Psychiatric Annals

On The Use of Neuroleptics in Children and Adolescents

Magda Campbell, MD

Abstract

Neuroleptics have a less specific role in child and adolescent psychiatry than in adult psychiatric patients. In adults, they are prescribed mainly to schizophrenic and other psychotic patients. In children, schizophrenia and manic-depressive illness are very rare; neuroleptics are prescribed in various, including non-psychotic conditions. The advent of neuroleptics failed to have the same impact on child psychiatry as it had on adult psychiatry, partly due to the fact that the goals of treatment differ in children and adults. In adults, the goal is to decrease symptoms, while in children, in addition to this, one hopes to promote development. This is a difficult task to achieve with any type of treatment. In children and adolescents, administration of neuroleptics should be viewed only as an adjunct to psychosocial treatments, and it should not interfere with the individual's development and functioning.

BEHAVIORAL EFFECTS

Hyperactivity, impulsivity, temper tantrums, stereotypies, tics (motor and vocal), insomnia, withdrawal, hallucinations and delusions are the target symptoms which may respond to neuroleptic administration.

The high-potency neuroleptics (eg, trifluoperazine, haloperidol and thiothixene) appear to be of greater therapeutic value than the low-potency neuroleptics (eg, chlorpromazine and thioridazine) which often yield sedation1·2 at doses which may or may not decrease behavioral problems. This view is supported by clinical experience; the literature provides only inconclusive evidence and there is considerable disagreement with this viewpoint.3

DOSAGE AND REGULATION

Clinical experience and research have shown that in children individual differences are considerable in regard to therapeutic dose or tolerance of a dose. It seems that age and even diagnosis do not affect the dosage and that individual differences are large even within a descriptively-diagnostically homogeneous population.4"6 Severity of symptoms, on the other hand, may be significant: treatment resistant hospitalized patients require higher doses than outpatients.6,7 Since studies have demonstrated that a given drug at lower doses may yield significant decreases of symptoms in the absence of untoward effects, while at higher doses, behavioral toxicity and other side effects are observed,4,5 it seems justified to titrate the dosage of neuroleptic drugs individually in each child.

A stable baseline consisting of carefui clinical observation of behavior and measures of weight, height, blood pressure, pulse rate, eating and sleep patterns is required prior to medicating a child in order to monitor drug effects in a meaningful way. The starting dose should be as low as possible, increments should be slow and gradual, not more frequent than twice weekly. In this manner, acute dystonic reaction may be avoided.7 Increments should be made until therapeutic and/or untoward effects appear and only then the optimal dose should be determined. Doses recommended by the PDR should not be exceeded. For example, the starting dose for chlorpromazine or thioridazine in a child should be 10 to 25 mg/day. For haloperidol, it should not exceed 0.5 mg/day; in some cases, the initial dose has to be lowered to 0.25 mg/day. Ideally, the medication should be given in a single morning dose; however, because of the type of symptoms, or occurrence of untoward effects, it may be given in divided doses, 2 or 3 times a day.

UNTOWARD EFFECTS

Behavioral Toxicity. Worsening of preexisting symptoms or behavioral symptoms de novo are frequently seen in children, particularly in the younger age group, before central nervous system (CNS) untoward effects are observed. Irritability, crying, depression, hypoactivity, temper tantrums and excitability are most commonly noted.

Central Nervous System. Excessive sedation or sleepiness are frequently seen. This is perhaps more common with the low-potency neuroleptics2 and is dose related.5,6

Extrapyramidal side effects include acute dystonic reactions, parkinsonian reactions and akathisia. Acute dystonic reactions are seen in the…

Neuroleptics have a less specific role in child and adolescent psychiatry than in adult psychiatric patients. In adults, they are prescribed mainly to schizophrenic and other psychotic patients. In children, schizophrenia and manic-depressive illness are very rare; neuroleptics are prescribed in various, including non-psychotic conditions. The advent of neuroleptics failed to have the same impact on child psychiatry as it had on adult psychiatry, partly due to the fact that the goals of treatment differ in children and adults. In adults, the goal is to decrease symptoms, while in children, in addition to this, one hopes to promote development. This is a difficult task to achieve with any type of treatment. In children and adolescents, administration of neuroleptics should be viewed only as an adjunct to psychosocial treatments, and it should not interfere with the individual's development and functioning.

BEHAVIORAL EFFECTS

Hyperactivity, impulsivity, temper tantrums, stereotypies, tics (motor and vocal), insomnia, withdrawal, hallucinations and delusions are the target symptoms which may respond to neuroleptic administration.

