Sympathomimetic amines and central nervous system (CNS) stimulants are commonly referred to as stimulants. Two of these agents, methylphenidate (MPH) and amphetamine, are the drugs of choice for treating attention-deficit/hyperactivity disorder (ADHD). Particularly, the extended-release formulations of these medications may be preferable in variables such as med compliance and potential for abuse. Magnesium pemoline, which also falls into this category of drugs, was withdrawn from the market in 2005 by manufacturers because the increased risk of acute hepatic failure was unacceptable. Atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), is also approved by the FDA to treat ADHD; however, head-to-head comparisons suggest that stimulants are more effective than atomoxetine in improving hyperactivity, impulsivity, and inattention in such subjects (Starr and Kemner, 2005; Wigal et al., 2005; National Medical Association, FOCUS presentation, 2005; this is reviewed under the section “Atomoxetine versus Stimulants in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents”). Long-acting forms of the alpha-adrenergic agonists guanfacine and clonidine are now approved by the FDA for the treatment of ADHD as monotherapy and as adjunctive therapy to stimulant medications. Amantadine (AMT) is a novel agent whose actions on the dopamine system are indirect and appear to be involved more as a modulator of dysfunction in the dopamine system. AMT seems to have utility for individuals with brain injury from various causes who have moderate to severe mental retardation and exhibit behavioral problems.

The most useful recent comprehensive review of the use of stimulants in treating ADHD is “Practice Parameter for the Use of Stimulant Medications in the Treatment of Children, Adolescents, and Adults” (Greenhill et al., 2002).

Bradley’s (1937) report on the use of racemic amphetamine sulfate (Benzedrine) in children having behavioral disorders is usually cited as the beginning of child psychopharmacology as a discipline. Since this initial report, more research has been published on the stimulants and on ADHD than on any other childhood disorder. Double-blind, placebo-controlled studies have consistently found that stimulants are significantly superior to placebo in improving attention span and in decreasing hyperactivity and impulsivity. Although most of the earlier studies were in children, two double-blind studies have confirmed the clinical efficacy of MPH in treating adolescents diagnosed with attention-deficit disorder (ADD) who also had ADD as children (Klorman et al., 1988a, 1988b). Since then, many more studies on the use of stimulants, particularly the use of extended-release formulations, in adolescents and adults have been published.

Several investigators have reported that MPH also improved academic performance and/or peer interactions (e.g., Pelham et al., 1985, 1987; Rapport et al., 1994). Whalen et al. (1987) reported on 24 children between 6 and 11 years of age who were diagnosed with ADD or attention-deficit disorder with hyperactivity (ADDH) and who received either placebo, 0.3 mg/kg MPH daily, or 0.6 mg/kg MPH daily, in random order so that all children received each dosage level for a total of 4 days. The authors reported that all children showed decrements in negative social behaviors when rated during relatively unstructured outdoor activities at the 0.3-mg/kg level, compared with placebo. The youngest 12 children showed further improvement in social behavior at the higher dose.

Rapport et al. (1994) evaluated the acute effects of four dose levels (5, 10, 15, and 20 mg) of MPH on classroom behavior and academic performance of 76 children diagnosed with ADHD in a double-blind, placebo-controlled, within-subject (crossover) protocol. Compared with baseline, the subjects showed a nearly linear increase in normalization of behavior as the dose of MPH increased. On the Abbreviated Conners Teacher Rating Scale (CTRS), scores improved in 16% and normalized in 78% of the subjects. Attention, measured by on-task behavior, improved in 4% and normalized in 72% of the subjects. Academic efficiency, measured by the
percentage of academic assignments completed correctly, improved in 3% and normalized in 50% of the subjects. Hence, there are several different clinically significant subsets of children: those who improve in all domains, those who improve in the behavioral and attention domains but do not improve in the academic domain and require additional interventions (e.g., tutoring), those who show behavioral improvement but no significant improvement in attention or academic ratings, and a fourth subset who do not benefit from MPH in any of the three domains.

In a double-blind, placebo-controlled study of 40 children (age range, 6 to 12 years; mean, 8.6 ± 1.3 years) who were diagnosed with ADHD and treated with MPH, DuPaul et al. (1994) found that subjects (N = 12) who had additional internalizing symptoms such as anxiety or depression and who had high scores on the internalizing scale of the Child Behavior Checklist (CBCL) were significantly less likely to benefit from MPH at three different doses (5, 10, and 15 mg) in school, as evidenced by teachers’ ratings and in the clinic setting compared with subjects with borderline (N = 17) or low (N = 11) scores on the CBCL. There was a significant deterioration in functioning on MPH among some children. In particular, 25% of the subjects in the high internalizing group were rated on the Teacher Self-Control Rating Scale as showing a worsening in classroom behavior, compared with 9.1% in the low and none in the borderline internalizing groups. On the same scale, however, 50% of the high, 93.75% of the borderline, and 72.7% of the low internalizing groups were rated as improved or normalized. It appears that the presence of anxiety or depression may hinder the effectiveness of stimulant treatment or even worsen behavior.

