SYMPOSIUM: BEHAVIOR MODIFICATION BY DRUGS

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Based on a lecture to the American Academy of Pediatrics, October 21, 1971, Chicago, Illinois. ADDRESS FOR REPRINTS: Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114.

PEDIATRICS, Vol. 49, No. 5, May 1972 C. Keith Conners, Ph.D.

From Harvard Medical School and the Massachusetts General Hospital

A

NUMBER of myths have grown up

re-garding the behavioral effects and use of stimulant medications with children. The

first is that there is a type of child unique-ly responsive to stimulant compounds, namely, the hyperkinetic child. The second is that the hyperkinetic child is any child

who is sufficiently overactive to be consid-cred a menace by adults. The third is that the stimulant medications act primarily to reduce motor activity in a paradoxical “sed-ative” fashion; and finally, that the drugs do

not influence cognitive and perceptual functioning in these children. I believe that these myths are due partly to the historical accident of the manner in which they were first studied, partly to the imprecision in

di-agnosis and terminology of classification of

patients, and partly to the paucity of sys-tematic data on sufficiently large samples under sufficiently varied experimental

con-ditions. I would like to present the results

Abbreviations

BUN: Blood urea nitrogen

CBC: Complete blood count

DA: Dextroamphetamine or Dexedrine

LDH: Lactic acid dehydrogenase MP: Methyiphenidate or Ritalin NINDS: National Institute of

Neuro-logical Diseases and Stroke

P: Magnesium Pemoline or Cylert

SGOT: Spectophotometric method

WISC: Wechsler Intelligence Scale

for Children

WRAT: Wide Range Achievement Test

of studies which bear on these issues, and

try to draw some general conclusions re-garding the present state of knowledge with regard to the use of the various psy-chostimulants. In this paper I will deal with dextroamphetamine, methylphenidate, and magnesium pemoline.

I. METHYLPHENIDATE AND

DEXTROAMPHETAMINE

The children for this study were referred from schools, pediatricians, and social

agen-cies for either academic or behavioral diffi-culties, or both. The subjects retained for

the drug study comprised about % of the original referral sample. They were selected to fit the description of the child with “mm-imal brain dysfunction” as defined by the

National Institute of Neurological Diseases

and Stroke (NINDS ) Task Force I report. Specifically excluded were children with psychosis, gross neuropathy, delinquency, primary emotional disorders, or mental

re-tardation. Ages ranged from 74 months to 154 months, with a median of 112 months

(

9.3 years ). Seventy subjects (Ss )were male and five were female; 73 were white. About

9% of the sample fell into Class I of the Hollingshead social class index (low), with

34% in Class II, 26% in Class III, 20% in Class IV, and 11% in Class V.

A detailed social and medical history, neurologic and physical examination, par-ent and teacher symptom ratings, and a battery of neuropsychological tests were obtained. The psychological tests included:

Wechsler Intelligence Scale for Children

(

WISC ), Frostig Test of Visual Perception, a measure of verbal fluency, Wide Range

Achievement Test (WRAT), Bender

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Foc. 1. Effects of stimulant drugs on psychological tests. ( N = 25 per group. ) Values shown are change scores from pre-treatment to

post-treatment.

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PLACEBO (N’22)

CYLERT (N’18)

DEXEDRINE (N’21)

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Fic. 2. Effect of drug treatment on teacher ratings. The rating scale scores consist of sums of 10 items.

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childrens Embedded Figures Test, speech discrimination in background noise,

audi-tory synthesis, vigilance, and rote learning.

The patients are randomly assigned to the three treatment groups by a random

code devised and kept by the hospital

phar-macy, which supplied medication in

identi-cal matched capsules. The assignment re-sulted in 29 Ss assigned to

methylpheni-date, 24 to dextroamphetammne, and 22 to placebo. Dosage was increased once weekly. Each capsule contained either 5

mg dextoamphetamine (DA ) or 10 mg methylphenidate (MP ), or placebo.

Dos-age was gradually increased to a maximum

daily dosage of 15 mg DA or 30 mg MP in divided doses given 20 minutes before breakfast and lunch.

