Pediatric psychopharmacotherapy: a review of recent research.

/ Cktid Psyihoi Ps_ychml Vol. 33. No, 1, pp 153-195, 1992 Primed in Grcal Britain

002I-9630/92 J5 00 t 0.00 PcrgarnoH Prcs.i pic © 1992 Asxociaiion for Child Psychology and Psythiatry

Pediatric Psychopharmacotherapy: A Review of Recent Research Kenneth D. Gadow Introduction For the past 30 years, methylphenidate, thioridazine and imipramine (or their chemical equivalents) have been the mainstay of psychotropic drug therapy for children and adolescents, and they are prescribed primarily for the treatment of disruptive behavior disorders. This situation, however, is beginning to change with the discovery of new pharmacological agents and more importantly the evaluation of the psychotropic properties of drugs originally approved for the treatment of non-psychiatric disorders. In keeping with tradition, these new treatments are being adopted following purported success in adults with psychiatric disorders and without clear demonstration of safety and efficacy for patients in the pediatric age range and will probably enjoy a period of unrealistic expectation and application before settling in to their rightful place in the hierarchy of therapeutic agents. There is also a growing awareness that the mood and thought disorders of children and adolescents may respond differently to psychotropic medication than seemingly comparable disorders in adults, which may ultimately alter current treatment and drug prescribing patterns. Ironically, one of the biggest developments in pediatric psychopharmacotherapy in terms of the number of patients treated has not been the discovery of new drugs, but rather the creation of a new disorder, attention deficit disorder without hyperactivity (Safer & Krager, 1988). This review focuses on recent developments (since 1985) in drug therapy for childhood psychiatric disorders. Earlier studies are occasionally noted for purposes of showing continuity in research fmdings or to document the extent of research in a particular area. Given the fact that there are well over a dozen childhood disorders for which psychotherapeutic drugs are prescribed and literally scores of drug products (the availability of which varies from one country to the next), it was necessary to Keywords: Pharmacotherapy/drug therapy, attention-deficit hyperactivity disorder, mental retardation, toxicity. Accepted manuscript received 14 June 1991

Department of Psychiatry and Behavioral Science, State University of New York at Stony Brook, NY 11794-8790, U.S.A, Requests for reprints to: Professor Kenneth D, Gadow, Department of Psychiatry and Behavioral Science, Putnam Hall, South Campus, State University of New York at Stony Brook, Stony Brook, N \ ' 11794-8790, U,S,A,

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impose limits on the breadth and detail and the topics addressed. First, given the relatively high rate of placebo response for many childhood disorders, statements pertaining to efficacy refer to controlled (placebos, single- or double-blind conditions) studies. Occasionally, reference is made to uncontrolled studies to indicate directions for future research, but no attempt has been made to review them here. Second, topics of interest are limited to efficacy, dose and schedule of drug administration, toxicity, predicting drug response, relative efficacy with behavioral interventions, and the residual benefits of treatment. Third, the primary focus of this article is research findings that have implications for clinical management. Nevertheless, this is not a guide to drug therapy. Readers interested in this topic are referred to the following texts on pharmacotherapy: Aman and Singh, 1988; Barkley, 1990; Campbell, Green and Deutsch, 1985; Gadow, 1986a, b; Gadow and Poling, 1988; Werry, 1978; Werry and Aman 1991; Wiener, 1985. Lastly, this review does not address theories of neurosphysiological dysfunction or nutritional or dietary treatments (e.g. vitamins, hormones) or to discuss issues in research methodology or diagnostic ambiguities other than to note relevant implications for understanding reported drug effects when appropriate. The general organization of the material is by disorder (arranged alphabetically), which is not as straightforward as it sounds because notable changes were made to the diagnostic systems that were used during the time period covered in this review. Further, there is no one standard diagnostic interview to identify these disorders, and the psychometric properties of available instruments are modest. So as not to create the false impression that the studies reviewed here are comparable with regard to sample characteristics, generic labels have been adopted to categorize childhood disorders. A case can also be made for describing the efficacy of pharmocotherapy in terms of target behaviors (or symptoms) because drug effects are fairly non-specific. For example, the neuroleptics have been shown to suppress aggressive behavior in children with a variety of different diagnoses. Equally important is the fact that effective pharmacotherapy typically improves some but not all symptoms or characteristics of a disorder, which is particularly true of the developmental disabilities. From a reviewer's perspective, the picture is further complicated when researchers (a) infer changes (or lack of) in target behaviors on the basis of rating scales designed to provide global assessments of the disorder, (b) fail to identify subsamples of individuals with a particular disorder who exhibit target behaviors that are drug responsive, or (c) use dependent measures that do not adequately assess target behaviors or are not sensitive to treatment effects. In an effort to better describe research findings, this review examines drug efficacy with regard to disorders, and when appropriate, specific target behaviors. Although a serious effort was made to locate all controlled drug studies that had obvious implications for clinical management, important contributions to the literature have no doubt been overlooked. Their omission should be considered an oversight and not interpreted as the reviewer's opinion regarding their merit.

Efficacy Aggression

Aggression is a poorly developed concept, at least in terms of its behavioral referents.

Pediatric psychopharmacotherapy

in the pediatric psychopharmacology literature. It includes behaviors such as verbal aggression (e.g. cursing, threatening, malicious teasing), object aggression (e.g. breaking toys, destroying property), symbolic aggression (e.g. feigning physical attack, making offensive gestures), and physic2d aggression (e.g. striking, shoving, or tripping others). A distinction is sometimes made between an aggressive act that is initiated by the aggressee and one that is emitted in response to the provoking actions of another person and whether the aggressive act is directed toward a peer or an adult. Other behaviors that are subsumed under the rubric of aggression are defiance of authority figures, non-compliance, emotional lability, norm-violating behaviors, and a variety of antisocial activities that may or may not involve confrontation with the victim. This unwieldy use of the term is also evident in items constituting "Aggression" factors in behavior rating scales, the diagnostic symptoms of the disruptive behavior disorders, and the operational definition and labels of observation code categories. Because aggressive behavior is a relatively common characteristic of many childhood and adolescent disorders, its response to pharmacotherapy is discussed here as a target behavior. Traditionally, the most commonly prescribed drugs for the management of severe aggressive behavior have been the neuroleptics. Controlled studies show that they suppress aggressive behavior in conduct disordered, mentally retarded, autistic, and hyperactive children. Recent studies of their efficacy are noted later in the discussions of treatment for these disorders. Given the relative safety and efficacy of stimulant drugs, it is noteworthy that relatively little is known about their effect on specific forms of child and adolescent aggression. Drug-induced improvements in aggressive behavior are often inferred from rating scale data, but as previously noted, "Aggression" factor scores typically represent an amalgam of conduct problems. Recent direct observation studies of hyperactive children confirm and expand the findings of prior investigations by showing that methylphenidate suppresses a variety of aggressive behaviors in both structured and unstructured settings (Abikoff & Gittelman, 1985a; Hinshaw, Henker, Whalen, Erhardt & Dunnington, 1989; Pelham & Hoza, 1987), including physical aggression initiated by the hyperactive child and directed towards peers (Gadow, Nolan, Sverd, Sprafkin & Paolicelli, 1990). There is a growing number of case reports and open trials suggesting that lithium may be an effective treatment for aggressive behavior in children and adolescents (e.g. DeLong & Aldershof, 1987; Vetro, Szentistvanyi, Pallag, Vargha & Szilard, 1985), but controlled studies are limited. Campbell et ai (1984) found lithium to be highly superior to placebo in suppressing aggressive behavior in hospitalized prepubertal children with conduct disorder. The optimal dose of lithium was 500-2000 mg per day (blood levels from 0.32 to 1.51 mEq/1). The findings from uncontrolled studies suggest that the beta-adrenergic agent propranolol (e.g. Jenkins & Maruta, 1987; Kuperman & Stewart, 1987; Williams, Mehl, Yudofsky, Adams & Roseman, 1982) and the antiepileptic drug carbamazepine (reviewed by Evans, Clay & Gualtieri, 1987) may suppress aggressive behavior in some children and adolescents. The doses of propranolol reported in most studies range from 50 to 300 mg/kg per day (Ruedrich, Grush & Wilson, 1990), and the average dose for children and adolescents is 160 mg/day (Williams et ai 1982).

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Carbamazepine dosage guidelines for aggression appear to be the same as for seizure disorders, but there is really very little research on this in children. Anxiety disorders

With the exception of school refusal (separation anxiety) and obsessive compulsive disorder, psychopharmacological research on anxiety disorders in children and adolescents is extremely limited (reviewed by Gittelman & Koplewicz, 1986). Progress in this area is hindered in part by diagnostic ambiguities. One controlled study of imipramine (100-200 mg/day) for the treatment of school refusal (school phobia) in children and adolescents who were receiving psychotherapy found medication superior to placebo in facilitating school attendance (Gittelman-Klein & Klein, 1971). Treatment with medication resulted in considerable reduction in depression, severity of phobia, maternal dependence, physical complaints, and fear of going to school. A large percentage of children receiving placebo also returned to school. Another controlled study of imipramine and alprazolam for school refusal in severely symptomatic (anxiety and/or depression) children and adolescents did not find that either medication was superior to placebo (Bernstein, Garfinkel & Borchardt, 1990). However, the investigators noted several design limitations that may have attenuated drug effects. The mean daily dose of imipramine and alprazolam was 135 mg and 1.43 mg, respectively. A controlled study of low doses (40-75 mg/day) of clomipramine also failed to show efficacy for school phobia (Berney et al, 1981). Obsessive compulsive disorder has also been shown to be responsive to medication. In children symptoms commonly take the form of repetitive thoughts of violence, contamination, or doubt and ritualistic actions involving hand washing, counting, checking, and touching (Swedo, Rapoport, Leonard, Lenane & Cheslow, 1989). A study by Flament et al (1985) showed that clomipramine was superior to placebo in controlling these symptoms in children and adolescents. Unfortunately, most drug responders did not recover fully, and there was a relapse in symptoms after drug withdrawal. Patients with compulsions responded better than those with obsessions only. Doses ranged from 100 to 200 mg per day. One of the 19 subjects developed tonic-clonic seizures on clomipramine. A controlled study comparing the relative efficacy of clomipramine and desipramine found a high rate of symptom relapse when youngsters receiving clomipramine were switched to desipramine (Leonard et al, 1989). The mean dose of each drug was approximately 150 mg/day. The findings from one study (open trial) suggest that fluoxetine may be effective for obsessive compulsive disorder in children and adolescents (Riddle, Hardin, King, Scahill & Woolston, 1990). Study doses ranged from 10 to 40 mg per day. The efficacy of clomipramine-fluoxetine combination treatment has also been commented on (Simeon, Thatte Si. Wiggins, 1990). With regard to other anxiety disorders, most current research pertains to the more rapidly eliminated benzodiazepines. Simeon and Ferguson (1987), for example, reported that alprazolam produced moderate improvement (open study) in children with overanxious and avoidant disorder. Alprazolam (daily doses ranging from 0.003 to 0.025 mg/kg) was also found to be helpful in reducing anticipatory and acute situational anxiety (controlled study) in child cancer patients undergoing painlul medical procedures (Pfefferbaum et al, 1987).