ADHD and conduct disorder may frequently coexist; in fact, DSM-IV-TR (American Psychiatric Association [APA], 2000) notes that if either diagnosis is present, the other diagnosis is commonly found. Psychostimulants also reduce some forms of aggression present in children diagnosed with ADDH (Allen et al., 1975; Klorman et al., 1988b). Amery et al. (1984) compared dextroamphetamine and placebo in 10 boys diagnosed with ADDH with a mean age of 9.6 ± 1.6 years. Dextroamphetamine was administered in doses of 15 to 30 mg/day. The authors reported that scores on the Thematic Apperception Test Hostility Scale and Holtzman Inkblot Test Hostility Scale, and observations of overt aggression in a laboratory free-play situation, were reduced significantly (P < .05) during a 2-week period on dextroamphetamine, compared with a similar period on placebo. These data are important, as ADHD and conduct disorder frequently coexist and stimulants are often not considered in treating children whose conduct disorders are the primary consideration.

Approximately 75% of children with ADHD treated with stimulants will show favorable responses (Green, 1995). Among these favorable responses, there will be a spectrum. Some children will respond extremely well; others will benefit but to a lesser degree. Also, some children with ADHD (or an earlier equivalent diagnosis) will respond favorably to one stimulant drug but less favorably, not at all, or unfavorably to another. For example, Arnold et al. (1976) conducted a double-blind crossover study of D-amphetamine, L-amphetamine, and placebo in 31 children with minimal brain dysfunction (MBD). Both isomers were statistically superior to placebo and did not differ significantly from each other. Interestingly, of the 25 children with positive responses, 17 responded well to both isomers, 5 responded favorably to the D-isomer only, and three responded favorably to the L-isomer only (Arnold et al., 1976).

In a double-blind crossover study, Elia et al. (1991) compared MPH, dextroamphetamine, and placebo in treating 48 males (age range, 6 to 12 years; mean, 8.6 ± 1.7 years) with a history of hyperactive, inattentive, and impulsive behaviors that interfered with functioning both at home and at school. Following a 2-week baseline period, subjects were assigned randomly for 3-week periods during each week of which the dosage was increased, unless untoward effects prevented it, to one of three regimens: (a) MPH doses were given at 9 AM and 1 PM: subjects weighing <30 kg received during week 1, 12.5 mg; week 2, 20 mg; and week 3,
35 mg. Subjects weighing 30 kg or more received during week 1, 15 mg; week 2, 25 mg; and week 3, 45 mg. The actual mean dosage for all subjects for week 1 was 0.9 mg/kg; week 2, 1.5 mg/kg; and week 3, 2.5 mg/kg. (b) Dextroamphetamine doses were given at 9 AM and 1 PM: subjects weighing <30 kg received during week 1, 5 mg; week 2, 12.5 mg; and week 3, 20 mg. Those weighing 30 kg or more received during week 1, 7.5 mg; week 2, 15 mg; and week 3, 22.5 mg. The actual mean dosage for all subjects during week 1 was 0.4 mg/kg; week 2, 0.9 mg/kg; and week 3, 1.3 mg/kg. (c) Placebo dosage was held at the preceding week’s level, increased to a lower dosage than mandated by the next level, or decreased because of untoward effects in 19 subjects (40%), including seven on MPH, seven on dextroamphetamine, and five on both drugs. The authors reported that 38 (79%) subjects responded to MPH and that 42 (88%) responded to dextroamphetamine; overall, 46 (96%) of the 48 subjects had a positive clinical response to one or both stimulants as rated on the Clinical Global Impressions (CGI) Scale and, in particular, for restless and inattentive behaviors. Eight subjects did not respond to MPH, four did not respond to dextroamphetamine, and two did not respond to either drug. Elia et al. (1991) distinguished between behavioral nonresponse and untoward effects, which few investigators have done. They noted that, although behavioral nonresponse to stimulants is rare, when a wide range of doses is given, most subjects had some untoward effects. During week 2 or 3 of treatment, untoward effects required that for 19 (40%) of the subjects, the dose be only partially increased in 15 (6 on MPH, 4 on dextroamphetamine, and 5 on both), held constant in 2 (1 on each medication), and decreased in 2 subjects receiving dextroamphetamine. When behavioral nonresponders were combined with subjects having untoward effects, the rate of nonresponse was similar to that reported in the literature. The authors noted that making a definitive clinical decision regarding improvement was often difficult because behavioral improvements had to be balanced against untoward effects, and different symptoms responded independently to dosage, setting, and subject (Elia et al., 1991).

Wender (1988) notes that the development of tolerance to the therapeutic effects of stimulant medication is unusual and that when it occurs, it progresses gradually over a period of 1 or 2 years. If this occurs, a trial of another stimulant is suggested, because complete cross-tolerance among the stimulants does not occur (Wender, 1988). There is a suggestion that the efficacy of stimulants typically decreases with age (Taylor et al., 1987).

Gadow and Poling (1988) reviewed the literature on the use of stimulants in the mentally retarded and concluded that stimulants are highly effective in reducing symptoms of hyperactivity and conduct disorder in some individuals, regardless of the degree of their retardation.

