THE ASSESSMENT OF DRUG EFFECTS INCHILDREN AS COMPARED TO ADULTS

Klaus K . Minde~ M.D. and Gabrielle C. Weiss~ M.D.

Valid knowledge about drug effects in children remains today theCinderella of research in psychopharmacology. The reasons for thisneglect are multiple, encompassing conceptual as well as practicalproblems besetting the investigator. In the present communicationwe attempt to deal with certain of the difficulties inherent in the sub­ject and venture some suggestions which might help clarify ap­proaches to this area.

One major problem encountered in commonly used standardworks of drug therapy in children is the confounding of childrenand adults. Thus Logue and Bessman (1968, p; 65) in their chapteron pediatric psychopharmacology state: "The relation between thepsychiatrist and the patient is critical and frequently influences theresults both positively and negatively. The patient assumes thatimprovement is expected. The psychiatrist develops a positive atti­tude toward the patient, an impression is conveyed to the patient,and the patient responds favorably." This statement appears to bea transcription of thoughts more relevant to an adult populationthan to children. Kalinowsky and Hoch (1961) in their textbookmention children on nine brief occasions, mainly to point out rec­ommended dosages for particular medications. Their book offerssome general remarks about the need for controlled experiments,diagnostic accuracy, adequate dosages and length of drug trials,

Dr. Minde and Dr. We iss are Assistant Professors at th e Department of Psychiatry,McGill University, and the Montreal Children' s Hospital, Montreal, P.Q.

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but no discussion, for instance, on the possible influence of extra­pharmacological variables on drug effect in children.

Gradually, however, the special problems of drug research withchildren is coming to be recognized. Thus in a recent article Zrulland his colleagues (1966) evaluate some of the methodological diffi­culties specific to drug research with children, stressing the unre­liability of physicians and psychologists as evaluators of drug effects.Eisenberg (1959) in an earlier paper regrets that investigators oftengo about testing a new drug in children without using any the­oretical model, and mentions some special opportunities the studyof children affords, e.g., more easily comparable academic perform­ance and fewer previously learned experiences. Fish (1969) pointsout the generally neglected issues of defining comparable diagnosticgroups and the commonly faulty control for the initial severity ofthe psychiatric condition. Both Freedman et al. (1955) and Fish(1960) have been pioneers in devising methodologically superiorstudies which document possible solutions to such questions as initialratings and the evaluation of change on particular symptoms.

NATURAL ADvANTAGES OF DRUG RESEARCH WITH CHILDREN

The methodology of assessing drug effects in children actuallypresents certain specific advantages over that of work with adults.For instance, children have a shorter period of prior experience en­tering into the determination of current behavior, and modificationof the latter therefore is less influenced by long-established condi­tioned responses and potentially more dependent upon the pharma­cological agent and the immediate environment.

This statement must be qualified in the light of recent work ofThomas et al. (1957, 1963, 1968), Rutter et al. (1964), Murphy et al.(1962) as well as Richmond and Lustman (1955) and Wolff (1966)who demonstrate how very early temperamental patterns form whichchildren use to cope with their environment. Certain of these char­acteristics are apparently conducive to later psychological maladap­tation (Thomas et al., 1968; Rutter et al., 1964). As they are clearlymeasurable at an early age they could serve as variables upon whichdrug responses can be differentially evaluated. The work by Weissand her group (1968, 1969a) supports this thesis as it shows that

126 Klaus K. Minde-Gabrielle C. Weiss

children who from infancy onward showed symptoms of excessivemotor activity, high distractibility, negative mood, and poor adapt­ability respond better to amphetamines than to chlorpromazine.

A further variable of great importance is the fact that the be­havior of children and its modification can be reliably assessed atschool. This type of evaluation encompasses a greater part of thetotal child than the functionally equivalent assessment of workach ievement for the adult, as teachers are generally more interestedin the growth and development of children than is the basicallyeconomy-minded employer in the emotional welfare of his workers.There is also little inherent threat in a school observation, whereasthe future advancement of an employee may be impeded by asimilar procedure at work. In addition, one usually finds childrenof similar ethnic and socioeconomic background attending the sameschool, thus automatically providing a potential control popula­tion for any drug investigation.

Furthermore, the capacity to learn is one of the most essentialaspects of child development, and an assessment of changes inlearning patterns following the administration of drugs is oftenseen as a sensitive measure of psychological functioning, as wit­nessed by the number of drug studies which have used them as thedependent variable (Conners et al., 1963, 1964; Helper et al., 1963;Werry et al., 1966; Weiss et al., 1968, 1969a). The difficulty inusing general learning and intellectual performance as a parameterof change is their enormous complexity. This makes it virtuallyimpossible to state with certainty at present the exact effect suchdrugs as, for example, the amphetamines have on "learning" inchildren (Freeman, 1966).