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The findings from uncontrolled studies suggest that propranolol may produce symptomatic relief for children with post-traumatic stress disorder (Famularo, Kinscherff & Fenton, 1988) and adolescents with hyperventilation attacks (Joorabchi, 1977). Autism For the past two decades, Campbell and her colleagues at Bellevue Hospital in New York City have conducted most of the well-controlled pharmacological studies of autistic children. Her study samples have generally consisted of preschool-aged children in a hospital residential treatment program. Based upon her fmdings, haloperidol appears to be the most safe and effective drug for this disorder. Symptomatic improvement consists of decreased levels of social withdrawal, hyperactivity, stereotypies, fidgetiness, emotional lability, and abnormal object relations (Anderson et al, 1989; Cohen et al, 1980). Hypoactive autistic children are not helped by treatment with haloperidol, and their symptoms may become worse. The optimal dose for most preschool-aged autistic children ranges from 0.5 to 1.0 mg/day. Treatment with haloperidol has been shown to increase the effectiveness of a language-based behavior therapy program (Campbell et al, 1978) and appears to facilitate discrimination learning (Anderson et al, 1984). However, the latter finding was not replicated in a subsequent investigation (Anderson et al, 1989). The drug was found to remain effective even after 2.5 years of continuous administration (Campbell et al, 1983). More recently, these researchers have shown that a dosing schedule of 5 days on medication and 2 days off is just as effective as a 7-day-on medication schedule (Perry et al, 1989). The usefulness of simulants for the treatment of learning and behavior disorders in autistic children is controversial. Campbell, Fish, Shapiro, Collins and Koh (1972), for example, found that dextroamphetamine often exacerbated the symptoms of autism by increasing social withdrawal and stereotypies. Many youngsters also became more hyperactive and irritable. Their subject sample, however, was confined to preschoolers, an age group that is known to be overly sensitive to these types of reactions (Ounsted, 1955). Other investigators, however, report favorable outcomes (reduction in hyperactivity symptoms and aggression) for elementary school-aged autistic children receiving dextroamphetamine (Gcller, Guttmacher & Bleeg, 1981) or methylphenidate (Birmaher, Quintana & Greenhill, 1988; Strayhorn, Rapp, Donina & Strain, 1988; Vitriol & Farber, 1981). These reports pertain to only a few children, and, with the exception of the single-case study by Strayhorn et al (1988), are uncontrolled. Nevertheless, their findings suggest that further research on stimulant treatment is warranted. The most significant new development in pharmocothrrapy for autism is fenfluramine, a drug that is pharmacologically similar to amphetamine and originally approved for clinical use as an anoretic. Numerous reports about the safety and efficacy of fenfluramine as a treatment for autistic individuals have been published (reviewed by Aman & Kern, 1989; Campbell, 1988), Although the findings from more recent studies are less optimistic than initial reports (Barthelemy et al, 1989; Ekman et al, 1989; Sherman, Factor, Swinson & Darjes, 1989; Stern fial, 1990; Varley & Holm.

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1990), the likely outcome is that fenfluramine is not a general treatment for autism but is effective in suppressing certain types of target behaviors (and enhancing specific adaptive behaviors) in some individuals. Fenfluramine has been reported to decrease hyperactivity, distractability, and stereotypies and increase eye contact, social responsiveness, and language performance. The daily doses employed in most studies with children range from 1.2 to 2.1 mg/kg per day (mean = 1.5 mg/kg/day), which is divided into a morning and an afternoon or evening dose. There is some encouraging preliminary research on the opiate antagonist naltrexone as a symptomatic treatment for autism. For example, Campbell et al (1989) found that an open trial of 0.5-2.0 mg/kg per day doses of naltrexone reduced stereotypies, hyperactivity, and social withdrawal and increased verbal production in several preschool-aged autistic children. However, a subsequent double-blind study revealed somewhat less dramatic clinical improvement (Campbell et al, 1990). Naltrexone was shown (controlled case studies) to reduce self-injurious behavior in autistic mentally retarded adolescents (Barrett, Feinstein & Hole, 1989; Walters, Barrett, Feinstein, Mercurio & Hole, 1990). Preliminary clinical experience with two additional drugs warrants comment. An open trial of propranolol in mentally retarded autistic adults suggests that betaadrenergic blocking agents may be effective for controlling aggressive behavior (Ratey et al, 1987). The findings from an open trial of buspirone are also encouraging (Realmuto, August & Garfmkel, 1989). Conduct disorder

Conduct disorder is generally characterized by a pattern of aggressive, oppositional, and norm-violating behaviors. As previously noted, both lithium and the neuroleptics are effective for clinical management (Campbell et al, 1984). Molindone appears to be equally as efficacious as thioridazine (Greenhill, Solomon, Pleak & Ambrosini, 1985). Because evidence for the clinical efficacy of pharmacotherapy for conduct disorder is based primarily on behavior rating scale data, little is known about drug effects on specific target behaviors, especially more secretive forms of nonconfrontational aggression (e.g. fire setting, stealing) and low frequency antisocial behaviors (e.g. lying). Depression

The 1980s witnessed an outpouring of research on childhood depression, a disorder that was considered to be poorly defined in the 1970s (Conners, 1976; Rapoport, 1976). Unfortunately, the early enthusiasm for the efficacy of tricyclic drug therapy, which sprang from open trials and case studies, has begun to wane following reports of negative findings from controlled studies. To date, none o{ the double-blind investigations of tricyclics in depressed prepubertal children (Geller, Cooper, McCombs, Graham & Wells, 1989; Kashani, Shekim & Reid, 1984; Petti & Law, 1982; Puig-Antich et al, 1987) or adolescents (Geller, Cooper, Graham, Marsteller & Bryant, 1990; Kramer & Feiguine, 1981) has found medication to be superior to placebo. The findings from recent uncontrolled tricyclic studies of depressed adolescents


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are equally discouraging (Ryan et al, 1986; Strober, Freeman & Rigali, 1990a). However, owing to small sample size and other design limitations of these studies, many clinicians still consider efficacy of tricyclic antidepressants for childhood and adolescent depression to be an open question. Most attention has focused on the high rate of placebo response as a methodological impediment, biological variables that may attenuate drug response in younger patients, and the characteristics of youngsters who show a poor response to medication. Briefly, investigators have excluded placebo responders from the drug trial in an attempt to get a more clear-cut picture of drug responsivity (Geller et al, 1989, 1990), but this has not resulted in more compelling fmdings. Further many placebo responders later relapse suggesting that spontaneous improvement is a short-lived phenomenon. With regard to biological variables, it has been suggested that the increased level of gonadotropin during adolescence (Ryan et al, 1986) and differences in neurotransmission (Strober et al, 1990a) may account for the less than satisfactory response to tricyclics in adolescents compared with adults. To date, patients who are least likely to respond to tricyclic therapy are those with psychotic symptoms (delusions) (Puig-Antich et al, 1987; Strober et al, 1990a) or separation anxiety (Ryan et al, 1986). There is also one report that depressed prepubertal children with a concomitant conduct or opposition disorder are less likely to respond favorably to tricyclic antidepressants than pure depressives or youngsters with depression plus an anxiety-related disorder (Hughes et al, 1990). For patients who are refractory to tricyclic therapy, the results of an open trial suggest that the addition of lithium to the treatment regimen may be helpful (Ryan, Meyer, Dachille, Mazzie & Puig-Antich, 1988a). One chart review study found that MAOIs (used either alone or in combination with tricyclics) may be effective for adolescent patients who do not respond satisfactorily to tricyclics (Ryan et al, 1988b). However, dietary infractions were relatively common. With regard to the management of the treatment regimen, adolescents receiving divided doses (t.i.d) of imipramine can be safely switched to a once-a-day (before bed) schedule after the maintenance dose is established (Ryan et al, 1987). The findings from blood level-therapeutic response analyses are too contradictory to offer sound clinical recommendations for either children or adolescents. Reduction of tricyclic medication should be gradual, because withdrawal symptoms (sleep disturbance, nightmares, nausea, headache, and other physical complaints) may occur if medication is stopped abruptly (Geller, Cooper, Carr, Warham & Rodriguez, 1987). Eating disorders

The only eating disorder for which psychotropic medication has been found effective is bulimia nervosa. Placebo-controlled studies show that tricyclic antidepressants (imipramine, desipramine), MAO inhibitors (phcnelzine, isocarboxazid), and atypical antidepressants (fluoxetine, bupropion) can reduce the frequency of binging and vomiting (reviewed by Goldbloom, Kennedy, Kaplan & Woodside, 1989). Although research pertains to adult bulimics, adolescents were often included in study samples, suggesting but not confirming efficacy for teenagers.