Normal prepubertal boys and college-aged men reacted similarly to patients diagnosed with ADHD when given single doses of dextroamphetamine; they exhibited decreased motor activity and generally improved attentional performance (Rapoport et al., 1978a, 1980a). Hence, earlier teachings that stimulants have a paradoxical effect in hyperactive children are incorrect, and a positive response to stimulant medication cannot be used to validate the diagnosis of ADHD (Pliszka et al, 2007).

In 1999, the landmark studies of the authoritative Multimodal Treatment Study Group of Children with Attention-Deficit/Hyperactivity Disorder (MTA) Cooperative Group were published (MTA Cooperative Group, 1999a, 1999b). Its 14-month randomized, multisite, clinical trial of four different treatment strategies for 579 children, aged 7 to 9.9 years, diagnosed with ADHD combined type reaffirmed the treatment efficacy of the stimulants, when dosed in a t.i.d. fashion, especially MPH. Four types of treatment were compared: (a) medication
management, (b) intensive behavioral treatment, (c) combined medication and intensive behavioral treatment, and (d) standard community care by community providers. All four groups improved, but for most ADHD symptoms children in the medication and combination groups improved significantly more than those in the intensive behavior treatment and standard community care groups. Core ADHD symptoms improved equally with the combined treatment or with medication alone; however, the combined therapy may have provided modestly better outcomes for non-ADHD symptoms (e.g., oppositional and aggressive symptoms) and positive functioning (MTA Cooperative Group, 1999a, 1999b).

The stimulants undergo some metabolism in the liver but new data indicate stimulants may be metabolized primarily by gastrointestinal enzymes and are primarily excreted by the kidneys. Table 4.1 gives the site of metabolism, main metabolic products, time of peak plasma levels, serum half-lives, and routes of excretion of MPH and dextroamphetamine.

Sustained-release preparations make once-daily dosage possible. One early report found the clinical efficacy of sustained-release MPH to occur approximately 1 hour later and to be less than the standard-release form of MPH on several important measures of disruptive behavior in two studies of 22 boys with ADHD (Pelham et al., 1987). These authors thought that if once-daily dosage was necessary, then slow-release dextroamphetamine would often be preferable to sustainedrelease MPH. Birmaher et al. (1989) noted that the maximum serum level takes longer to develop when sustained-release tablets are administered and that peak serum levels are lower compared with those for an equivalent dose of standard MPH. These authors suggested that the relative inefficacy of sustained-release MPH could result from differences in pharmacokinetics or absorption, or from tachyphylaxis.

Some subsequent studies, however, have reported significantly different results. Pelham et al. (1990) administered standard MPH, 10 mg every morning and noon; sustained-release MPH, 20 mg every morning; dextroamphetamine spansule (long-acting), 10 mg every morning; pemoline (pemoline has subsequently been withdrawn from the market), 56.25 mg every morning; and placebo in random
order for 3 to 6 days. Each double-blind, placebo-controlled, crossover study involved 22 boys, ages 8.08 to 13.17 years, diagnosed with ADHD. Midday placebos were given during the periods when long-acting drugs were administered. Subjects were rated on measures of social behavior and classroom performance and on a continuous performance task. All four medication conditions had similar time courses, with effects evident between 1 and 9 hours after ingestion, and they were significantly, and approximately equally, better than placebo. The effects of the three long-acting preparations were as great, or almost as great, at 9 hours as at 2 hours after ingestion. Only 15 (68%) of the 22 patients improved sufficiently for the authors to recommend that they continue to receive stimulant medication. For these 15 patients, dextroamphetamine spansules were recommended for 6, pemoline for 4, sustained-release MPH for 4, and standard MPH for 1. The clinical implications of this study are potentially very important because they suggest that the great majority (i.e., 14 [93.3%] of 15 children with ADHD) derive more overall benefit from long-acting forms than from standard-release forms of stimulants. At the time of the study over 20 years ago, it was estimated that approximately 90% of children receiving medication for ADHD were prescribed MPH, and, of these, only approximately 10% received the sustained-release form. It should be noted that early forms of long-acting MPH such as Ritalin SR used an inferior waxbead delivery system and were inconsistent in delivery and results. Later MPH preparations such as Ritalin LA, Metadate CD, Focalin XR, and Concerta utilized more sophisticated delivery systems that seemed to provide more consistent and prolonged stimulant effect.

Fitzpatrick et al. (1992) compared the efficacy of standard and sustained-release MPH, and a combination of the two forms, in a double-blind, placebo-controlled study of 19 children (17 males and 2 females; age range, 6.9 to 11.5 years) diagnosed with ADD. Dosage of sustained-release MPH was 20 mg/day for all patients. Patients weighing <30 kg and >30 kg received 7.5 and 10 mg, respectively, in the morning and at noon, when on standard MPH only, and 5 and 7.5 mg, respectively, in the morning and at noon, when receiving standard MPH in combination with sustained-release MPH. Patients were rated on several scales by parents, teachers, and clinicians. All three active drug conditions were significantly better than placebo and were approximately equivalent in efficacy.

