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The Use of Psychotropic Drugs in Children
The Use of Psychotropic Drugs in Children
John S. Werry, M.D.
Abstra
The use of psychotropic drugs in children has developed more slowly than in adult psychiatry, but this use has increased greatly in the last five years with clinical indications strikingly different from those in adults. It has also provoked much more controversy with press exposes leading to governmental hearings (Conference on the use of stimulant drugs, 1971; Lipman, 1974), scientific symposia (Cruz et aI., 1973), position statements (American Academy of Pediatrics, 1975), spirited apologies (Eisenberg, 1972; Gittelman-Klein, 1975; Wender, 1971, 1975; Werry, 1974), equally spirited criticisms (Grinspoon and Singer, 1973; Ounsted, 1974; Rie et aI., 1976), and a rush of books for parents and professionals alike (Cantwell, 1975; Millichap, 1975; Safer and Allen, 1976; Wender, 1971, 1973). Criticisms made seem reducible to two main arguments: (l) that some of the drugs used are undesirable or downright dangerous; and (2) that doctors are putting creative, bored, dissenting, oppressed, or otherwise rightfully troublesome children into chemical strai~ackets.
Dr. WeT1')' is Professor a.nd Head, Department of Ps.vchiatry, Universitv of Aucklarui. Much of the work described here and the preparation of this review were supported by the Medical Research Council of New Zealand, USPHS Grant No. MH 18909, CIBA-GEIGY (U.K.) and Searle (Australasia). Reprints may be requested from the author at the Department of Psychiatry, School of Medicine, University of Auckland, P.B., Auckland, New Zealand.
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DIAGNOSIS
A lot of the criticism centers on the ability of doctors to diagnose by objective scientific criteria rather than those dictated by personal or social imperatives. To make an objective diagnosis in medicine, at least two conditions must be met; first, there must be a set of explicit rules by which to make the diagnosis, particularly the spelling out of the necessary and sufficient criteria (including disqualifying ones) by which the diagnosis can be made. An attempt to do this can be seen in the diagnostic system and decision tree developed by NIMH for its battery of measures to be used in pediatric psychopharmacology (Fish, 1971; Psychopharmacology Bulletin, 1973; Werry, 1973). Second, in addition to the set of rules, there must be accurate ways of detecting these necessary and sufficient criteria. Here too, considerable effort has been made in the last few years, examples of which can be seen in the following: (1) Development of norms for various symptom-rating scales, most notably Conners' Teacher Questionnaire (TQ) (Conners, 1973; Gittelman-Klein et aI., 1976; Kupietz et aI., 1972; Werry et aI., 1975b). (2) Cross-validation of ratings by parents, teachers, doctors, and observers (Abikoff et aI., 1977; Gittelman-Klein et aI., 1976; Rapoport and Benoit, 1975; Rie et aI., 1976; Werry et aI., 1966). (3) Objective methods of measurement of symptomatology such as mechanical devices for motor activity (Millichap and Johnson, 1974; Montagu and Swarbrick, 1975; Rie et aI., 1976; Sprague et aI., 1970), EEG procedures (Conners, 1974; Satterfield and Cantwell, 1975), other psychophysiological procedures (Satterfield and Cantwell, 1975), behavior observations (Abikoff et aI., 1977; Rapoport et aI., 1974a; Sprague et aI., 1970), neurological measures (Rapoport and Quinn, 1975) and biochemical estimations (Greenberg and Coleman, 1976; Rapoport et aI., 1974b). (4) Development of a standard set of measures for demographic, background, and anamnestic data by NIMH (Psychopharmacology Bulletin, 1973). While much of modern medicine is obsessed with laboratory measures, the reluctance of child psychiatrists to move in this direction means that much of the current technology described above has little use in routine clinical practice except perhaps for simple questionnaires like Conners' TQ, crude norms of which are available to help objectify the diagnosis of abnormality. Such is the state of the art, however, that in the end most clinical use of psychotropic drugs with children becomes a matter of using very crude
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diagnostic or symptomatic signposts and submitting the drug to an empirical trial to see if it suits the child concerned. SOME PRINCIPLES OF PRESCRIBING
Much of the clinical use of psychotropic drugs in children is substantially the same as with any kind of therapy. Obviously it must be based on good history taking and examination and the development of rapport with parents and child alike. The reason for the treatment, its likely results, good and bad, must be explained and parents and child's questions answered directly and honestly. Good, all-round clinicians are likely to do a better job than those who use medication as a means of maintaining distance from their patients or in the fruitless search for magical cures. It is rare to find a child who so benefited by medication that no other management is necessary (Douglas, 1975; Sroufe and Stewart, 1973; Werry, 1968). Drugs should never be regarded as definitive treatment in themselves any more than the converse view that because another treatment may produce some change in this or other patients, this necessarily excludes any role for medication (e.g., AylIon et aI., 1975). In short, drug treatment should be seen as synergistic, and not in competition with other treatment. As with other treatments, it is prudent to obtain an untreated baseline before commencing treatment since, as was shown by Eisenberg et al. (1961), many children will respond to simple reassurance particularly where anxiety is a prominent symptom. Also, children's problems in general have a strong tendency to improve "spontaneously" (Levitt, 1971; Magder and Werry, 1966; Robins, 1972). In the case of medication, one useful tactic to detect this nonspecific im provement is to begin with a placebo, which should be regarded as a clinical as well as a research tool. In my own studies with hyperactive children, I have obtained an improvement rate of between 18 and 45 percent with placebo, though the degree was usually rather small (Werry, 1975b). Placebo may also be usefully employed at some later stage if a favorable result from medication has been obtained, to see if the child still needs medication. It will help prevent self-fulfilling prophecies of parents and teachers who have often developed their own kind of dependence on the child's medication (Sleator et aI., 1974). When the decision to commence medication has been taken, the lowest dose possible should be used initially. As a rule of thumb, I usually begin with half the minimum recommended dose, since previous studies have suggested that many of the recommended
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doses, particularly for stimulants, may be too high for some children (Werry and Sprague, 1974). The dose is then increased in some manner consistent with commercially available preparations, with dose monitoring for clinical and side effects. To do this requires close cooperation with teachers and parents and some standardized system of examination (see below). In adjusting doses it is important to be awal'e of the pharmacological propenies of the drug being used. In general, psychotropic drugs are long-acting drugs, so that serious accumulation can develop if dosage is increased more frequently than at say 4- to 5-day intervals. The important exception to this is, of course, the stimulants, but it perhaps bears repeating that the benzodiazepines such as diazepam (Valium) are not short-acting drugs and after successive doses, serum half life may be as long as 24-48 hours (Greenblatt and Shader, 1974). ASSESSI;,\(; CLINICAL EffECTS
Drug effects can be estimated using most of the formalized methods described above under diagnosis; but until child psychiatry has a better laboratory footing, child psychiatl'ists will have to continue to rely primarily on clinical impressions derived from parents, teachers, children, and their own observations, though in the latter respect it is important to note that these are virtually useless for detecting anything except overdosage, side effects, and toxic effects. This is because child psychiatrists rarely have the time to get adequate samplings of the child's behavior in the office wheloe the whole situation is so contrived that the child's behavior is highly atypical. The clinical global impression in which improvement (unspecified) is rated on a simple 7-point scale remains one of the simplest and best measures in psychopharmacology (Lipman et aI., 1965; Psychopharmacology Bulletin, 1973: Werry and Sprague, 1972), though obviously it does not indicate in ,,,hat particular way the child has improved. Fuller discussion of this problem can be found in various reviews (Conners, 1972; Psychopharmacology Bulletin, 1973; Sprague and Werry, 1971, 1974; Werry and Sprague, 1972). Most of the children seen by child psychiatrists for whom drugs may be indicated are brought because of problems of social behavior, and one may easily overlook the fact that drugs have important influences upon nervous system function in general, including such cognitive functions as attention, memory, and learning. Some attempt to assess these effects is highly desirable since a quieter child
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is nearly always perceived as an improved child, yet this improvement may be at the expense of mental alertness. A number of tests of cognitive function have established their place in pediatric psychopharmacology (Sprague, 1973; Sprague and Werry, 1971, 1974), but most of them require complicated equipment and their validity outside the artificial testing situation remains to be established. A good teacher or parent will very quickly detect mental dulling or, conversely, improvement in alertness, and both these sources of information should be used regularly. Physiological measures such as cardiovascular (Aman and Werrv, 1975£1, 1975b), metabolic (Safer and Allen, 1975), developmel~tal neurological (Rapoport and Quinn, 1975), EEG and psychophysiological measures (Conners, 1974; Satterfield and Cantwell, 197:'») are receiving increased attention as ways of detecting drug effects, but most of them at the moment are more useful for monitoring side effects or establishing basic pharmacological action than for estimating clinical effect. In summary then, assessing the clinical effects of drugs differs little from monitoring progress of any therapy; namely, seeking clinical information from as many of the child's environments as possible and, of course, from the' child, although this is the most difficult area of all and probably the most neglected in pediatric psychopharmacology, TOXIC AND SIDE EFFECTS
The discO\'ery of the growth-inhibiting effect of the stimulants in some cases (Safer and Allen, 1975) is a salutary lesson about the necessity for careful medical surveillance in' pharmacotherapy which is a feature that distinguishes it from other forms of treatment. To do this properly, one must be prepared to conduct a shortened physical examination, including some routine interrogation of all body systems, not merely those at which treatment is aimed; record ~t regular intervals th~ chilcl"s height and weight and plot these measurements on a growth chart; and quickly screen other physical systems, particularly by the nervous system. The NI~fH Pediatric Psvchopharmacological Package (Psychopharmacology Bulletin, 197;)) outlines some formal methods of doing all this, none of which ordinarih' takes more than a few minutes. Blood tests are abhorrent to ~hildren and need be done only if there are clear indications of toxic effects or where an entirely new drug, the toxicity of which is unknown, is being studied. S~rious
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side effects of psychotropic drugs are fortunately infrequent in children, but minor discomforts are not and are frequently overlooked because of the failure to interrogate parents and child properly or to make routine physical examinations. In a discussion of side effects the point about possible mental dulling must be reemphasized (Stores, 1975; Werry and Sprague, 1972). Occasionally, one will encounter a child who undergoes a significant personality change which, even when it represents a significant improvement, is understandably unacceptable to parents (Werry et aI., 1975b). Children on long-term medication should, in addition to regular assessments, have their response to medication and the continuing necessity for it checked at least once a year by stopping the drug or preferably by substitution of placebo (Sleator et al., 1974). "Drug holidays" are to be encouraged to prevent both side effects and the development of tolerance and hence to obviate the necessity for increased dosage which may precipitate such undesirable effects as growth suppression. Many children, though by no means all, al"e able to go without stimulant drugs particularly on weekends and holidays (Safer and Allen, 1975; Werry and Sprague, 1972). The most important thing about side effects and the safety of psychotropic drugs in children is to remember that pharmacotherapy is a medical procedure requiring a degree of surveillance appropriate to the particular drug, the stage of treatment, and the individual child. This presupposes in the child psychiatrist not only a retention of medical skills but also an up-to-date knowledge of the pharmacology of the drugs commonly used. TYPES OF USEFUL DRUGS
There are several kinds of drugs useful in children. However, it must be emphasized that all of them are by no means effective in every child with a given condition, and each decision to try medication must be regarded as a kind of mini clinical trial. Where several drugs of the same group are available, most of them will be found to have comparable clinical efficacy; the only thing that is likely to differ much is the type and/or frequency of side effects. It is a good principle in psychopharmacology to get to know one or two drugs of a particular class really well and, after one particular drug has been started, to give it a fair trial since there are likely to be many powerful influences upon a child's behavior besides his or her internal chemistry producing clinical fluctuations.