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Enuresis (nocturnal)

Enuresis is generally included in discussions of pediatric psychopharmacotherapy because the disorder is responsive to tricyclic antidepressants, which are the preferred pharmacological agents (Blackwell & Currah, 1973), and not because enuretic children are usually comorbid for psychiatric disturbance (they are not). There are also several placebo-controlled studies indicating that that antidiuretic hormone desmopressin is also an effective treatment for this disorder (reviewed by Klauber, 1989). It has a rapid onset of action and negligible side effects. Child patients are generally treated with doses ranging from 20 to 40 /Ag administered intranasally at bedtime. Desmopressin's efficacy for nocturnal enuresis is related to its ability to increase water absorption in the kidneys, which reduces the volume of water entering the bladder. The drawbacks of desmopressin treatment are the relatively high cost of the medication and the likelihood of relapse when medication is discontinued (Miller, Goldberg & Atkin, 1989). Gradual tapering of the dose during the withdrawal period (which may last several months) reduces the probability of relapse. Hyperactivity

The disorder that has traditionally received the greatest attention from clinical psychopharmacologists is hyperactivity. It is not surprising, therefore, that most recent research pertains to this disorder, and is, to some extent, a confirmation or extension of findings from previous investigations. For the purposes of discussion, recent developments in drug therapy for hyperactivity that bear on clinical practice are categorized as follows: specification of drug effects, dose and schedule of drug administration, special clinical populations (age, gender), comorbidity, drug assessment procedures, and relative efficacy. Because the great bulk of research pertains to stimulants, studies of other pharmacological agents are addressed separately. Before reviewing specific drug effects, it should be noted that hyperactive children acquired a new label from the American Psychiatric Association in 1987, attention-deficit hyperactivity disorder (ADHD), a name that sorts well with its stated primary characteristics but generally does poor justice to the behaviors that prompt medical referral. Specification of drug effects. During the past 5 years, researchers have examined in greater detail the responsiveness of specific aspects of child symptomatology and performance to stimulant drug therapy. The areas that have received the greatest attention are interpersonal interactions, dose-response relationships, cognitive function, and academic performance. (For various reasons, the latter is addressed here as a separate topic.) There are also several reports of how stimulants affect mood. Advances in understanding the effects of stimulant medication on interpersonal interactions have been achieved primarily with the aid of direct obser\'ation procedures. Observation settings vary depending in part on the goals and objectives ol the study, desired degree of experimental control, and ease of data collection, and include clinicbased playrooms or treatment rooms, special laboratory schools, and public schools. Given the reciprocal nature of social interactions, an understanding of drug effects involves not only the behavior of the hyperactive child (proband), but also the behavior of care providers and peers. Briefly, stimulants have been shown to reduce negativistic


social interactions in probands in both structured (classroom) and unstructured (lunchroom, playground) settings (e.g. Abikoff & Gittelman, 1985a; Gadow et al, 1990; HirxshdLW et al, 1989; Wallander, Schroeder, Michelli & Gualtieri, 1987; Whalen et ai 1987), with greater improvement achieved at moderate (0.6 mg/kg b.i.d.) than low (0.3 mg/kg b.i.d.) doses. Both parents and teachers respond to symptom attenuation by being less controlling of and less negative toward hyperactive children when the latter are receiving methylphenidate compared with placebo (Barkley & Cunningham, 1979; Humphries, Kinsbourne & Swanson, 1978; Whalen, Henker & Dotemoto, 1980). These reactions to improvement in child behavior are dose-related (at least for mothers); they are more evident at moderate-to-high (0.7 mg/kg b.i.d.) than low (0.3 mg/kg b.i.d.) doses (Barkley, Karlsson, Pollard & Murphy, 1985). Stimulant-induced improvements in proband behavior result in less controlling behaviors by peers (Cunningham, Siegel & Offord, 1985) and greater peer acceptance (Whalen et al, 1989) in laboratory school settings. In public school classrooms, peers may even engage in less non-physical aggression on days when the proband is receiving medication compared with placebo (Gadow et al, 1991b). Hyperactive children initiate fewer social interactions (especially the negative variety) in the classroom when receiving stimulant medication, and peers respond in like manner by interacting with and attending to the proband less frequently (Wallander et al, 1987). Methylphenidate's positive effect on attending to task can have beneficial implications for social activities such as playing baseball (Pelham et al, 1990b). At the present time it is extremely difficult to draw conclusions from the recent literature on the cognitive effects of stimulant drugs that can be considered a new research development that has significant implications for clinical management. One of the primary reasons why it is so difficult to summarize this literature is that there are numerous measures of cognitive performance, which are based on divergent theories or components of mental activity. Even more frustrating is the fact that rather simple modifications of the same task generate very different patterns of drug effects. Further, unless a particular cognitive task can be linked in some way to the rationale for treatment (learning disability, academic underachievement) or covaries with an important target behavior or symptom of behavioral toxicity, conclusions about clinical implications are highly speculative. This having been said, there has been a considerable amount of research on this topic in recent years, and it remains an exciting area of inquiry. Readers interested in measurement and interpretation issues associated with commonly used cognitive and learning tasks are referred to recent articles that address this subject (Douglas, Barr, Amin, O'Neill & Britton, 1988; Rapport, Quinn, DuPaul, Quinn & Kelly, 1989). Recent studies of the effect of methylphenidate on mood indicate that in normal children medication lessens the degree of dysphoria that children experience when participating in laboratory activities (Peloquin & Klorman, 1986). Hyperactive adolescents receiving methylphenidate report mood elevation on medication compared with placebo (Klorman, Coons & Borgstedt, 1987; Klorman, Brumaghim, Fitzpatrick & Borgstedt, 1990). Another study found a reduction in self-reports of anger-hostility in hyperactive children receiving 0.7 mg/kg of methylphenidate compared with placebo (Walker, Sprague, Sleator & Ullmann, 1988). Teacher ratings of the hyperactive child's mood indicate a reduction in anxiety and depressive symptoms on methylphenidate

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compared with placebo (Barkley, McMurray, Edelbrock & Robbins, 1990; Handen, Feldman, Gosling, Breaux & McAuliffe, 1991; Nolan, 1988). Dose and schedule of drug administration. The dose and schedule of drug administration remains one of the most controversial aspects of stimulant treatment. This is odd given the long history of clinical research on these drugs and the fairly restricted range oi therapeutic doses. There are several possible explanations for this state of affairs, two of which are briefly noted here. First, and possibly most important, is the failure to formulate theories of (or rationales for) drug therapy that are linked to specific target behaviors (e.g. on-task behavior, academic productivity, aggression, disruptive behavior). This inherent ambiguity with regard to the objectives of therapy makes definite statements about the minimal effective dose next to impossible because the criterion for improvement is not clearly defined. In other words, it is highly probable that the optimal dose of medication is not the same for all types of target behaviors. Second, the accuracy and ecological validity of many measures that are currently used to assess drug effects have yet to be demonstrated. This is particularly true of laboratory analog devices, but the same can be said for behavior rating scales and direct observation codes. It is important to note that individual variability in response to stimulant medication is not a satisfactory explanation for the impasse on the dosage issue because there is no reason why optimal dose cannot be operationally defined in terms of the magnitude of change in target behaviors that are linked to a particular theory of (or rationale for) treatment. The considerable degree of individual responsivity to stimulants and the poor correlation between drug response on various measures of cognitive and behavioral function, which has been commented upon for many years (Bradley, 1937; Conners, 1972; Gittelman-Klein & Klein, 1975; Turner & Carl, 1939), raise questions about the usefulness of general dosage guidelines other than to indicate the upper and lower end of the therapeutic range and particular subgroups of the patient population that may respond to higher or lower than average doses. The biggest dose issue is not really a matter of how much to use as it is a problem of how to go about it (see section on procedures for assessing response to medication). Third, there has always been some confusion between individual dose verus total daily dose (e.g. 0.5 mg/kg morning and noon versus 1.0 mg/kg morning only) with regard to dose-dependent effects, a distinction that some reviewers still fail to make. In this article, reported stimulant doses refer to the individual dose that actually preceded the onset of or served as the basis for the drug response evaluation. Perhaps the most significant dosage issue is whether the dose-response effects of stimulants vary for different behaviors and mental operations. One research team (Sprague & Sleator, 1973, 1977) observed that methylphenidate-induced improvements in cognitive performance (group data) appeared to plateau at morning doses between 0.3 and 0.7 mg/kg and were negated at higher doses (1.0 mg/kg). whereas teacher ratings of symptom severity continued to decrease as the dose of medication increased. (These investigators were careful to note the important difference between group and individual subject analyses.) Numerous researchers have documented this plateau effect (group data) on cognitive and academic performance. Ironically, the pursuit of ever more rigorous procedures for the analysis of dose effects has resulted in the recent popularization of trend analysis, which can be a cul-de-sac of clinical awareness.


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With this procedure, it is possible to show, for example, that performance improves in linear fashion across behavioral, cognitive, or academic domains, when in fact comparisons between doses do not show statistically significant increases in performance, even with treatment sensitive within-subject designs (e.g. Douglas et al, 1988; Rapport et al, 1988). Furthermore, single-subject presentations of the data sometimes show that many ^'representative" subjects do not experience clinically significant gains in academic performance, for example, between 10, 15 and 20 mg doses administered in the morning (e.g. Rapport, DuPaul, Stoner & Jones, 1986; Rapport et ai 1987, 1988; Vyse & Rapport, 1989). In other words, evidence for a statistically significant linear trend is occasionally interpreted as indicating that the larger the dose the greater the therapeutic effect, when in fact larger doses produce trivial clinical gains over smaller doses. Unfortunately, the investigators' efforts to prevent this misconception are not always successful. With regard to dosage formulations, one report indicated that the therapeutic effect of one 20 mg tablet of Ritalin-SR administered at breakfast was equivalent to a 10 mg tablet of Ritalin given twice a day (Whitehouse, Shah & Palmer, 1980). The fmdings from a more recent study indicate that standard methylphenidate (10 mg Ritalin b.i.d.) is superior to Ritalin-SR (20 mg) in suppressing certain forms of disruptive behavior (Pelham et al, 1987). A study comparing the relative efficacy of standard methylphenidate (10 mg/b.i.d.), sustained-release methylphenidate (20 mg/q.a.m.), pemoline (56.3 mg/q.a.m), and sustained release dextroamphetamine (10 mg/q.a.m.) found that all four drug conditions were superior to placebo on most measures of social behavior (Pelham et al, 1990a). All four drugs produced treatment effects lasting from 1 to 9 hours after ingestion. Sustained-release dextroamphetamine and pemoline produced the most consistent response to medication (i.e. reduced dayto-day variability to the greatest degree). With regard to generic formulations, controlled studies of comparative efficacy in hyperactive children have not been published. Special clinical populations. Three of the most studied patient characteristics with regard to potential differential responsivity to stimulant medication are age, gender, and IQ(see mental retardation). For many years, researchers have reported a favorable (group data) but more variable and somewhat less satisfactory (smaller percentage of clinically favorable drug responders) response to stimulant medication in preschoolaged children (reviewed by Gadow, 1986a), which is consistent with the findings from recent studies (Barkley, 1988; Speltz, Varley, Peterson & Beilkc, 1988). In spite of their established use (in the U.S.) for the treatment of hyperactive preschoolers (Gadow, 1976), and research indicating clinical improvement in specific individuals, many clinicians still believe that stimulants are either ineffective or "contraindicated" for young children. Ironically, although adolescents were frequently included in early studies of stimulant treatment for narcolepsy (Prinzmetal & Bloomberg, 1935) and learning and behavior disorders (Molitch & Sullivan, 1937), the allegation that they might not respond as favorably as younger children or be more sensitive to adverse growth effects led to the clinical mythology that they were "contraindicated" for adolescents. A flurry of recent studies showing the efficacy of stimulant treatment for hyperactive adolescents will at long last put this issue to rest (Brown & Sexson, 1988; Coons, Klorman &

