in children with minimal brain dysfunction - Europe PMC

Individual responses to methylphenidate and caffeine in children with minimal brain dysfunction* B.D.

GARFINKEL,f

md; C.D.

Webster,$

ph

d; L.

Sloman,§

Summary: Eight children with minimal brain dysfunction

studied for their individual responses to two stimulant medications methylphenidate hydrochloride and caffeine citrate. Four types of behavioural responses were observed in the double-blind crossover experiment: four children responded favourably to both psychostimulants, one responded to methylphenidate alone and two responded to the placebo. The behaviour of one child deteriorated while he was taking methylphenidate and caffeine. In general, methylphenidate was superior to caffeine in diminishing hyperactive and aggressive behaviour. It is apparent that such stimulant medication exerts its therapeutic effects in these two areas primarily and would therefore be useful as one aspect of a complete treatment program for children with this syndrome. were

.

Resume: Les reactions individuelles a deux medicaments stimulants le chlorhydrate de methylphenidate et le citrate de cafeine ont ete observees chez huit enfants souffrant de dysfonctions cerebrales minimales. Dans nos experiences a double anonymat et a entrecroisement nous avons note quatre formes de comportements differentes: quatre enfants ont reagi favorablement aux deux psychotoniques, un a reagi uniquement au methylphenidate et deux ont reagi au placebo. Le comportement d'un des enfants s'est aggrave alors qu'il prenait le methylphenidate et la cafeine. En general, le methylphenidate a ete plus efficace que la cafeine en attenuant le comportement hyperactif et agressif des enfants. II est clair que la medication exerce ses effets principalement dans ces deux regions et qu'elle ne serait par consequent utile que comme un element d'un traitement global des enfants souffrant de ce syndrome. .

.

From The Hospital for Sick Children and Clarke Institute of Psychiatry, Toronto ?This paper was prepared for the Sept. 20, 1975 issue of the Journal commemorating the centennial of The Hospital for Sick Children, Toronto, but because of space limitations could not be included. tResearch fellow, The Hospital for Sick Children Foundation child care training department, University of Victoria, tDirector, BC Victoria, §Senior psychiatrist, child and adolescent unit, Clarke Institute of

Psychiatry Reprint requests to: Dr. B.D. Garfinkel, Department of psychiatry, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8

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Minimal brain dysfunction is a heterogeneous syndrome characterized by excessive non-goal-directed motor activity, distractibility, impulsivity and short attention span, in asso¬ ciation with impaired learning and coordination.1 Hyper¬ activity has been observed in approximately 5% of children of elementary school age,2 and an additional 3% have specific reading disabilities.3 Millichap4 has shown that 55 to 89% of children with minimal brain dysfunction respond favourably to various pharmacologic agents. Since 1937, when Bradley5 first described the efficacy of amphetamine in treating such children, sympathomimetic drugs have re¬ mained the pharmacologic agents of first choice.6 Other psychotropic agents, including major tranquillizers,7'8 tri¬ cyclic antidepressants,9"11 anxiolytics,12'13 lithium carbonate14 and benztropine mesylate,15 have been tried but have been less efficacious or have produced intolerable side effects. The physician relying on sympathomimetic agents as part of his therapeutic regimen must manage both immediate and long-term side effects. Such immediate effects as anorexia, irritability, insomnia and stomach-ache are common,6 and long-term use of stimulants has been reported to re¬ duce weight gain and possibly growth in stature.16 The child may have a true therapeutic response to the pharmacologic agent, or behaviour may improve as a result of parent and physician expectations a placebo effect.17 However, 30% of these children will have minimal or no response to stimulant medication.18 In a previous study19 we found, by group-analysis statis¬ tical techniques, that methylphenidate hydrochloride was superior to caffeine citrate in the overall management of children with minimal brain dysfunction. We had used a larger number of measures to evaluate behavioural changes. We observed, however, that in reporting the statistical re¬ sults only, information on the individual child's response had not been demonstrated. In the present study we evalu¬ ated the children's individual responses to demonstrate the differential effects of the medications and a placebo; we hoped in this way to distinguish the child who responds to stimulant medication from the "nonresponder" and the

"placebo-responder".