The high-potency neuroleptics (eg, trifluoperazine, haloperidol and thiothixene) appear to be of greater therapeutic value than the low-potency neuroleptics (eg, chlorpromazine and thioridazine) which often yield sedation1·2 at doses which may or may not decrease behavioral problems. This view is supported by clinical experience; the literature provides only inconclusive evidence and there is considerable disagreement with this viewpoint.3

DOSAGE AND REGULATION

Clinical experience and research have shown that in children individual differences are considerable in regard to therapeutic dose or tolerance of a dose. It seems that age and even diagnosis do not affect the dosage and that individual differences are large even within a descriptively-diagnostically homogeneous population.4"6 Severity of symptoms, on the other hand, may be significant: treatment resistant hospitalized patients require higher doses than outpatients.6,7 Since studies have demonstrated that a given drug at lower doses may yield significant decreases of symptoms in the absence of untoward effects, while at higher doses, behavioral toxicity and other side effects are observed,4,5 it seems justified to titrate the dosage of neuroleptic drugs individually in each child.

A stable baseline consisting of carefui clinical observation of behavior and measures of weight, height, blood pressure, pulse rate, eating and sleep patterns is required prior to medicating a child in order to monitor drug effects in a meaningful way. The starting dose should be as low as possible, increments should be slow and gradual, not more frequent than twice weekly. In this manner, acute dystonic reaction may be avoided.7 Increments should be made until therapeutic and/or untoward effects appear and only then the optimal dose should be determined. Doses recommended by the PDR should not be exceeded. For example, the starting dose for chlorpromazine or thioridazine in a child should be 10 to 25 mg/day. For haloperidol, it should not exceed 0.5 mg/day; in some cases, the initial dose has to be lowered to 0.25 mg/day. Ideally, the medication should be given in a single morning dose; however, because of the type of symptoms, or occurrence of untoward effects, it may be given in divided doses, 2 or 3 times a day.

UNTOWARD EFFECTS

Behavioral Toxicity. Worsening of preexisting symptoms or behavioral symptoms de novo are frequently seen in children, particularly in the younger age group, before central nervous system (CNS) untoward effects are observed. Irritability, crying, depression, hypoactivity, temper tantrums and excitability are most commonly noted.

Central Nervous System. Excessive sedation or sleepiness are frequently seen. This is perhaps more common with the low-potency neuroleptics2 and is dose related.5,6

Extrapyramidal side effects include acute dystonic reactions, parkinsonian reactions and akathisia. Acute dystonic reactions are seen in the form of oculogyric crisis, torticollis, retrocollis, opisthotonos, or tongue protrusion; other groups of muscles may also be involved. These reactions usually occur early in treatment, as early as after the first dose. Relief can be achieved by diphenhydramine (Benadryl) 25 mg intramuscularly or orally. Parkinsonian reactions include tremor, cogwheeling, rigidity, drooling and mask-like face. The effects are rarely seen in preschool children; they are more frequent in schoolage patients and adolescents, developing in the first few weeks of drug administration. Antiparkinsonian drugs are not recommended; lowering of the dose is preferred. Akathisia, in the form of motor restlessness and agitation, is difficult to differentiate from hyperactivity in children. Acute dystonic reactions are more frequent with high-potency drugs, such as haloperidol or fluphenazine, than with low-potency drugs: chlorpromazine and thioridazine.

Seizures were reported with several neuroleptics, particularly with chlorpromazine; thioridazine appears to be a safer drug for patients with pre-existing seizure disorder.

Other Untoward Effects. Enuresis has been observed in both retarded and children of normal intelligence.2 It can be avoided in many cases if the dosage is given in the morning and/or in the afternoon, rather than in the evening, before bedtime. Cardiovascular effects have not been reported in children, with the exception of one study where tachycardia produced by chlorpromazine was reported.

Transient increases of serum oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase, and transient leukopenia have been reported from laboratory findings. Baseline assessments, and occasional checks are recommended. In cases of acute febrile illness, drug treatment should be discontinued and complete blood count including differential determined.