These studies, in which the medications were administered for relatively short periods, have relatively small numbers of subjects and need to be replicated with larger populations. They do, however, alert the clinician to the likelihood that sustained-release preparations are more efficacious than thought initially, and they may be the preferred dosage forms for most children with ADHD, especially when considering compliance issues and abuse potential.

Since the preceding studies were published, several new stimulant preparations with increased duration of action have appeared in the market. Adderall XR, which is a preparation of four amphetamine salts, has a duration of action that increases significantly with increases in dose and is compared to MPH and reviewed later under the discussion of amphetamines; Vyvanse, a D-isomer amphetamine pro-drug, has also been released. Extended-release forms of MPH in tablet, beaded-capsules, a patch, and an extended-release MPH preparation that uses an osmotic release oral system (OROS) of medication delivery combined with a semipermeable membrane to achieve a reported 12-hour duration of effect, have all been marketed. These drugs are further discussed later.

Known hypersensitivity to the medication and glaucoma are significant contraindications. There are several other conditions such as tics, seizures, autism, and psychosis that were once considered absolute contraindications to the implementation
of psychostimulant therapy. Indeed such warnings are still cited in the manufacturers’ product information (PIs) literature that accompanies most psychostimulant products. However, more recent literature tends to qualify such conditions as relative contraindications based on the clinical findings that many patients with these conditions still benefit markedly by the utilization of these agents even when these conditions are a comorbid health issue. Today, a review of the relevant literature suggests that if risks and benefits are carefully assessed and explained to the patient, it is reasonable to proceed with a trial of a psychostimulant while carefully monitoring the patient. The following discussions of the literature will further clarify the “relative” nature of these contraindications as they apply to various comorbid conditions.

Stimulants may cause stereotypies, tics, and psychosis de novo in sensitive individuals or if given in high-enough doses. Stimulants are relatively contraindicated in children and adolescents with a history of schizophrenia or other psychosis, pervasive developmental disorders, or borderline personality organization, because they appear to worsen these conditions in some cases. However, stimulants have been given to some patients with these diagnoses under conditions of close scrutiny with very beneficial results. If the patients are also being treated simultaneously with mood-stabilizer medications, the above risks may be diminished.

There is controversy over whether the stimulants should be given to children and adolescents with tic disorder, Tourette syndrome (TS), or a family history of such. Their use in pervasive developmental disorders and in TS or with tic disorders is discussed in greater detail later.

Stimulants may aggravate symptoms of marked anxiety, tension, and agitation and are contraindicated when these symptoms are prominent (PDR, 2005, p. 2353). Stimulants also have the potential to cause hypertensive crises when used with monoamine oxidase inhibitors (MAOIs). They should not be used concomitantly with an MAOI or within 14 days of an MAOI being discontinued.

Stimulants have a potential to be abused. They should not be prescribed to patients who have a history of drug abuse or when there is a likelihood that family members or friends would abuse the medication. In some cases in which the family is unreliable but stimulants are the drug of choice, it is worthwhile to attempt to work out a way to dispense and store all the stimulant medication at school because, for most children, coverage during the time in school is the foremost consideration.

Magnesium pemoline was withdrawn from the market in 2005 because its potential risks were greater than its potential benefits. Reports of acute hepatic failure, some of which were fatal and others which necessitated liver transplants, were the reason for this. The reader who wishes to have information regarding magnesium pemoline may consult the prior editions of this book.

There is some evidence that, overall, the untoward effects of MPH occur less frequently and with less severity than those from dextroamphetamine (Conners, 1971; Gross and Wilson, 1974). Gross and Wilson (1974) noted that side effects were infrequently severe enough to necessitate immediate discontinuation of the medication (1.1% of 377 patients for MPH and 4.3% of 371 patients for dextroamphetamine).

The most frequent and troublesome immediate untoward effects include insomnia, anorexia, nausea, abdominal pain or cramps, headache, thirst, vomiting, lability of mood, irritability, sadness, weepiness, tachycardia, and blood pressure changes. Many of these symptoms diminish over a few weeks, although the cardiovascular changes may persist.

Since 1972, disturbances in growth—decrements in both height and weight percentiles—have been reported for both MPH and dextroamphetamine, and the long-term untoward consequences of these effects have been of particular concern (Safer et al., 1972). There has been controversy about the significance of these changes. Mattes and Gittelman (1983) reported significant decreases in height and weight percentiles over a 4-year period. A subsequent controlled study found a significant reduction in growth velocity during the period when stimulants are actively administered (Klein et al., 1988). Despite this adverse effect on growth during the active treatment phase, it appears that an accelerated rate of growth or growth rebound occurs once the stimulant is discontinued and that there is usually no significant compromise of ultimate height attained (Klein and Mannuzza, 1988). It seems likely, however, that some children are at greater risk for growth suppression than others, and serial heights and weights of any child receiving stimulant medication should be plotted carefully on a growth chart (e.g., the National Center for Health Statistics Growth Chart) (Hamill et al., 1976).