Patients and methods Patients The study included 10 children in whom the condition met all the criteria for minimal brain dysfunction as deCMA JOURNAL/OCTOBER 18, 1975/VOL. 113 729

scribed by Wender:20 hyperactivity, short attention span, impulsivity, affective disturbance, poor school performance, and intelligence quotient of 90 or more as determined by the Wechsler Intelligence Scale for Children (WISC). Non¬ specific neurologic signs and perceptual-cognitive disturb¬ ances were observed in 5 of the 10 children. Two children were subsequently eliminated from the study because of medical illness (infectious hepatitis and epilepsy). The sub¬ jects completing the study were boys from 6 to 10 years of age (mean age, 104.6 months). Their mean weight was 36.69 kg. None had intercurrent medical or surgical prob¬ lems. All eight children were full-day (8.45 am to 3 pm) pa¬ tients 5 days a week in the child and adolescent unit of the Clarke Institute of Psychiatry. They had failed to re¬ spond to commonly used outpatient modalities of treatment, both pharmacologic (sympathomimetics, major tranquillizers and anxiolytics) and psychotherapeutic, and were not benefiting adequately from school attendance in either a regular classroom or a special education class. Six of the eight had previously been receiving methylphenidate but not in the 2 weeks before the

study began.

Experimental program The study lasted 9 weeks: the first 2 weeks and last week were baseline periods, during which the children were observed only and received no medication; the intervening 6-week period was divided into three 10-day drug periods. No medication was administered during the weekends, which effectively produced 2^-day "washout" periods. The order in which each child received the three medications was randomly assigned by the hospital pharmacist; in such a crossover design each patient serves as his own control. Because no one involved with the children (including par¬ ents, teachers, child care workers, nurses, attending physi¬ cians and authors) was aware of the agent each child was receiving, a double-blind procedure was ensured. The child received his medication at 9 and 12

am as a

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80 70 60 50 40

hot drink, prepared by adding hot water to a mixture of 2.2 g of decaffeinated coffee (concentrations: caffeine,

0.195%; sodium, 0.018%; potassium, 4.32%; iron, 0.023%; and chlorogenic acid, 12.0%) and the powdered 10 mg of methylphenidate hydrochloride, medication 150 mg of caffeine citrate, or 100 mg of lactose (the placebo). The appearance of each dry mixture was the same and the taste of the three drinks was similar. The total daily dose of caffeine was approximately 160 mg (caffeine content of caffeine citrate, 75.45 mg; that of decaffeinated coffee, 4.29 mg) and the total daily doses of methyl¬ phenidate and lactose were 20 and 200 mg, respectively. Throughout the study periods hospital staff and parents were advised not to give the children unreported medica¬ tion, drinks or food known to contain caffeine (tea, cola drinks, coffee, cocoa, chocolate). The child's diet was regulated for the noon meal and morning and afternoon

snacks. Behavioural assessment Children were independently rated on the 39-item Conners' Teacher Rating Scale21 by two child-care workers after the children had left for home. The presence and degree of abnormal behaviour were rated on a 4-point scale: 0, "not at all"; 1, "just a little"; 2, "quite a bit"; 3, "very often". Scores for two behavioural factors, aggression and hyper¬ activity, out of a potential five factors, were determined by Conners' factor analysis of the 39 items.22 These two factors have been shown to reflect pharmacologic thera¬

peutic changes.10

Results Positive therapeutic effects of methylphenidate and caffeine Four of the eight children showed similar therapeutic responses to the two stimulant drugs: each had a pro¬ nounced response to methylphenidate and a lesser response to caffeine. Day-by-day data during the experimental pro¬ gram and mean rating scores are shown in Figs. 1 and 2 for the four responding subjects. In subject 4 the response to 20 mg of methylphenidate was impressive (Fig. 1). The therapeutic effect was ap¬ parent on the 1st day of administration; when the drug was discontinued his scores returned to baseline. Caffeine also produced a pronounced effect on the 1st day of administration but, though it was apparently therapeutic

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FIG. 1.Scores on rating scale over days (left) for subjects 4 (upper panel) and 5 (lower panel) and mean scores for each phase of the experiment (right). The scores are those determined by the rater who was most in contact with the child. Lower scores indicate improvement in behaviour. *

730 CMA

JOURNAL/OCTOBER 18, 1975/VOL. 113

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FIG. 2.Scores on rating scale over days (left) for subjects 7 (upper panel) and 8 (lower panel) and mean scores for each phase of the experiment (right). Scores determined as for Fig. 1.

