Psychiatric Annals

The Psychopharmacologic Treatment of Children and Adolescents with Attention Deficit Disorder

Mina K Dulcan, MD

Abstract

INTRODUCTION

Attention Deficit Disorder (ADD) a "new" diagnosis created for DSM-III, ' includes the subtypes with hyperactivity, without hyperactivity, and residual. Douglas describes the following primary deficits in ADD: 1) lack of investment, organization, and maintenance of attention and effort in completing tasks, 2) inability to inhibit impulsive responding, 3) lack of modulation of arousal levels to meet the demands of the situation, and 4) unusually strong inclination to seek immediate reinforcement.2 Unfortunately, the majority of studies have included a heterogeneous group of children with often unspecified degrees of learning disabilities, overactivity, aggression, brain damage, and family pathology.

Recent studies3·4 estimate that 3% of prepubertal school children have been diagnosed by a physician as hyperactive, with an additional 3% identified as hyperactive by the school but not diagnosed by a physician. The ratio of boys to girls ranges from 4 to 13 to 6-8 to 1.4

In the 1930s clinicians began using the then available psychostimulant compounds to treat a variety of child psychiatric problems which had not responded to psychotherapy.5·6 In the subsequent three decades, treatment with first dextroamphetamine (Dexedrine) and then in the 1950s methylphenidate (Ritalin) became increasingly popular treatment for a disparate group of "hyperactive" children who had symptoms of anxiety, minimal brain dysfunction, aggression, psychosis, depression, hysteria and/or school phobia. The 1970s saw a professional and lay backlash.7-10 Teachers and physicians were accused of being in league with pharmaceutical companies to "drug" children, especially poor ones, into submission. A useful result of the outcry was a wave of more scientific studies of the characteristics of children who might benefit and the short and long term effects of stimulant medication. Currently the use of these compounds is largely limited to children with ADD. Two recent school based studies found that .6% to 1% of students are currently receiving stimulants.3,4

Although some have asserted that positive response to stimulants is both necessary and sufficient to make a diagnosis of ADD, this is clearly not the case. Studies of mixed diagnostic groups have not shown differential efficacy by diagnosis6,11 and normal children respond to these medications in ways similar to hyperactive children. The evidence does not yet support either specific effects of drugs on the hyperactive syndrome or a core syndrome of hyperactivity that is uniquely responsive to drugs.12

Table

1 . American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed Ï. Washington. DC. American Psychiatric Association. 1980.

2. Douglas Vl; Attentional and cognitive problems, in Ruiter M (cd); Developmental Neuropsychiatry. New York. The Guilford Press. 1983.

3. Bosco ?, Robin SS; Hyperkinesia: Prevaîencc and treatment, in Whakn CK. Henker B (eds): Hyperactive Children. New York. Academic Press, Inc., 1980.

4. Sandoval I. Lambert NM. SassoneD: The identification and labclingof hyperactivity in children: An interactive model, in Whalcn CK, Henker B teds); Hyperactive Children. New York. Academic Press. Inc.. 1980.

5. Wiener IM. Iaffc S: History of drug therapy in children and adolescent psychiatric disorders, in Wiener [M (cd): Psychopharmacology in Childhood and Adolescence. New York. Basic Books. Inc.. 1977.

6. Bradicv C: The behavior of children receiving benzedrine. Am I Psychiatry 1957; 94:577-585.

7. Fish B: The "one child one drug" myth of stimulants in hyperkinesia: Importance of diagnostic categories in evaluating treatment. Arch Gen Psychiatry 1971;25:193-203.

8. Grinspoon L. Singer SB: Amphetamines in the treatment of hyperkinetic children. Harvard Educational Review 1973; 43:515-555.

9. O'l.eary KD: Pills or skills for hyperactive children. / .Appi Behov Ana! 1980: 13:191-204.

10. Schräg P. Divoky D: The Myth of the Hyperactive Child and Other Means of Child Contrai. New York, Pantheon, 1975.

11. Arnold LE. Christopher |, Hucstis…

INTRODUCTION

Attention Deficit Disorder (ADD) a "new" diagnosis created for DSM-III, ' includes the subtypes with hyperactivity, without hyperactivity, and residual. Douglas describes the following primary deficits in ADD: 1) lack of investment, organization, and maintenance of attention and effort in completing tasks, 2) inability to inhibit impulsive responding, 3) lack of modulation of arousal levels to meet the demands of the situation, and 4) unusually strong inclination to seek immediate reinforcement.2 Unfortunately, the majority of studies have included a heterogeneous group of children with often unspecified degrees of learning disabilities, overactivity, aggression, brain damage, and family pathology.