John S. Werry Stimulants
The most useful, best investigated and, interestingly, historically oldest (since 1937) drugs are the stimulants, particularly dextroamphetamine (Dexedrine) and methylphenidate (Ritalin). Understandably, it is this group which has giyen most cause for alarm, since stimulants haye been a major public health problem in several countries (e.g., Japan and Sweden). There are a g)'eat deal of data attesting to the usefulness of stimulants in children diagnosed by \\·hateyer method as hyperkinetic (Conners, 1972; Gittelman-Klein. 1973), and in indiyidual cases the effect can sometimes be classified as dramatic. So well established is the efficacy of the stimulants in improving behavior that they are now the standard against which new drugs such as the antidepressants or pemoline in the treatment of the hyperkinetic syndrome are compared (Conners, 1974; Rapoport et al.. 1974a; ""aizer et aI., 1974; Winsberg et aI., 1912). However, there are reasons for caution. The dose for the stimulants cited in American papers (e.g., American Academy of Pediatrics, 1975) of 2mg/kg for methylphenidate or an average daily dose for a child of about 80mg or, in the case of dextroamphetamine, half that dose, should be regarded as exceptional rather than average. The only systematic studies of dosage (Sprague and Sleator, 1975; Werry and Sprague, 1974) suggest that many child)'en will respond to a dose of methylphenidate as low as O.3mg/kg or 10-ISmg daily. Because of the relatively short action of the stimulants, some children require a second dose around lunchtime. but it is surprising in view of the pharmacological action of the drug how infrequently this is necessary. Doses in excess of 20mg of methylphenidate or 0.5mg/kg may produce anorexia. weight loss, and growth inhibition (Safer and Allen, 1975). This is not necessarily, as suggested by the American Academy of Pediatrics (1975), apparently echoing Eisenberg (1972), simply a temporary affair to which the child adjusts after a short period; it may persist as long as medication is given. Cessation of medication may lead to a compensatory growth spurt (Safer and Allen, 1975). If weight loss occurs and is still present after 2 to 3 months on medication despite attempts to lower the dose and the use of "drug holidays," another stimulant may be tried, though a discontinuation of stimulant therapy is more likely to be necessary. Other side effects of stimulants are tearfulness, rebound irritability, stomachaches, insomnia, toxic psychosis, and personality change (Conners, 1972; Greenberg et aI., 1975; Shader and di Mascio, 1970; Werry and Sprague, 1974). No development of
Thf Use of PIJcholropic Drugs in Childrfn drug abuse or dependency in the long term has yet been apparent in the few long-term follow-up studies, some now of 20 years duration (Beck et al.. 1975; Denhoff, 1973; Eisenberg. 1972; Lipman. 1974; Weiss, 1975), but caution is still necessary since most of these studies were unable to locate a significant nUli1ber of subjects and also since there may be a tendency to drug dependence, notably alcoholism, in the families of some hyperkinetic children (Satterfield and Cantwell, 197:); Good,,'in et aI., 1975). The response of hyperkinetic children to stimulants has often been called paradoxical, but there is good reason to helieve that the reduction in motor activity is due to heightened efficiency and attentiveness (Conners, 1972; WelTY and Aman. 1975), \'\'hich is the usual pharmacological effect in the majority of persons whether adult or child, normal or abnormal (Weiss and Laties, 1962). The beneficial effect of stimulants is also said to be specific to hyperkinetic children, but the clinical evidence is certainly contrarv. For example, Bradley, the originator of stimulant the'rapy, rq)orted that shy, withdra\\"l1 children were benefited (Conners, 1972) and controlled treatment trials have shown that unsocialized, aggressive, and even overanxious children respond (Arnold et aI., 1976; Conners, 1972). As far as the efficacy or freedom f!'Om side effects of different stimulants is concerned, there seems little to choose between the amphetamines and methdphenidate (Winsberg et aI.. 1974) despite claims to the contrary (Weiss et aI., 1971). Surprisingly, neither does there appear to be any great difference in effect or dosage between the dextro andlevo rotatorv isomers of amphetamine (Arnold et aL 1976). Further research with these drugs is indicated, particularly into their indications in other psychiatric disorders of childhood and into their basic pharmacological action in both animals (Millichap and Johnson. 1974; Shaywitz et aI., 1976; Silbergeld and Goldberg. 1975) and children (e.g., Arnold et aI., 1976),
Antipsychotics (Major Tranquilfiun, NeUfolfptics) While the increasing use of the term anti psychotics to describe this group of drugs is clearly preferable to major tranquillizers, it creates difficulty in child psychiatry where most of the indications for their use are in non psychotic conditions. Investigation of their value in childhood psychosis has emanated largely from a single center, the Bellevue group of Bender, Fish, and now Campbell, who claim a useful, though limited role for this group of drugs. This claim is supported by a few studies by other investigators (Campbell, 1975).
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Despite the wide use of these drugs in non psychotic, emotionally disturbed, and mentally retarded children, controlled studies are relatively few and most of these have involved only hyperkinetic children (Campbell, 1975; Conners, 1972; Gittelman-Klein et aL, 1976; Sprague and Werry, 1971, 1974; Werry et aL, 1966). The clinical consensus seems to be that anti psychotics can be useful in disorders marked by psychomotor excitation including hyperkinesis. In the latter condition, however, they lag considerably behind the stimulants in popularity (Krager and Safer, 1974; Sprague and Sleator, 1973). While both types of drugs quiet hyperkinetic children, in contrast to the stimulants, the anti psychotics do so by exerting a general depressant effect (Conners, 1972; Sprague and Werry, 1971, 1974; Werry and Aman, 1975). Their wide use of anxiolytics can be supported even less in children than in adults, since good studies here are very few indeed (Campbell, 1975; Conners, 1972; Sprague and Werry, 1971, 1974). It seems probable that any anxiolytic effect would be due to the mild antihistaminic type sedation which is rapidly dissipated upon repeated administration. Other side effects are much as would be expected from this group of drugs as reported in adults (Shader and di Mascio, 1970), except that dystonias are said to be more common in children and a shortlived extrapyramidal rebound syndrome has been reported to occur in psychotic children after withdrawal of anti psychotics (Polizos et aL, 1973). The most popular drug in this group is probably thioridazine (Mellaril), no doubt because of its strong sedative action and relative absence of extrapyramidal side effects. Its most important side effects, apart from atropinic ones, are seizures and retinitis pigmentosa, neither of which are likely to appear in normal clinical dosage of say less than 400 to 500mg per day. The use of anti psychotics in which extrapyramidal, rather than atropinic, side effects predominate (e.g., trifluoperazine [Stelazine], fluphenazine [Prolixin], and haloperidol [Haldol)) should be avoided except where there are special indications for their use, such as with fluphenazine deconoate, a long-acting injectable preparation, and with haloperidol in Gilles de la Tourette syndrome, or where the dosage can be kept well below that which produces extrapyramidal symptoms. This is because of the increasingly common, very distressing, and basically untreatable syndrome of tardive dyskinesia (usually presenting as choreoathetotic movements of the lips and tongue) thought to be due to postsynaptic sensitization to dopamine, the transmission of which is blocked by these drugs. In summary then, the antipsychotics seem to have a place in
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child psychiatry for the management of hyperactive, aggressive behavior of varying etiologies, in childhood psychosis, and in Gilles de la Tourette syndrome. However, since their introduction into child psychiatry came some 15 years or so ago when the technology of clinical investigation in pediatric psychopharmacology was extremely primitive, they need much fuller investigation particularly in studies where diagnosis in groups or SUbgroups is carefully defined and reasonably homogeneous (Gittelman-Klein et aI., 1976). The Antidepressants
Again, the difference between adult and child psychopharmacology is well illustrated by the inappropriateness of the term antidepressant for describing the growing clinical indications for the use of these drugs in child psychiatry. Discussion here will be restricted to the tricyclics since controlled trials of monoamine oxidase inhibitors are extremely infrequent and where they have been done, there is good reason to question the diagnoses of the children concerned (Conners, 1975a; Graham, 1974; Rapoport, 1976; Werry, 1975a). The oldest and most popular pediatric use of the tricyclics is in enuresis, but, while their symptomatic effect has been clearly established, any curative effect extending beyond the treatment is extremely doubtful (Angst and Theobald, 1970; Blackwell and Currah, 1973). Further, such use may cause unpleasant, though usually not dangerous, side effects, as well as significant unintended psychotropic action (Werry et aI., 1975a). The nature of their effect in enuresis is unclear and while thought to be primarily anticholinergic (Blackwell and Currah, 1973), recent work has suggested an a adrenergic action (Mahony et aI., 1973) and/or a local anesthetic action (Shaffer, 1974). Their use as true antidepressants is quite unestablished largely because the delineation of a true depressive syndrome in children, though frequently posited, has remained elusive (Conners, 1975a; Graham, 1974; Rapoport, 1976; Werry, 1975a). With one or two possible exceptions (see Conners, 1975a), subjects in clinical trials of antidepressants in children have had a mixed bag of symptoms which only a vivid imagination could subsume under a single nosological category similar to antidepressant-responsive depression in adults. The conclusion that, because a therapeutic effect has been obtained, depression must have existed in some masked or equivalent form ignores the many other pharmacological actions of these drugs (Graham, 1974). The search for new drugs less tarnished by past association with problems of drug abuse and dependency than the stimulants has
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led to systematic trials of the tricyclic antidepressants in hyperkinetic children. While most of these controlled trials (Greenberg et aI., 1975; Quinn and Rapoport, 1976; Rapoport et aI., 1974a; Waizer et aI., 1974; Winsberg et aI., 1972, Vepes et aI., 1976) have shown the antidepressants to be of some value, their response is typically less regular and less marked than that of the stimulants and the side effects are more troublesome. How they work in hyperkinesis is unclear, but their effect on cognitive function suggests that it is by some action analogous to that of the stimulants, rather than by their often associated sedative effects (Werry et £11., 1975b; Vepes et aI., 1976). This suggests that the antidepressant action seen in adults is simply one end of a continuum, of which stimulation is an earlier point (Werry et aI., 1975b). The side effects of tricyclics include the usual autonomic blocking effects, weight loss, stomachache, irritability, and tearfulness (Greenberg et aI., 1975; Quinn and Rapoport, 1976; Rapoport et aI., 1974£1; Waizer et aI., 1974; Winsberg et aI., 1972; Werry et aI., 1975b). As with methylphenidate, dosage is a controversial issue since, as used in the hyperkinetic syndrome, it has been considerably higher (sometimes well over 200mg a day) than that used in the treatment of enuresis where the close has not usually exceeded 50 to 75mg. These higher doses can produce much more serious side effects, notably seizures (Brown et aI., 1974; Petti and Campbell, 1975) and cardiotoxic effects (Martin and Zaug, 1975; Winsberg et aI., 1975) with one instance of sudden death in a 7-year-old girl (Saraf et aI., 1974). As a consequence the Food and Drug Administration has ruled (Hayes et aI., 1975) that 5mg/kg is the maximum allowable clinical dose in children and that as these doses are reached EKG monitoring is essential. My own position is similar to that of Rapoport et al. (1974a); namely, not to exceed lOOmg daily except in exceptional cases. A new and interesting, but so far experimental, use of the antidepressants is in pathological separation anxiety as seen in school phobias and, in the preschool child, in disturbed sleep characterized by nightmares and reluctance of the child to stay in his own bed (Gittelman-Klein and Klein, 1973). In summary, while the tricyclic antidepressants are a significant addition to the group of drugs valuable in child psychiatry, particularly in the management of the hyperkinetic syndrome and possibly also in separation anxiety, their use at the moment should be regarded as still being explored and requiring close medical surveillance. There is no reason to suspect any substantial difference in the therapeutic effect between different tricyclics, though side
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effects such as sedation may differ. Dosage for all is similar too. One should probably begin around I mg/kg; and in increasing the dose, it is important to remember that these are long-acting drugs with excretion rates measured in days or even weeks. Although this has not yet been established to be so in children, antidepressants may prove to have some latency in onset of activity as they do in adults. Anxiolytics and Sedatives
There are few reliable data on the usefulness of this group of drugs in children, though it is widely held that they make some children, especially psychotic and hyperkinetic children, worse (Campbell, 1975; Conners, 1972; Greenblatt and Shader, 1974; Ounsted, 1974; Stores, 1975). Such data as there are suggest they may have a useful role in minor disturbances marked by disturbed sleep and anxiety. Studies with the benzodiazepines (Greenblatt and Shader, 1974) and, to a lesser extent, the antihistamines (Campbell, 1975; Conners, 1972) are encouraging enough to make further investigation desirable. There is little doubt that both types of drugs are widely used in children by family physicians and that the lack of evaluation of their effects, good or bad, and of their proper indications is a significant gap in our knowledge. Generally speaking, these drugs are fairly benign and dosage ceilings have not yet been established. Manufacturers' recommended doses err on the conservative side, and if they are to be used, it is suggested that dosage be increased every 4 to 5 days (to avoid cumulative effects) until a therapeutic effect is obtained or evidence of side effects emerges. It should be borne in mind that, as demonstrated by Eisenberg et £II. (1961), anxiety in children is highly placebo sensitive. Further, anxiety is typically acute and situational as in school phobia, so that anxiolytics may well impair function in between the acute stress periods. Other Drugs