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Borgstedt, 1987; Garfinkel et al, 1986; Klorman et al, 1987, 1990). Study doses of methylphenidate ranged from 10 to 15 mg per dose, administered two to three times per day. Owing to the much lower prevalence of hyperactivity in girls than boys and the practice of increasing homogeneity by excluding girls from research protocols, relatively little is known about this disorder in females. The fmdings from recent studies (controlled) indicate that girls respond to stimulant drug therapy in much the same way as do boys (Barkley, 1989; Pelham, Walker, Sturges & Hoza, 1989). Comorbidity. One of the negative consequences of the syndromal approach to diagnosis has been the somewhat reluctant acceptance that hyperactive children who are referred for psychiatic evaluation (and subsequently participate in pharmacological research) are extremely heterogeneous with regard to not only primary symptoms but are also typically comorbid for psychiatric disturbance. For example, many clinic-referred hyperactive children meet the diagnostic criteria for conduct disorder or oppositional disorder and learning disability or academic underachievement (Biederman, Newcorn & Sprich, 1991). In addition, a significant minority exhibits one or more of the following symptoms: anxiety, depression, or tics. Comorbidity raises a number of empirical questions for clinical psychopharmacologists, two of which are noted here. (1) What effect does the primary drug for one disorder have on the symptoms ofother concurrent disorders? (e.g. does methylphenidate exacerbate tics in hyperactive children with tic disorder?). (2) Does the presence of another disorder alter drug response? (e.g. is academic underachievement (productivity) of comparable severity less likely to improve with the same dose of methylphenidate in aggressive than nonaggressive hyperactive children?). Both questions are, of course, interrelated with the goal being the identification of treatments that are optimal for specific subgroups of patients. What little research has been done in this area suggests that the presence of anxiety or depressive symptoms in hyperactive children is associated with a less favorable response to stimulant medication. In one controlled study, children with comorbid overanxious disorder were less likely to respond satisfactorily to methylphenidate, but a coexisting oppositional disorder or conduct disorder did not attenuate response to stimulant medication (Pliszka, 1989). There was no evidence that methylphenidate treatment actually exacerbated anxiety symptoms. It is noteworthy that the hyperactive group with overanxious disorder was less severe symptomatically (hyperactivity and aggression) than the children who were not comorbid. Another study of predictors of response to stimulant treatment in hyperactive children found that the presence of anxiety and depressive symptoms was associated with a less favorable response to medication (Taylor et al, 1987). One reviewer ofstudies of tricyclic drug therapy concluded that these drugs may be somewhat more clinically desirable for hyperactive children with depressive symptoms than methylphenidate (Pliszka, 1987). Most of the research on the heterogeneity of hyperactive children has addressed in some shape, way, or form the presence or absence of negativistic (disruptive, oppositional, and aggressive) behaviors. However, the fact that this literature is generally based on syndromes and behavior rating scales (and not target behaviors and direct observations) in the absence of empirically based rationales for treatment makes it difficult to draw conclusions about drug efficacy. Brieily, there is some


indication that hyperactive children respond differently to methylphenidate depending on the presence or absence of concomitant conduct problems. For example, one direct observation study (Cunningham, Siegel & Offord, 1991) of peer interactions in a laboratory setting revealed that hyperactive boys with conduct problems (determined on the basis of parent ratings) showed a different pattern of response to a low (0.15 mg/kg) and moderate (0.5 mg/kg) dose of methylphenidate for different target behaviors (on-task, controlling behavior, social interaction). Conversely, other investigators who have compared drug response in aggressive and non-aggressive (based on parent or teacher rating factor scores) hyperactive children have reported that both subgroups respond similarly to stimulant medication (Barkley, McMurray, Edelbrock & Robbins, 1989; Klorman et al, 1988). Another study comparing methylphenidate response in ADD children with (ADD -\- H) and without (ADD - H) hyperactivity (on the basis of teacher rating scale scores) found that the ADD - H group was less likely to show clinical improvement and more likely to respond favorably to a lower dose than the ADD -i- H group (Barkley, DuPaul & McMurray, 1991). The latter were rated by parents as having more pervasive behavior problems at home and more pervasive and severe conduct problems in school than ADD - H youngsters. Many children with tic disorders who are referred for psychiatric evaluation meet the diagnostic criteria for ADHD or ADD without hyperactivity. Although there is some very preliminary evidence that methylphenidate may be an effective treatment for hyperactivity in children with tic disorders (Sverd, Gadow & Paolicelli, 1989), the primary clinical management concern is the appropriateness of stimulant medication, given their ability to induce tics and stereotypies. Because this is really a toxicity issue, the management of such children is addressed later in the section on toxicity. In sum, much more attention is being given to the assessment of comorbid conditions in samples of hyperactive children and their potential implications for response to medication. However, owing to the number and diversity of these disorders, investigators will ultimately have to turn to multivariate approaches to adequately address this issue (Loney, personal communication, April 1991). Non-stimulant drugs. Stimulants are among the most safe and effective drugs for the management of child and adolescent psychiatric disorders, and for this reason, there has been little pressure to identify alternative therapeutic agents. Nevertheless, not all hyperactive children respond satisfactorily to stimulant treatment, and the problem may be particularly troublesome for patients with complex symptomatology. The drugs receiving the most attention in recent years as potential alternatives to the stimulants are desipramine and clonidine. Desipramine was found to be effective (controlled study) for the treatment of hyperactivity in children and adolescents, many of whom were non-responders to stimulants, in doses up to 5.0 mg/kg per day (Biederman, Baldessarini, Wright, Knee & Harmatz, 1989a; Donnelly et al, 1986). Gualtieri and Evans (1988) found that although imipramine improved hyperactive behavior and inattention, it also impaired motor performance. Clonidine was found to be an effective treatment (controlled study) for hyperactivity (Hunt, Minderaa & Cohen, 1985), and there is some suggestive evidence (open trial) that desipramine may be useful for the management of hyperactivity symptoms in children with tic disorders (Riddle, Hardin, Gho, Woolston & Leckman, 1988).

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Of the drugs found not to be effective for the treatment of hyperactivity in nonautistic or non-retarded children, the most noteworthy is fenfluramine (Donnelly et al, 1989). Procedures for assessing response to medication. Research on procedures for evaluating

response to medication in real world settings and monitoring patient progress has lagged far behind efforts to document efficacy. For example, although the findings from numerous treatment survey studies indicate that procedures for assessing response to medication in hyperactive children leave a lot to be desired (see Gadow, 1991), guidelines for improving clinical management are limited. Nevertheless, some progress is being made in this area as evidenced by recent reports of more empirically based models for evaluating response to drug therapy in standard clinical settings (Barkley, Fischer, Newby & Breen, 1988; Fine & Jewesson, 1989; Gadow, Nolan, Paolicelli & Sprafkin, 1991a; Ottinger, Halpin, Miller, Demian & Hannemann, 1985; McBride, 1988; Pelham & Hoza, 1987; Rapport, 1991; UUmann & Sleator, 1986). Examples of some of the procedures that are part of these models are placebo controls, double-blind conditions, direct observation techniques, specification of target behaviors, operationally defined dosage adjustment rules, and side effect instruments for caregivers. Relative efficacy. Because behavioral and pharmacological interventions generally address different aspects of the symptom complex and are generally considered to have different mechanisms of action, researchers have been most interested in whether a combination treatment package is superior to either treatment administered individually. Pelham and Murphy (1986) conducted an exhaustive review of 21 studies of hyperactive children (published through 1984) in which a combination of a behavioral and pharmacological intervention was used. They concluded "that there is considerable evidence that the combination of behavior therapy and psychostimulant medication is a more effective short-term treatment than either alone for the average ADD child" (pp. 137-138). Additional studies in this area are consistent with this interpretation (Hinshaw, Buhrmester & Heller, 1989; Pelham etal, 1988; Satterfield, Satterfield & Schell, 1987), but conflicting findings have been reported (Horn et al, 1991). It is important to emphasize that the superiority of the combination treatment package is not evident when the behavioral intervention is not effective, as in the case of cognitive behavior therapy (Abikoff & Cittelman, 1985b; Abikoff e; al, 1988; Brown, Borden, Wynne, Schesler & Clingerman, 1986). Learning disability/academic underachievement

From an educational perspective, academic underachievers are a heterogeneous lot and include all children who perform significantly below average on standardized achievement tests. Some children do poorly because they are of below average intellectual ability (slow learners). Others have the intellectual aptitude to do better, but, for some reason (generally presumed to be linked in some way to neurological dysfunction) do not (learning disabled). The term underachiever is also applied to children who are capable of better work (i.e. have both the aptitude and skills), but for some reason do not do daily work assignments (underproductive). Because school grades are based in large part on the amount oi correct work completed,