Vincent et al. (1990) reported no significant deviations from expected height and weight growth velocities in 31 adolescents diagnosed with ADHD who had received MPH continuously for a minimum of 6 months to a maximum of 6 years after their 12th birthdays. Mean age at the beginning of the study was 12.9 ± 0.8 years. The mean daily dose was 34 ± 14 mg or 0.75 ± 0.29 mg/kg and did not differ significantly with age or sex. The results suggested that early adolescent growth is not significantly adversely affected by MPH.

Faraone et al. (2005) reported on the long-term effects of extended-release mixed amphetamine salts extended release (MAS XR) on growth in 568 children (mean age, 8.7 ± 1.8 years; age range, 6 to 12 years; 78% male, 73% White, 12% Black, 9% Hispanic), in a multicenter, open-label study. Subjects received doses of 10 to 30 mg/day for a period of 6 to 30 months. Based on the Centers of Disease Control norms, subjects experienced decreases in weight, body mass index (BMI), and height percentiles over the period of study; these decrements were greatest for the heaviest and tallest children; these deficits occurred primarily during the first year, and decreases in weight, BMI, and height were not significant during the second year on medication. The height deficit was significant for subjects whose baseline heights were greater than the 25th percentile (P = .001 for the second quartile and P < .0001 for the third and fourth quartiles). The height loss was only 1.2 percentile points for the shortest children at baseline, whereas the tallest children at baseline experienced a 10 percentile decrease in height at the end of
the study. The authors noted that monitoring growth parameters was essential but that for most children, the decreases caused by MAS XR was not likely to be of clinical concern.

Charach et al. (2006) followed up 79 subjects, age range 6 to 12 years, who were diagnosed with ADHD by DSM-III-R criteria (APA, 1980a) and maintained on stimulant medication, annually for up to 5 years to determine the long-term effects of stimulants on their heights and weights. Subjects were taking various preparations of amphetamine and MPH, which were converted to an equivalent daily dose of MPH in mg/kg/day based on their potency. Small but statistically significant effects were found. Based on a statistical model, patients receiving >1.5 mg/kg/day of MPH show a decrease in expected weight gain after 1 year and subjects receiving >2.5 mg/kg/day have a decrease in expected height after 4 years on medication; the higher the dose, the greater the decrease in expected weight or height. Regular monitoring of height and weight is indicated for children and adolescents administered stimulants as a long-term treatment.

A few children treated with stimulants may develop a clinical picture resembling schizophrenia. This condition occurs most frequently when untoward effects such as disorganization are misinterpreted as a worsening of presenting symptoms and the dosage is further increased until prominent psychotomimetic effects occur. It may also occur when stimulants are administered to children with borderline personality disorders or schizophrenia, conditions in which stimulants are relatively contraindicated. In most such cases, the psychotic symptomatology improves rapidly after discontinuation of the drug (Green, 1989).

Some parents express concern that treatment with stimulants will predispose their child to later drug abuse or addiction. Most available evidence indicates that this is not the case. Although drug abuse itself is of major concern in our culture, children diagnosed with ADHD who have been treated with stimulants appear to be at no greater risk for drug or alcohol abuse as teenagers and adults than controls (Weiss and Hechtman, 1986). Past research looking for a link between ADHD medications and substance abuse has produced conflicting conclusions from no association, a protective effect and an increased risk. But many of those studies had methodological limitations to varying degrees, and not all of the studies followed their samples a sufficient period of time into late adolescence and early adulthood. A National Institutes of Health funded study at the Massachusetts General Hospital attempted to overcome the deficiencies of previous studies (Biederman et al., 2008). This was accomplished by following the study subjects up to a median age of about 22, including an assessment for psychiatric problems such as conduct disorder that are associated with substance abuse, and applying rigorous methods to accurately analyze the data. The research study team interviewed 112 young men (ranging in age from 16 to 27), previously diagnosed with ADHD, over a span of a decade about their use of alcohol, tobacco, and other psychoactive drugs. Seventy-three percent of the subjects had been medicated with stimulants at some time in their treatment, but only 22% were currently taking the stimulant medications. The study found no relationship between having ever received stimulant treatment and the risk of future alcohol or other substance abuse. The age at which stimulant treatment began and how long it continued also had no impact on substance use. The study demonstrated that the use of psychostimulant treatments in ADHD children does appear to increase the risk for substance abuse in adulthood, but unfortunately also suggests there is no protective effect as well. Such data indicating low compliance of stimulant therapy during these critical years of late adolescence and young adulthood, however, begs the question. If stimulant med compliance into young adulthood was greater, would substance abuse be less?

For children (6 to 12 years of age) taking OROS MPH in doses up to 54 mg daily, the most frequent adverse events (AEs) were headache (14%), upper
respiratory tract infection (8%), abdominal pain (7%), vomiting (4%), loss of appetite (4%), insomnia (4%), increased cough (4%), and pharyngitis (4%). The most frequent AEs for adolescents taking OROS MPH in doses up to 72 mg daily were headache (9%), accidental injury (6%), and insomnia (5%) (PDR, 2006).

Rebound effects may occur beginning approximately 5 hours after the last dose of short-acting MPH. Behavioral symptoms of rebound are often identical to those of the ADHD being treated and, in some cases, may even exceed baseline levels prior to administration of stimulants.