Recent studies3·4 estimate that 3% of prepubertal school children have been diagnosed by a physician as hyperactive, with an additional 3% identified as hyperactive by the school but not diagnosed by a physician. The ratio of boys to girls ranges from 4 to 13 to 6-8 to 1.4

In the 1930s clinicians began using the then available psychostimulant compounds to treat a variety of child psychiatric problems which had not responded to psychotherapy.5·6 In the subsequent three decades, treatment with first dextroamphetamine (Dexedrine) and then in the 1950s methylphenidate (Ritalin) became increasingly popular treatment for a disparate group of "hyperactive" children who had symptoms of anxiety, minimal brain dysfunction, aggression, psychosis, depression, hysteria and/or school phobia. The 1970s saw a professional and lay backlash.7-10 Teachers and physicians were accused of being in league with pharmaceutical companies to "drug" children, especially poor ones, into submission. A useful result of the outcry was a wave of more scientific studies of the characteristics of children who might benefit and the short and long term effects of stimulant medication. Currently the use of these compounds is largely limited to children with ADD. Two recent school based studies found that .6% to 1% of students are currently receiving stimulants.3,4

Although some have asserted that positive response to stimulants is both necessary and sufficient to make a diagnosis of ADD, this is clearly not the case. Studies of mixed diagnostic groups have not shown differential efficacy by diagnosis6,11 and normal children respond to these medications in ways similar to hyperactive children. The evidence does not yet support either specific effects of drugs on the hyperactive syndrome or a core syndrome of hyperactivity that is uniquely responsive to drugs.12

Table

TABLEPHARMACOKINETIC PROFILES

TABLE

PHARMACOKINETIC PROFILES

PHARMACOLOGY

At present there are three psychostimulant medications in common use for treating ADD: dextroamphetamine and methylphenidate, sympathomimetic amines, and pemoline.

Dextroamphetamine is thought to potentiate both dopamine and norepinephrine, principally via stimulation of release of newly synthesized catecholamines into the synaptic cleft, inhibiting presynaptic reuptake and inhibiting monoamine oxidase.13·14 The pharmacokinetics of dextroamphetamine in children have been described relatively recently (Table).15·18 The behavioral effects peak 1 to 4 hours following an oral dose, corresponding to the absorption, distribution and early metabolism phases. No significant correlation has yet been found across individuals in behavioral response ratings and plasma amphetamine levels.

Sustained-release dextroamphetamine has a later and longer peak plasma level which is not accompanied by a longer period of significant behavioral response.16 Although there seems to be no advantage of the sustained release preparation in duration of action, there are no data on possible differences in rebound effects or individual response.

Methylphenidate, a piperidine derivative which is structurally related to amphetamine, acts by releasing stored catecholamines from the reserpine-sensitive presynaptic vesicular pool, decreasing their reuptake, inhibiting monoamine oxidase, and perhaps also by direct post-synaptic action. Like amphetamine, methylphenidate is poorly bound to plasma proteins. It is rapidly converted to an inactive metabolite, ritalirtic acid. The pharmacokinetic profile for hyperactive children is similar to that for normal and hyperkinetic adults(Table). 19"21 Even with chronic usage methylphenidate obeys acute dose kinetics rather than steady state,17·19 because the short half-life does not permit accumulation overnight.

Swanson and Chan,21·22 questioning the standard recommendation to give methylphenidate before meals,23·24 investigated the effect of food on the absorption of an oral dose. They found no significant difference in any of their cognitive, behavioral, or physiologic measures, or ritalinic acid peak level between methylphenidate 30 minutes before or 30 minutes after breakfast. Although one study, using exceedingly global outcome measures, claims that sustained release methylphenidate given in the morning is equivalent in clinical effect and side effects to 10 mg given in the morning and at noon,25 there are no objective data that blood levels actually persist longer after a sustained release preparation.

Pemoline is a mild central nervous system stimulant structurally dissimilar to amphetamine and without significant sympathomimetic activity.26 Because the half-life has been reported to average 12 hours,27 once a day administration has been recommended. Pemoline's therapeutic effect is reported to lag by 3 to 4 weeks with the maximum effect delayed until 6 to 8 weeks. This is partially explained by slow titration and low dose. The clinical effect was found to last 2 weeks after the drug was discontinued.28,29 Children show considerably more intersubject variability than adults in pemoline elimination half-life (4 to 15 1/2 hours) and time to peak plasma concentration (1 to 3 hours) (Sallee R, Perei J, personal communication, March 1984). Since blood levels are not readily available, clinical judgment must determine whether a second dose of pemoline to boost plasma levels would be beneficial for an individual child.