Long Term Untoward Effects. Of the expected side effects, weight gain is the most common. The "rabbit syndrome" is a late-onset extrapyramidal side effect, characterized by fast perioral muscle movements.8 Both withdrawal and tardive dyskinesias occur in children and in adolescents, as early as 3'/2-months of cumulative treatment with neuroleptics.9 It has been confirmed that the topography and the type of movements is the same in children and adolescents as in adults, orobuccolingual involvements being most common. Blinking, movements of upper and lower extremities, toes, and trunk, "bon-bon sign," and bizarre sounds have also been reported.9- n In a prospective9,10 and in a retrospective11 study about 20% of children developed tardive or withdrawal dyskinesias; girls were overrepresented. In most cases, the abnormal movements were transient, lasting from less than a month up to 9 months;9,10 however, persistent dyskinesias in children and adolescents were also reported.11 In patients who have a high baseline rating for abnormal movements (eg, stereotypies in autistics and in mentally retarded individuals; motor and vocal tics in Tourette's syndrome) baseline assessment prior to drug administration is essential, since at times it is difficult and even impossible to differentiate withdrawal dyskinesias from recurrence of stereotypies or tics after drug withdrawal.9' Both stereotypies and tics are often suppressed during neuroleptic administration.4,5 Supersensitivity psychosis was reported in only one girl.9

COGNITIVE EFFECTS

The effects of neuroleptics on cognition and learning have not been adequately studied. Most of the research was done in institutionalized and mentally retarded patients and the results cannot be generalized to other populations. There is suggestive evidence that the effects of neuroleptics on cognition and learning may be dose related4,5,7 and that they depend on diagnosis.5,6,12,13 For example, administration of low doses of haloperidol results in improvement of cognitive functions and/ or facilitation of learning4,5,7 while on higher doses no change or even deterioration of cognition was reported.7,12

INDICATIONS

1. Schizophrenic Disorders

These conditions are seen in adolescents but only rarely in prepubertal children.13 Clinical experience indicates that neuroleptics are less effective in schizophrenic children than in adults, although follow-up studies are not available. Little research has been done in this area. There is only one doubleblind and placebo controlled study; it involves 75 hospitalized adolescents, ages 13 to 18 years, with acute schizophrenia or with acute exacerbation of chronic schizophrenia, (autistic patients were excluded). Both loxapine (mean daily dose 87.5 mg) and haloperidol (mean daily dose 9.8 mg) were statistically superior to placebo in alleviating schizophrenic symptomatology as measured by rating scales; there were only a few statistically significant therapeutic differences between the two drugs.14 However, while in each active drug group about two-thirds of the patients developed parkinsonian side effects, sedation was more commonly associated with loxapine than with haloperidol.

In 21 chronic schizophrenic adolescents, thioridazine (91 to 228 mg/d, mean, 178) was more sedative than thiothixene (4.8 to 42.6 mg, mean, 16. 2). 2 Only about half of the patients responded to treatment: there were no statistically significant differences in the efficacy between the two drugs.

There are several earlier studies but all have methodological flaws: the samples are small, heterogenous (eg, schizophrenics mixed with autistics), and/or ill-defined, and no controls were used.16 The patients' ages in these studies range from 6 to 22 years; the drugs administered are trifluoperazine (13-20 mg/d), fluphenazine (0.75 to 16 mg/d), haloperidol (0.75 to 16 mg/d), thiothixene (6 to 30 mg/d), and pimozide (1 to 2 mg/d),

2. Tourette's Syndrome

Haloperidol and pimozide are perhaps the most effective drugs in treating this disorder, which usually starts in childhood. Adverse effects, particularly excessive sedation, detract from the therapeutic efficacy of haloperidol. However, when given in conservative doses (0.5-3.0 mg/d), haloperidol yielded little or no impairment of cognitive functions.16 in a long-term follow-up study (for up to 8.5 years) involving 80 patients, some of whom were children, 13% discontinued treatment because of untoward effects.17 Seventy-five percent of those who continued to take haloperidol showed an 80% decrease of symptoms. These authors recommend 2 to 10 mg of haloperidol daily, with a low starting dose and slow increments, by steps of 0.25 mg.

3. Infantile Autism

It has been demonstrated in well controlled, well designed, double-blind studies that haloperidol in conservative doses will significantly decrease behavioral symptoms in the absence of untoward effects in normo- or hyperactive young autistic children.4·5 In addition to behavioral improvements, haloperidol facilitates language acquisition4 and discrimination learning5 in the laboratory. All these changes take place when the drug is administered in a structured educational setting, over a period of 3 months. Specifically, significant decreases in stereotypies, withdrawal, hyperactivity, fidgetiness, abnormal object relationships, negativism, angry and labile affect were found on rating scales on daily doses of 0.5 to 3.0 mg (mean, 1.11) or 0.019 to 0.217 mg/kg/d (mean, 0.058) in carefully diagnosed autistic children, ages 2.33 to 6.92 years (mean, 4.58).5 The relationship between decrease of symptoms and haloperidol levels in serum was significant.18 Above therapeutic doses, excessive sedation was the most common untoward effect, followed by acute dys tonic reaction (in 11 of 40 patients) (Campbell M, Anderson LT, Small AM, et al, unpublished data). These gains were maintained over a period of 6 months to 2 V2 years.10