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underproductivity is often considered a serious problem. Although no one would question the link between practice and skill acquisition, productivity is often inappropriately equated with learning. It is also generally assumed that most of what is taught in school is important for functioning in adult life, a topic that is fortunately beyond the scope of this review. When underproductivity occurs in a child with comorbid psychiatric disturbance, a causal link is often inferred. Improved academic productivity subsequent to pharmacotherapy is then interpreted as confirmation of the causal hypothesis. The following is a brief overview of recent research on psychotropic drugs and academic performance; for more detailed discussions, see other reviews by this author (Gadow, 1985a, 1986a, 1988). In addition, there are several informative literature reviews of the effects of psychoactive drugs on tasks of cognitive and learning performance (Aman & Rojahn, 1991; Judd, Squire, Butters, Salmon & Pailer, 1987; Werry, 1988). Because reading is so important to school success, it is not surprising that psychopharmacologists have focused most of their attention on reading disability. Considerable progress has been made in recent years in understanding the basic processes that underlie reading disability and its probable genetic transmission (Pennington, 1990). Briefly, for a significant number of reading disabled (dyslexic) children, their primary difficulties with learning written language appear to be due to deficits in phonological coding (Vellutino, 1987; Wagner & Torgesen, 1987). Further, there is evidence that the spoken language precursor to this problem is a deficit in phonemic segmentation and awareness skills. This research on the etiology and basic mechanisms of reading disability holds great promise for understanding drug effects. At the present time, none of the drugs that are in current clinical use has been proven to ameliorate phonological processing deficits. Stimulants. The findings from several recent studies (Douglas, Barr, O'Neill »& Britton, 1986; Douglas f^ a/, 1988; Pelham, Bender, Caddell, Booth & Moorer, 1985; Rapport et al, 1986) indicate that stimulants increase the amount of accurate school work completed by hyperactive children (usually during a specific period of time). This effect is fairly robust in that it has been observed in various settings (e.g. special clinics, laboratory schools, public elementary schools) and appears to be greater for some academic tasks (e.g. arithmetic computation activities) than for others (e.g. spelling). These findings are highly consistent with the results of previous research on academic productivity (e.g. Bradley & Bowen, 1940). Unfortunately, studies of stimulant drug therapy for reading disability in nonhyperactive learning disabled children have been negative (Aman & Werry, 1982; Gittelman, Klein & Feingold, 1983; Gittelman-Klein & Klein, 1976). The only new study in this area examined the response to methylphenidate (0.3, 0.5, 0.7 mg/kg b.i.d.) and placebo in hyperactive children with reading problems who were receiving instruction in a special after-school reading program (Richardson, Kupietz, Winsberg, Maitinsky & Mendell, 1988). Medication effects were evaluated over a 6-month period. Although statistical analyses did not reveal a main effect of the drug, a subgroup of good responders (determined on the basis of teacher ratings of classroom behavior) were said to have benefited from stimulant treatment (Richardson, Kupietz & Maitinsky, 1987). The biggest gain in reading performance was achieved during the lirst 3 months, with medication and placebo groups improving a similar amount during

K. D Gadow

the last 3 months. Based upon the results of different reading tests, these investigators concluded that the drug appeared to improve word recognition skills, but not phonic word-attack strategies. In other words, it may not be addressing the primary deficit associated with reading disability. They hypothesized that methylphenidate may improve word retrieval ability. The fact that the children's ages ranged from 7 to 12 years and there were only 10-14 children in each dosage condition (randomized group design) makes the interpretation of these findings somewhat tentative. It has been alleged for a number of years that antimotion sickness medication is an effective treatment for developmental dyslexia (Levinson, 1980). However, controlled studies of one such agent, meclizine, failed to show a beneficial effect on reading, but it did improve ocular motor stability during fixation (Fagan, Kaplan, Raymond & Edgington, 1988). Piracetam. In the past 10 years much attention has been focused on piracetam's ability to improve cognitive performance and its potential role in the treatment of dyslexia. Most of the research on dyslexia in children was conducted in the U.S. as part of a multi-center project sponsored by the manufacturer (Di Ianni et al, 1985). A second round of multi-eenter studies was scheduled to commence in fall 1985, but, after discussions with the Food and Drug Administration, the corporate sponsor decided to abandon the project. With regard to reading skills per se, the primary drug effect was a statistically significant (p = 0.04) increase in reading rate. The mean rate of improvement was 7.0 and 3.2 words per minute for piracetam and placebo, respectively. Given the large sample size (240 boys between 8 and 13 years old) and the absence of drug effects on other measures of reading ability, these findings are somewhat discouraging. On a more positive note, side effects were minimal. Relative efficacy. With regard to the relative efficacy of pharmacological, behavioral, and combination treatments for enhancing academic performance, one reviewer concluded that certain behavioral interventions were clearly superior to stimulant medication in facilitating academic performance in hyperactive, learning disabled, and hyperactive-learning disabled children (Gadow, 1985a). Moreover, although stimulant drugs enhance a variety of learning-related behaviors (e.g. attention span) and have been shown to increase academic productivity, they do not appear to markedly facilitate academically oriented behavioral interventions unless the latter are ineffective. The findings from several investigations pertain to this issue. Pelham, Milich and Walker (1986), for example, conducted a study in which they assessed the effects of two reinforcement schedules and methylphenidate on learning a nonsense spelling word test. Both reinforcement and medication resulted in large beneficial effects on learning, and optimal performance was achieved when medication and reinforcement were administered in combination. As previously noted, Richardson et al (1987) reported that methylphenidate enhanced the efficacy of a specialized reading program in a subsample of favorable responders. Collectively, the findings from both studies challenge the aforementioned conclusion regarding the enhanced efficacy of combination treatments for academic performance. Lasdy, another study found that an academically based cognitive training program administered in combination with stimulant medication was not more effective for improving academic underachievement in hyperactive children than medication alone (Abikoff ^7 ai 1988).

Pediatrit psychopharmacotherapy

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Aiania (bipolar disorder)

There is little evidence for discreet episodes of mania occurring in prepubertal children, but a number of investigators believe that an atypical form of bipolar disorder characterized by periods of overactivity, behavioral disturbance, mood volatility and/or withdrawal occurs in genetically vulnerable children (Carlson, 1984; DeLong & Aldershof, 1987). Uncontrolled studies suggest that children exhibiting such symptoms may be responsive to treatment with lithium (DeLong tSc Aldershof, 1987; Varanka, Weller, Weller & Fristad, 1988), implying but not confirming continuity with adult bipolar disorder. Weller, Weller and Fristad (1986) provide guidelines for adjusting lithium dosage in prepubertal children. The existence and treatment of mania is somewhat better established in adolescents, but there are no controlled studies of drug treatment in this age group. The findings from open trials suggest that lithium may be useful (e.g. Kelly, Koch & Buegel, 1976). There is also some evidence from a naturalistic prospective follow-up study that prophylactic lithium therapy may greatly reduce the risk of relapse (Strober, Morrell, Lampert & Burroughs, 1990b). However, non-compliance with a long-term treatment regimen was a common problem, even in a highly structured clinical setting. Aiental retardation

Although psychotropic drugs are not prescribed for mental retardation per se, pharmacotherapy for psychiatric disorders in this population is a specialized area of study because there are often important diagnostic, drug response, and environmental differences between mentally retarded and non-retarded individuals that bear on clinical management (reviewed by Aman & Singh, 1988; Gadow & Poling, 1988). Presented here are recent developments in the treatment of various disorders (arranged alphabetically) in mentally retarded people. Given the similarities in the behaviors that are typically targeted for pharmacotherapy, studies of adults are included in this review. Affective disorders. A fairly compelling case can be made for the existence of affective disorders in mentally retarded people (even among inviduals who are severely mentally retarded) and the use of conventional psychological and pharmacological therapies to treat them (Sovner & Hurley, 1983). Unfortunately, controlled studies of drug efficacy are few in number, and case reports and open trials dominate the literature. Recently, imipramine was found to produce deterioration of symptoms (decreased activity) in one study of severely and profoundly mentally retarded individuals, who were selected for study on the basis of social withdrawal, sleep and weight loss, tearfulness, sad affect, and limited degree of overt behavior (Aman, White, Vaithianathan & Field, 1986). In another study, imipramine appeared to improve behavior, sleep, and eating in a moderately retarded woman (Field, Aman, White & Vaithianathan, 1986). An ever increasing number of case reports and open trials suggest that pharmacotherapy may be effective for the treatment of bipolar disorder in mentally retarded children, adolescents and adults. Several authors have commented on the efficacy of lithium (Glue, 1989; McCracken & Diamond, 1988; Steingard & Biederman, 1987). There is one open trial of divalproex sodium (a valproate derivative)

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in mentally retarded adults, which suggests that this drug may be efficacious for bipolar disorder (Sover, 1989), and another series of case reports of valproic acid in mentally retarded children that also suggests possible efficacy for mood disorder (Kastner, Friedman, Plummer, Ruiz & Henning, 1990). Aggression. There has been a considerable amount of attention directed toward betaadrenergic blocking agents (primarily propranolol) for the treatment of aggressive behavior in mentally retarded children and adults. To date, research reports are limited to uncontrolled case studies and open trials (Jenkins & Maruta, 1987; Kuperman & Stewart, 1987; Polakoff, Sorgi & Ratey, 1986; Ratey et al, 1986; Ruedrich et al, 1990; Silver & Yudofsky, 1985). There are a number of reports that suggest lithium is an effective antiaggression agent in mentally retarded individuals (Gadow & Poling, 1988), one of which is a controlled study (Tyrer, Walsh, Edwards, Berney & Stephens, 1984). Given the oftencited problem of inadequate drug monitoring procedures in institutional settings, the decision to conduct a clinical trial of lithium for a mentally retarded person should receive careful consideration. Fenfluramine also appears to be efficacious for the control of aggressive behavior. Selikowitz, Sunman, Pendergast and Wright (1990) reported (controlled study) that fenfluramine suppressed aggressive behavior in mentally retarded children and adults with Prader-Willi syndrome. There is one controlled study of intramuscular pipothiazine palmitate for the management of aggressive mentally retarded adults (Lynch, Eliatamby &. Anderson, 1985). Pipothiazine (25-50 mg/day) was found to be superior to placebo in suppressing aggressive behavior. The antiaggressive effects of various drugs have been commented upon in recent uncontrolled trials and case reports: buspirone (Ratey, Sovner, Mikkelsen & Chmielinski, 1989), midazolam (Bond, Mandos & Kurtz, 1989), and clopenthixol (Mlele & Wiley, 1986). The findings from a controlled study of milenperone (a member of a new group of neuroleptics) for the treatment of aggressive behavior in mentally retarded adults were equivocal (De Cuyper, Van Praag & Verstraeten, 1985). Nonstudy medications were not discontinued prior to the drug evaluation. Behavior disorders. White and Aman (1985) conducted a controlled study of pimozide (6 mg/day) in eight moderately to profoundly mentally retarded individuals. Behavior ratings indicated improvement in irritability, hyperactivity, and non-compliance. Conversely, haloperidol (0.025 and 0.05 mg/kg/day) was found to have only minimal beneficial effect (compared with placebo) on chronically medicated moderately to profoundly mentally retarded residents (Aman, Teehan, White, Turbott & Vaithianathan, 1989). There was a slight decrease in stereotypies and an increase in motor activity when receiving the higher dose. However, responsiveness to instruction improved under reinforcement conditions when receiving the 0.05 mg/kg dose. The most favorable responders were individuals with initially high levels of stereotypic behavior. The findings from another study showed that thioridazine (2.50 mg/kg/day) reduced hyperactivity and self-injurious behavior (compared with placebo and a 1.25 mg/kg/day dose) in a group of moderately to profoundly mentally retarded people, but clinical improvement was associated with increased lethargy (Aman &