The pharmacodynamics of the psychostimulants remain controversial.13,14,30,31 The study of the relationship between plasma drug level and clinical effect is complicated by the finding that the dose response curves vary according to the effects measured.20,3234 Sprague and Sleator suggested that positive effects on behavior occurred at a higher mg/kg dose than cognitive effects and that in fact, cognitive performance was impaired at the level at which behavior improved.35 Several studies have confirmed that drug effects on a global rating scale of behavior completed by parents and teachers (the Conners' Abbreviated Symptom Questionnaire) are maximum at a dose of 1 mg/kg.33,36 Some studies have found improvement on tests of cognitive functioning maximal at a dose of .3 mg/kg with deteriorating of performance at 1 mg/ kg 2.35.37-40 The performance of children with ADD varies according to context and task parameters, decreasing generalizability between studies.2 In contrast, the frequency and severity of side effects have been repeatedly shown to increase directly with increasing dose. A further complicating factor is that ADD children have been found to include negative, as well as positive placebo responders.35

There is a long standing myth that hyperactive children have a paradoxical response to stimulant medication. In a series of studies using dextroamphetamine, Rapoport and her colleagues amply demonstrated that this was not the case.41"45 In response to a single dose of dextroamphetamine they found parallel responses in hyperactive boys, normal boys, and normal college men on the following measures: truncal activity during a cognitive task (decreased), reaction time (decreased), word recall (increased), vigilance (increased), nontask related speech (decreased), task related speech (increased), and insomnia (increased). The only significant difference with age was in mood. Adults reported euphoria, while children in both groups reported a wide variety of feelings with "funny" being the most common. The boys experienced a rebound period after 5 hours, characterized by increased excitability and talkativeness.41

THERAPEUTIC EFFECTS

On global judgments, parents, teachers, and clinicians rate 75% of hyperactive children on stimulant medication "improved" compared to 40% on placebo. Twenty-five percent are judged "no change" or "worse."46 There is extreme inconsistency in effects within and across drug studies, with a low correlation among change scores on various measures. Conners was able to group subjects according to profiles of pretest data. Drug effects were consistent within each group with significant differences in drug response pattern and visual evoked potentials between groups.47 Unfortunately, this preliminary finding does not seem to have been pursued or replicated.

SHORT-TERM EFFECTS

Motor Effects. Stimulants have been found to decrease activity on a variety of laboratory measures.48 In the natural environment, effects on activity depend on the context.49,50 In an experimental classroom methylphenidate reduced hyperactive boys' gross motor movement, vocalization, noise, and disruption to a level indistinguishable from normal peers.51 Methylphenidate also produces an improvement in handwriting.52,53

Cognitive Effects. Stimulants improve performance on a variety of cognitive laboratory tasks measuring sustained attention, distractibility, and impulsivity, but there is no evidence of significant improvement in measures of academic achievement.46,48,54-56 This finding is not only discouraging, but also puzzling, since there are ample case examples of children whose school grades improve on medication. It is, however, unreasonable to expect medication alone, without educational remediation, to make up for accumulated deficits. Dextroamphetamine enhances the cognitive encoding and processing operations the child typically uses.44 Since hyperactive children use more immature strategies than their peers, with the use of drugs there may be a tendency for improvement to occur more on simple than complex tasks. Methylphenidate has not been demonstrated to increase or decrease memory 24 hours after initial learning.38 Stimulants have been found to have no beneficial effect on primary reading retardation in the absence of hyperactivity.57

Interpersonal Effects. The ability of stimulant medication to decrease classroom disruption51,53,58,59 and improve behavior as rated by parents and teachers is well documented,47,54 and the effects are interactive. In an experimental setting, when methylphenidate increases children's compliance to maternal commands and reduces off task behaviors, the mothers give fewer commands and more positive attention.60 Teachers engage in significantly more controlling, guiding, or disciplinary actions and are more intense in all interactions with hyperactive children on placebo than with either normal children or hyperactive children on methylphenidate.61

LONG-TERM EFFECTS

There has not been any demonstration of longterm therapeutic effects attributable to stimulant treatment.46,62,63 The possibility has not been conclusively disproven, however, since all of the follow-up studies have serious methodologic flaws and do not account for factors which have been shown to be associated with poor prognosis such as: low IQ, aggression, poor mother-child relationship, brain damage, low socioeconomic status, and poor family environment.63-65 In addition, it may be unreasonable to expect a drug to have longterm effects after it is discontinued.

SIDE EFFECTS

All stimulant medications produce similar side effects. There is a group of common, short term side effects which are usually dose related and diminish or disappear following several weeks of treatment or dose reduction. At a dose of 1 mg/kg of methylphenidate a significant proportion of children have troublesome untoward effects.35 The most frequently reported side effects are insomnia, anorexia, weight loss, irritability, and abdominal pain.29,46,66 It is important to compare reported side effects of medication with placebo. In one study of pemoline the only side effect for which the incidence on medication was greater than placebo was sleep problems.28 Dextroamphetamine has actually been found to decrease the frequency of stomachaches compared to placebo.11 It may be difficult to distinguish whether insomnia is due to drug, a preexisting sleep disorder, or a rebound effect. Sleep laboratory studies have demonstrated few clinically significant drug-induced changes in sleep parameters. Sleep disturbances reported by parents were not demonstrated, perhaps in part due to the novelty of the sleep lab setting.6769

Other side effects which are occasionally reported include dizziness, nausea, euphoria, nightmares, dry mouth, constipation, lethargy, anxiety,46 hyperacusis, and fearfulness.67 Side effects noted only with pemoline include lip licking and biting and light picking of fingertips.