Rapoport et al. (1978a) reported that normal children who received short-acting dextroamphetamine experienced behavioral rebound approximately 5 hours after a single acute dose. Symptoms included excitability, talkativeness, overactivity, insomnia, stomachaches, and mild nausea. Long-acting formulations of stimulants may reduce the risk of rebound effects but may still occur albeit much later in the day when serum concentrations taper off approximately 8 to 12 hours after dosing.

Stimulants can exacerbate existing tics and precipitate tics and stereotypies de novo. Because of this, manufacturers state its use is contraindicated in patients with motor tics, a diagnosis of TS or a family history of TS. There is some disagreement among experts regarding whether stimulants should be given to persons with tics, TS, or a family history of either condition.

In a study of 1,520 children diagnosed with ADDH and treated with MPH, Denckla et al. (1976) reported that existing tics were exacerbated in 6 cases (0.39%) and tics developed de novo in 14 cases (0.92%). After the discontinuation of MPH, all 6 of the tics that had worsened returned to their premedication intensity, and 13 of the 14 new tics completely remitted.

Shapiro and Shapiro (1981) reviewed the relationship between treating ADDH with stimulants and the precipitation or exacerbation of tics and Tourette syndrome (TS). They also noted that they had treated 42 patients for symptoms of both MBD and TS with a combination of MPH and haloperidol. Dosage of MPH ranged from 5 to 60 mg/day and was individually titrated for each patient. The authors also used MPH (dose range, 5 to 40 mg/day) in 62 additional patients with TS to counteract the untoward effects of haloperidol, such as sedation, amotivation, dysphoria, cognitive impairment, and dullness. Shapiro and Shapiro (1981) concluded that the evidence suggests that stimulants do not cause or provoke TS, although high doses of stimulants can cause or exacerbate tics in predisposed patients. Clinically, they noted that tics seemed less likely to be exacerbated by stimulants in patients who were also taking haloperidol for TS; when tics did increase in intensity, they remitted within 3 to 6 hours, the approximate duration of the usual clinical effects of MPH.

Lowe et al. (1982) reported on a series of 15 patients diagnosed with ADDH who were treated with stimulant medications, including MPH, dextroamphetamine, and pemoline. These patients subsequently had tics develop de novo, or had existing tics worsen, sometimes into full-blown cases of TS. Nine subjects had existing tics; eight had family histories of tics or TS. Twelve of the 15 cases eventually required medication for control of the tics. The authors considered the presence of TS or tics to be a contraindication to stimulant medication and that stimulants should be used with great caution in the presence of a family history of tics or TS. They also considered the development of tics after treatment with stimulants sufficient reason to discontinue the use of stimulant medication.

Lowe et al. (1982) noted that the early clinical signs of TS may be difficult to differentiate from ADDH. Shapiro and Shapiro (1981) noted that approximately 57% of children with tics or TS had concomitant minimal brain dysfunction, although most children with MBD do not develop either tics or TS.

Comings and Comings (1984) investigated the relationship between TS and ADDH. They found that ADDH was present in 62% of 140 males <21 years of age diagnosed with TS. A study of their family pedigrees suggested that the TS gene could be expressed as ADDH but without tics. The authors thought that their data implied that patients diagnosed with ADDH and treated with stimulants who subsequently developed tics had ADDH as a result of the TS gene and probably would have developed tics or TS even if they had not received stimulants. It is unclear whether stimulant medication might hasten the expression of such symptoms.

Gadow et al. (1992) treated 11 boys, aged 6.1 to 11.9 years (mean, 8.3 ± 1.96 years), diagnosed with comorbid tic disorder and ADHD, with MPH. The drug was administered under double-blind conditions; each subject was assigned to random 2-week periods of placebo and MPH in doses of 0.1, 0.3, and 0.5 mg/kg/day. The authors noted that MPH significantly decreased hyperactive and disruptive behaviors in class and reduced physical aggression on the playground. Vocal tics were also significantly reduced in the lunchroom and classroom. Based on this and other studies cited in their report, the authors concluded that MPH is a safe and effective treatment for some children with comorbid ADHD and tic disorder over a short-term period; however, they cautioned that a risk of protraction or irreversible worsening of tics may exist for some individuals and that the consequences of long-term treatment of such patients are unknown.

Gadow et al. (1995) conducted a double-blind, placebo-controlled, 8-week study in which 34 prepubertal children, 31 males and 3 females, 6.08 to 11.9 years of age, diagnosed by DSM-III-R (APA, 1987) criteria with ADHD and comorbid chronic motor tic disorder or TS were treated with placebo and MPH in doses of 0.1, 0.2, and 0.5 mg/kg given twice daily (usually before leaving for school and at noon) for 2 weeks for each condition. Most children were additionally diagnosed with opposition defiant or conduct disorder. Tics were rated on five different scales by one of the authors and on the Global Tic Rating Scale by parents and teachers.