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histogram illustrates, its effect diminished Subject 5's response to methylphenidate was also strong, though not as pronounced as that of subject 4 (Fig. 1). The effectiveness of caffeine in this child increased slightly with time. The pharmacologic responses of subject 7 (Fig. 2) were similar to those of subject 5. Subject 8's response to methylphenidate was pronounced and increased with time. While receiving caffeine his con¬ dition seemed to improve first, then to decline. As the histogram shows, his overall response to caffeine was less than that to methylphenidate. Apparent placebo effects Subjects 2 and 6 had what appeared to be placebo effects. The day-by-day data and the mean scores over each period are shown in Fig. 3. From the histograms it is clear that both subjects behaved better when receiving the placebo than under baseline conditions. Subject 2 showed a steady improvement in behaviour with repeated administration of methylphenidate; this change in behaviour would be obscured if only his mean performance during that phase were considered. Subject 6 also showed a steady improvement in be¬ haviour with methylphenidate therapy but the trend was not as great. Whether caffeine is judged to have impaired this child's performance depends on whether his scores while taking this medication are compared with those dur¬ ing placebo administration or those during the baseline phases. If, as seems most reasonable, the placebo scores are compared, then caffeine had deleterious effects on the child. If, however, the baseline scores are compared, then caffeine did not yield a negative behavioural response. Adverse effects of methylphenidate and caffeine Subject 3's mean scores (Fig. 4) suggest that both methyl¬ phenidate and caffeine impaired performance, whether his behaviour while receiving the drug is compared with that while receiving the placebo or with that during the baseline phases. This child had been receiving methylphenidate for 2 years before the start of this study and one of the reasons for his admission to day treatment was for reassessment of methylphenidate therapy. He was also one of the three oldest boys in the study (9 years, 8 months) and may represent an emergence of a stimulant response to psychoactive medications. over

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therapeutic effect of methylphenidate with therapeutic response to caffeine Subject 1 showed an adverse response to caffeine (Fig. 4), his scores with caffeine being higher than those during the baseline and placebo phases. However, examination of the day-by-day data makes it hard to justify this conclusion, for there was definite deterioration in behaviour as the experiment continued. It would seem, therefore, that this child's problems were increasing during the course of treatment. Caffeine, unlike methylphenidate, did not atPositive no

tenuate the overall

deterioration in behaviour. A case,

though, can be made for a positive response to methyl¬ phenidate because, from the 2nd day of administration, his behaviour remained stable; also, his mean score while receiving methylphenidate was lower than that during the first baseline phase, which is contrary to the general trend. Therapeutic index The value of pharmacologic agents can also be assessed by computing a therapeutic index, which is simply the difference between the mean of the placebo-phase scores and the mean of the drug phase divided by the mean of the placebo phase. Such indexes may be positive or negative, indicating an improvement or a deterioration in the child's behaviour as a result of drug administration. In the present study such therapeutic indexes were com¬ puted not only for the total rating-scale score but also for the two factors, aggression and hyperactivity, that have consistently shown the greatest response to pharmacologic agents (Table I).23 As the indexes show, subjects 4, 5, 7 and 8 responded to both drugs, but less well to caffeine, and the children's responses were unambiguous. The overall drug-induced therapeutic effects as shown by the indexes in Table I are consistent with the data in Figs. 1 and 2. When a therapeutic effect is not observed for the factors of aggression and hyperactivity (subjects 2, 6, 3 and 1) the effects are likely to be ambiguous. More specifically, the overall effects of medicine may be absent, minimal or even adverse. An examination of the total therapeutic indexes along with the aggression and hyperactivity scores

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FIG. 3.Scores on rating scale over days (left) for subjects 2 (upper panel) and 6 (lower panel) and mean scores for each phase of the experiment (right). Scores determined as for Fig. 1.

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FIG. A.Scores on rating scale over days (left) for subjects 3 (upper panel) and 1 (lower panel) and mean scores for each phase of the experiment (right). Scores determined as for Fig. 1.