Anorexia is commonly reported, probably worsened by the tradition of giving medication one halfhour before meals, although hyperactive children are often problem eaters even prior to treatment, in a retrospective study, Loney found that 83% of the subjects treated with methylphenidate experienced no appetite suppression after one month of treatment.71

The most studied but still unclear side effect is growth retardation, initially reported by Safar.72 Initial weight loss in some subjects is reported in almost all studies, probably due to anorexia. After the first few months weight loss ceases but there is a tendency for weight gain to be less than that which would be predicted. Findings regarding height are less clear, in part due to differing methodologies in measuring and predicting height and different drug doses.73"75 To summarize, stimulant medication has a variable effect on height, which seems to be more severe with dextroamphetamine than with methylphenidate or pemoline, and increases with increasing dose. Slowing of growth may be minimized by the use of drug holidays. In a small proportion of children, growth retardation may be sufficient to reach clinical significance. Concluded from follow-up studies, adolescent height and weight were related to: severity of early weight and appetite suppression, number and length of drug holidays, duration of methylphenidate treatment, and occurrence of nausea or vomiting as an initial side effect.71

Endocrine studies have yet to elucidate the mechanism of growth retardation. In several studies, methylphenidate has not produced changes in human growth hormone (HGH) or prolactin.68,76 Although dextroamphetamine does not consistently change HGH, one study found a significant decrease in the mean sleep related prolactin secretion which correlated with loss in height velocity.67 Growth inhibition, when it occurs, may be secondary to alterations in cartilage metabolism.68

Some investigators have raised concerns about possible, although as yet undocumented, long-term sequelae of cardiovascular responses to stimulant medication.77 In chronically medicated children, methylphenidate leads to significant dose-related increases in heart rate, systolic blood pressure, and mean blood pressure which are similar throughout rest, exercise, and recovery.78 The effect on heart rate, however, varies widely, with some children even showing a reduction. Pemoline studies have shown no effect on blood pressure,28,29,66 and an inconsistent effect on heart rate.

A rare but potentially serious side effect is the production or precipitation of a movement disorder79,80 (Sallee R, Perei J, personal communication, March 1984) which is not related to dose or duration of drug treatment and may persist despite withdrawal of medication. Full blown Tourette's syndrome requiring treatment with haloperidol has been reported following methylphenidate,81,82 pemoline,82,83 and dextroamphetamine.82 Lowe recommends that the presence of motor tics or Tourette's syndrome be an absolute contraindication to stimulant treatment, a family history of either be a relative contraindication, stimulants should be withdrawn immediately if tics appear, and haloperidol and stimulants should not be used together.82 Comings asserts that some Tourette's syndrome children have such severe hyperactivity that methylphenidate should be added to haloperidol, and that tics are not always exacerbated by stimulants.84

Additional relatively rare side effects are transient if medication is withdrawn promptly. These include hypersensitivity phenomena, such as conjunctivitis, formication, skin rash, angioneurotic edema, and urticaria.85 Psychotic episodes including hallucinations have been reported during treatment with and following withdrawal of methylphenidate and dextroamphetamine.46,86-88 There is also a report of an acute dyskinesia.89

Dysphoria is a not uncommon side effect.90,91 Cantwell reported several cases of children who developed mild to moderate depressive episodes on both methylphenidate and dextroamphetamine.92

Some side effects have been more controversial. Despite efforts to demonstrate, state dependent learning,48,57,93,94 perseveration,95 hypoactivity,46,51,70 and decreased curiosity96 have not been consistently found at doses less than 1 mg/kg. Although there has been one published case report of an adolescent abusing prescribed methylphenidate,97 there is no indication that stimulant treatment increases the rate of adolescent or adult drug abuse.

There have been no reports of significant stimulant induced changes in liver functions or blood count.46,98 Although clinical lore cautions that stimulants may lower the seizure threshold, this has not been reported even in a large series of cases of children with known epilepsy.99 In fact, dextroamphetamine raises the photo-Metrazol threshold of hyperkinetic children.100 In a single case study methylphenidate decreased the frequency of temporal spike wave discharges (Strayhorn IM, personal communication, March 1984). Methylphenidate inhibits the enzymes which metabolize anticonvulsants, thus raising their blood levels.5

EMANATIVE EFFECTS

As described by Whalen and Henker40,101 cmanative effects are indirect and inadvertent psychosocial consequences which may be desirable or undesirable. They range from psychological changes in the treated child in self-esteem and selfefficacy, through effects on teachers and parents to influence on larger, societal attitudes and practices.