I/I

White, 1988). There are a number of favorable reports of carbamazepine for the treatment of behavior disorders in mentally retarded people, and they continue to appear (Langee, 1989), but controlled studies are wanting. Drooling. There is one controlled study showing that the synthetic anticholinergic drug benztropine (doses from 1 to 6 mg/day) is an effective treatment for severe drooling in mentally retarded children and adults (Camp-Bruno, Winsberg, GreenParsons & Abrams, 1989). Transdermad scopolamine (1.5 mg/2.5 cm") is also useful (Brodtkorb et al, 1988). Eating disorders. Selikowitz et al (1990) found fenfluramine to be an effective shortterm (6 weeks) treatment for food craving and obesity in some mentally retarded children and adults with Prader-Willi syndrome. Drug therapy resulted in significant weight loss and improvement in food-related behaviors. Daily doses for 5-7-year olds and 8-15-year olds were 30 and 60 mg, respectively. Hyperactivity (attention-deficit hyperactivity disorder). Prior to 1985, approximately 40

studies were published on the effects of stimulant drugs in mentally retarded children and adults (Gadow, 1985b; Sprague & Werry, 1971). Briefly, the findings of these studies indicated (to at least some reviewers) that stimulants were an effective treatment for some hyperactive children, particularly individuals in the mild to moderate range of mental retardation. There was little evidence that these drugs were generally effective for severely and profoundly mentally retarded individuals. However, there was room for disagreement as to whether or not the literature really supported these conclusions, and consequently the establishment of efficacy remained an open issue. Fortunately, the findings from several recent studies should put an end to the debate. Collectively, they provide fairly strong evidence that stimulants are a safe and effective treatment for hyperactivity in some mild to moderately retarded children and adolescents (Aman, Marks, Turbott, Wilsher & Merry, 1991a,b; Burgio, Page & Gapriotti, 1985; Gadow & Pomeroy, 1990; Gadow, Pomeroy & Nolan, 1991c; Payton, Burkhart, Herson & Helsel, 1989; Handen, Breaux, Gosling, Ploof& Feldman, 1990; HelseU/fl/, 1989; Schell et al, 1986). Nevertheless stimulant drug response may be more variable or idiosyncratic (Gadow & Pomeroy, 1990; Gadow et al, 1991c; Helsel et al, 1989) and certain side effects more troublesome (Handen et al, 1991) in mentally retarded children than in non-retarded peers. There is also some preliminary evidence that fenfluramine may be useful for the control of hyperactivity and aggression in some mentally retarded children (Gadow & Pomeroy, 1990; Selikowitz et al, 1990). Schizophrenia. There are no controlled studies of pharmacotherapy for schizophrenia in mentally retarded individuals. Menolascino, Ruedrich, Golden and Wilson (1985) did, however, conduct a study comparing the effects of thiothixene and thioridazine in mentally retarded and non-retarded adult schizophrenics. With medication, patients in both groups were "more attentive, acted more appropriately, could be approached more easily and participated more actively in their ongoing daily treatment programs" (p.302). For the mentally retarded patients, the average amount of time it took the drugs to reach optimal effectiveness differed [thiothixene, (A/=12 days) versus thioridazine, {M = 29 days)]. Interestingly, as a group, the mentally retarded patients required less medication than the non-retarded group. Self-injurious behavior. A number of investigators have noted that phenothiazines and

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haloperidol reduce self-injurious behavior in mentally retarded people (reviewed by Farber, 1987; Gadow & Poling, 1988). On the basis of a series of uncontrolled case reports, Mikkelsen (1986) noted that efficacy may be achieved with low doses (0.25-6 mg/day) of haloperidol. The most exciting new pharmacological development for the treatment of self-injurious behavior in mentally retarded people is naltrexone. Controlled studies show that in certain individuals this drug produces dramatic reduction in self-injury (Bernstein, Hughes, Mitchell & Thompson, 1987; Sandman, Barron & Colman, 1990). However, because large-scale studies of the safety and efficacy of naltrexone have yet to be conducted, the standard caveats regarding clinical application apply. A controlled case study by Barrett, Payton and Burkhart (1988) suggests that carbamazepine may also suppress self-injurious behavior in some individuals. Stereotypies. One of the best documented effects of neuroleptic medication in mentally retarded individuals is the suppression of stereotypic behaviors (Gadow & Poling, 1988). This conclusion is supported by some (Aman et al, 1989; Aman & White, 1988) but not all (Lewis et al, 1986) recently published studies. Pervasive developmental disorder

In 1980 the American Psychiatric Association formulated the diagnostic category childhood onset pervasive developmental disorder to characterize a group of "autisticlike" children who did not meet all the established criteria for a diagnosis of either autism or childhood schizophrenia. Children with pervasive developmental disorder experience marked impairment in social relationships in combination with three or more of the following: anxiety, abnormalities of speech or affect, resistance to changes in their environment, odd motor movements, hyper- or hyposensitivity to stimuli, or self-injurious behavior. Fisher, Kerbeshian and Burd (1986) reported (open trial) that haloperidol had a marked effect on facilitating language development in children with pervasive developmental disorder. Another open trial study of neuroleptic treatment in children with pervasive developmental disorder found that low doses of haloperidol or fluphenazine (mean = 0.04 mg/kg/day) produced clinically significant improvements in peer relations and reductions in hyperactivity and aggression (Joshi, Capozzoli & Coyle, 1988). Side effects were minimal. Schizophrenia

One of the least researched disorders in children and adolescents is schizophrenia. Controlled studies in prepubertal children are non-existent, at least as the disorder is currently defined in DSM-3R (American Psychiatric Association, 1987). Although children who meet these criteria were no doubt included in earlier investigations of childhood autism and psychosis, their response to medication has not been examined separately from other clinical syndromes. Controlled studies of schizophrenia in adolescents are limited to one investigation by Pool, Bloom, Mielke, Roniger and Gallant (1976), in which haJoperidol and loxapine were found to be superior to placebo in controlling psychotic symptoms. The findings from another study suggest that many youths show little or no clinical improvement


1 7J

with neuroleptic treatment (Realmuto. Erickson, Yellin, Hopwood & Greenberg, 1984). Because older adolescents are often included in studies of schizophrenia in adults, it is generally considered that the efficacy of neuroleptic treatment for this age group is well established. There is one open trial of clozapine in schizophrenic adolescents who showed either poor response to traditional neuroleptics or experienced severe extrapyramidal reactions (Siefen & Remschmidt, 1986). Marked improvement in symptoms was observed in more than half of the subjects. However, due to its serious risks, clozapine is unlikely to become a standard alternative for treatment-resistant patients. Teicher and Gold (1990) note that there is currently (early 1990) no age restriction for the Clozaril (clozapine) Patient Management System in the U.S. Sleep Disorders

There are relatively few controlled studies of pharmacotherapy for sleep disorders in children. The findings from one study of diphenhydramine (1 mg/kg) in children (2-12 years old) showed that medication was superior to placebo in decreasing the amount of time to fall asleep and the number of awakenings during sleep over a 1-week interval (Russo, Gururaj & Allen, 1976). A controlled study of trimeprazine (30-60 mg before bed) for night wakening problems in 1-2 year old children found that medication decreased awakenings, but clinical improvement was limited (Richman, 1985). A 6-month follow-up showed that sleep problems continued and that shortterm treatment (2 weeks) with trimeprazine had no lasting benefits. Flurazepam (15 mg before bed) was found to reduce (after 2 weeks) sleepwalking, bruxism, and night terrors in children and adolescents when they were switched from placebo to medication (Reimao & Lefevre, 1982). The findings from uncontrolled studies suggest that stimulants may be a useful treatment for narcolepsy in children and adolescents (Kotagal, Hartse & Walsh, 1990; Prinzmetal & Bloomberg, 1935). There do not appear to be any other recent developments in the pharmacological treatment of sleep disorders. Stuttering

The findings from several controlled studies, some of which included adolescents, indicate that haloperidol is an effective treatment for stuttering (e.g. Wells & Malcolm, 1971). Uncontrolled studies of children suggest drug efficacy in individual cases as well (Gattuso & Leocata, 1962; Tapia, 1969). There is little additional drug research on this disorder in children other than a case report of an adolescent stutterer who was apparently treated successfully with 10 mg/day of propranolol (Kymissis & Martin, 1990). Tourette syndrome

Although there are numerous investigations of psychotropic drug therapy for Tourette syndrome (reviewed by Cohen, Bruun & Leckman, 1988; Shapiro, Shapiro. Young & Feinbcrg, 1988), placebo-controlled double-blind studies published in refereed journals are a rarity, which is troubling given the relatively high rate of