CMA JOURNAL/OCTOBER 18,

1975/VOL. 113 731

gives the physician a reliable measure of the therapeutic efficacy of stimulant medication and can indicate the types of behaviour on which the drug appears to be exerting its major effect (for example, in subject 1 the effect of methylphenidate is much greater on aggression than on hyperactivity). Discussion The present paper describes in detail responses of individual patients to two psychostimulants. In a previous study19 the children were treated as a group for statistical purposes using standard analysis of variance techniques. A study analysing a group response provides the physician with valuable information about which medication to prescribe. It is, perhaps, not surprising that since the minimal brain dysfunction syndrome has not as yet been shown to occur in a homogeneous population of children, the physician will likely observe varied responses to medications.18 The present study of the specific patient enables one to evaluate more fully the individual child's responses and thus examine the nature of that variability. In the children studied there were four specific types of reaction to stimulant medication. Four children had a positive response to both medications, and the response to caffeine was consistently smaller than that to methylphenidate. One child's behaviour worsened while he was receiving each of the stimulants. Another had a small positive response to methylphenidate but no response to caffeine. The other two children appeared to show placebo effects, one having a questionably adverse reaction to caffeine; both showed very small positive responses to methylphenidate. Some of the variability in the present data might have been more adequately explained had it been possible to monitor absorption, distribution and excretion of the drugs as the experiment progressed, especially since a fixed dose of each stimulant was administered. The differential rates of response pose interesting questions for further research into serum concentrations of psychotropic medications. The data from the present study provide strong confirmation of the powerful effects of methylphenidate in children with minimal brain dysfunction. Seven of the eight children showed a positive therapeutic response to this stimulant. However, when the data are plotted day by day, specific differences in response between the children can be detected. One child showed an immediate response to the drug (Fig. 1, top panel). Other children (for example, subjects 2 and 8, Figs. 2 and 3) exhibited a gradual response to this medication. It appears that a trial of at least 2 weeks is necessary to judge the therapeutic efficacy of stimulant drugs in these children. Persistence of therapeutic Table I-Therapeutic indexes for total rating-scale (five-factor) score and scores of aggression and hyperactivity

Subject Unambiguous* responders 4 5 7 8 Ambiguousf responders 2 6 3 1

Methylphenidate Aggres- Hypersion activity Total

Caffeine Aggres- Hypersion activity Total

63 43 39 46

41 44 31 37

44 32 43 39

22 21 17 19

8 30 18 27

14 22 16 17

31 6 -4 63

11 3 2 19

0 0 -6 28

-1 -45 -17 -43

-8 -25 -43 -16

5 -38 -21 -23

8Positive response in the three parameters: total score, aggression and hyperactivity. tPositive response is not present in all three parameters.

732 CMA JOURNAL/OCTOBER 18, 1975/VOL. 113

effects over a 1 0-day period, as demonstrated here, do not necessarily indicate long-term beneficial effects.16 Results of follow-up studies indicate that therapy with drugs alone yields disappointing results.24 Pharmacologic agents are most useful in combined programs of remedial education, parental counselling and psychotherapy.25 This study is the first to include behavioural assessments by child care workers using Conners' Teacher Rating Scale. None of our workers had difficulty in completing the rating each day. If the physician is to study effects of stimulant medications systematically, he should regard both the child's teacher and the parent as allies and encourage the use of such rating scales by them. Our results indicate the value of examining, where possible, the effects of stimulant medication on two specific behavioural factors - aggression and hyperactivity. The three other behavioural factors evaluated with Conners scale - anxiety, sociability and impulsivity - did not change appreciably during the different experimental phases, as others have reported.10 It is clear that sympathomimetics are not a panacea for this syndrome, but only attenuate specific aspects of disordered behaviour. The value of medication in the overall management of these children appears to 'be in heightening their responsiveness to remedial programs by diminishing specific types of disordered behaviour.