CLINICAL CONSIDERATIONS

Evaluation

Before consideration for stimulant treatment, a child or adolescent must have a thorough evaluation.70 The interview with the child may or may not be helpful in diagnosing ADD, since these youngsters are not overactive in every setting. In addition, these children are often unaware of or deny difficulties. In a novel situation with an unfamiliar adult, children are least likely to display impulsivity, inattention, or hyperactivity. Positive findings, therefore, are much more significant than negative. If the child can be observed in an unstructured setting, for example the waiting room, this may be helpful.

Information from a child's teacher is absolutely essential for a diagnosis of ADD. In drug studies, teachers have consistently been found to be more reliable than parents in discriminating medication from placebo. It is important to remember, however, that teachers vary widely in their tolerance for activity and impulsivity, and in their ability to structure a class.

Psychological or educational testing is not necessary for a diagnosis of ADD, although it is important in assessing educational potential and achievement. The presence of inattention and impulsivity is more significant than their absence.

Any child or adolescent needing psychiatric evaluation should have a physical examination. Elaborate neurological testing or an EEG is not necessary unless there are focal symptoms. The presence or absence of soft neurological signs or minor physical anomalies is not helpful in the individual case.102 A careful search for tics in the identified patient and family should be conducted, and baseline pulse, blood pressure, height and weight determined.

Standard assessment measures can be extremely useful. Questionnaires tend to tap global impressions which weight heavily highly salient (novel, intense, extreme, out of context) behaviors.103 Observational measures of attention and activity show much greater reliability and stability if behavior is sampled and averaged over more than one time period.104

The questionnaires most commonly used for ADD are those developed by Conners. The Parent Symptom Questionnaire (CPSQ)105106 has been demonstrated to differentiate between normal and clinical populations, between hyperkinetic and other clinically referred children,107 and between stimulant and placebo treatment.70 The most recent revision has 48 items for boys and girls ages 3 to 17. 108 The Conners Teacher Rating Scale (CTRS)108 reliably differentiates a stimulant treated group from placebo.46,109

A 10-item Hyperkinesis Index contained in the CPSQ and the CTRS has been developed into an Abbreviated Symptom Questionnaire (CASQ) which has an identical format for parents and teachers.106 It is sensitive to drug induced changes and is useful for repeated measures. A score of 1.5 has been found to be two standard deviations greater than the mean for normals110 and has commonly been used as a cutoff for studies of hyperactivity. Because the score on the CASQ has been found to decrease from first to second administration,111,112 it should be given more than once to establish a baseline.

It must be remembered that these instruments measure an adult's perception of a child's behavior. There is some evidence that teacher personality characteristics are related to ratings on the CASQ.51 A teacher's opinions regarding stimulant medication or goals for a child's class placement may affect his or her reports. The CASQ does, however, differentiate between ADD boys on medication or placebo even when raters are blind to the nature of the study.113

The Child Behavior Checklist114 may be especially useful in detecting children with ADD in heterogeneous clinical populations. Parallel versions for parent and for teacher are available, with norms for boys and girls separately in age ranges 4-5, 6-11, and 12-16 years. Child Behavior Profiles can be obtained from the parent form on boys and girls in the three age ranges, and currently for 6-11 year old boys from the teacher form. Teacher profiles for 12-16 year old boys will be available in the near future (Edelbrock, personal communication, March 1984). Each of the profiles includes factors which are relevant to ADD. The teacher profile reliably distinguishes psychiatrist diagnosed boys with ADD from other clinically referred boys, and ADD with hyperactivity from ADD without hyperactivity.115

Actual observation of the child in the natural environment70 or in specially structured playroom settings,116 while more difficult to accomplish, may be extremely useful. A school visit offers the opportunity to evaluate the child's behavior in the context of the teacher's attitudes and methods and in comparison to the rest of the class.

DECISION TO MEDICATE

Indications for stimulant medication are the presence of inattention, impulsivity, and hyperactivity which have been persistent and of sufficient severity to cause functional impairment at school, and usually also at home and with peers. There is preliminary clinical evidence that stimulants may also be indicated for children and adolescents with inattention and impulsivity but without hyperactivity· Before prescribing medication the clinician must insure that the parents are sufficiently reliable to administer the medication safely and as prescribed. It is the opinion of this author that under most circumstances interventions such as parent counseling and school consultation should be attempted first. If successful, this spares children who may not require medication. In any case, a longer period of observation is provided prior to starting medication. In addition, the clinician will have demonstrated that he or she is willing to try Other approaches and does not unthinkingly medicate children. Children with severe impulsivity, which may be dangerous to themselves or others, may require more rapid institution of medication along with other interventions.