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placebo responsivity (especially in longer-term studies given natural fluctuations in symptom severity) and the inherent difficulties in assessing changes in tic status. For many clinicians, haloperidol has long been the most effective and reliable ticsuppression agent; yet it was only recently that the first controlled random assignment group study was actually published (Shapiro et al, 1989). The mean age of the study sample was 21 years (range = 8-46 years). In this study, haloperidol was found to be slightly more effective than pimozide for tic control, and both drugs were more efficacious than placebo. Other neuroleptics such as fluphenazine are purportedly just as effective as haloperidol (Singer, Gammon & Quaskey, 1986), but controlled studies are wanting. The most significant "new" development in the treatment of Tourette syndrome is clonidine, an alpha-adrenergic agonist originally approved for the management of hypertension. Although it was first reported as an effective treatment for Tourette syndrome over 10 years ago (Cohen, Young, Nathanson & Shaywitz, 1979), there have been few controlled studies of its efficacy, and their findings are mixed. Because the drug is widely used, this has resulted in a sometimes heated debate about clinical efficacy. Unfortunately, recently published placebo-controlled double-blind studies of Tourette syndrome patients will not resolve the controversy. The findings from one study (Leckman et al, 1991) support, whereas the results of a second investigation (Goetz et al, 1987) fail to confirm, the efficacy of clonidine as a motor tic-control agent. In both cases study samples consisted of children and adults. Clonidine treatment is initiated at a small daily dose (0.05 mg) that is gradually increased over several weeks to 0.15-0.30 mg per day. Because clonidine has a short half-life, it is administered in small doses three to four times per day. An alternative dosing procedure is the transdermal patch, which requires changing only once a week. Clonidine purportedly has a slower onset of action than haloperidol and may take 3 weeks or more to produce a therapeutic response. Tolerance to beneficial effects is a problem for some children. Abrupt drug withdrawal can lead to a marked worsening in tics (the severity of which may be greater than baseline levels), and they may not abate with the reintroduction of medication or the previously effective dose (Leckman et al, 1986).

Toxicity Stimulants

Stimulants have been prescribed for so many years for childhood psychiatric disorders that most recent reports of toxicity are simple confirmations or elaborations of established facts. Rating scale studies have shown, contrary to expectation, that teachers rate some potential side effects (e.g. mood disturbance, unusual motor movements, some somatic complaints) as being more severe or frequent on placebo than on medication (Barkley et al, 1990; Handen et al, 1991; Nolan, 1988). Parent ratings of side effects are more likely than teacher ratings to show increased levels of somatic complaints on medication compared with placebo. With regard to the induction of new disorders or the exacerbation of comorbid conditions, most research


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reports pertain to seizure and tic disorders. There is growing evidence that the risk of seizure induction or exacerbation as a result of stimulant therapy is limited (Crumrine, Feldman, Teodori, Handen & Alvin, 1987; McBride, Wang & Torres, 1986), a conclusion already reached by many clinicians given the long-standing tradition (in the U.S.) of prescribing these drugs to children with seizures disorders (Gadow, 1976; Gadow & Kalachnik, 1981). Considerable attention has been focused on the appropriateness of stimulant medication for hyperactivity in children with comorbid tic disorder or who have a first or second degree relative with tic disorder. It has been stated the stimulants are contraindicated for such patients, and, in the case of the latter group, if stimulants are prescribed, treatment should be terminated at the first sign of tic induction (Lowe, Cohen, Detlor, Kremenitzer & Shaywitz, 1982). Others, however, have noted that stimulant treatment does not pose a risk for many individuals (Erenberg, Cruse & Rothner, 1985) and may actually delay the onset of tic disorder in vulnerable patients (Comings & Comings, 1984), and that the risk of irreversible tic exacerbation is small (Price, Leckman, Pauls, Cohen & Kidd, 1986). The fmdings from one single-blind (Sverd et al, 1989) and one double-blind (Konkol, Fischer & Newby, 1990) placebocontrolled study also suggest that for some hyperactive children with tic disorder, methylphenidate is a safe and effective treatment for hyperactivity. It has also been noted that all of the commonly prescribed drugs for the treatment of hyperactivity or tic disorders are capable of inducing or exacerbating tics, and the risk of tic exacerbation or the induction of movement disorders de novo during the onset of or the withdrawal from medication appears to be comparable for the various classes of drugs that are currently considered appropriate for the treatment of hyperactivity or tic disorders (Gadow & Sverd, 1990). Stimulant medication is also known to induce or exacerbate other types of movement disorders. The findings from a recent controlled study of hyperactive children indicate that stimulant-induced movement disorders and overfocused/obsessive compulsive behaviors are fairly common in treated children and that dosage adjustments or the selection of a different stimulant can often (but not always) produce a satisfactory clinical response (Borcherding, Keysor, Rapoport, Elia & Amass, 1990). Stimulantinduced stereotypies have been reported for a number of years (Bradley, 1950), but a recently published series of case reports indicates that children can engage in these behaviors (e.g. finger-tip or finger-nail biting) to the point of producing self-injury (Sokol, Campbell, Goldstein & Kriechman, 1987). With regard to growth, there is additional support for the conclusion of the Pediatric Advisory Panel of the Food and Drug Administration that chronic stimulant drug therapy in childhood has relatively little effect on growth in height (Roche, Lipman, Overall & Hunt, 1979). For example, one study of adolescents treated with methylphenidate for at least 6 months found no deviation from expected height and weight growth velocities (Vincent, Varley »&: Leger, 1990). Another study of hyperactive children treated with methylphenidate (dose not specified) compared youngsters who did ("on group") and did not ("off group") receive medication during the summer. After two summers, the on-medication group was significantly shorter (M = 1.5 cm) than the off group indicating that methylphenidate treatment reduces growth velocity in this age group and at study doses (Klein, Landa, Mattes & Klein, 1988). However,

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another investigation by the same research team compared hyperactive children treated with medication (mean dose and duration of treatment was 45 mg/day and 2.2 years, respectively) with a normal comparison group and found no significant group differences in height when measured during adolescence or early adulthood (Klein & Mannuzza, 1988). Stimulants produce dose-dependent increases in heart rate and blood pressure, which are generally considered to be clinically insignificant for most children. However, some segments of the patient population may experience greater increases than others. For example, Brown and Sexson (1988) found a mean increase in diastolic blood pressure of 14 mm between placebo and 0.5 mg/kg/b.i.d. of methylphenidate (mean unit dose = 21 mg) in hyperactive black adolescents. Although the medication mean was still within the normal pediatric range, they recommended closer monitoring of medication when higher therapeutic doses are used with teenagers. Methylphenidate, when used in combination with imipramine, may result in behavioral toxicity (emotional lability, aggressive behavior, psychotic symptoms) (Grob & Coyle, 1986). Several recent reports pertain to pemoline toxicity. There is some evidence that the risk of drug-induced movement disorder (dyskinesias, choreoathetoid movements) may be greater for pemoline than other stimulants (Sallee, Stiller, Perel & Everett, 1989). Jafle (1989) reviewed the reports of two deaths in children receiving pemoline. One child had a liver disease (prior to treatment), and the other child died of toxic hepatitis resulting from an overdose of pemoline. He recommended that baseline and periodic liver function tests be conducted for child patients receiving pemoline therapy and that liver disease/dysfunction should be a contraindication to the use of this drug. The abrupt cessation of long-term pemoline therapy may precipitate severe depressionlike symptoms, e.g. crying spells, suicidal threats, social withdrawal, depressed affect, and somatic complaints (Brown. Borden. Spunt & Medenis, 1985). There is some evidence that hyperactive mentally retarded children may be at greater risk of developing certain side effects (motor tics, severe social withdrawal) than nonretarded children (Handen ^/a/, 1991). Morever, the severity of these reactions may require the discontinuation of treatment. Tricyclic antidepressants

Assessing the risks of cardiotoxicity is one of the most important topics in recent research on tricyclic drug therapy for childhood disorders. Earlier reports raised concerns about the use of these drugs in child patients with heart disease (Winsberg, Goldstein, Yepes & Perel, 1975) and suggested dosage limits (Hayes, Panitch & Barker, 1975). In hyperactive or depressed children and adolescents, doses of desipramine ranging up to 5 mg/kg per day generally produce only minor changes in heart function, with few or no troublesome cardiovascular side effects (Bartels, Varley, Mitchell & Stamm, 1991; Biederman et al, 1986b; Donnelly et al, 1986; Schroeder et al, 1989). Biederman et al. (1989b) note that desipramine treatment at doses greater than 3.5 mg/kg per day or blood levels above 150 ng/ml may increase diastolic blood pressure, heart rate and the risk of asymptomatic electrocardiographic changes (e.g. prolongation of PR interval and increased QRS duration). They recommend that "a scrum level


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below 300 ng/ml, ECG PR interval < 200 msec, and Q.RS duration < 120 sec appear to be more important clinical dosing parameters than accepting an arbitrary absolute dosage limit in optimizing responses and avoiding cardiovascular toxicity" (p.910). The optimal dosage range appears to be 2.5-5.0 mg/kg per day for most hyperactive children. Careful clinical monitoring of blood levels and heart function is mandatory when prescribing desipramine. The fact that the tricyclics are generally characterized as relatively benign when monitored (including baseline and dosage adjustment EKGs) and stored appropriately (locked containers) is somewhat inconsistent with reports of sudden death in a 6-yearold girl treated with imipramine (Saraf, Klein, Gittelman-Klein & Groff, 1974) and more recently in three prepubertal children receiving desipramine (Biederman, 1991; Riddle et al, 1991; Sudden death, 1990). Whether or not all patients who are at risk can be effectively screened prior to, or detected after, the onset of tricyclic therapy with existing procedures is not known. Neuroleptics