All 34 subjects responded with dramatic clinical improvement in hyperactivity and inattentive, disruptive, oppositional, and aggressive behaviors when treated with MPH. Teachers noted significant improvement in symptoms on the 0.1 mg/kg dose. There were no statistically or clinically significant adverse effects on the severity of tics with MPH treatment, but in the classroom, there was an increased frequency of motor tics on the 0.1 mg/kg/dose compared with placebo and in the physician’s 2-minute motor tic count on the 0.5 mg/kg/dose. Teachers rated vocal tics as significantly less frequent on all three doses of MPH than placebo. The authors concluded that MPH was a safe and effective treatment for most children diagnosed with comorbid ADHD and tic disorder. They also cautioned that it can be extremely difficult to determine whether MPH or natural fluctuations are responsible for observed changes in the frequency or intensity of tics and that MPH is reported to have a negative effect on tics in some children (Gadow et al., 1995).

Gadow et al. (1999) continued to follow prospectively the 34 children who participated in their 1995 study at 6-month intervals for an additional 2 years of open treatment with MPH. There was no significant change in mean group scores rating severity or frequency of motor or vocal tics during the 2-year maintenance period compared with baseline or double-blind placebo ratings. Direct observations in the simulated classroom were almost identical at baseline, during the double-blind placebo protocol and the 2-year follow-up. Although there was no evidence that MPH maintenance therapy for up to 2 years exacerbated vocal or motor tics for their subjects as a group, the authors cautioned that their results do not rule out the possibility of this occurring in specific individuals. Behavioral
improvements in ADHD symptomatology were maintained during the 2-year follow-up; however, behavioral problems associated with oppositional defiant and conduct disorders did not maintain their gains. Over the 2-year period, there was a significant increase of approximately 10 beats per minute in heart rate, which was not felt to be clinically significant, and slightly less weight gain (0.72 kg) and less height gain (0.67 cm) than expected, both of which are so small as to not be of concern for most children.

Castellanos et al. (1997) conducted a 9-week, double-blind crossover, placebocontrolled treatment protocol (in three separate cohorts) with a total of 20 males (mean age 9.4 ± 2.0 years, range 6 to 13 years) diagnosed with comorbid ADHD and TS comparing MPH, dexedrine (DEX), and placebo at various doses. Doses of stimulants were quite high at the upper range (e.g., 45 mg/dose [90 mg/day] for MPH and 22.5 mg/dose [45 mg/day] for DEX). Efficacy was determined by ratings on the Tourette Syndrome Unified Rating Scale and the Conners teachers’ hyperactivity ratings. Medication was administered at breakfast and lunch daily. Because of the three separate cohorts, only a summary of the overall findings will be given here. Target ADHD behaviors of all subjects improved on teachers’ ratings on stimulants, and there was no significantly greater improvement at the higher doses. At the lowest dose (12.5 or 15 mg/dose for MPH and 5 or 7.5 mg/dose for DEX), there was no significant change of tic severity. At highest drug doses, tic severity was significantly increased but DEX increased the severity significantly more than MPH or placebo. Of particular clinical interest was the finding that the increases in tics that occurred at higher doses of MPH tended to diminish over time and return to placebo levels when MPH was maintained or increased; this occurred in 17 of the 20 subjects. This diminution in tic severity also occurred with DEX but less significantly (in 9 of 20 subjects, P < .01). The authors concluded that stimulants (usually MPH is preferred) at the lowest effective dose should be considered as a possible treatment for children with comorbid ADHD and TS. Some clinicians would advocate that the purified D-isomer of MPH, which is available in shortand long-acting formulations, may have theoretical and true clinical benefit in providing a less tic-promoting effect than D- and L-MPH formulations.

To further investigate whether treatment with MPH causes tics de novo or worsens preexisting tics in children diagnosed with ADHD, Law and Schachar (1999) conducted a 1-year-long randomized, placebo-controlled, prospective study of 91 such children who had never received medication for ADHD or tics. Inclusion criteria included the following: presence of at least 8 of the 14 DSM-III-R (APA, 1987) criteria for the diagnosis of ADHD in either the school or the home setting and a minimum of 5 such criteria in the other setting; ADHD symptoms beginning before age 7 and of at least 6 months duration; Full Scale Intelligence Quotient (FSIQ) >80 (based on the Block Design and Vocabulary subtests of the WISC-III) (Wechsler, 1974); and no primary anxiety of affective disorder. Exclusion criteria were as follows: severe motor or vocal tic disorder or TS, as it was assumed that MPH would exacerbate such tics, but subjects with mild to moderate tics were permitted, as the authors assumed the risk of their worsening would be less and they would be more easily managed if they did occur.

Subjects were recruited from 302 consecutive referrals to an ADHD program in an urban pediatric hospital. Admission criteria were met by 105 children, and 91 elected to participate in the study. Mean age was 8.35 ± 1.55 years. Of the 46 randomly assigned to the MPH group, 11 (23.9%) had preexisting tics; of the 45 randomly assigned to the placebo group, 16 (35.6%) had preexisting tics. Study medication was begun at doses of 5 mg at breakfast and at noon on schooldays; the use of weekend and holiday medication was decided by the caregiver. Medication was increased by 10 mg weekly (each dose increased by 5 mg) until a target dose of 0.7 mg/kg/day was achieved or untoward effects precluded further increase. If families elected to switch to the alternative medication, which was an
option, another blinded titration to reach the target goal was performed. Tics were rated on a 10-point scale: 0 = no tics, 1 to 3 = mild tics, 4 to 6 = moderate tics, and 7 to 9 = severe tics.