Efforts to find predictors of drug responsiveness among groups of hyperactive children have been noticeably unsuccessful. The most promising predictors are the child's behavior and laboratory measures related to attention span.118 A better motherchild relationship and lack of parental psychopathology may predict better medication response. A high level of anxiety in the child has been found in some studies to predict poor response.70 Taylor asserts that no current measure can predict the response of an individual child within a group of hyperactive children.12

The literature affords little help to the clinician in selecting one of the stimulant drugs for a specific child. Methylphenidate is the most commonly used in practice. Some clinicians advocate dextroamphetamine as the drug of first choice because it is less expensive.89 Unfortunately, the refusal of medical assistance in some states to pay for dextroamphetamine negates this advantage for families at the lowest income levels. Experience indicates that dextroamphetamine is more likely than methylphenidate or pemoline to stimulate gratuitous comments from pharmacists to parents about "speed" or "drugs." If there is concern about possible abuse of medication, pemoline may be the safest. If short stature is a serious concern, then pemoline or methylphenidate is preferable to dextroamphetamine. Pemoline may also be indicated if administering medication during the school day is impossible or severely stigmatizing.

There have been very few studies which directly compare stimulant drugs. In large reviews combining the results of multiple separate studies one found methylphenidate slightly more efficacious than dextroamphetamine,55 and another found no difference.48 Two double-blind crossover studies comparing dextroamphetamine and methylphenidate found both drugs efficacious in 50% to 80% of the respondents. The remainder responded to only one of the drugs.11,89

In group comparison studies, methylphenidate and dextroamphetamine were found to be equal to or slightly better than pemoline.26,27,118 Some children who improved on pemoline did not subsequently have a good response to methylphenidate.25 Clinical experience suggests that as many as 20% of those who respond poorly to one stimulant medication have a positive response to another.70

INITIATING MEDICATION

Once the decision is made to prescribe stimulants, preparation of the child, the family, and the teacher is essential. Children on stimulants tend to attribute their problems to physiologic causes rather than personal or social factors and to attribute behavior change to medications or to physiologic causes such as "growing out of jt »65.101 Although not yet directly tested, it would seem clinically sound practice to emphasize that it is the child, family, and medication working together that lead to improvement. Parents should be cautioned not to look only to medication or the lack of it as a cause of the child's behavior. Whalen and Henker suggest that a "cognitive innoculation" program such as self-control training precede a medication trial to minimize possible detrimental effects on the child's sense of self-efficacy.40

Although most medicated hyperactive children recognize the need for stimulants and some of the beneficial effects, most dislike taking the medication.101,119,120 Reasons given include actual or feared social stigma and humiliation by peers and teachers, a belief that taking medication means they are defective, and a belief that medication will decrease their abilities, especially at athletics. Objections often increase with age and older children are especially likely to fear drug abuse.

Myths regarding ADD and stimulants are very common among parents, and if not spontaneously brought up, they should be addressed by the clinician. Parents vary widely in their initial attitudes toward medication, ranging from highly favorable to strongly opposed, and require different emphasis in preparation.

Virtually every parent at some time changes the child's dose without consulting the physician. While this practice should be discouraged, it should not be discouraged so strongly that the practice goes underground. Parents may be given some discretion on a third daily dose. Parents should not make the child responsible for taking his own medicine. An unsupervised c 'Id ' likely to forget, throw away, or worse, give away or sell the pills. Finally, there is a danger of impulsive overdose if entire bottles are left available to children. Parents should of course be instructed to inform any physician treating their child of the stimulant medication, especially if another medication is to be prescribed. Gualtieri lists known drug interactions with stimulants.121 Although not reported in the literature, parents should be cautioned against the use of dextroamphetamine or methylphenidate with sympathomimetics, which are often included in over the counter drugs.

Teachers need just as much, if not more, education than parents, but usually receive much less.122 Particularly to be cautioned against is the common practice of asking a loud or impulsive child in front of the class whether he has taken his pill! Teachers have been found to attribute the success of a medicated ADD child to the stimulant, not to ability or effort. This might lead a teacher to feel that a hyperactive child on medication was less worthy of credit or praise for accomplishment, leading to the child having less pride in his accomplishments and subsequently emitting less effort.123 These effects have not been systematically studied but careful preparation of the teacher may avoid possible negative effects. Teachers surveyed reported their most common complaints regarding stimulants and hyperactivity to be: inadequate information regarding drug effects and changes in treatment regimen, side effects that may impair school performance, and disagreements with parents and physicians regarding treatment practices which were inadequately discussed.124 Schools have a wide variety of rules and procedures regarding dispensing of medications during the school day. The parent and physician should collaborate in making an arrangement which provides the greatest supervision with the least risk of stigma.

Compliance with stimulant medication is a major problem. Kauffman suggests that poor compliance with medication regimens may be in part responsible for the variable and conflicting results from drug studies and the lack of evidence for long term efficacy of stimulants.125 When assessed directly, compliance has been found to be no better than 60% in both short and long term protocols.125,126

Determination of the appropriate dose for an individual child remains controversial. The trend is toward lower maximum doses than originally recommended (Table). Sprague and his colleagues have been strong advocates for using a standard .3 to .6 mg/kg dose.35 Titration using a laboratory performance test following a single dose has been advocated but not widely pursued.127 Recent data favor the use of mg/m2.19 Most practical is individual titration within mg/kg or mg/m2 limits, while assessing side effects and positive clinical effects. However, it is difficult to set absolute limits because plasma levels vary at the same mg/kg dose, due to differences in absorption.15,20 (Sallee R, Perei J, personal communication, March 1984). Blood levels are not a currently useful clinical tool.