There is sufficient evidence indicating that in this population, the low-potency neuroleptics (eg, chlorpromazine) yield excessive sedation with little clinical improvement.15 Trifluoperazine (2-20 mg/ d), on the other hand, yielded increases in verbal production and alertness and decreases in withdrawal and anergy in retarded autistic children.19 Other drugs explored were thiothixene, fluphenazine and molindone: all 3 appeared to be promising in this population.15

4. Conduct Disorder, Undersocialized, Aggressive Type

Haloperidol has shown to be an effective treatment for these children6'7 both in clinic and in a therapeutic hospital setting, while the stimulants are usually ineffective.20 Twenty-four outpatients, ages 4 to 12 years, showed a marked decrease in target symptoms on daily doses of 0.025 or 0.05 mg/kg of haloperidol compared to placebo.7 In 61 treatment-resistant and hospitalized children with a behavioral profile of aggressiveness and explosiveness, there was a significant decrease of these symptoms at doses of 1 to 6 mg/d (mean, 2.95) or 0.04 to 0.21 mg/kg/d (mean, 0.096) of haloperidol, when compared to placebo, under double-blind conditions.6 Haloperidol was as effective as lithium; however, of the 20 children who were receiving haloperidol, 4 were sedated even at optimal doses. Above optimal doses and during dosage regulation sedation (in 16), acute dystonic reaction (in 10) and drooling (in 6) were the most common untoward effects. These drugs will not cure social ills, when prescribed judiciously, however they will decrease such target symptoms as severe aggressiveness and explosiveness.

5. Attention Deficit Disorder with Hyperactivity

Administration of neuroleptics is justified only when a severely symptomatic child fails to respond to a stimulant drug. Both ehlorpromazine in daily doses of 75 to 200 mg21'23 and thioridazine in daily doses of 50 to 300 mg (mean, 160)23 were found to be therapeutically effective in this population in well-designed, double-blind and placebo controlled studies. However, in a sample of 155 children, whose mean age was 102.59 months, thioridazine was inferior to methylphenidate alone or to the combination of methylphenidate and thioridazine after 12 weeks of treatment.23

6. Mental Retardation Associated with Behavioral Symptoms

A numer of mentally retarded individuals exhibit behavioral symptoms, usually hyperactivity, impulsivity and aggressiveness directed against self or others. More than 50% of institutionalized retarded individuals are on chronic neuroleptic maintenance, most frequently thioridazine. However, until recently, the efficacy of this class of drugs was not assessed critically in this population.

In a well designed, double-blind and placebo controlled study involving 40 mentally retarded adolescents with behavioral problems, of whom 20 responded to thioridazine and 20 failed to do so, there were no differences on test scores of the Leiter International performance scale while receiving the drug. This was true whether the test scores were obtained under standard or under reinforcement conditions. However, when the medication was discontinued, under reinforcement conditions IQ test scores increased in both responders and nonresponders. In addition, discontinuation of thioridazine in nonresponders resulted in statistically and clinically significant decreases in maladaptive behaviors.24

7. Bipolar Disorder

Manic-depressive illness is extremely rare before puberty and, except for two single-case reports, there is no study on the efficacy of neuroleptics in this condition in the literature. In adults however, haloperidol has been found to be of therapeutic value in this condition.

CONCLUSION

In recent years, the following advances in research have been made in this long-neglected area: a few studies are available where the subjects are better defined and diagnostic criteria are spelled out; study design is improved and efficacy is now being more critically assessed; emphasis is not only on effects of neuroleptics on behavioral symptoms, but also on their effects on cognition and learning and their safety. Attempts are also being made to relate bioavailability of drug to clinical efficacy. Future research should compare therapy with neuroleptics to psychosocial treatments.

REFERENCES

1. Campbell M: Psychopharmacology. in Noshpitz JD (ed): Basic Handboook of Child Psychiatry. New York. Basic Books, 1979, vol 3, pp 376-409.