We wish to thank General Foods Ltd. of Canada for supplying samples of coffee and for technical assistance; the day-treatment staff of the Clarke Institute of Psychiatry; and Mr. J. Eisen. References 1. RAPOPORT JL, QUINN P0, LAMPRECHT F: Minor physical anomalies

and plasma dopamine-beta-hydroxylase activity in hyperactive boys. Am I Psychiatry 131: 386, 1974 2. WERNER E, BIERMAN JM, FRENCH FE, et al: Reproductive and environmental casualties: a report on the 10-year follow-up of the children of the Kauai Pregnancy Study. Pediatrics 42: 112, 1968 3. Mosuusoi.t J, STEWART M: Evidence for polygenetic inheritance in the hyperactive child syndrome. Am I Psychiatry 130: 791, 1973 4. MILLICHAP JG: Drugs in management of minimal brain dysfunction. Ann NY Acad Sci 205: 321, 1973 5. BRADLEY C: The behaviour of children receiving Benzedrine. Am I Psychiatry 94: 577, 1937 6. MILLIcHAP JG: Drugs in management of hyperkinetic and perceptually handicapped children. JAMA 206: 1527, 1968 7. SPRAGUE RL, BARNES KR, WERRY 35: Methylphenidate and thioridazine: learning reaction time, activity, and classroom behaviour in disturbed children. Am I Orthopsychiatry 40: 615, 1970 8. WERRY JS, WEISS G, DOUGLAS V, et al: Studies on the hyperactive child. III. The effect of chiorpromazine on behaviour. I Am Acad Child Psychiatry 5: 292, 1966 9. HUESSY HK, WRIGHT AL: The use of imipramine in children's behavsour disorders. Acta Paedopsychiatry (Easel) 37: 194, 1970 10. WINSBERG BO, BIALER I, KUPIETZ 5, et al: Effects of imipramine and dextroamphetamine on behaviour of neuropsychiatrically impaired children. Am I Psychiatry 128: 1425, 1972 11. KRAKOWSKI AJ: Amitriptyline in treatment of hyperkinetic children: a double blind study. Psychosomatics 6: 355, 1965 12. ZRULL JP, WESTMAN JC, ARTHUR B, et al: A comparison of chlordiazepoxide, d-amphetamine, and placebo in the treatment of hyperkinetic syndrome in children. Am I Psychiatry 120: 590, 1963 the 13. GREENBERG LM, DEEM MA, MCMAHON 5: Effects of dextroamphetamine, chiorpromazine and hydroxyzine on behaviour and performance in hyperactive children. Am I Psychiatry 129: 532, 1972 14. GREENHILL LL, RIEDER RO, WaNDER PH, et al: Lithium carbonate in the treatment of hyperactive children.

Arch Gen Psychiatry 28: 636, 1973 15. CARMAN JS, TUCKER LS: Benztropine in childhood hyperkinesis. Lancet

2: 1337, 1973 16. SROUFE LA, STEWART MA: Treating problem children with stimulant drugs. N Engi I Med 289: 407, 1973 17. STEINBERG GG, TROsHINsKY C, STEINBERG HR: Dextroamphetamine responsive behaviour disorder in school children. Am I Psychiatry 128: 174, 1972 18. SATrERFIELD JH, CANTWELL DP, SATFERFIELD BT: Pathophysiology of the hyperactive child syndrome. Arch Gen Psychiatry 31: 839, 1974

19. GARFINKEL BD, WEBSTER CD, SLOMAN L: Methylphenidate and caffeine in the treatment of children with minimal brain dysfunction.

Am I Psychiatry 132: 723 1975 20. WENDER PH: Minimal brain dysfunction in children: diagnosis and management Pediatr Clin North Am 20: 187, 1973 21. CONNERS CK: A teacher rating scale for use in drug studies with children. Am I Psychiatry 126: 884, 1969 22. CONNERS CK, EISENBERG L, BARCAI A: Effects of dextroamphetamine on children: studies on sublects with learning disabilities and school behaviour problems. Arch Gen Psychiatry 17: 478, 1967 23. KUPIETZ 5, BOTTI E: Behaviour measurement in pediatric psychopharmacology. Am I Psychiatry 131: 106, 1974 24. MINDE K, WEISS G, MENDELSON N: A 5-year follow-up study of 91 hyperactlve school children. I Am Acad Child Psychiatry 11: 595, 1972 25. WEiss G, KRUGER E, DANIELSON U, et al: Effect of long-term treatment of hyperactive children with methylphenidate. Can Med Assoc I

112: 159, 1975