Though popular on the Continent, lithium has not yet found a place in pediatric psychopharmacology (Rapoport, 1976). Trials of its effect in hyperkinetic children are not encouraging (Greenhill et £II., 1973; Whitehead and Clark, 1970), though it may yet prove to have some place in the management of childhood psychosis (Campbell, 1975). Despite wide use, anticonvulsants, with the possible exception of sulthiame (Ospolot), have no proven role in children's behavior disorders unaccompanied by frank epilepsy (Conners, 1972; Looker and Conners, 1970; Stores, 1975), particu-
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larly since they can have unpleasant or even serious side effects including possible mental impairment (Stores, 1975; Trimble and Reynolds, 1976). Caffeine had a brief burst of popularity in hyperkinesis as a result of uncontrolled trials, but typically, this did not survive more stringent testing (Conners, 1975b; Huestis et aI., 1975). Pemoline, which has recently appeared on the market as Cylert, is useful in hyperkinesis though its action seems to be largely that of another stimulant (Conners, 1974; Page et aI., 1974). Hallucinogens, vitamins (including megavitamin therapy), and glutamic acid have all been tried and failed to earn themselves a useful place (Campbell, 1975; Sprague and Werry, 1971, 1974). The latest popular remedy for hyperkinesis, the exclusion of certain foods and additives from the diet (Feingold, 1975), has not yet been properly investigated (National Advisory Committee on Hyperkinesis and Food Additives, 1975; Werry, 1976). Preliminary data accruing from properly controlled studies suggest that this treatment is probably ineffective, is cumbersome, and carries \\·ith it a slight nutritional risk in inadequately supervised cases of subnutrition (Werry, 1976). The role of actylcholine analogues like deanol (Deanel") is still being debated, though recent theoretical interest in the role of acotylcholine in the brain makes it an interesting new type of substance with distinct possibilities in basic research in pediatric psychopharmacology (Lewis and Young, 1975). SYMPTOMS AND FUNCTIONS AFFECTED
Motor Activity Reduction in motor activity is a common therapeutic goal with drugs in children, particularly in the hyperkinetic syndrome. While most of the data supporting this effect on motor activity is subjective (based largely on parent and teacher ratings), direct measurements of motor activity have in some, though by no means all, instances confirmed this, particularly with stimulants (Millichap and Johnson, 1974; Montagu and Swarbrick, 1975; Sprague et aI., 1970). Apart from one study with imipramine (Werry et aI., 1975a), data from other drugs are lacking. As noted above, reduction in motor activity can be achieved in two distinct ways: by sedation or by increasing attentiveness. While the former is likely to be general, the latter would be detected only in situations where there is a demand for increased attention, which may explain some of the conflicting results between parent and teacher ratings and direct measurements of motor activity.
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Cognitive Function
The effect of drugs upon cognitive function such as attention, persistence, and short-term memory appears to be what would be predicted from their pharmacology: stimulants appear to enhance it (though, as noted above, chiefly in situations where boredom or incipient failure is characteristic [Sroufe, 1975; Rie, 1975; Weiss and Laties, 1962; Werry and Aman, 1975]), while antipsychotics tend to depress it (Conners, 1972; Gittelman-Klein et aI., 1976; Sprague and Werry, 1971, 1974; Werry and Aman, 1975). The effect of antidepressants is largely unstudied, but preliminary work suggests an action similar to stimulants (Werry et aI., 1975a; Yepes et aI., 1976). Despite decades of use as anticonvulsants, the effect of sedatives such as barbiturates, and now the benzodiazepines, upon cognitive function is unknown, with traditional complacency now giving way to increasing concern (Stores, 1975). Before selecting or dismissing a drug because of its effect upon cognitive function it should be remembered that these effects are small in usual clinical dosage, and knowledge about effects is based on laboratory situations. In the clinical situation, teacher reports and, to a lesser extent, parent ratings around homework should be used, backed up where possible by laboratory measures. Where the evidence is conflicting, a good clinician must, as always, look at the whole picture and make decisions accordingly. Mood and Self Image
This is surely one of the most neglected areas in pediatric psychopharmacology. It is difficult to assess drug effects on mood and inner comfort objectively and to do so in any manner requires patience and the development of a good relationship with the child. Such data as there are suggest that, as would be expected, drugs may improve or deteriorate mood states, self image, and comfort level. This depends on the drug but more particularly on the child, since the same drug may produce diametrically opposed effects in different children, as has been noted with the stimulants or the antidepressants (Conners, 1972; Gittelman-Klein and Klein, 1973; Rapoport et aI., 1974a; Rie et aI., 1976; Stores, 1975; Werry et aI., 1975a). It is particularly important to look for these effects since it is quite possible for a child to be improved in behavior yet made miserable by medication. Much more work is needed in this area.
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Social Behavior
Most of the impetus for the use of drugs in children comes from disturbances in their social behavior; therefore it is not surprising that this area of function is the best documented. Cooperativeness, impulsivity, willingness to listen and to consider others, obedience, and aggression are typical target behaviors which may be influenced in some children either positively or negatively by medication. Reliance for assessment of these has to be placed on parents and teachers, tempered by the knowledge that, unlike the child, they are complainants. Family Dynamics
While most parents welcome any improvement produced by medication, in some cases the family dynamics will be so upset that treatment will be discontinued or resisted. Not surprisingly, there is some evidence that family structure influences the effect of medication. For example, Loney et al. (1975) found that "well managed" children responded better than "poorly managed" children. Because investigators in psychopharmacology are not usually skilled in this area, the interaction between drugs and family dynamics has received very little attention. It should, however, be fairly generally recognized that drug treatment must be combined with other kinds of treatments and not simply administered in traditional medical fashion. Physiological Systems
A characteristic of most psychotropic drugs is that they affect many bodily systems. While most of these effects are small, they can cause significant levels of discomfort. No doctor should administer psychotropic drugs to children without a sound knowledge of clinical psychopharmacology and without some system of interrogating and examining for these physical effects. DIAGNOSTIC AND SYMPTOMATIC INDICATIONS
None of these indications as set out in summary form in table I is absolute. Some children with such a diagnosis may not need medication or, if they do, may not respond to it. Some may respond, but side effects may prevent continuation. Most of the indications have been discussed in detail above except Gilles de la Tourette syndrome. This condition is said to respond specifically to large doses of haloperidol, i.e., around 10mg or more (Ayd, 1972; Shapiro et
The Use ofPs.ychotropic Drugs in Children
461
Table I ()rug~
I. Slilllulallls (IU-I.Olllg/kg llIeilwlphenic!;tll"l ') :\111 ips\"{· hoI ics (no 1lI""illlum dose) 3. TrinTlic antidepressants (do nol e"c('cd !img/kg) 4. Iknzodi"l.epines (no ma"illlum) :1. :\llIihisl"mines
and
C:ondilion~
H \·,K'rk i ne~is: conduel disorders H\verkinesis: P"c!]()lIlotor e"citalion: Cilles de b Tourclle syndroml' (haloperidol): childhood schizophITni,,: Cll1lduCl disonkrs H\perkinC'sis: enuresis (suppress"nl onl\"): sep"ralion an"iel\· (0) An"ietY S\·;npIOlns: sleep diSlurhances Sleep disturhanc('s
(~)
aI., 1973; Woodrow, 1974). While controlled trials have not been reponed, this disorder is so distressing and so difficult to treat that haloperidol should certainly be given a good trial. It is worth noting that haloperidol, panicularly in this dosage, if continued for any length of time, might produce tardive dyskinesia ,,·hich could be mistaken for a return of the tics. U;\,ANSWEREO QUESTIONS
While the short-term benefits of such drugs as the stimulants in the hyperkinetic syndrome are faidy dear, the extent [() \\·hich they inHuel1Ce long-term prognosis is unknown. Although some argue that stimulants should be given to every hyperkinetic child to prevent later psychiatric disability, what little evidence is available so far is largely negative and suggests that this is a quite unwarranted assumption (Riddle and Rapopon, 1976; Weiss, 1975). This area requires patient study under the well-known difficulties and discouragements of longitudinal studies. Another question is whether or not the changes upon attention and othel· cognitive functions pl-esage definitive changes in academic achievement. The dramatic changes in writing and the organization of written material produced by methylphenidate illustrated in a recent study (Schain and Reynard, 1975) are pan of the clinical experience of every child psychiatrist who has used stimulants in the hyperkinetic syndrome. However. systematic studies are few and those which exist fail to demonstrate changes in academic achievement (Gittelman-Klein and Klein, 1976; Rie et aI., 1976). As with long-term clinical benefit, overly optimistic assumptions about the power of stimulants to influence learning problems must be resisted until the evidence is clearer. A third problem concerns future drug abuse and dependency, particularly with the stimulants. While long-term studies show that
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this is clearly not a common outcome of stimulant therapy (Beck et aI., 1975; Denhoff, 1973; Lipman, 1974; Weiss, 1975), the subject attrition from these studies means it still remains a possibility for a minority of children, particularly those from more disturbed backgrounds. The statement by the Conference on the Use of Stimulant Drugs (1971) that there can be no real risk of future drug dependency because the stimulants do not cause euphoria in hyperkinetic children is based on questionable assumptions. As Conners (1972) and Rapoport (1976) point out, stimulants may not cause euphoria, but they certainly can cause a state in some children suggestive of a sense of well-being. A similar effect has also been noted with imipramine (Gittelman-Klein and Klein, 1973; Werry et aI., 1975a). Fourth, there is little information on exactly how long stimulants and other drugs should be given, though there is tacit acceptance of a relatively long-term administration. On the other hand, Sleator et al. (1974) have demonstrated that by annual substitution of placebo, about 20 percent per year of children on long-term stimulant medication will be found to need their drugs no longer. Studies of this nature are infrequent and where data are lacking, dogma flourishes. Fifth is the question of frequency and seriousness of long-term physical effects, notably growth retardation, of the stimulants (e.g., Gross, 1976), tardive dyskinesia with the antipsychotics, and intellectual deterioration with sedatives and anticonvulsants (Stores, 1975; Trimble and Reynolds, 1976). Sixth, what is the frequency with which children are being kept on medication for reasons of social control when such use is accompanied by sedation, minor but significant physical discomfort, negative mood changes, and substantial changes in personality? Seventh, to what extent is it true, as charged by Rie (1975), that the use of medication leads to oversimplified concepts of etiology and of treatment in children with behavior problems? Last, what are the exact disgnostic indications for and predicators of drug response? At the moment, most drug therapy is fumbling empiricism, but there are many hopeful signs that a more rational approach may ultimately be possible. For example, theory (Wender, 1971), animal work aimed at reproducing paradigms particularly of the hyperkinetic syndrome (Corson et aI., 1976; Shaywitz et aI., 1976; Silbergeld and Goldberg, 1975), biochemical investigations (Greenberg and Coleman, 1976; Rapoport et aI., 1974b), pharmacological studies aimed at relating structure and function as suggested by Wender (1971, 1975) (e.g., Arnold et aI.,
463
The Use of Psychotropic Drugs in Children
1976), and electrophysiological techniques (Conners, 1974; Satterfield and Cantwell, 1975) suggest a considerable and laudable intellectual ferment in pediatric psychopharmacology. SUMMARY A D
CO
CLUSIO S
This brief overview of research and clinical aspects of psychotropic drugs in children has revealed more ignorance than knowledge. Only the stimulants have a well-tested place in children and even there much is largely unknown, such as the impact on achievement and the exact diagnostic indications. Most other drugs still require further careful study before definitive statements about their usefulness and safety can be made, though the antidepressants and antipsychotics would seem to have a worthy role. Most of the diagnostic indications for pharmacotherapy are not yet well delineated. The hyperkinetic syndrome has preempted most of the attention of the few really experienced and competent investigators in pediatric psychopharmacology for the last 10 years to the neglect of all other conditions, except perhaps childhood psychosis, Gilles de la Tourette syndrome, and enuresis. Anxiety symptoms, neurotic conditions, personality disorders, and borderline states have received little serious attention, though indications that medication may playa useful role in some of these conditions are quite strong. Much of the problem lies in the shortage of investigators in pediatric psychopharmacology and the quite unnecessary view of it as a competitor rather than an adjunct to psychological, behavioral, and remedial treatments. Criticisms made about the use of drugs, particularly the stimulants, as dangerous or as chemical straitjackets along the lines made by medical procedures in general by IIIich (1975) have not been supported by investigations. For example, far from the oppressed poor being cudgeled into line with stimulants as originally charged by critics, it is actually the children of the affluent who are much more prone to receive them (Krager and Safer, 1974; Sprague and Sleator, 1973). While it is indisputably true that some doctors do, and always will, misprescribe or overprescribe psychotropic drugs in children, this is no more an argument against such treatment when properly indicated and supervised than it is against any useful yet overprescribed treatment such as penicillin or Vitamin B 12. The poor clinician and the outof-date physician are as serious a concern to the medical profession as they are to its critics. The only answer to such criticisms is for child psychiatrists to produce hard data obtained by careful, properly controlled, and
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ethical studies and then for such information to be used in clinical practice. To achieve this, pediatric psychopharmacology has somehow to attract its share of the intellectually curious and scientifically inclined. In turn, educators and clini~ians in child psychiatry must remember that they are first and foremost physicians and that medicine is not simply a humanitarian exercise but an applied biosocial science.