2. RealmutotiM, Erickson WD. YeIMn AM, el al: Clinical comparison of thiothixene and thioridazine in schizophrenic adolescents. Ami Psychiatry 1984: 14l:3)440-442.

3. IClein DF. Gittelman R. Quitkin F. et al: Diagnosis and Drug Treatment of Psycltiatric Disorders: Adults and Children. Baltimore. Williams & Wilkins, 1980.

4. Campbell M. Anderson LT. Meier M. el al: A comparison of haloperidol and behavior therapy and their interaction in autistic children. J Am Acad OuId Psychiatry 1978; 17:640-655.

5. Anderson UT, Campbell M. Grega DM. et al: Haloperidol in infantile autism: Effects on learning and behavioral symptoms. Am / Psychiatry 1984; 141:1195-1202.

6. Campbell M, Small AM, Creen WH. el al: A comparison of haloperidol and lithium in hospitalized aggressive conduct disorder children. Arch Gen Psychiatry. 1984;41:650-656.

7. Worry JS, Aman MG: Methylphenidate and haloperidol in children. Arch Gen Psychiatry 1975; 32:790-795.

8. Villeneuve A: The rabbit syndrome: A peculiar extrapyramidal reaction. Can / Psychiatry 1972; 17:69-72.

9. Campbell M. Grega DM, Green WH, et al: Neiiroleptic-induced dyskinesias in children. Clin Neurophamtacol 1983; 6:207-222.

10. Campbeil M. Perry R. Bennett WG. et al: Long-term therapeutic efficacy and drug-related abnormal movements: A prospective study of haloperidol in autistic children. Psychophamtacol Bull 1983; 19(l):80-83.

11. Paulson GW, Rizvi CA. Crane GE: Tardive dyskinesia as a possible sequel of long-term therapy with phenolhiazines. Neurology 1975; 14:953-955.

12. Piatt JE. Campbell M, Grega DM, et al : Cognitive effects of lithium carbonate and haloperidol in treatment resistant aggressive children. Arch Gen Psychiatry 1984;41:657-662.

13. Green WH, Campbell M. Hardesty AS1 et al: A comparison of schizophrenic and autistic children. / Am Acad Child Psychiatry 1984; 23:399-409.

14. Pool D, Bloom W. Mielke DH. et al: A controlled evaluation of loxitane in seventy-five adolescent schizophrenic patients. Current Therapeutic Research 1976; 19:99-104.

15. Campbell M: Use of drug treatment In infamile autism and childhood schizophrenia: A review, in Lipton MA. DiMascio A. Killam KF (eds): Psychopharmacology: A Generation of Progress. New York. Raven Press. 1978. pp 1451-1461.

16. Bogomolny A. Erenberg G, Rothner AD: Behavioral effects of haloperidol in young Tourette syndrome patients, in Friedhoff Al . Chase TN (eds) : Gilles de la 'Courette syndrome. Advances in Neurology. New York. Raven Press. 1 982, vol 35. pp 377-382,

17. Shapiro AK, Shapiro E: The treatment and etiology of tics and Tourette syndrome. Compr Psychiatry 1981 : 22:193-205.

18. Poland RB, Campbell M, Rubin RT. et al: Relationship of serum haloperidol levels and clinical response in autistic children, abstracted lllh ClNP Congress. 1982. vol II. ? 591.

19. Fish B, Shapiro T, Campbell M: Long-term prognosis and the response of schizophrenic children to drug therapy: A controlled study of trifluoperazine. Am /Psychiatry 1966; 123:32-39.

20. Campbell M. Cohen IL. Small AM: Drugs in aggressive behavior. / Am Acad Child Psychiatry 1982; 21:107-117.

21. Rapoport iL, Abramsort A. Alexander D. et al: Playroom observations of hyperactive children on medication. / Am Acad Child Psychiatry 1971 ; 10:524-534.

22. Werry [S. Weiss G. Douglas V, et ai: Studies on the hyperactive child: III. The effect of chlorpromazine upon behavior and learning ability. / ,4"» Acad Child Psychiatry 1966; 5:292-312,

23. Gittclman-Klein R, Klein DF, Katz S. ct at: Comparative effects of methylphenidate and thioridazine in hyperkinetic children: I, Clinical results. Arch Gen Psychiatry 1976; 33:1217-1231.

24. Breuning SE. Ferguson DG, Davidson NA, et al: Effects of thioridazine on the intellectual performance of mentally retarded drug responders and nonresponders. Arch Gen Psychiatry 1983; 40:309-313.

10.3928/0048-5713-19850201-08

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