If tics developed during the treatment, the current dose of medication was continued for 1 week. If the tic did not diminish, medication was decreased by 5-mg amounts until the tic was rated as mild or disappeared. In most cases of mild tic, parents and children elected to continue with the protocol, as the clinical improvement outweighed the impact of mild tics. During the 1-year protocol, 27 (60%) of the subjects on placebo requested to change to the alternative medication because of inadequate clinical improvement; none switched because of onset of a tic disorder. No patient receiving MPH elected to switch medications. At the end of 1 year for a total of 72 subjects, there remained 18 subjects in the placebo group; the MPH group was increased by the 27 subjects who switched from placebo and decreased by one subject because of follow-up difficulties.

The mean dose of MPH at the end of dose titration was 0.5 mg/kg/day. The target of 0.7 mg/kg/day was not reached for many subjects because of untoward effects, both physiologic (insomnia, dizziness, decreased appetite, headache, and daytime drowsiness) and behavioral (staring and preoccupations), and development or worsening of tics. Because of the switches from placebo to MPH, the final distribution of subjects whose tics predated the study’s onset was 21 (29.2%) of the 72 subjects in the MPH group and 6 (33.3%) of the 18 subjects in the placebo group.

By the end of the study, 10 (19.6%) of the 52 subjects with no preexisting tics who received MPH and 2 (16.7%) of the 12 subjects remaining in the placebo group had developed clinically significant tics that were of moderate intensity or worse, including one child in the MPH group who developed Tourette-like symptoms. There was no significant difference in the development of tics de novo between the groups (P = .59). The 12 subjects who developed tics were managed by maintaining the dose of MPH at the level when tics emerged in 8 cases, reducing the MPH dose in 3 cases, and adding clonidine in 1 case. Among the 27 subjects with preexisting tics, 7 (33.3%) of the 21 receiving MPH had worsening of their tics, including 1 boy who developed Tourette-like symptoms; 2 (9.2%) experienced no change in their tics; 5 (23.8%) experienced improvement; and 7 (33.3%) had complete remission of their tics. Of the 6 such patients in the placebo group, 2 (33.3%) had worsening of tics and 4 had complete remission of their tics. Hence, in both the MPH group and the placebo group, 66.7% (14/21 and 4/6) of the subjects with preexisting tics experienced improvement or no change in their tics, and tics worsened in 33.3% of the subjects (7/21 and 2/6). There was no significant difference between the groups (P = .70).

Tics de novo developed throughout the 1-year treatment in both groups. In the MPH group, 20 subjects developed new tics: 12 (60%) within 4 months, 6 (30%) between 4 and 8 months, and 2 (10%) between 8 and 12 months. In the placebo group, 9 subjects developed new tics: 1 (11.1%) within 4 months, 5 (55.6%) between 4 and 8 months, and 3 (33.3%) between 8 and 12 months. Only 12 of these 29 subjects who developed new tics were reported to still have tics at the end of the study, illustrating both the waxing and waning natural course of tics as well as the response to decreasing the dose of MPH in some cases. Law and Schachar (1999) concluded that titration of MPH to an optimal average maintenance dose of 0.5 mg/kg/day does not cause tics de novo or worsen preexisting tics of moderate severity or less, more often than placebo in children being treated for ADHD for up to 1 year.

Sverd (2000) recently reviewed the use of MPH to treat children with comorbid ADHD and tic disorders. Sverd concluded that the literature supports that ADHD is genetically related to TS in a substantial proportion of cases, that stimulants cause tics de novo or exacerbation of tics relatively infrequently, and that MPH
may be safely used to treat children diagnosed with ADHD and comorbid tic disorder.

Currently, a conservative approach would consider the stimulants relatively contraindicated in treating children and adolescents with tics or TS, and a reason for caution in the presence of family history of such. In fact, two manufacturers of MPH products state that it is contraindicated in patients with motor tics or with a family history or diagnosis of TS. A review of the relevant literature, however, suggests that if risks and benefits are carefully assessed, it is reasonable to attempt a trial with MPH or amphetamine (there are more data for MPH) in such patients if they are carefully monitored.

The stimulants are the most frequently prescribed psychiatric drugs during childhood. In 1977, more than half a million children were being treated with MPH in the United States alone (Sprague and Sleator, 1977). By 1987, it was conservatively estimated that in the United States, 750,000 youth were being treated with medication for hyperactivity or inattentiveness (Safer and Krager, 1988). In Baltimore County, 6% of all public elementary school students were receiving such medication; MPH accounted for 93% of the drugs prescribed, and other stimulants accounted for another 6% (Safer and Krager, 1988). In more recent times with the development of improved long-acting formulations of MPH and amphetaminebased products, there is much greater balance in the prescription of MPH versus amphetamine products.