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CRl:Z. F. DE I.A. Fox. B.. & ROBERTS, R. (197:1). Minimal hrain dl'sfunclion. All II. N.Y. Act/d. . Sci.• ~o;u -:196. DENIIOFF. Eo (197:1). NalUral lift- histon' of children with minimal brain cl\·sfunnion. Alln. N.Y. Acad. Sci.. ~05: 188-~O". . . DOUGLAS. V. (1975). Are drugs en(lugh~ Int. I Mellt. Hlth. 4: 199-21~. EISENBERG. L (1972). Svmposium: Beha\,ior modification by drugs: I II. Pediatrics. 49:709-715. - - - GILBERT. A .. CYTRYN. 1... & \IOLLlNG. P. (1961). The effectiveness of psychotherapy alone and in conjunction with perphenazine or placebo in the treatment of neurotic and hyperactive children. A mer. I Psychint., I 17: I088-1 09:~. FEINGOLD. B. (1975). Wh.~ Vour Child 1.< Hyperartive. !'\ew York: Random House. FISH, B. (197\). The one child one dl'Ug myth of slimulants in hyperkinesis. Arch. Gen. Psychint.• 2,,: 19:1-203. GITTELMAN-KLEIN. R (1975). Re\'ie\\' of clinical pS\'chopharmacological Ireatment of hyperkinesis. In: Progre.H in Psychiatric DnI~ Treatment. ed. D. Klein & R. Gillelman-Klein. New York: Brunner-:\lazel, pp. 661-674. - - - & KU:tN. D. (197:1). Sc.hool phobia.). Nem Ment. Dis., 150:199-215. - - - - - - (1976), Methylphenidate effects in learning disabilities: I. Arch. Gell. Psychint., 33:655-664. - - - - - - KATZ. S.• SARAI', K.. & POLLACK. E. (1976). Comparative effens of methvlphenidate and thioridazine in hypc'rkinetic children. Arch. Gen. Psy·chiat., ;1;~: 1~ 17-1 ~31. GOODWIN. D .. SCHULSINGER. F.. HER\lA:"SEN. L. GL·ZE. S.. & WtJ\OKL'R, G. (197,,). Alcoholism and the hvperactive child syndrome. I Nerv. Ment. Di,., 60:349-:1.53. GRAHA\l. P. (\ 974). Depression in prepubertal children. Develpm. Med. Child Neurol.• \6:340-349. GREF:"lIERG. A. & COl.EMA:". M. (1976). Depressed 5-hydroxyindole levels associated with hyperactive and aggressive behavior. ATCh. Gen. Ps)'chiat., 3:1:3:~ 1-336. - - - YELLIN, A .. SPRING, C, & MtTCALF. :\1. (\975). Clinical eHecls of imipramine and methylphenidale in hyperactive children. Int. I Ment. Hlth, 4: 144-156. GREENBLATT. D. & SHADER. R. (1974). Be20diazepines in Clillical Practice. :\ew York: Raven Press. GREENHtLL. L.. RtEDER. R.. WEJ\DER, P.. B1THBAL'\I. :\1.. & KAHN. T. (1973). Lithium carbonate in the lrealmem of hyperauive children. Arch. Gen. Psychiat., 38:636-640. GRINSPOON. L & SIl'GER. S. (197:1). Amphetamines in the treatment of hyperkinetic children. Harvard Educ. Rev., 43:5 I 5-555. GROSS. M. (1976). Crowth of hyperkinetic children taking mClhdphenidate. dextroamphetamine. imipramine or desipramine. Pediatrics, 58:423-4:11. HA YES. T.. PAr-' ITCH. 1\-1.. & BARKER, Eo (I ~17:»). Imipramine dosage in children. Amer. j. Psvchiat., 132:546-547. Ht:ESTIS, R., ARM>l.D. 1... & S~'ELTZER. D. (\975). Caffeine versus methylphenidale and d-amphetarnine in minimal brain d\·sfunl'lion. Amer. j. Ps),dtiat.. 132:868-8iO. ILLICH, I. (1975). Medical Nemesis. London: Calder & Bovars. KRAGER. A. & SAFER. D. (]974). Type and prevalence of ~edication used in the treatment of hvperactive children. New Eng. j. Med., 291: 1118-1120. KUPIETZ. A .• BIALER. I.. & WINSBERG, B. (1972), A behavior rating scale for assessing improvement in behaviorally deviant children. A mer. I Ps)'chiat., 128: J 432-1436. LEVITT. E. (\971). Research on psychotherapv with children. In: Handbook of Psychotherapy and Behavior Change, ed. A. Bergin & A. Garfield. :-.iew York: WileI'. pp. 474-494. LEWIS. J. & YOL·:"G. R. (1975). Deanol and methdphenidate in minimal brain dysfunction. Clin. Pharm. Ther., 17:534-540. LtPS1Al', R. (1974). :\IMH-PRB support of research in minimal brain dysfunction in children. In: Clinical Use of Stimulant Drugs in Chidren, ed. C. K. Conners. Amsterdam: Excerpta \1edica. pp. 202-213. - - - COLE. J., P.~RK. 1.., & RICKELS. K. (1965). Sensitivity of symptom and nonsvmptom!()cused criteria of oUlpatiem drug efficacy. A mer. I Ps~chiat., 122:24-27. LONEY. J.. CO""LY. H., & SIMa:". B. (1975). Parental managemenf, self concept and drug response in minimal brain dysfunction. j. Learn. Diabil., 8: \87 -190.
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LOOKER, A. & CONNERS, C. K. (1970), Diphenyldantoin in children with severe temper tantrums. Arch. Gen. Psychiat., 23:80-89. MAGDER, D. & WERRY, J. (1966), Defection from a treatment waiting list in a child psychiatric clinic. This Journal, 5:708-720. MAHONY, D., LAFERTE, R., & MAHONY, J. (197:1), Studies on enuresis: IV. Urology, 1:317-323. MARTIN, G. & ZAUG, P. (1975), Electrocardiographic monitoring of enuretic children receiving therapeutic doses of imipramine. A mer. I Psychiat., 132:540-542. MILLICHAP, J. (1975), The Hyperactive Child with Minimal Brain Dysfunction. Chicago: Year Book Medical Publishers. - - - & JOHNSON, F. (1974). Methylphenidate in hyperactive behavior. In: Clinical Use of Stimulant Drugs in Children, ed. C. K. Conners. Amsterdam: Excerpta Medica, pp. 130-139. MONTAGU, J. & SWARBRICK, L. (1975), Effective amphetamines in hyperkinetic children: stimulant or sedative? Develpm. Med. Child Neurol., 17:293-298. l':ATIONAL ADVISORY COMMITTEE ON HYPERKINESIS AND FOOD ADDITIVES (1975), Pirst Report. New York: Nutrition Foundation. OUNSTED, C. (1974), High activity or hyperactivity? Develpm. Med. Child Neurol., 16:685. PAGE, J., BERNSTEIN, J., JANICKI, R., & MICHAEl.LEI, F. (1974), A multi-clinic trial of pemoline in childhood hyperkinesis. In: Clinical Use of Stimulant Drugs in Children. ed. C. K. Conners. Amsterdam: Excerpta Medica. PETTI, T. & CAMPBELL, M. (1975), Imipramine and seizures. Amer. I Psychiat., 132:538-540. POLIZOS, P., ENGF.I.HARDT, D., HOFFMAN, S., & WAIZER,.J. (1973), Neurological consequences of psychotropic drug withdrawal in schizophrenic children. I Aut. Child. Schiw., 8:247-253. PSYCHOPH.iRM.iCOW(;Y BULLETIN (1973), Pharmacotherapy of Children (Special Issue). QUINN, P. & RAPOPORT, J. (1976), A one-year follow-up of hyperactive boys treated with imipramine or methylphenidate. Amn'. I Psychiat. (in press). RAPOPORT, J. (1976), Pediatric psychopharmacology in childhood depression. In: Progress ill Psychiatric Drug Treatment, ed. D. Klein & R. Gittelman-Klein. New York: Brunner'.Iaze!. - - - & BENOIT, M. (1975), The relation of direct home observations to the clinic evaluation of hyperactive school age boys. I Child Psychol., 16: 141-147. - - - & QUINN, P. O. (1975), Minor physical anomalies (stigmata) and early developmental deviation. Int. I Ment. Hlth, 4:29-44. - - - - - - BRADBARD, G., RID Dl.E, K., & BROOKS, E. (1974a), ImiPJOamine and methylphenidate treatment of hyperactive boys. Arch. Gen. Psychiat., 30:789-793. - - - - - - & LAMBRECHT, F. (1974b), Minor physical anomalies and plasma dopaminebeta-hydroxylase activity on hyperactive boys. Amer. I Psychiat., 131 :386-390. RIDDLE, K. & RAPOPORT, J. (1976), A two-year follow-up of 72 hyperactive boys. I Nero. Ment. Dis., 162:126-134. RIE, H. (1975), Hyperactivity in children. A mer. I Dis. Child., 130:783-789. - - - RIE, E., STEWART, S., & AMBUEL, J. (1976), Effects of methylphenidate on under achieving children. I Consult. Clin. Psychol., 44:250-260. ROBINS, L. (1972), Follow-up studies of behavior disorders in children. In: Psychopathological Disorders of Childhood, ed. H. Quav &J. Werry. New York: Wiley, pp. 414-450. SAFER, D. & ALLEN, R. (1975), Side effects from long-term use of stimulants in children. Int. I Ment. Hlth, 4:105-118. - - - - - - (1976), H.vperactive Children. Baltimore: University Park Press. SARAF, K. R., KLEIN, D., GITTELMAN-KLEIN, R., & GROFF, S. (1974), Imipramine and side effects in children. Psychopharmacologia, 37:265-274. SATTERFIELD, J. & CANTWEl.L, D. (1975), Psychopharmacology in the prevention of antisocial and delinquent behavior. Int. I Ment. Hlth, 4:227-237. SCHAIN, R. & REYNARD, C. (1975), Observations on effects of a central stimulant drug (methylphenidate) in children with hyperactive behavior. Pediatrics, 55:709-716. SHADER, R. & 01 MASCIO, A. (1970), Psychotropic Drug Side Effects. Baltimore: Williams & Wilkins. SHAFFER, D. (1974), Personal communication.