All tests and ratings \‘ere scored and

ad-ministered without knowledge of the treat-ment condition, before treatment and after

6 weeks on treatment. Results were ana-lyzed by a one-way analysis of covariance for each variable separately. Individual comparisons were made between

treat-ments by t-tests. Some of these results are displayed in Figure 1. The results showed

the following significant (p < .05) treat-ment effects: WISC Full Scale IQ, WISC Verbal IQ, similarities, digit span, object

as-sembly, Frostig perceptual quotient (

eye-motor coordination, figure-ground, form

constancy ), verbal fluency, teacher symp-tom ratings, Bender Gestalt, Draw-A-Man, Porteus Mazes, speech-noise test,

continu-ous vigilance test (omissions and commis-sions ) . Rote learning and embedded figures showed effects significant at the 10% level. All differences were in favor of the

drug-treated Ss. Only two measures, WISC arith-metic and similarities, were significantly dif-ferent between the two active drugs, both in favor of Ritalin. Analysis of side effect reports

showed that both drugs produced

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4: L ‘.5 15 10 0 2 WEEK I IJ

4 6 8

OF TREATMENT

FIG. 3. Effect of drug treatment on parent ratings of impulsivity. 25 L 20 (#5 15 10 P.-,‘ PLACEBO (N’27) CYLERT (N:25) DEXEDRI NE (N:25)

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FIG. 4. Effect of drug treatment on 10-item parent rating form. 25

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FIG. 5. Report of insomnia over 8-week treatment

period. Only at day 28 were drug treatments

dif-ferent from placebo.

PLACEBO This was especially true for the side effects

rated as moderate to severe, although the

percentage of subjects receiving those

rat-CYLERT . 7’ . 11

DEXEDRINE ingswas qul e sma

II. MAGNESIUM PEMOLINE (P) AND

DEXTROAMPHETAMINE (DA)

This study involved a similar population of children as in the previous study. The same parent and teacher rating scales, a global improvement rating, and the

follow-ing psychological tests were employed:

WISC, Draw-A-Man, Bender Gestalt,

Por-tens Mazes, Illinois Test of Psycholinguistic Abilities, Frostig, WHAT, Gray Oral Read-ing, vigilance, Gates Reading Survey, and visual evoked response under attending and

nonattending conditions. In addition, the following laboratory measures were

col-lected at baseline, 4 weeks, and 8 weeks during the 8-week study: complete blood

count (CBC ), hematocrit, hemoglobin, platelets, blood urea nitrogen (BUN ),

alka-line phosphatase, spectophotometric

method (SCOT), lactic acid

dehydroge-nase (LDH ), bilirubin, and complete

un-nalysis. Of 132 patients examined, 84 were admitted to drug study, and 81 completed

the 8 weeks of treatment. There were 74

males and 10 females; all Caucasian except for one Negro. Fifty-nine children had both behavior and academic problems, 19 had behavior problems only, and six had

aca-demic problems only. The age range was 6 to 12 years, with a mean age of 8.24 years.

Social class distribution was almost identi-cal to the previous study.

Patients were randomly assigned, double-blind, to the three treatments, with P ad-ministered in tablets containing 25 mg mag-nesium pemoline Cylert (18.75 mg pemo-line) and DA in 5 mg matched tablets. P was given only in the morning with equiva-lent numbers of placebos administered in

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ARTICLES 705

125 mg, with a mean resulting dose of 82 mg. DA was given up to 40 mg per day in

divided doses, with a mean of 20 mg. The number of dosage adjustments during the study were 6.2, 6.7, and 7.3 for Cylert, DA, and placebo respectively. Weight, pulse,

and blood pressure were obtained with a physical examination at 2, 4, 6, and S weeks. Abbreviated parent and teacher ratings on a 10-item scale were obtained at weekly in-tervals, and all psychological tests were

administered at baseline and then at 8 weeks.

Rating Results

A global clinical rating by the staff showed highly significant treatment effects due to drugs. At both 4 and 8 weeks both drugs were superior to placebo. By the end of treatment 96% of the DA and 77% of the P subjects were rated as improved or much improved, with 30% of the placebo patients rated as improved, and none much improved. Similar results were obtained from the teacher’s global ratings of

aca-demic progress.

The teacher symptom rating was factor analyzed, and the results analyzed by

mul-tivaniate analysis of variance. Significant

treatment effects were found for the defi-ance, inattentiveness, and hyperactivity

factors for both drugs. Although DA showed an earlier effect than Cylert, by the end of 8 weeks the two treatments were

in-distinguishable on these factored measures. Identical results were found for the abbre-viated teacher ratings (Figure 2).

DA showed significant effects by 2 weeks, whereas Cylert showed clear differences from placebo only at 6 weeks and

after-wards.

The 93-item parent symptom list was also factor analyzed, and of the eight factor scores, four showed significant treatment effects: conduct disturbance, impulsivity

(Figure 3), immaturity, and antisocial be-havior. Not affected by treatments were

anxiety, somatic complaints, obsessional traits, and hyperactivity. The abbreviated parent rating showed a highly significant

treatment effect (Figure 4) similar to that found with the teacher ratings. In most of

the effects an early DA response is seen by

2 weeks, but there are no drug-drug differ-ences by 8 weeks.

The psychological test battery was first tested for a drug effect by a multivaniate analysis of variance, producing a highly significant effect (p < .004) . Individual analysis of variance showed that spelling, reading, Porteus Mazes, Frostig perceptual quotient, eye-motor coordination, and

fig-ure-ground scores were significantly differ-ent from placebo, with no drug-drug

differ-ences.

