70. Swanson JM, Sandman CA, Deutsch C, et al: Methylphenidate hydrocloride given with or before breakfast. I. Behavioral, cognitive, and electrophysiologic effects. Pediatrics 72:49, 1983 71. Ullmann RK: ACTeRS useful in screening learning disabled from attention deficit disordered (ADD-H) children. Psychopharmacol Bull 21:339, 1985 72. Ullmann RK, Sleator EK: Responders, nonresponders, and placebo responders among children with attention deficit disorders: Importance of a blinded placebo evaluation. Clin Pediatr 25:594, 1986 73. Ullmann RK, Sleator EK, Sprague RL: A change of mind: The Conners Abbreviated Rating Scales reconsidered. J Abnorm Child Psychol 13:553, 1985 74. Ullmann RK, Sleator EK, Sprague RL: A new rating scale for diagnosis and monitoring of ADD children. Psychopharmacol Bull 20:160, 1984 75. Varley C, Trupin E: Double-blind assessment of stimulant medication for attention deficit disorder: A model for clinical application. Am J Orthopsychiatry 53:542, 1983 76. Wender PH: Minimal Brain Dysfunction in Children. New York, John Wiley & Sons, 1971 77. Wender PH, Epstein RS, Kopin IJ: Urinary monoamine metabolites in children with minimal brain dysfunction. Am J Psychiatry 127:1411, 1971 78. Werry JS: Studies on the hyperactive child. IV. An empirical analysis of the minimal brain dysfunction syndrome. Arch Gen Psychiatry 19:9, 1968 79. Werry JS, Sprague RL: Methylphenidate in children: Effect of dosage. Aust N Z J Psychiatry 60:512, 1977 80. Winsberg B, Matinsky S, Kupietz S: Is there dose-dependent tolerance associated with chronic methylphenidate therapy in hyperactive children: Oral dose and plasma considerations. Psychopharmacol Bull 23:107, 1987 81. Winsberg BG, Kupietz SS, Sverd 1. et al: Methylphenidate oral dose plasma concentrations and behavioral response in children. Psychopharmacology 76:329, 1982
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82. Winsberg BC, Yepes LE: Antipsychotics (major tranquilizers, neuroleptics). In Werry JS (ed): Pediatric Psychopharmacology: The Use of Behavior Modifying Drugs in Children. New York, Brunner/Mazel, 1978, p 234 83. Wolraich ML: Behavior modification therapy in hyperactive children. Clin Pediatr 18:563, 1979 84. Wolraich ML: Stimulant drug therapy in hyperactive children: Research and clinical implications. Pediatrics 60:512, 1977 85. Wolraich ML, Copeland L: Disorders of behavioral development: Attention deficit disorder-hyperactivity. In Wolraich ML: The Practical Assessment and Management of Children with Disorders of Development and Learning. Chicago, Year Book Medical Publishers, 1987, p 269 86. Yu-cun A, Yu-feng W: Urinary 3-methoxy-4-hydroxyphenylglycol sulfate excretion in seventy-three school children with minimal brain dysfunction syndrome. BioI Psychiatry 19:861, 1984 87. Zametkin AJ, Rapoport JL: Neurobiology of attention deficit disorder with hyperactivity: Where have we come in 50 years? J Am Acad Child Adolesc Psychiatry 26:676, 1987 88. Zametkin AJ, Karoum F, Rapoport JL: Phenylethylamine excretion in attention deficit disorder. J Am Acad Child Adolesc Psychiatry 23:310, 1984 89. Zametkin AJ, Karoum F, Rapoport JL, et al: Treatment of hyperactive children with monoamine oxidase inhibitors: I. Clinical efficacy. Arch Cen Psychiatry 42:962, 1985 Kluge Children's Rehabilitation Center and Research Institute 2270 Ivy Road Charlottesville, VA 22901