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SHAPIRO, A., SHAPIRO, E., & WAYNE, H. (1973), Treatment of Tourette's syndrome with haloperidol. Arch. Gen. Psychiat., 28:92-97. SHAYWITZ, B., KLOPPER, j., YAGER, R., & GORDON, j. (1976), Paradoxical response to amphetamine in developing rats with 6-hydroxydopamine. Nature, 261: 153-1.~6. SILBERGELD, E. & GOLDBERG, A. (1975), Pharmacological and neurological investigation of lead-induced hyperactivity. Neuropharmacology, 14:431-444. SLEATOR, E., VON NEUMANN, A., & SPRAGUE, R. (1974), Hyperactive children. j. A mer. Med. Assn., 229:316-317. SPRAGUE, R. (1973), Recommended performance measures for psychotropic drug investigations. Psychopharm. Bull., Special Issue. Pharmacotherapy of Children, pp. 85-88. - - - BARNES, K., & WERRY, j. (1970), Methylphenidate and thioridazine. Amer. j. Orthopsychiat., 40:615-628. - - - & SLEATOR, E. (1973), Effects of psychopharmacological agents on learning disorders. Ped. Clin. N. Amer., 20:719-735. - - - - - - (1975), What is the proper dose of stimulant drugs in children. Int. j. Ment. Hlth, 4:75-104. - - - & WERRY, j. (1971), Methodology of psychopharmacological studies with the retarded. In: International Review of Research in Mental Retardation, ed. N. R. Ellis. New York: Academic Press, 5:147-219. - - - - - - (1974), Psychotropic drugs in handicapped children. In: Second Review of Special Education, ed. L. Mann & D. Sabatino. Philadelphia: JSE Press, pp. I-50. SROUFE, L. (1975), Drug treatment of children with behavior problems. In: Review of Child Development Research, ed. F. Horowitz. Chicago: University of Chicago Press. - - - & STEWART, M. (1973), Treating problem children with stimulant drugs. New Eng. j. Med., 289:407-412. STORES, G. (1975), Behavioural effects of anti-epileptic drugs. Develpm. Med. Child Neurol., 5:647-658. TRIMBLE, M. & REYNOLDS, E. (1976), Anticonvulsant drugs and mental symptoms. Psychol. Med., 6: 169-178. WAlZER, j., HOFFMAN, S., Pouzos, P., & ENGELHARDT, D. (1974), Outpatient treatment of hyperactive school children with imipramine. A mer. j. Psychiat., 131 :587-591. WEISS, B. & LAnES, V. (1962), Enhancement of human performance by caffeine and the amphetamines. Pharma. Rev., 14:1-36. WEISS, G. (1975), The natural history of hyperactivity in childhood and treatment with stimulant medication at different ages. Int. j. Ment. Hlth, 4:213-226. - - - MINDE, K., DOUGLAS, B., WERRY, j., & SYKES, D. (1971), Comparison of the effect of chlorpromazine, dextroamphetamine and methylphenidate on the behavior and intellectual functioning of hyperactive children. Can. Med. Assn. j., 104:20-25. WENDER, P. (1971), Minimal Brain Dysfunction in Children. New York: Wiley. - - - (1973), The Hyperactive Child. New York: Crown. - - - (1975), Speculations concerning a possible biochemical basis of minimal brain dysfunction. Int. j. Ment. Hlth, 4: 11-28. WERRY, j. S. (1968), Developmental hyperactivity. Ped. Clin. N. Amer., 50:581-599. - - - (1973), Diagnosis for psychopharmacological studies. Psychopharm. Bull., Special Issue, Pharmacotherapy of Children, pp. 88-96. - - - (1974), Minimal brain dysfunction (neurological impairment) in children. N. Z. Med. j., 80:94-100. - - - (l975a), Discussion of "classification and treatment of childhood depression and depressive equivalents by C. K. Conners." In: Depression, ed. D. Gallant & G. Simpson. New York: Spectrum, pp. 196-199. - - - (l975b), Placebo, methylphenidate, haloperidol, and imipramine in emotionally disturbed children. Thesis submitted to the University of Otago for the degree of Doctor of Medicine. - - (1976), Diet and hyperactivity. Med. j. Aust., 2:281-282. - - - & AMAN, M. (1975), Methylphenidate and haloperidol in children. Arch. Gen. Psychiat., 32:790-795.
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- - '- & SPRAGl'F. R. (I 97:!). Psychopharmacolog\. In: Mental Retardation. ed . .I. Wortis. New York: Grune & Stratton. 4:63-79. - - - - - - (1974). Methylphenidate in children. Awt. & N. Z . .J. Psvchiat.. 8:9-19. - - - - - - & COHEN. :\1. (1975b). Conners' teacher rating scale f()l' use in drug studies with children. I Almonn. Child Psydwl.• :l::! 17-:!:!9. - - - WEISS. G., DOlTGLAS, V.. & MARTIr\,.J. (1966), Studies on the Il\peractiye child: III. This Joumal, 5:29:!-:~1:!. WHITEHEAD, P. & CLARK. L. (1970), Effect of lithium carbonate, placebo and thioridazine on hyperactiye children. A mer. I Psychiat., I :!7: I :!4-1 :!5. WINSBERG, B., BIALER, I., KlTPIF:TZ, S., & TOlltAS, J. (197:!), Effects of imipramine and dextroamphetamine on behayior of neuropsvchiatrically impaired children. ArneI'. j. Psychiat., 1:!8:14:!5-1431. - - - GOLDSTElr\. So, YEPES, 1.., & PEREL, J. (1975), Imipramine and electrocardiographic abnormalities in hyperactiye children. A mer. j. Psychiat., I 32::,)4:!-545. - - - PRESS, M., BIALER, I., & Kt·PIETI., S. L. (1974), Dextroamphetamine and methylphenidate in the tratment of hyperactiye/aggressiye children. Pediatrics, 53::!:lli-:!41. WOODROW, L. (1974), Gilles de la Tourette disease. A mer. I Ps,chiat., 131: 1O()()-I OO:l. YEPES, L., BALKA, B., Wlr\SlIERG, B., & BIALER, I. (197(;), Amitriptyline and methylphenidate treatment of behaYiorallY disordered children. j. ChiM Psychol. (in press).
John S. Werry, M.D.
Abstra
The use of psychotropic drugs in children has developed more slowly than in adult psychiatry, but this use has increased greatly in the last five years with clinical indications strikingly different from those in adults. It has also provoked much more controversy with press exposes leading to governmental hearings (Conference on the use of stimulant drugs, 1971; Lipman, 1974), scientific symposia (Cruz et aI., 1973), position statements (American Academy of Pediatrics, 1975), spirited apologies (Eisenberg, 1972; Gittelman-Klein, 1975; Wender, 1971, 1975; Werry, 1974), equally spirited criticisms (Grinspoon and Singer, 1973; Ounsted, 1974; Rie et aI., 1976), and a rush of books for parents and professionals alike (Cantwell, 1975; Millichap, 1975; Safer and Allen, 1976; Wender, 1971, 1973). Criticisms made seem reducible to two main arguments: (l) that some of the drugs used are undesirable or downright dangerous; and (2) that doctors are putting creative, bored, dissenting, oppressed, or otherwise rightfully troublesome children into chemical strai~ackets.
Dr. WeT1')' is Professor a.nd Head, Department of Ps.vchiatry, Universitv of Aucklarui. Much of the work described here and the preparation of this review were supported by the Medical Research Council of New Zealand, USPHS Grant No. MH 18909, CIBA-GEIGY (U.K.) and Searle (Australasia). Reprints may be requested from the author at the Department of Psychiatry, School of Medicine, University of Auckland, P.B., Auckland, New Zealand.