Various investigators (Conners et al., 1963, 1964) have attemptedto avoid this problem by devising a particular test battery whichis said to measure only specific learning functions. Even here, how­ever, such general factors as drug-induced changes in attention orthe level of anxiety can decrease the validity of the applied learn­ing task and should be carefully evaluated in each instance.

Another important advantage in working with children are themore standardized academic and social expectations which facili­tate intergroup comparisons and the selection of untreated con­trol groups.

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Finally, there is the absence of any reported addiction in chilodren to such drugs as, for example, amphetamines. This findingmay be due partially to a particular reaction of this age group topsychoactive drugs, but could also be related to the fact thatnormally the respective parent has complete physical control overmedication given to his child. Hence any sign of habituation canbe met with immediate and complete drug withdrawal.

PROBLEMS IN DRUG RESEARCH WITH CHILDREN

There are at the same time specific problems in the methodologyof assessing drug effects in children. Children are more responsivethan adults to small fluctuations in their immediate environment.Hence any change attributed to drug effect must be carefully evalu­ated against unexpected new circumstances in the child's milieu,the possible benefit of the accompanying advice to parents or thedifferent expectations of a teacher who now knows "that some­thing is happening." This problem is reduced, but not eliminated,by using a control group of children who receive the identicalcare other than the active medication. It is noteworthy as wellthat a well-known "seasonal variation" in the frequency and na­ture of referrals to any child psychiatry department exists (Eisen­berg, 1959) which makes it hazardous, for example, to comparechildren referred in the summer with those first seen during thewinter months.

As children are rarely hospitalized for psychiatric reasons, drugevaluations are usually carried out on an outpatient population.This requires some means of monitoring actual drug intake. Veryfew investigators appear to be concerned about this variable, al­though studies dealing with adult outpatients (Willcox et al. , 1965)report a high incidence (up to 50 percent) of patients who fail totake their medication. How far this applies to children who do notusually "like" the taste of pills is largely unknown, although Ep­stein et al. (1968) who measured drug excretion in a small numberof children were able to enforce regular drug intake in their sample.

Despite great efforts on the part of many people (Jenkins .et al.,1966) the most recent nomenclature of child psychopathology(G.AP. Report, 1966) retains a phenomenological orientation

128 Klaus K. Minde-Gabrielle C. Weiss

which does not allow differentiation based on etiology. For exam­ple, the child who. is hyperactive may have brain damage with orwithout mental retardation, be very anxious, show developmentallags, an acting-out personality disorder or a combination thereof.Fish (1969) has suggested that the same symptom varies in its re­sponse to a particular medication depending on the intelligence,severity, and type of psychopathology of the individual.

A further difficulty is that children respond with more individualvariation to an identical mgm/Kg dose of medication. In general,they are less sensitive to drugs than adults and require larger dosesper kilogram of weight. This clinical observation of the authors(Weiss et al., 1969), though unconfirmed by any known publishedreport, is generally recognized by investigators familiar with thedrug treatment of both adults and children. No adequate explana­tion for the phenomenon has been advanced, although it providessupport for the type of methodology in drug studies wherein dosesare individualized for each child in order to obtain maximum ther­apeutic benefit rather than administered in identical amounts toall children in the study. The exact age of the child patient hasalso been said to affect responses to psychoactive drugs.

In a well-documented study by Fish (1960) children above 10years of age were found to respond differently to some medicationthan younger children. This has not been confirmed either in theliterature or by observations of the present authors (Weiss et al.,1969). One of the characteristics of the pediatric age group is thatchildren only rarely ask for symptomatic relief for psychiatricproblems: it is others who complain about them. This reduces thevalue of advising the patient to serve as a judge of change, andmakes an assessment of pre-drug and post-drug intrapsychic func­tioning more difficult. Since drugs are usually given to children toalter behavior rather than their subjective feelings, it is importantto measure well-defined behaviors or "target symptoms" as the de­pendent variables. Comments such as "a simplified behavioristicrating scale was used ... evaluated by trained observers before thebeginning of treatment and bi-weekly during the treatment pro­cedures" (Leven and Impastato, 1961) or similarly vague statementsare often the only description in the literature of dependent vari­ables and their measurement. Even when an explicit listing of items

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in a behavior inventory is given (Cytryn et al., 1960; MoIling et al.,1962), the scales are frequently not validated and their reliabilityis often not established.