The primary focus of neuroleptic toxicity pertain to extrapyramidal syndromes and behavioral toxicity. The three extrapyramidal syndromes that have received the most attention in recent years are akathisia, neuroleptic malignant syndrome, and tardive dyskinesia. The symptoms of akathisia are not well formulated in children, and this reaction can be easily misidentified as a worsening of symptoms (Bruun, 1988). In children with Tourette syndrome, it has been hypothesized that worsening of tics in children receiving maintenance neuroleptic treatment may really be a symptom of akathisia, which typically responds to dosage reduction. There is one uncontrolled study of the treatment of neuroleptic-induced akathisia in adolescents which suggests that clonazepam may be effective in some cases (Kutcher, Mackenzie, Galarraga & Szalai, 1987). There are now several reports of neuroleptic malignant syndrome in children and adolescents (Caroff, 1980; Diamond & Hayes, 1986; Geller & Graydanus, 1979; Merry, Werry, Merry & Birchall, 1986; Tenenbein, 1985-1986). Given the limited amount of information on this reaction in the pediatric age range, guidelines for clinical management must be extrapolated from studies of adults. There is also a growing number of reports of neuroleptic malignant syndrome in mentally retarded people (Diamond & Hayes, 1986; James, 1988; McCracken & Diamond, 1988; McNally & Calamari, 1988; Slack & Stoudemire, 1989; Ward & Corbett, 1989). Tardive dyskinesia continues to be a major clinical concern when prescribing neuroleptic medication, and in the pediatric age range most of the attention has focused on individuals with developmental disabilities given the relatively high rate of drug use for this segment of the patient population. Reports of dyskinesias in child and adolescents treated with neuroleptics indicate that this is a fairly common side effect. For example, Campbell, Adams, Perry, Spencer and Overall (1988) reported that 30% of children in a prospective long-term study of autistic children treated with haloperidol developed dyskinesia. Of the children in the dyskinetic group, 80% developed withdrawal dyskinesia, which emerged approximately 2 weeks following the

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discontinuation of medication. The dyskinesias lasted from several days to several months (mean duration was 4 weeks); in no case were they irreversible. Approximately one fourth of the dyskinetic group developed tardive dyskinesia. One of the major complications in treating autistic children with neuroleptic medication is the differentiation of stereotypies from drug-related dyskinesias (Meiselas et al, 1989). Pretreatment baseline evaluations of movement disorders are essential for adequate monitoring of drug effects. Prior to 1980 research on tardive dyskinesia in mentally retarded people was limited to one study (Paulson, Rizvi & Crane, 1975). However, within the last decade there has been considerable increase in research on tardive dyskinesia, prompted in part by a number of lawsuits in which enormous sums were awarded to plaintiffs (Gualtieri, Sprague & Cole, 1986b; Kalachnik & Slaw, 1986). More recent studies indicate that persistent tardive dyskinesia occurs in 30-40% of mentally retarded people treated with neuroleptic medication (Kalachnik et al, 1984; Gualtieri, Schroeder, Hicks & Quade, 1986a; Richardson, Haugland, Pass & Craig, 1986) and withdrawal dyskinesia in an additional 29% (Gualtieri f/a/, 1986a). The findings from studies of the amount of drug exposure and the severity of symptoms are mixed (Gualtieri et al, 1986a; Rao, Cowie & Mathew, 1987; Stone, Alvarez & Ellman, 1989a). There is some preliminary indication that gradual drug withdrawal may result in less severe tardive dyskinesia than abrupt discontinuation of medication (Schroeder & Gualtieri, 1985). The assessment and monitoring of tardive dyskinesia in mentally retarded people is complicated by the high rate of dyskinesias in this patient population (Stone, May, Alvarez & Ellman, 1989b) and the need for additional research on the differentiation between tardive dyskinesia and other movement disorders (Sprague & Newell, 1987). One of the most significant clinical developments in this area has been the formulation of a psychometrically sound assessment instrument for use with developmentally delayed people (Granger, Yurkunski, Miller, Swanson & Crinella, 1987; Kalachnik, Sprague & Slaw, 1988; Sprague, Kalachnik & Slaw, 1989). Neuroleptics are known to induce a variety of behavioral and affective disturbances in children. One type of reaction, school phobia, has been observed in Tourette syndrome patients treated with haloperidol or pimozide (Bruun, 1988; Linet. 1985; Mikkelsen, Detlor & Cohen, 1981). Bruun (1988) believes that this school phohia reaction may be part of a drug-induced dysphoria syndrome.

Carbamazepine

Although initial concerns about the somatic toxicity (e.g. hematological abnormalities) of carbamazepine appear to have been overstated (Livingston, Pauli & Berman, 1974), there is a growing awareness of the potential for behavioral toxicity in the pediatric age range. One study of 20 children receiving carbamazepine for aggressive behavior found that six patients developed adverse behavioral reactions including mania, hypomania, increased impulsivity, and aggression (Pleak, Birmaher, Gavrilescu, Abichandani & Williams, 1988). There are also reports of tic induction in children receiving carbamazepine who were tic-free prior to treatment (E\'ans et al, 1987).


Clonidine

Controlled studies of clonidine treatment for Tourette syndrome report the following untoward effects as being the most common; sedation, fatigue, dry mouth, faintness or dizziness, irritability, and restlessness (Goetz et al, 1987; Leckman et al, 1991). Troublesome side effects generally abate with dosage reduction. Fenfluramine

Although there are reports of neurotoxicity in laboratory animals receiving large doses of fenfluramine, side effects in children at clinical doses are minimal. They consist primarily of gastrointestinal upset, diarrhea, irritability, drowsiness, anorexia, and weight loss (Aman & Kern, 1989). Fluoxetine

The assessment of fluoxetine toxicity in children and adolescents is limited to a few case reports and open trials. In children reveiving fluoxetine for obsessive compulsive disorder, reported side effects include motor restlessness, pressured speech, and gastrointestinal upset (Riddle et al, 1990). Some patients receiving fluoxetine have developed or experienced an exacerbation of self-injurious behavior, which in some cases was severe enough to require hospitalization (King et al, 1991). It is too early to tell the exact role, if any, fluoxetine played in these observed changes in symptom status. Given the limited information on this drug in child patients, careful monitoring of behavioral toxicity is warranted.

Summary In the past 5 years, we have witnessed the continuation of important trends in clinical research that began earlier in the decade. With regard to the treatment of specific disorders in children and adolescents, the most significant developments have been the examination of the tricyclics for the treatment of depression and the initiation of controlled studies for the treatment of Tourette syndrome. Unfortunately, the findings from the depression studies have been uniformly negative, and the results of research on both depression and tic disorders show a relatively high rate of placebo responsivity, which raises nagging questions about the role of case reports and open trials. Another important trend in pediatric psychopharmacotherapy is the search for substitutes for the neuroleptics. Potential candidates include agents such as lithium, naltrexone, fenfluramine, clonidine, and carbamazepine. The most underresearched disorders are a combination of the least common (e.g. schizophrenia, mania) and those that are apparently perceived as less serious (e.g. sleep disorders, certain anxiety disorders). Not surprisingly, the most studied disorder and treatment is hyperactivity and stimulant medication, respectively. Considerable progress has been made in understanding the social implications of the associated symptoms and their response to stimulant drugs, aided greatly by the use of direct observation procedures.

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Researchers are beginning to attend to the implications of comorbidity for assessing response to medication. There has been additional confirmation of efficacy of stimulant treatment for preschoolers and adolescents. Dose-response issues remain to some extent unresolved, the primary impediments being interpretive misconceptions associated with trend analysis, an overreliance on the syndromal perspective and too little attention to target behaviors and their clinical implications, and the failure to operationalize the minimal effective dose with regard to the normalization and supranormalization of target and collateral behaviors. Disagreement over whether hyperactivity is a learning or a behavior disorder (or both) and what academic underproductivity means clinically and socially is also impeding progress. With regard to developmental disorders, controlled studies indicate that fenfluramine and naltrexone are effective for managing associated symptoms in some individuals. However, given the limited amount of research on these agents, their status as clinically useful palliatives must be considered tentative. Pharmacological research involving mentally retarded individuals with comorbid psychiatric disturbance appears to be increasing, but controlled studies are few in number. There also appears to be more interest in children and adolescents in community placements, which is a healthy trend away from the traditional focus on people in residential facilities. However, children and adolescents in the 70-85 I Q range have been virtually ignored. The fmdings from several recent studies confirm the efficacy of stimulant treatment for hyperactivity in children with mild to moderate mental retardation. There is much interest in alternatives to neuroleptic medication, and the most viable candidates at present are lithium, propranolol, and carbamazepine. Fenfluramine may also be of value for some children. Reports of drug toxicity are a mixed picture. On the negative side, there is an increasing awareness of the dangers of drug therapy, the most notable being fatalities and extrapyramidal syndromes (neuroleptic malignant syndrome, tardive dyskinesia) resulting from tricyclic and neuroleptic drug therapy, respectively. The role of stimulants in the irreversible induction or exacerbation of tic disorders remains controversial. On a more positive note, there is growing evidence that the tricyclics are well tolerated by most children and adolescents (a conclusion of little satisfaction unless fatalities can be reliably avoided) as are some of the newer agents currently under investigation (e.g. fenfluramine, carbamazepine, propranolol, naltrexone). However, a more complete realization of their toxicity will be achieved only after more widespread application and in-depth study. It is extremely difficult to summarize the significance of recent developments in pediatric psychopharinacology from the perspective of the practitioner. Newer and safer products are of course the primary goal of this endeavor, and it does appear as if progress is being made along these lines. However, with regard to the realities of day-to-day clinical management, much more can and should be done, several examples of which are briefly noted here. There is an enormous need for psychometrically sound, cost-effective, and ecologically valid instruments for assessing response to psychotropic medication (to include behavioral and somatic toxicity) and reliable procedures for determining efficacy at the individual patient level. It would also be useful to have more information on the relative safety and efficacy of commonly prescribed drugs (and commercial preparations). There is also a desperate need for


1o1

researchers to describe in greater detail response to medication in terms of specific target behaviors (including the internalizing disorders) and the rationale for their pharmacological management, so that caregivers can make more prudent decisions regarding treatment. In their entirety the studies noted in this review do indicate a move in the direction of greater clinical relevance, which combined with recent advances in diagnosis and potential developments in understanding the neurophysiology of psychopathology bodes well for the treatment of children and adolescents with psychiatric disorders and their families. Acknowledgements—The preparation of this manuscript was supported in part by Biomedical Research Support grant No. RR05736 from the U.S. Public Health Service. The author would like to acknowledge the painstaking efforts of an anonymous reviewer whose comments on an earlier draft of this article were most helpful. The opinions, interpretations, and conclusions presented in this review are those of the author; they are not necessarily shared by others working in this field.

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