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DIAGNOSIS
A lot of the criticism centers on the ability of doctors to diagnose by objective scientific criteria rather than those dictated by personal or social imperatives. To make an objective diagnosis in medicine, at least two conditions must be met; first, there must be a set of explicit rules by which to make the diagnosis, particularly the spelling out of the necessary and sufficient criteria (including disqualifying ones) by which the diagnosis can be made. An attempt to do this can be seen in the diagnostic system and decision tree developed by NIMH for its battery of measures to be used in pediatric psychopharmacology (Fish, 1971; Psychopharmacology Bulletin, 1973; Werry, 1973). Second, in addition to the set of rules, there must be accurate ways of detecting these necessary and sufficient criteria. Here too, considerable effort has been made in the last few years, examples of which can be seen in the following: (1) Development of norms for various symptom-rating scales, most notably Conners' Teacher Questionnaire (TQ) (Conners, 1973; Gittelman-Klein et aI., 1976; Kupietz et aI., 1972; Werry et aI., 1975b). (2) Cross-validation of ratings by parents, teachers, doctors, and observers (Abikoff et aI., 1977; Gittelman-Klein et aI., 1976; Rapoport and Benoit, 1975; Rie et aI., 1976; Werry et aI., 1966). (3) Objective methods of measurement of symptomatology such as mechanical devices for motor activity (Millichap and Johnson, 1974; Montagu and Swarbrick, 1975; Rie et aI., 1976; Sprague et aI., 1970), EEG procedures (Conners, 1974; Satterfield and Cantwell, 1975), other psychophysiological procedures (Satterfield and Cantwell, 1975), behavior observations (Abikoff et aI., 1977; Rapoport et aI., 1974a; Sprague et aI., 1970), neurological measures (Rapoport and Quinn, 1975) and biochemical estimations (Greenberg and Coleman, 1976; Rapoport et aI., 1974b). (4) Development of a standard set of measures for demographic, background, and anamnestic data by NIMH (Psychopharmacology Bulletin, 1973). While much of modern medicine is obsessed with laboratory measures, the reluctance of child psychiatrists to move in this direction means that much of the current technology described above has little use in routine clinical practice except perhaps for simple questionnaires like Conners' TQ, crude norms of which are available to help objectify the diagnosis of abnormality. Such is the state of the art, however, that in the end most clinical use of psychotropic drugs with children becomes a matter of using very crude
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diagnostic or symptomatic signposts and submitting the drug to an empirical trial to see if it suits the child concerned. SOME PRINCIPLES OF PRESCRIBING
Much of the clinical use of psychotropic drugs in children is substantially the same as with any kind of therapy. Obviously it must be based on good history taking and examination and the development of rapport with parents and child alike. The reason for the treatment, its likely results, good and bad, must be explained and parents and child's questions answered directly and honestly. Good, all-round clinicians are likely to do a better job than those who use medication as a means of maintaining distance from their patients or in the fruitless search for magical cures. It is rare to find a child who so benefited by medication that no other management is necessary (Douglas, 1975; Sroufe and Stewart, 1973; Werry, 1968). Drugs should never be regarded as definitive treatment in themselves any more than the converse view that because another treatment may produce some change in this or other patients, this necessarily excludes any role for medication (e.g., AylIon et aI., 1975). In short, drug treatment should be seen as synergistic, and not in competition with other treatment. As with other treatments, it is prudent to obtain an untreated baseline before commencing treatment since, as was shown by Eisenberg et al. (1961), many children will respond to simple reassurance particularly where anxiety is a prominent symptom. Also, children's problems in general have a strong tendency to improve "spontaneously" (Levitt, 1971; Magder and Werry, 1966; Robins, 1972). In the case of medication, one useful tactic to detect this nonspecific im provement is to begin with a placebo, which should be regarded as a clinical as well as a research tool. In my own studies with hyperactive children, I have obtained an improvement rate of between 18 and 45 percent with placebo, though the degree was usually rather small (Werry, 1975b). Placebo may also be usefully employed at some later stage if a favorable result from medication has been obtained, to see if the child still needs medication. It will help prevent self-fulfilling prophecies of parents and teachers who have often developed their own kind of dependence on the child's medication (Sleator et aI., 1974). When the decision to commence medication has been taken, the lowest dose possible should be used initially. As a rule of thumb, I usually begin with half the minimum recommended dose, since previous studies have suggested that many of the recommended
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doses, particularly for stimulants, may be too high for some children (Werry and Sprague, 1974). The dose is then increased in some manner consistent with commercially available preparations, with dose monitoring for clinical and side effects. To do this requires close cooperation with teachers and parents and some standardized system of examination (see below). In adjusting doses it is important to be awal'e of the pharmacological propenies of the drug being used. In general, psychotropic drugs are long-acting drugs, so that serious accumulation can develop if dosage is increased more frequently than at say 4- to 5-day intervals. The important exception to this is, of course, the stimulants, but it perhaps bears repeating that the benzodiazepines such as diazepam (Valium) are not short-acting drugs and after successive doses, serum half life may be as long as 24-48 hours (Greenblatt and Shader, 1974). ASSESSI;,\(; CLINICAL EffECTS
Drug effects can be estimated using most of the formalized methods described above under diagnosis; but until child psychiatry has a better laboratory footing, child psychiatl'ists will have to continue to rely primarily on clinical impressions derived from parents, teachers, children, and their own observations, though in the latter respect it is important to note that these are virtually useless for detecting anything except overdosage, side effects, and toxic effects. This is because child psychiatrists rarely have the time to get adequate samplings of the child's behavior in the office wheloe the whole situation is so contrived that the child's behavior is highly atypical. The clinical global impression in which improvement (unspecified) is rated on a simple 7-point scale remains one of the simplest and best measures in psychopharmacology (Lipman et aI., 1965; Psychopharmacology Bulletin, 1973: Werry and Sprague, 1972), though obviously it does not indicate in ,,,hat particular way the child has improved. Fuller discussion of this problem can be found in various reviews (Conners, 1972; Psychopharmacology Bulletin, 1973; Sprague and Werry, 1971, 1974; Werry and Sprague, 1972). Most of the children seen by child psychiatrists for whom drugs may be indicated are brought because of problems of social behavior, and one may easily overlook the fact that drugs have important influences upon nervous system function in general, including such cognitive functions as attention, memory, and learning. Some attempt to assess these effects is highly desirable since a quieter child
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is nearly always perceived as an improved child, yet this improvement may be at the expense of mental alertness. A number of tests of cognitive function have established their place in pediatric psychopharmacology (Sprague, 1973; Sprague and Werry, 1971, 1974), but most of them require complicated equipment and their validity outside the artificial testing situation remains to be established. A good teacher or parent will very quickly detect mental dulling or, conversely, improvement in alertness, and both these sources of information should be used regularly. Physiological measures such as cardiovascular (Aman and Werrv, 1975£1, 1975b), metabolic (Safer and Allen, 1975), developmel~tal neurological (Rapoport and Quinn, 1975), EEG and psychophysiological measures (Conners, 1974; Satterfield and Cantwell, 197:'») are receiving increased attention as ways of detecting drug effects, but most of them at the moment are more useful for monitoring side effects or establishing basic pharmacological action than for estimating clinical effect. In summary then, assessing the clinical effects of drugs differs little from monitoring progress of any therapy; namely, seeking clinical information from as many of the child's environments as possible and, of course, from the' child, although this is the most difficult area of all and probably the most neglected in pediatric psychopharmacology, TOXIC AND SIDE EFFECTS
The discO\'ery of the growth-inhibiting effect of the stimulants in some cases (Safer and Allen, 1975) is a salutary lesson about the necessity for careful medical surveillance in' pharmacotherapy which is a feature that distinguishes it from other forms of treatment. To do this properly, one must be prepared to conduct a shortened physical examination, including some routine interrogation of all body systems, not merely those at which treatment is aimed; record ~t regular intervals th~ chilcl"s height and weight and plot these measurements on a growth chart; and quickly screen other physical systems, particularly by the nervous system. The NI~fH Pediatric Psvchopharmacological Package (Psychopharmacology Bulletin, 197;)) outlines some formal methods of doing all this, none of which ordinarih' takes more than a few minutes. Blood tests are abhorrent to ~hildren and need be done only if there are clear indications of toxic effects or where an entirely new drug, the toxicity of which is unknown, is being studied. S~rious
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side effects of psychotropic drugs are fortunately infrequent in children, but minor discomforts are not and are frequently overlooked because of the failure to interrogate parents and child properly or to make routine physical examinations. In a discussion of side effects the point about possible mental dulling must be reemphasized (Stores, 1975; Werry and Sprague, 1972). Occasionally, one will encounter a child who undergoes a significant personality change which, even when it represents a significant improvement, is understandably unacceptable to parents (Werry et aI., 1975b). Children on long-term medication should, in addition to regular assessments, have their response to medication and the continuing necessity for it checked at least once a year by stopping the drug or preferably by substitution of placebo (Sleator et al., 1974). "Drug holidays" are to be encouraged to prevent both side effects and the development of tolerance and hence to obviate the necessity for increased dosage which may precipitate such undesirable effects as growth suppression. Many children, though by no means all, al"e able to go without stimulant drugs particularly on weekends and holidays (Safer and Allen, 1975; Werry and Sprague, 1972). The most important thing about side effects and the safety of psychotropic drugs in children is to remember that pharmacotherapy is a medical procedure requiring a degree of surveillance appropriate to the particular drug, the stage of treatment, and the individual child. This presupposes in the child psychiatrist not only a retention of medical skills but also an up-to-date knowledge of the pharmacology of the drugs commonly used. TYPES OF USEFUL DRUGS
There are several kinds of drugs useful in children. However, it must be emphasized that all of them are by no means effective in every child with a given condition, and each decision to try medication must be regarded as a kind of mini clinical trial. Where several drugs of the same group are available, most of them will be found to have comparable clinical efficacy; the only thing that is likely to differ much is the type and/or frequency of side effects. It is a good principle in psychopharmacology to get to know one or two drugs of a particular class really well and, after one particular drug has been started, to give it a fair trial since there are likely to be many powerful influences upon a child's behavior besides his or her internal chemistry producing clinical fluctuations.
John S. Werry Stimulants
The most useful, best investigated and, interestingly, historically oldest (since 1937) drugs are the stimulants, particularly dextroamphetamine (Dexedrine) and methylphenidate (Ritalin). Understandably, it is this group which has giyen most cause for alarm, since stimulants haye been a major public health problem in several countries (e.g., Japan and Sweden). There are a g)'eat deal of data attesting to the usefulness of stimulants in children diagnosed by \\·hateyer method as hyperkinetic (Conners, 1972; Gittelman-Klein. 1973), and in indiyidual cases the effect can sometimes be classified as dramatic. So well established is the efficacy of the stimulants in improving behavior that they are now the standard against which new drugs such as the antidepressants or pemoline in the treatment of the hyperkinetic syndrome are compared (Conners, 1974; Rapoport et al.. 1974a; ""aizer et aI., 1974; Winsberg et aI., 1912). However, there are reasons for caution. The dose for the stimulants cited in American papers (e.g., American Academy of Pediatrics, 1975) of 2mg/kg for methylphenidate or an average daily dose for a child of about 80mg or, in the case of dextroamphetamine, half that dose, should be regarded as exceptional rather than average. The only systematic studies of dosage (Sprague and Sleator, 1975; Werry and Sprague, 1974) suggest that many child)'en will respond to a dose of methylphenidate as low as O.3mg/kg or 10-ISmg daily. Because of the relatively short action of the stimulants, some children require a second dose around lunchtime. but it is surprising in view of the pharmacological action of the drug how infrequently this is necessary. Doses in excess of 20mg of methylphenidate or 0.5mg/kg may produce anorexia. weight loss, and growth inhibition (Safer and Allen, 1975). This is not necessarily, as suggested by the American Academy of Pediatrics (1975), apparently echoing Eisenberg (1972), simply a temporary affair to which the child adjusts after a short period; it may persist as long as medication is given. Cessation of medication may lead to a compensatory growth spurt (Safer and Allen, 1975). If weight loss occurs and is still present after 2 to 3 months on medication despite attempts to lower the dose and the use of "drug holidays," another stimulant may be tried, though a discontinuation of stimulant therapy is more likely to be necessary. Other side effects of stimulants are tearfulness, rebound irritability, stomachaches, insomnia, toxic psychosis, and personality change (Conners, 1972; Greenberg et aI., 1975; Shader and di Mascio, 1970; Werry and Sprague, 1974). No development of
Thf Use of PIJcholropic Drugs in Childrfn drug abuse or dependency in the long term has yet been apparent in the few long-term follow-up studies, some now of 20 years duration (Beck et al.. 1975; Denhoff, 1973; Eisenberg. 1972; Lipman. 1974; Weiss, 1975), but caution is still necessary since most of these studies were unable to locate a significant nUli1ber of subjects and also since there may be a tendency to drug dependence, notably alcoholism, in the families of some hyperkinetic children (Satterfield and Cantwell, 197:); Good,,'in et aI., 1975). The response of hyperkinetic children to stimulants has often been called paradoxical, but there is good reason to helieve that the reduction in motor activity is due to heightened efficiency and attentiveness (Conners, 1972; WelTY and Aman. 1975), \'\'hich is the usual pharmacological effect in the majority of persons whether adult or child, normal or abnormal (Weiss and Laties, 1962). The beneficial effect of stimulants is also said to be specific to hyperkinetic children, but the clinical evidence is certainly contrarv. For example, Bradley, the originator of stimulant the'rapy, rq)orted that shy, withdra\\"l1 children were benefited (Conners, 1972) and controlled treatment trials have shown that unsocialized, aggressive, and even overanxious children respond (Arnold et aI., 1976; Conners, 1972). As far as the efficacy or freedom f!'Om side effects of different stimulants is concerned, there seems little to choose between the amphetamines and methdphenidate (Winsberg et aI.. 1974) despite claims to the contrary (Weiss et aI., 1971). Surprisingly, neither does there appear to be any great difference in effect or dosage between the dextro andlevo rotatorv isomers of amphetamine (Arnold et aL 1976). Further research with these drugs is indicated, particularly into their indications in other psychiatric disorders of childhood and into their basic pharmacological action in both animals (Millichap and Johnson. 1974; Shaywitz et aI., 1976; Silbergeld and Goldberg. 1975) and children (e.g., Arnold et aI., 1976),
Antipsychotics (Major Tranquilfiun, NeUfolfptics) While the increasing use of the term anti psychotics to describe this group of drugs is clearly preferable to major tranquillizers, it creates difficulty in child psychiatry where most of the indications for their use are in non psychotic conditions. Investigation of their value in childhood psychosis has emanated largely from a single center, the Bellevue group of Bender, Fish, and now Campbell, who claim a useful, though limited role for this group of drugs. This claim is supported by a few studies by other investigators (Campbell, 1975).