Since the complaints about a child usually come from the homeand the school, an assessment of change should include observationsof change from the natural confines of the child's environment.The studies of Zrull et al. (1966) as well as a recent investigationby Rutter and Graham (1968) indicate that a psychiatrist, whetheralone or in combination with a psychologist, is not a reliable in­strument for measuring short-term changes in children's behavior.However, measurement of changes in behavior made by the teacherand the parents who see the child in his natural setting agree sig­nificantly with each other. This is partly due to the ability ofchildren to inhibit behavior labeled as "psychologically unsound"for the time they spend with physicians or psychologists. Further­more, these professionals usually provide a one-to-one relationshipwhich is often less stressful for the child than the larger familygroup or school. Even though children frequently lack the ade­quate cognitive and affective development needed to describechanges in their subjective feelings due to drug effects, an attemptshould nevertheless be made to evaluate this important variable.For example, gross reduction of hyperactivity might not at alltouch upon a severe hopelessness accompanying this symptom, al­though the latter might be the main force perpetuating the presentacademic failure. Again, some drugs (e.g., amphetamines) improvebehavior but generate a feeling of sadness in the child. The mostvalid measures of change in a child. can thus be obtained by meansof a combination of observations of behavior, that is, from othersobserving the child in his natural environment and subjectivelyfrom the child himself.

Finally, one must constantly be aware that natural growth anddevelopment of children confound the evaluation of behavioralchanges. This problem is familiar to all investigators of child de­velopment (Bayley, 1965) but becomes particularly vexing in long­term studies. Yet long-term investigations are potentially of greatimportance as they alone can document the effect of drugs on suchcomplex functions as intelligence and development of impulse con­trols which do not change after brief drug therapy. Possible meth-

130 Klaus K. Minde-Gabrielle C. Weis~

ods of overcoming these shortcomings might be the further devel­opment of such criteria as were first explored by Thomas et al(1963) and Wolff (1966), for example, the delineation of variousbehavior patterns occurring over the first decade of life, whichmay consequently be used as yardsticks of long-term changes.

SUGGESTIONS FOR THE EVALUATION OF DRUG EFFECTS

IN PEDIATRIC PSYCHOPHARMACOLOGY

Methods of assignment to control and active groups should be:'reported and statistics defined in detail. This applies equally to

adult and child psychopharmacological research, but has so farfound less acceptance in child psychopharmacology. The alterna­tive research design obviating the necessity of assigning children tctwo groups is that of using each child as his own control. Here the:'patient is given placebo and active drug in random order (Latinsquare design) and his behavior reassessed after he has remained apredetermined time on the drug. This technique has obvious ad­vantages and has become the method of choice by several investi­gators.

Physiological, psychological, and social variables must be con­trolled, i.e., any drug study should endeavor to use populationswhich are matched in severity of illness, age, sex, and intelligence:'and have received similar "extratherapeutic" treatment (e.g., coun­seling of parents, guidance to schools, etc.). In addition, the sample:'should be matched for season of referral, socioeconomic, and racialbackground.

Behavior should be assessed within the child's normal range 01activity, i.e., the home or school, and not be observed from psy­chological or psychiatric interviews alone.

Freyhan's (1959) idea of using target symptoms as dependentvariables in the assessment of drug changes has been one answeito the poor agreement on psychiatric diagnoses in children. Theestablishment of objective descriptive criteria such as hyperactivitjor hypoactivity, anxiety, etc., will prove methodologically superioiuntil such broad phenomenological classifications as suggested b1Fish (1969) have been further evaluated. Nevertheless, even widthe poor state of agreement on diagnoses, its complete disregarc

Assessment of Drug Effects 131

would be likely to enhance difficulties encountered. For example,a hyperactive psychotic child can be expected to have a differentresponse to drugs given to reduce hyperactivity from that of a non­psychotic youngster.

Dependent variables should be assessed at fixed intervals fol­lowing drug ingestion since psychological functioning and beha­vior in children are strongly influenced by fatigue and the mainlyshort-term effect of some drugs such as amphetamines. Controlfor these factors is generally easy but 'nevertheless frequentlyneglected.

A strong attempt must be made to incorporate validation meas­ures into rating scales because many scales in child psychiatryrepresent chance effects, are insensitive to important individualdifferences or obscure the descriptive picture by a halo effect. Itthus appears mandatory to employ different judges and to attemptto use more than one measure for each behavior (e.g., hyperactivityshould be rated by mothers and teachers), thus increasing the re­liability of results and control for situational and personal factors.

Furthermore, methods to assess change have to be "drug sensi­tive." Negative results when attempts are made to assess such com­plex areas as intelligence and global behavior following drug trialsof 6 weeks or less do not necessarily speak against any long-termdrug effect, but the studies should be supplemented by more spe­cific and more sensitive measures of change (Werry et al., 1966;Weiss et al., 1969a).

In conclusion, we suggest that despite the numerous difficultiesencountered in drug research with children, it is particularly inthis age group that fundamental contributions toward understand­ing the action and use of drug therapy can be made.

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