Laboratory studies showed no children cx-periencing abnormal changes over the course

of treatment, and analyses of variance mdi-cated no group changes attributable to the

treatments. Systolic, diastolic, and pulse-pressure were unchanged for all three

groups in the study. Weight changes were

+

.5

kg, + 1. 1 kg, and + .9 kg for DA, P, and placebo groups respectively. These changes were nonsignificant between

groups.

The major side effects of both drugs were

insomnia and anorexia. By the end of the

treatment period fewer than 5% of patients were experiencing moderate or severe in-somnia, and all of these were on DA. Both drugs produced most insomnia between the seventeenth and twenty-eighth day of

treatment, but only at day 28 were there ac-tually drug-placebo significant differences

(Figure 5).

In summary, both of these studies

pro-vide unequivocal evidence of improved be-havior as judged by clinicians, parents, and

teachers, and both studies show significant

drug effects on some cognitive, perceptual, and achievement measures. However, some inconsistencies are rather striking. Some of

the most drug sensitive measures, such as the vigilance task, did not show effects found in the earlier study, and indeed, in

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the more recent pemoline study, and failed to do so in two earlier DA studies. It seems unlikely that these differences reflect the difference in length of treatment or dosage

schedules; rather, we suspect that they are likely to be fortuitous results of the sample composition. Such inconsistencies led us to

analyze the predictive value of various

post-drug measuring instruments were used, we were able to obtain 178 previously treated subjects (100 on drugs, 78 on pla-cebo). The various psychological tests were converted to change scores and intercorre-lated. This showed that the changes tended to be largely independent of one another, with relatively little communality among

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ARTICLES 707

tests. However, by factor analysis of the

change measures we were able to arrive at six standardized change factors, which we

labelled academic performance, attention, perceptual, reading, impulsiveness, and

classroom disturbance. These change scores were then predicted from stepwise multiple

regression equations, with correlations of .73, .82, .63, .58, .70, and .57 respectively.

Clearly there are a number of rather differ-ent types of response to the drugs, and

these are predicted by different patterns of

baseline performance on psychological

tests.

This result is further clarified by

subject-ing the baseline measures to a computer profile analysis, which reveals at least seven

somewhat distinct patterns of performance in our already selected population (Fig. 6). When these separate groups are analyzed for drug placebo differences, it is found that the

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drug-treat-tention. They show significant drug effects on the perceptual-motor factor. This group also shows a very large hemispheric asymmetry on visual evoked response, with the left side smaller than the right. Group II is very poor on perceptual integration and spatial

orientation, and tend to show improvement primarily in attention-related tests and aca-demic ratings. Group III is quite poor in

spatial orientation but good in eye-motor coordination. They show improvement sim-ilar to Group II in attention but in contrast

to Group II do not show a related degree of improvement in academic ratings by teach-ens. Group IV is low in perceptual integra-tion but good in spatial orientation, and tend to show improvement only on tests such as the Bender Gestalt. This group also has marked hemispheric evoked response

asymmetry, but with a markedly larger left-than right-sided amplitude. Group V

con-stitutes about 20% of the sample and show no drug treatment effects whatsoever. Their baseline profile is essentially flat, with some

report of conduct and classroom distur-bance by parent and teacher, but no test deficits. Group VI shows marked hemisphe-ric asymmetry (small left-sided ampli-tudes) of the evoked response, are low in achievement, and rated poorly by teachers

for classroom conduct. This group shows significant drug effects on academic

perfor-mance, and spelling and arithmetic. Group

smaller left-sided amplitudes. They show changes due to drugs mainly in reading tasks.

Thus, it is apparent that there is both physiological and psychological

hetero-geneity in this group of children with pre-sumed “minimal brain dysfunction.” All

children with this diagnosis do not respond in the same way to drug therapy, and the

type of response appears to depend on the profile of abilities, and possibly on underly-ing physiological responsiveness in the ce-rebral cortex. Clearly, whether a child should receive this form of therapy depends on a careful assessment of the probability that he will respond for the target symptom or deficit of most concern. Some poor read-ers do indeed show remarkable progress with adjunctive analeptic therapy, but many more do not; some behavior problem

children show improvement in behavior but not in learning, and vice-versa. While the present studies are preliminary, and do not

as yet offer useful diagnostic tools for the physician, they appear to dispel some of the

myths surrounding this treatment. No sin-gle syndrome of hyperkinesis is uniquely re-sponsive to therapy, motor activity itself is not among the more important types of

changes found with these children, and sev-eral patterns of change of perceptual and

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1972;49;702

Pediatrics

C. Keith Conners

DYSFUNCTION

EFFECTS OF STIMULANT DRUGS IN CHILDREN WITH MINIMAL BRAIN