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Despite the wide use of these drugs in non psychotic, emotionally disturbed, and mentally retarded children, controlled studies are relatively few and most of these have involved only hyperkinetic children (Campbell, 1975; Conners, 1972; Gittelman-Klein et aL, 1976; Sprague and Werry, 1971, 1974; Werry et aL, 1966). The clinical consensus seems to be that anti psychotics can be useful in disorders marked by psychomotor excitation including hyperkinesis. In the latter condition, however, they lag considerably behind the stimulants in popularity (Krager and Safer, 1974; Sprague and Sleator, 1973). While both types of drugs quiet hyperkinetic children, in contrast to the stimulants, the anti psychotics do so by exerting a general depressant effect (Conners, 1972; Sprague and Werry, 1971, 1974; Werry and Aman, 1975). Their wide use of anxiolytics can be supported even less in children than in adults, since good studies here are very few indeed (Campbell, 1975; Conners, 1972; Sprague and Werry, 1971, 1974). It seems probable that any anxiolytic effect would be due to the mild antihistaminic type sedation which is rapidly dissipated upon repeated administration. Other side effects are much as would be expected from this group of drugs as reported in adults (Shader and di Mascio, 1970), except that dystonias are said to be more common in children and a shortlived extrapyramidal rebound syndrome has been reported to occur in psychotic children after withdrawal of anti psychotics (Polizos et aL, 1973). The most popular drug in this group is probably thioridazine (Mellaril), no doubt because of its strong sedative action and relative absence of extrapyramidal side effects. Its most important side effects, apart from atropinic ones, are seizures and retinitis pigmentosa, neither of which are likely to appear in normal clinical dosage of say less than 400 to 500mg per day. The use of anti psychotics in which extrapyramidal, rather than atropinic, side effects predominate (e.g., trifluoperazine [Stelazine], fluphenazine [Prolixin], and haloperidol [Haldol)) should be avoided except where there are special indications for their use, such as with fluphenazine deconoate, a long-acting injectable preparation, and with haloperidol in Gilles de la Tourette syndrome, or where the dosage can be kept well below that which produces extrapyramidal symptoms. This is because of the increasingly common, very distressing, and basically untreatable syndrome of tardive dyskinesia (usually presenting as choreoathetotic movements of the lips and tongue) thought to be due to postsynaptic sensitization to dopamine, the transmission of which is blocked by these drugs. In summary then, the antipsychotics seem to have a place in
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child psychiatry for the management of hyperactive, aggressive behavior of varying etiologies, in childhood psychosis, and in Gilles de la Tourette syndrome. However, since their introduction into child psychiatry came some 15 years or so ago when the technology of clinical investigation in pediatric psychopharmacology was extremely primitive, they need much fuller investigation particularly in studies where diagnosis in groups or SUbgroups is carefully defined and reasonably homogeneous (Gittelman-Klein et aI., 1976). The Antidepressants
Again, the difference between adult and child psychopharmacology is well illustrated by the inappropriateness of the term antidepressant for describing the growing clinical indications for the use of these drugs in child psychiatry. Discussion here will be restricted to the tricyclics since controlled trials of monoamine oxidase inhibitors are extremely infrequent and where they have been done, there is good reason to question the diagnoses of the children concerned (Conners, 1975a; Graham, 1974; Rapoport, 1976; Werry, 1975a). The oldest and most popular pediatric use of the tricyclics is in enuresis, but, while their symptomatic effect has been clearly established, any curative effect extending beyond the treatment is extremely doubtful (Angst and Theobald, 1970; Blackwell and Currah, 1973). Further, such use may cause unpleasant, though usually not dangerous, side effects, as well as significant unintended psychotropic action (Werry et aI., 1975a). The nature of their effect in enuresis is unclear and while thought to be primarily anticholinergic (Blackwell and Currah, 1973), recent work has suggested an a adrenergic action (Mahony et aI., 1973) and/or a local anesthetic action (Shaffer, 1974). Their use as true antidepressants is quite unestablished largely because the delineation of a true depressive syndrome in children, though frequently posited, has remained elusive (Conners, 1975a; Graham, 1974; Rapoport, 1976; Werry, 1975a). With one or two possible exceptions (see Conners, 1975a), subjects in clinical trials of antidepressants in children have had a mixed bag of symptoms which only a vivid imagination could subsume under a single nosological category similar to antidepressant-responsive depression in adults. The conclusion that, because a therapeutic effect has been obtained, depression must have existed in some masked or equivalent form ignores the many other pharmacological actions of these drugs (Graham, 1974). The search for new drugs less tarnished by past association with problems of drug abuse and dependency than the stimulants has
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led to systematic trials of the tricyclic antidepressants in hyperkinetic children. While most of these controlled trials (Greenberg et aI., 1975; Quinn and Rapoport, 1976; Rapoport et aI., 1974a; Waizer et aI., 1974; Winsberg et aI., 1972, Vepes et aI., 1976) have shown the antidepressants to be of some value, their response is typically less regular and less marked than that of the stimulants and the side effects are more troublesome. How they work in hyperkinesis is unclear, but their effect on cognitive function suggests that it is by some action analogous to that of the stimulants, rather than by their often associated sedative effects (Werry et £11., 1975b; Vepes et aI., 1976). This suggests that the antidepressant action seen in adults is simply one end of a continuum, of which stimulation is an earlier point (Werry et aI., 1975b). The side effects of tricyclics include the usual autonomic blocking effects, weight loss, stomachache, irritability, and tearfulness (Greenberg et aI., 1975; Quinn and Rapoport, 1976; Rapoport et aI., 1974£1; Waizer et aI., 1974; Winsberg et aI., 1972; Werry et aI., 1975b). As with methylphenidate, dosage is a controversial issue since, as used in the hyperkinetic syndrome, it has been considerably higher (sometimes well over 200mg a day) than that used in the treatment of enuresis where the close has not usually exceeded 50 to 75mg. These higher doses can produce much more serious side effects, notably seizures (Brown et aI., 1974; Petti and Campbell, 1975) and cardiotoxic effects (Martin and Zaug, 1975; Winsberg et aI., 1975) with one instance of sudden death in a 7-year-old girl (Saraf et aI., 1974). As a consequence the Food and Drug Administration has ruled (Hayes et aI., 1975) that 5mg/kg is the maximum allowable clinical dose in children and that as these doses are reached EKG monitoring is essential. My own position is similar to that of Rapoport et al. (1974a); namely, not to exceed lOOmg daily except in exceptional cases. A new and interesting, but so far experimental, use of the antidepressants is in pathological separation anxiety as seen in school phobias and, in the preschool child, in disturbed sleep characterized by nightmares and reluctance of the child to stay in his own bed (Gittelman-Klein and Klein, 1973). In summary, while the tricyclic antidepressants are a significant addition to the group of drugs valuable in child psychiatry, particularly in the management of the hyperkinetic syndrome and possibly also in separation anxiety, their use at the moment should be regarded as still being explored and requiring close medical surveillance. There is no reason to suspect any substantial difference in the therapeutic effect between different tricyclics, though side
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effects such as sedation may differ. Dosage for all is similar too. One should probably begin around I mg/kg; and in increasing the dose, it is important to remember that these are long-acting drugs with excretion rates measured in days or even weeks. Although this has not yet been established to be so in children, antidepressants may prove to have some latency in onset of activity as they do in adults. Anxiolytics and Sedatives
There are few reliable data on the usefulness of this group of drugs in children, though it is widely held that they make some children, especially psychotic and hyperkinetic children, worse (Campbell, 1975; Conners, 1972; Greenblatt and Shader, 1974; Ounsted, 1974; Stores, 1975). Such data as there are suggest they may have a useful role in minor disturbances marked by disturbed sleep and anxiety. Studies with the benzodiazepines (Greenblatt and Shader, 1974) and, to a lesser extent, the antihistamines (Campbell, 1975; Conners, 1972) are encouraging enough to make further investigation desirable. There is little doubt that both types of drugs are widely used in children by family physicians and that the lack of evaluation of their effects, good or bad, and of their proper indications is a significant gap in our knowledge. Generally speaking, these drugs are fairly benign and dosage ceilings have not yet been established. Manufacturers' recommended doses err on the conservative side, and if they are to be used, it is suggested that dosage be increased every 4 to 5 days (to avoid cumulative effects) until a therapeutic effect is obtained or evidence of side effects emerges. It should be borne in mind that, as demonstrated by Eisenberg et £II. (1961), anxiety in children is highly placebo sensitive. Further, anxiety is typically acute and situational as in school phobia, so that anxiolytics may well impair function in between the acute stress periods. Other Drugs
Though popular on the Continent, lithium has not yet found a place in pediatric psychopharmacology (Rapoport, 1976). Trials of its effect in hyperkinetic children are not encouraging (Greenhill et £II., 1973; Whitehead and Clark, 1970), though it may yet prove to have some place in the management of childhood psychosis (Campbell, 1975). Despite wide use, anticonvulsants, with the possible exception of sulthiame (Ospolot), have no proven role in children's behavior disorders unaccompanied by frank epilepsy (Conners, 1972; Looker and Conners, 1970; Stores, 1975), particu-
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larly since they can have unpleasant or even serious side effects including possible mental impairment (Stores, 1975; Trimble and Reynolds, 1976). Caffeine had a brief burst of popularity in hyperkinesis as a result of uncontrolled trials, but typically, this did not survive more stringent testing (Conners, 1975b; Huestis et aI., 1975). Pemoline, which has recently appeared on the market as Cylert, is useful in hyperkinesis though its action seems to be largely that of another stimulant (Conners, 1974; Page et aI., 1974). Hallucinogens, vitamins (including megavitamin therapy), and glutamic acid have all been tried and failed to earn themselves a useful place (Campbell, 1975; Sprague and Werry, 1971, 1974). The latest popular remedy for hyperkinesis, the exclusion of certain foods and additives from the diet (Feingold, 1975), has not yet been properly investigated (National Advisory Committee on Hyperkinesis and Food Additives, 1975; Werry, 1976). Preliminary data accruing from properly controlled studies suggest that this treatment is probably ineffective, is cumbersome, and carries \\·ith it a slight nutritional risk in inadequately supervised cases of subnutrition (Werry, 1976). The role of actylcholine analogues like deanol (Deanel") is still being debated, though recent theoretical interest in the role of acotylcholine in the brain makes it an interesting new type of substance with distinct possibilities in basic research in pediatric psychopharmacology (Lewis and Young, 1975). SYMPTOMS AND FUNCTIONS AFFECTED
Motor Activity Reduction in motor activity is a common therapeutic goal with drugs in children, particularly in the hyperkinetic syndrome. While most of the data supporting this effect on motor activity is subjective (based largely on parent and teacher ratings), direct measurements of motor activity have in some, though by no means all, instances confirmed this, particularly with stimulants (Millichap and Johnson, 1974; Montagu and Swarbrick, 1975; Sprague et aI., 1970). Apart from one study with imipramine (Werry et aI., 1975a), data from other drugs are lacking. As noted above, reduction in motor activity can be achieved in two distinct ways: by sedation or by increasing attentiveness. While the former is likely to be general, the latter would be detected only in situations where there is a demand for increased attention, which may explain some of the conflicting results between parent and teacher ratings and direct measurements of motor activity.