Since ADD is usually not a clinical emergency, the dose can be gradually increased by one pill once or twice a day each week. Since a few children can be maintained on a morning dose only, it may be useful to begin with one daily dose and add the midday dose if necessary. As noted above,21,22 medication can be given after breakfast and lunch to minimize anorexia. The need for a third dose, usually small and given no later than 3 or 4 PM, is individually determined. Indications would be symptoms in the late afternoon or evening which interfere with homework, peer activities, or sleep, or severe behavior problems at home which cannot be managed with appropriate contingencies. Depending on the severity of symptoms and whether children are symptomatic at home as well as at school, many children can be maintained on a reduced or even no dose of medication on weekends.

MAINTENANCE

Children should have a summer "drug holiday" of at least two to four weeks to minimize possible effects on growth. If the medication seems to lose its effect, an increased dose may be required due to tolerance89 or an increase in the child's weight, but the physician should first consider the possibility of noncompliance and/or a change in the family or school environment as a cause for clinical deterioration.

Careful monitoring of drug treatment is essential. A double-blind trial is the best way to assess effectiveness. Although this may not be possible for the individual clinician, Varley has demonstrated its practicality in a clinic.128 In some cases it may be helpful to initially keep the teacher blind. Nearly all children should receive a trial off medication once a year. It would be ideal if the child, the parent, and the teacher were blind to this (ie, placebo substituted by clinician), but again this is not always possible. Some authors advocate a drug-free trial at the beginning of the school year but others would argue that this is the worst possible time. During the first few weeks of school, teachers form impressions of students which will be relatively unchangeable in the course of the year. If the child does still need medication, he or she is then off to a bad start. It is better to try in late winter or early spring when the child is well known to peers and teachers, and before the end of school causes whole classrooms to become inattentive and excitable. For youngsters on relatively large doses, tapering may be a better practice than abrupt discontinuation. It should be noted that medication should not be automatically discontinued at puberty, but that the duration of need for medication is a highly individual matter.

Standardized reports from teachers should be obtained on a regular basis using the CASQ. Academic testing is essential to assess the child's progress. Regular contact with the teacher is also important but unfortunately often omitted in practice. In one study, 20% of the parents surveyed stated that the physician did not even inquire whether or how the medication affected school performance!134 Parents should be seen regularly to assess both drug effects and other difficulties which might require intervention, at this time the CASQ and standardized side effect questionnaires may be used.68,129 Height and weight should be checked at least twice a year, every three months if the child is short.74 Blood pressure and pulse rate should be monitored at times of dose increase.

SPECIAL POPULATION

Questions often arise regarding such special populations as preschoolers, adolescents, and the mentally retarded. While ADD is often identified prior to age six, the treatment of young children is controversial. Methylphenidate is not recommended for children less than six,24 although it is commonly used in the community. Dextroamphetamine is recommended for age 3 and over.24 In two doubleblind studies using methylphenidate vs. placebo in 3 to 6 year olds identified as hyperactive, the efficacy was found to be even more variable than in groups of older children, with a higher incidence of side effects, especially sadness, irritability, and clinginess, along with insomnia and anorexia.130-131 Stimulants should be used in this age group only in the most severe cases where parent training and placement in a highly structured, well staffed preschool program have been unsuccessful or are not possible.

Major concerns with adolescent populations include possible growth retardation, abuse of medication, and increased sensitivity to peer opinion. Pemoline would seem to be the drug of choice for many adolescents, but a youngster who has been doing well on methylphenidate or dextroamphetamine should not automatically be switched to pemoline just because he or she reaches puberty. A double-blind crossover trial in ADD adolescents without conduct disorder previously identified as methylphenidate responders, showed 70% significantly improved on methylphenidate.132

The evaluation and treatment of children with mental retardation is especially complex. Many studies of stimulants in mentally retarded patients have been with severely impaired institutionalized populations. Varley reports preliminary findings with a group of 10 mildly retarded children and adolescents with ADD living at home. Half of the patients improved on methylphenidate compared to placebo.133 This is a somewhat lower rate than usually reported in children and adolescents of normal IQ.

ADDITIONAL TREATMENT

There is widespread agreement that stimulant medication should not be the only treatment for ADD for an individual's entire "career." Even children who respond positively do not show improvement in all areas where there are deficits. Unfortunately, despite long standing recommendations for multimodality treatment,134,135 an integrated approach is not consistently carried out in practice.3,124 The stimulant induced decrease in intensity of problem behaviors takes the pressure off schools to evaluate and remedy academic deficiencies and off parents to learn better management techniques or to arrange for experiences which will improve a child's peer relations.