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Cognitive Function
The effect of drugs upon cognitive function such as attention, persistence, and short-term memory appears to be what would be predicted from their pharmacology: stimulants appear to enhance it (though, as noted above, chiefly in situations where boredom or incipient failure is characteristic [Sroufe, 1975; Rie, 1975; Weiss and Laties, 1962; Werry and Aman, 1975]), while antipsychotics tend to depress it (Conners, 1972; Gittelman-Klein et aI., 1976; Sprague and Werry, 1971, 1974; Werry and Aman, 1975). The effect of antidepressants is largely unstudied, but preliminary work suggests an action similar to stimulants (Werry et aI., 1975a; Yepes et aI., 1976). Despite decades of use as anticonvulsants, the effect of sedatives such as barbiturates, and now the benzodiazepines, upon cognitive function is unknown, with traditional complacency now giving way to increasing concern (Stores, 1975). Before selecting or dismissing a drug because of its effect upon cognitive function it should be remembered that these effects are small in usual clinical dosage, and knowledge about effects is based on laboratory situations. In the clinical situation, teacher reports and, to a lesser extent, parent ratings around homework should be used, backed up where possible by laboratory measures. Where the evidence is conflicting, a good clinician must, as always, look at the whole picture and make decisions accordingly. Mood and Self Image
This is surely one of the most neglected areas in pediatric psychopharmacology. It is difficult to assess drug effects on mood and inner comfort objectively and to do so in any manner requires patience and the development of a good relationship with the child. Such data as there are suggest that, as would be expected, drugs may improve or deteriorate mood states, self image, and comfort level. This depends on the drug but more particularly on the child, since the same drug may produce diametrically opposed effects in different children, as has been noted with the stimulants or the antidepressants (Conners, 1972; Gittelman-Klein and Klein, 1973; Rapoport et aI., 1974a; Rie et aI., 1976; Stores, 1975; Werry et aI., 1975a). It is particularly important to look for these effects since it is quite possible for a child to be improved in behavior yet made miserable by medication. Much more work is needed in this area.
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Social Behavior
Most of the impetus for the use of drugs in children comes from disturbances in their social behavior; therefore it is not surprising that this area of function is the best documented. Cooperativeness, impulsivity, willingness to listen and to consider others, obedience, and aggression are typical target behaviors which may be influenced in some children either positively or negatively by medication. Reliance for assessment of these has to be placed on parents and teachers, tempered by the knowledge that, unlike the child, they are complainants. Family Dynamics
While most parents welcome any improvement produced by medication, in some cases the family dynamics will be so upset that treatment will be discontinued or resisted. Not surprisingly, there is some evidence that family structure influences the effect of medication. For example, Loney et al. (1975) found that "well managed" children responded better than "poorly managed" children. Because investigators in psychopharmacology are not usually skilled in this area, the interaction between drugs and family dynamics has received very little attention. It should, however, be fairly generally recognized that drug treatment must be combined with other kinds of treatments and not simply administered in traditional medical fashion. Physiological Systems
A characteristic of most psychotropic drugs is that they affect many bodily systems. While most of these effects are small, they can cause significant levels of discomfort. No doctor should administer psychotropic drugs to children without a sound knowledge of clinical psychopharmacology and without some system of interrogating and examining for these physical effects. DIAGNOSTIC AND SYMPTOMATIC INDICATIONS
None of these indications as set out in summary form in table I is absolute. Some children with such a diagnosis may not need medication or, if they do, may not respond to it. Some may respond, but side effects may prevent continuation. Most of the indications have been discussed in detail above except Gilles de la Tourette syndrome. This condition is said to respond specifically to large doses of haloperidol, i.e., around 10mg or more (Ayd, 1972; Shapiro et
The Use ofPs.ychotropic Drugs in Children
461
Table I ()rug~
I. Slilllulallls (IU-I.Olllg/kg llIeilwlphenic!;tll"l ') :\111 ips\"{· hoI ics (no 1lI""illlum dose) 3. TrinTlic antidepressants (do nol e"c('cd !img/kg) 4. Iknzodi"l.epines (no ma"illlum) :1. :\llIihisl"mines
and
C:ondilion~
H \·,K'rk i ne~is: conduel disorders H\verkinesis: P"c!]()lIlotor e"citalion: Cilles de b Tourclle syndroml' (haloperidol): childhood schizophITni,,: Cll1lduCl disonkrs H\perkinC'sis: enuresis (suppress"nl onl\"): sep"ralion an"iel\· (0) An"ietY S\·;npIOlns: sleep diSlurhances Sleep disturhanc('s
(~)
aI., 1973; Woodrow, 1974). While controlled trials have not been reponed, this disorder is so distressing and so difficult to treat that haloperidol should certainly be given a good trial. It is worth noting that haloperidol, panicularly in this dosage, if continued for any length of time, might produce tardive dyskinesia ,,·hich could be mistaken for a return of the tics. U;\,ANSWEREO QUESTIONS
While the short-term benefits of such drugs as the stimulants in the hyperkinetic syndrome are faidy dear, the extent [() \\·hich they inHuel1Ce long-term prognosis is unknown. Although some argue that stimulants should be given to every hyperkinetic child to prevent later psychiatric disability, what little evidence is available so far is largely negative and suggests that this is a quite unwarranted assumption (Riddle and Rapopon, 1976; Weiss, 1975). This area requires patient study under the well-known difficulties and discouragements of longitudinal studies. Another question is whether or not the changes upon attention and othel· cognitive functions pl-esage definitive changes in academic achievement. The dramatic changes in writing and the organization of written material produced by methylphenidate illustrated in a recent study (Schain and Reynard, 1975) are pan of the clinical experience of every child psychiatrist who has used stimulants in the hyperkinetic syndrome. However. systematic studies are few and those which exist fail to demonstrate changes in academic achievement (Gittelman-Klein and Klein, 1976; Rie et aI., 1976). As with long-term clinical benefit, overly optimistic assumptions about the power of stimulants to influence learning problems must be resisted until the evidence is clearer. A third problem concerns future drug abuse and dependency, particularly with the stimulants. While long-term studies show that
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this is clearly not a common outcome of stimulant therapy (Beck et aI., 1975; Denhoff, 1973; Lipman, 1974; Weiss, 1975), the subject attrition from these studies means it still remains a possibility for a minority of children, particularly those from more disturbed backgrounds. The statement by the Conference on the Use of Stimulant Drugs (1971) that there can be no real risk of future drug dependency because the stimulants do not cause euphoria in hyperkinetic children is based on questionable assumptions. As Conners (1972) and Rapoport (1976) point out, stimulants may not cause euphoria, but they certainly can cause a state in some children suggestive of a sense of well-being. A similar effect has also been noted with imipramine (Gittelman-Klein and Klein, 1973; Werry et aI., 1975a). Fourth, there is little information on exactly how long stimulants and other drugs should be given, though there is tacit acceptance of a relatively long-term administration. On the other hand, Sleator et al. (1974) have demonstrated that by annual substitution of placebo, about 20 percent per year of children on long-term stimulant medication will be found to need their drugs no longer. Studies of this nature are infrequent and where data are lacking, dogma flourishes. Fifth is the question of frequency and seriousness of long-term physical effects, notably growth retardation, of the stimulants (e.g., Gross, 1976), tardive dyskinesia with the antipsychotics, and intellectual deterioration with sedatives and anticonvulsants (Stores, 1975; Trimble and Reynolds, 1976). Sixth, what is the frequency with which children are being kept on medication for reasons of social control when such use is accompanied by sedation, minor but significant physical discomfort, negative mood changes, and substantial changes in personality? Seventh, to what extent is it true, as charged by Rie (1975), that the use of medication leads to oversimplified concepts of etiology and of treatment in children with behavior problems? Last, what are the exact disgnostic indications for and predicators of drug response? At the moment, most drug therapy is fumbling empiricism, but there are many hopeful signs that a more rational approach may ultimately be possible. For example, theory (Wender, 1971), animal work aimed at reproducing paradigms particularly of the hyperkinetic syndrome (Corson et aI., 1976; Shaywitz et aI., 1976; Silbergeld and Goldberg, 1975), biochemical investigations (Greenberg and Coleman, 1976; Rapoport et aI., 1974b), pharmacological studies aimed at relating structure and function as suggested by Wender (1971, 1975) (e.g., Arnold et aI.,
463
The Use of Psychotropic Drugs in Children
1976), and electrophysiological techniques (Conners, 1974; Satterfield and Cantwell, 1975) suggest a considerable and laudable intellectual ferment in pediatric psychopharmacology. SUMMARY A D
CO
CLUSIO S
This brief overview of research and clinical aspects of psychotropic drugs in children has revealed more ignorance than knowledge. Only the stimulants have a well-tested place in children and even there much is largely unknown, such as the impact on achievement and the exact diagnostic indications. Most other drugs still require further careful study before definitive statements about their usefulness and safety can be made, though the antidepressants and antipsychotics would seem to have a worthy role. Most of the diagnostic indications for pharmacotherapy are not yet well delineated. The hyperkinetic syndrome has preempted most of the attention of the few really experienced and competent investigators in pediatric psychopharmacology for the last 10 years to the neglect of all other conditions, except perhaps childhood psychosis, Gilles de la Tourette syndrome, and enuresis. Anxiety symptoms, neurotic conditions, personality disorders, and borderline states have received little serious attention, though indications that medication may playa useful role in some of these conditions are quite strong. Much of the problem lies in the shortage of investigators in pediatric psychopharmacology and the quite unnecessary view of it as a competitor rather than an adjunct to psychological, behavioral, and remedial treatments. Criticisms made about the use of drugs, particularly the stimulants, as dangerous or as chemical straitjackets along the lines made by medical procedures in general by IIIich (1975) have not been supported by investigations. For example, far from the oppressed poor being cudgeled into line with stimulants as originally charged by critics, it is actually the children of the affluent who are much more prone to receive them (Krager and Safer, 1974; Sprague and Sleator, 1973). While it is indisputably true that some doctors do, and always will, misprescribe or overprescribe psychotropic drugs in children, this is no more an argument against such treatment when properly indicated and supervised than it is against any useful yet overprescribed treatment such as penicillin or Vitamin B 12. The poor clinician and the outof-date physician are as serious a concern to the medical profession as they are to its critics. The only answer to such criticisms is for child psychiatrists to produce hard data obtained by careful, properly controlled, and
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ethical studies and then for such information to be used in clinical practice. To achieve this, pediatric psychopharmacology has somehow to attract its share of the intellectually curious and scientifically inclined. In turn, educators and clini~ians in child psychiatry must remember that they are first and foremost physicians and that medicine is not simply a humanitarian exercise but an applied biosocial science.
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