One recommendation is to make a careful evaluation and plan for treatment of specific deficits. Virtually all parents require some education regarding ADD and techniques to manage these difficult children. Although not without méthodologie flaws, studies have indicated that families of hyperactive children have a higher than average incidence of marital discord, of alcoholism and sociopathy in the males, and hysteria and depression in the females.70,136,137 Marital therapy and/ or treatment of parental psychopathology may be indicated. Special classes, tutoring, and/or a change in classroom management techniques may be required. The child may benefit from individual treatment to address sequelae of ADD. Social skills training may improve peer relations.138

There are promising beginnings in combining pharmacologic with a variety of other treatment interventions.135 Gittelman found ADD with hyperactivity children receiving methylphenidate and behavior modification at home and school to be equal to control children on all study measures.139 Pelham found similar additive effects of stimulants, contingency management, and tutoring.138 Studies with less intensive psychotherapeutic interventions have not found significant additive effects with pharmacotherapy.140,141 Single case studies have shown additive effects of dextroamphetamine and self-control training and contingent reinforcement for correct responses on testing,142 and activity feedback and reinforcement.143 A great deal of work remains in the study of the interaction between stimulants and psychotherapeutic treatments.

Finally, some authors have suggested adding other medications to stimulants. Cantwell suggests that if children on stimulants develop significant depression Imipramine may be added.92 Discontinuing the stimulant with substitution of Imipramine if necessary seems more parsimonious.144 Others have suggested adding thioridiazine to stimulants to treat evening behavior problems, insomnia, and/or anorexia.145 Given the negative effects of major tranquilizers on learning and the possibility of tardive dyskinesia, a better approach, if these side effects are severe, is to decrease the dose of stimulants, change the timing, or change to another stimulant.

ALTERNATIVE TREATMENT METHODS

Other compounds have been suggested for the treatment of hyperactivity. Imipramine is effective in some children but is not the first choice for most.144 Thorazine96 and haloperidol146 are less effective than methylphenidate and have more side effects. Carbidopa/levodopa (Sinemet) is more effective than placebo but significantly less so than dextroamphetamine.'47 Caffeine has been repeatedly shown to have virtually no efficacy despite significant side effects.11,146

A wide variety of nonpharmacologic alternatives to stimuìant treatment have been suggested. Most common is behavioral interventions via parent training, teacher training, and/or directly by the clinician.9,148,149 Barkley describes in detail models of behavioral treatment for the home and classroom which may be useful to the clinician.70 Behavioral treatments have been found to be effective in the short term for hyperactive children for behaviors and settings specifically targeted. Studies comparing behavioral and pharmacologic interventions have had mixed results.141,150,151 To be effective, programs should be specifically designed for ADD.152

Cognitive therapy approaches for ADD children have developed from the work of Vygotsky,153 Luria,154 Spivack and Shure,155 and Douglas.156 Models use a variety of self-control and problemsolving strategies.152,157"164 Response cost, positive reinforcers, and/or a self-reinforcement component may facilitate change.149,152 Studies comparing methylphenidate and cognitivebehavioral treatments show each to have some benefit.159,165

The more controversial alternative etiologies and treatment deserve mention because they receive great attention in the media and often arise in discussions with parents and teachers. The most widely publicized has been diet.165 Reviews of the methodologically satisfactory studies70,166"170 indicate that 5% to 10% of hyperkinetic children may show behavioral improvement on the so called Kaiser-Permanente diet but that these changes are not as dramatic as those induced by stimulants. Preschool children are more likely to respond than older. Controversy, however, continues.171 Although dietary treatments appeal to parents,170 it is virtually impossible to insure compliance in a child who is of school age.

Other factors related to diet which some have implicated in the etiology of hyperactivity are food allergies, vitamin deficiencies, and sugar. Barkley70 summarizes the lack of evidence for these theories.

Preliminary findings indicate that hyperactive children with elevated but "non-toxic" lead levels and without a "known cause" for hyperactivity (eg, birth trauma) improve after treatment with lead chelating agents.172 Although lead toxicity is probably not causal in the majority of ADD children, it should be considered, especially if there is a history of pica or other significant environmental exposure to lead.

CONCLUSION

With appropriate evaluation and monitoring, pharmacotherapy is a safe and efficacious treatment for some symptoms in children and adolescents with ADD, The deficits which are not addressed by medication may be remediated by other interventions. Multiple measures of outcome are essential since ADD is a complex disorder and stimulants have actions which are far from simple. There are hints that combined treatments may be best, either to address multiple areas of symptoms or to increase efficacy beyond that of either intervention alone. A great deal of work remains to be done with more homogeneous and carefully described populations, standardized and controlled treatment interventions, and prospective long term follow-up studies.

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